The Treatment of Bipolar Depression

Results of a MEDLINE Search By, Ivan K. Goldberg, M.D.

J Clin Psychiatry. 2011 Jun;72(6):744-50. Epub 2010 Oct 19.

Levetiracetam in the management of bipolar depression: a randomized,
double-blind, placebo-controlled trial.

Saricicek A, Maloney K, Muralidharan A, Ruf B, Blumberg HP, Sanacora G, Lorberg
B, Pittman B, Bhagwagar Z.

Department of Psychiatry, Yale University, New Haven, Connecticut, USA.

OBJECTIVE: To study the efficacy of adjunctive levetiracetam therapy compared
with placebo in the treatment of subjects with depression with bipolar disorder.
METHOD: This double-blind, placebo-controlled clinical trial randomly assigned
outpatients with bipolar disorder type I and type II who were experiencing a
major depressive episode (Structured Clinical Interview for DSM-IV Axis I
Disorders-Clinician Version criteria) to treatment with either placebo or
adjunctive levetiracetam (up to 2,500 mg/d flexibly dosed) for 6 weeks. The
subjects were recruited from October 2005 to June 2008. The primary efficacy
measure was mean change from baseline to week 6 in the Hamilton Depression Rating
Scale (21-item). Secondary efficacy assessments included the Montgomery-Ã…sberg
Depression Rating Scale, the Beck Depression Inventory, the Clinical Global
Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the
Young Mania Rating Scale.
RESULTS: Of 42 subjects randomly assigned to placebo or drug, 32 received at
least 1 postbaseline assessment and thus were included in the analysis. The mean
(SD) levetiracetam daily dose at endpoint evaluation was 1,132 (425) mg/d. There
was no significant difference in the mean change from baseline to week 6 in the
Hamilton Depression Rating Scale scores for levetiracetam compared with placebo.
There were no significant differences in any of the secondary outcome measures.
CONCLUSIONS: Levetiracetam adjunctive therapy was not superior to placebo in the
short-term treatment of subjects with depression with bipolar disorder in the
population studied.

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Psychiatr Danub. 2011 Jun;23(2):189-93.

Adherence to Turkish psychiatric association guideline for bipolar depression
treatment in a specialized mood disorders outpatient unit.

Alt?nba? K, Smith D, Oral ET.

Bak?rköy Research and Training Hospital for Psychiatry, Neurology & Neurosurgery,
Ra?it Tahsin Mood Disorders Outpatient Unit, Istanbul, Turkey.
kursataltinbas@gmail.com

BACKGROUND: Bipolar patients spend up to one third of their lives in depression
however, acute treatment guidelines mainly focused on the manic phase of illness.
With recent attention to the importance of evidence-based medicine in psychiatry,
a number of treatment guidelines have emerged to aid clinicians in clinical
decision making. Here, we aim to measure concordance with the Turkish Psychiatric
Association Treatment Guideline for Bipolar Disorders (TPATGBD) for the
depressive phase of illness.
SUBJECTS AND METHODS: Bipolar patients attending the Rasit Tahsin Mood Disorders
Outpatient Unit of Istanbul Bak?rköy Research and Training Hospital for
Psychiatry, Neurolgy & Neurosurgery, were assessed using standardized forms based
on a nation-wide mood disorders follow-up program. Concordance of implementations
with the TPATGBD were evaluated step by step for each level of depression
severity.
RESULTS: Concordance rates with the first step recommendations of the guideline
were 29.4%, 27.4% and 87.5% for mild-moderate, moderate-severe (without
psychosis) and severe depression (with psychosis), respectively. Concordance
rates with the second step recommendations of the guideline were lower for
bipolar depressions without psychosis. Overall, adherence to the guideline did
not impact on time to remission (p=0.19).
CONCLUSIONS: Despite considerable efforts to develop and disseminate
evidence-based guidelines, they are not widely followed by clinicians and
important opportunities clearly exist to educate clinicians about the feasibility
and utility of clinical guidelines for bipolar disorder. Systematic studies in
the future are required to clarify our understanding of clinicians’ attitudes to
the use of guidelines and to explain the discrepancy between guidelines and
clinical practice.

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Bipolar Disord. 2011 May;13(3):294-302. doi: 10.1111/j.1399-5618.2011.00923.x.

Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar
depression: a preliminary report.

Sajatovic M, Gildengers A, Al Jurdi RK, Gyulai L, Cassidy KA, Greenberg RL, Bruce
ML, Mulsant BH, Ten Have T, Young RC.

Department of Psychiatry, Case Western Reserve University School of Medicine,
University Hospitals Case Medical Center, Cleveland, OH, USA.
martha.sajatovic@uhhospitals.org

AIMS: This is a multisite, 12-week, open-label trial of lamotrigine augmentation
in 57 older adults (? 60 years; mean ± SD age = 66.5 ± 6.7 years) with either
type I or type II bipolar depression.
METHODS: Primary outcome measure was change from baseline on the
Montgomery-Ã…sberg Depression Rating Scale (MADRS). Secondary outcome measures
included Hamilton Depression Rating Scale (HAM-D), Clinical Global
Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule
II (WHO-DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess
side effects.
RESULTS: A total of 77.2% of the study subjects had bipolar I disorder. The mean
(SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement
in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients
for whom final MADRS score was available: 31 (57.4%) met remission criteria and
35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the
study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1
manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related
and were resolved with drug discontinuation. The most common UKU adverse effects
were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%),
increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%),
weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased
sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8,
14%). No significant changes in electrocardiogram or laboratory tests were
observed.
CONCLUSIONS: In bipolar depressed elders, lamotrigine was associated with
improvement in depression, psychopathology, and functional status. There was a
moderate number of adverse events, although relationship of adverse events
(particularly falls) to study medication could not be clearly determined in this
uncontrolled trial. Controlled studies are needed to further evaluate efficacy
and tolerability of lamotrigine therapy in geriatric bipolar depression.

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Eur Neuropsychopharmacol. 2011 May;21(5):362-9. Epub 2010 Nov 5.

Factors associated with initial treatment response with antidepressants in
bipolar disorder.

Pacchiarotti I, Valentí M, Bonnin CM, Rosa AR, Murru A, Kotzalidis GD, Nivoli AM,
Sánchez-Moreno J, Vieta E, Colom F.

INTRODUCTION: Controversy in antidepressant (AD) use in bipolar depression relies
in its potential induction of mood switches and ineffectiveness. Responders to
acute AD add-on treatment maintain response with continued treatment, whilst
partial/non-responders fail to reach remission despite continuation treatment. We
aimed to identify response predictors to acute AD addition in bipolar depression
in order to optimize treatment choice in bipolar depression and avoid unnecessary
AD exposure of people unlikely to respond.
METHODS: Two hundred and twenty-one DSM-IV-TR depressed bipolar – type I and II –
patients were treated with AD on an observational study. AD response was defined
as an at least 50% drop from baseline of their HDRS17 score after 8weeks of
treatment. One hundred and thirty-eight patients (138, 62.4%) fulfilled response
criteria (RI) whilst 83 patients (37.6%) did not (NRI). In all cases AD therapy
was on top of previously prescribed stabilizers and/or atypical antipsychotics.
RESULTS: RI patients were more likely to have had previous response to ADs,
whereas NRI had a higher number of previous mood switches with ADs during past
depressive episodes. Psychotic symptoms were more frequent amongst RI, whilst
lifetime history of atypical depression was more frequent amongst NRI. NRI had
more total, depressive, and hypomanic, but not manic or mixed, episodes in the
past than RI. Analyzed through a logistic regression, higher previous response to
ADs and lower rate of past hypomanic episodes in RI were the variables explaining
intergroups (RI vs. NRI) differences.
DISCUSSION: Taking into account the proper caution in the use of Ads in bipolar
disorder, there is a subgroup of bipolar patients who might benefit from
adjunctive Ads. Looking at specific clinical factors during the course of the
illness could help physicians in deciding whether to use an antidepressant in a
bipolar depressed patient already treated with mood stabilizers.

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J Clin Psychiatry. 2011 May;72(5):704-15.

The pharmacologic treatment of bipolar disorder.

Sachs GS, Dupuy JM, Wittmann CW.

Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston, MA
02114, USA. sachsg@aol.com

Over the past half century, substantial clinical trial data have accumulated to
guide clinical management of bipolar disorder, and 13 medications have gained US
Food and Drug Administration approval for the treatment of mania or bipolar
depression or the maintenance treatment of bipolar disorder. While the number of
studies has grown and many controversies related to pharmacologic treatment of
bipolar disorder are not yet resolved, the task of transforming the accumulated
evidence into useful guidance for clinical practice becomes more manageable and
less error prone by limiting consideration to the highest quality studies.
Therefore, this article emphasizes points of relative clarity by highlighting
findings supported by double-blind, placebo-controlled clinical trials with
samples of at least 100 subjects. A MEDLINE search was conducted and augmented by
a manual search of bibliographies, textbooks, and abstracts from recent
scientific meetings for randomized controlled trials published in English between
1950 and April 2010 with at least 100 subjects. Keywords used in the search
included randomized controlled trial, mania, hypomania, depression, relapse
prevention, placebo, antidepressant, switch, and maintenance treatment of bipolar
disorder. A paradigm for implementing evidence-based treatment is offered along
with consideration of patterns emerging across clinical trials.

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CNS Neurosci Ther. 2011 Apr;17(2):110-7. doi: 10.1111/j.1755-5949.2011.00234.x.

Treatment strategies for dosing the second generation antipsychotics.

Schwartz TL, Stahl SM.

Department of Psychiatry State, University of New York Upstate Medical
University, NY, USA. schwartt@upstate.edu

BACKGROUND: The second generation antipsychotics now have clinical approvals for
the treatment of schizophrenia, bipolar depression, bipolar mania, autism, major
depressive disorder and are used furthermore off-label to treat other mental
disorders. Each agent is unique in its pharmacodynamic profile and allows for
unique dosing strategies to be employed when treating these different disorders.
Aims: To review relevant data regarding the second generation antipsychotics and
their empirical dosing strategies. To further review and comment theoretically in
these areas where substantial, definitive data are lacking.
MATERIALS AND METHODS: A MEDLINE and recent textbook review was conducted
regarding each second generation antipsychotic and cross-referenced with searches
for major mental disorders. The findings are compiled in the review below.
DISCUSSION: The second generation antipsychotics are clearly delineated in the
treatment of psychosis and mania and share similar mechanisms of action to
achieve these results: dopamine-2 receptor antagonism for efficacy and
serotonin-2a receptor antagonism for EPS tolerability. From here, each agent has
a unique pharmacodynamic and pharmacokinetic profile where some agents carry
more, or less antidepressant, anxiolyic, or hypnotic profiles. Choosing an agent,
and dosing it in low, middle, or high ranges may result in differential
effectiveness and tolerability.
CONCLUSION: The second generation antipsychotics have many clinical applications
in psychiatric practice. This article serves to review this and also suggests
ways clinicians may optimize treatment based upon patient diagnosis and utilizing
appropriate dosing of each individual second generation antipsychotic.

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J Affect Disord. 2011 Apr;130(1-2):171-9. Epub 2010 Nov 10.

Clinical value of early partial symptomatic improvement in the prediction of
response and remission during short-term treatment trials in 3369 subjects with
bipolar I or II depression.

Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, Evoniuk G,
Jansen W, Leon AC, Minkwitz M, Pikalov A, Stassen HH, Szegedi A, Tohen M, Van
Willigenburg AP, Calabrese JR.

Case Western Reserve University, University Hospitals Case Medical Center,
Cleveland, OH, USA. kemp.david@gmail.com

OBJECTIVE: To evaluate the clinical value of early partial symptomatic
improvement in predicting the probability of response during the short-term
treatment of bipolar depression.
METHODS: Blinded data from 10 multicenter, randomized, double-blind,
placebo-controlled trials in bipolar I or II depression were used to determine if
early improvement (?20% reduction in depression symptom severity after 14 days of
treatment) predicted later short-term response or remission. Sensitivity,
specificity, efficiency, and positive and negative predictive values (PPV, NPV)
were calculated using an intent to treat analysis of individual and pooled study
data.
RESULTS: 1913 patients were randomized to active compounds (aripiprazole,
lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to
placebo. In the pooled positive studies, early improvement predicted response and
remission with high sensitivity (86% and 88%, respectively), but rates of false
positives were high (53% and 59%, respectively). Pooled negative predictive
values for response/remission (i.e. confidence in knowing the drug will not
result in response or remission) were 74% and 82%, respectively, with low rates
of false negatives (14% and 12%, respectively).
CONCLUSION: Early improvement in an individual patient does not appear to be a
reliable predictor of eventual response or remission due to an unacceptably high
false positive rate. However, the absence of early improvement appears to be a
highly reliable predictor of eventual non-response, suggesting that clinicians
can have confidence in knowing when a drug is not going to work during short-term
treatment. Patients who fail to demonstrate early improvement within the first
two weeks of treatment may benefit from a change in therapy.

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J Affect Disord. 2011 Apr;130(1-2):192-7. Epub 2010 Oct 18.

Predictors of response to ultrabrief right unilateral electroconvulsive therapy.

Loo CK, Mahon M, Katalinic N, Lyndon B, Hadzi-Pavlovic D.

School of Psychiatry, University of NSW, Sydney, Australia.
colleen.loo@unsw.edu.au

BACKGROUND: Recent trials have demonstrated clinically meaningful efficacy and
minimal cognitive side effects with ultrabrief pulsewidth right unilateral (RUL)
ECT. In many countries it is gradually being adopted into clinical practice and
further information on predictors of response is needed.
METHODS: Data collected from 75 depressed patients who received ultrabrief RUL
ECT in a prospective research trial were analysed for predictors of response.
Mood improvement was assessed with the Montgomery-Asberg Depression Rating Scale.
Improvement in unipolar versus bipolar depression was analysed.
RESULTS: Sixty-one percent of patients met the criteria for response and 36% met
the criteria for remission. Logistic regression identified index episode duration
?one year (OR=10.50, p=.006), fewer failed antidepressant treatments (OR=0.46,
p=.003), previous ECT course (OR=7.33, p=.01), and absence of concurrent
antidepressant (OR=0.09, p=.005) as predictors of response. Psychotic features
(OR=7.18, p=.032) and baseline depression severity (OR=0.90, p=.017) were
predictors of remission. There was a trend towards greater improvement in bipolar
than unipolar depression in the first week of treatment (p=0.077).
LIMITATIONS: Data were obtained from a prospective but non-randomised clinical
trial which was designed to evaluate efficacy rather than to examine predictors
of response. Treatment decisions (concurrent medication, switching to other types
of ECT) were made on clinical grounds.
CONCLUSIONS: This preliminary study suggests that predictors of response for
ultrabrief RUL ECT are similar to those identified for other types of ECT
previously studied.

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J Affect Disord. 2011 Mar;129(1-3):64-7. Epub 2010 Sep 16.

Long-term naturalistic follow-up of lithium augmentation: relevance to
bipolarity.

Inoue T, Abekawa T, Nakagawa S, Suzuki K, Tanaka T, Kitaichi Y, Boku S, Nakato Y,
Toda H, Koyama T.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, North
15, West 7, Kita-ku, Sapporo 060-8638, Japan. tinoue@med.hokudai.ac.jp

BACKGROUND: Whether bipolarity (unrecognized bipolar disorder) is related to the
treatment response to lithium augmentation in antidepressant-refractory
depression remains unclear. This study of responders and non-responders to
lithium augmentation of 29 antidepressant-refractory patients with major
depression, whom we had studied during 1995-1997, compared the bipolar diagnosis
at the follow-up based on diagnostic confirmation after long-term follow-up.
METHODS: Before being classified as stage 2 treatment-resistant depression, these
patients had been treated adequately with at least two tricyclic or heterocyclic
antidepressants from different pharmacological classes (a minimum of the
equivalent of 150 mg of imipramine for 4 weeks). During 1995-1997, 29 patients
received lithium augmentation. Their treatment responses were recorded. Mean
follow-up was 8.0 years (range, 1-13 years). Bipolar conversion and full
remission were evaluated.
RESULTS: After the long-term follow-up, diagnoses were changed to bipolar
depression in 3 of 4 lithium responders and 3 of 25 lithium non-responders;
lithium augmentation was more effective for unrecognized bipolar patients. Only
the family history of bipolar disorder predicted subsequent bipolar conversion.
LIMITATIONS: Treatment was not controlled in this naturalistic study, which had a
small sample size.
CONCLUSIONS: Results of this long-term follow-up study suggest that bipolarity is
related to a positive response to lithium augmentation in stage 2
treatment-resistant major depression. The family history of bipolar disorder
suggests false unipolar depression, and therefore indicates lithium responders.

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J Affect Disord. 2011 Mar;129(1-3):321-6.

Differential outcome of bipolar patients receiving antidepressant monotherapy
versus combination with an antimanic drug.

Pacchiarotti I, Valentí M, Colom F, Rosa AR, Nivoli AM, Murru A, Sánchez-Moreno
J, Vieta E.

Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic Barcelona,
IDIBAPS, CIBERSAM, University of Barcelona, Catalonia, Spain.

INTRODUCTION: Despite antidepressants are widely used in treating bipolar
depression, there is much debate about their utility and their potential dangers,
involving mood switches and suicidality. Our hypothesis was that the pattern of
initial antidepressant prescription, i.e., alone (AM) or in combination with
stabilizers (AC) might impact the long-term outcome of patients with bipolar
disorder (BP). We aimed to test this hypothesis and to identify outcome measures
that could be predicted by initial AM or AC treatment in patients with BP.
METHODS: We included 95 patients with DSM-IV BP from a pool of 138 patients
following a BP program. Patients were rated for initial AM vs. AC treatment when
they were first seen in primary care and subdivided into two groups accordingly.
Differences in their clinical course were sought investigating course both
retrospectively and prospectively (mean follow-up 10 years). Primary outcome
measures comprised suicidality and switch rate.
RESULTS: There were significantly more patients who switched in the AM group than
in the AC group. The number of suicide attempts was higher in the AM group.
Significance was retained after performing logistic regression.
LIMITATIONS: Sample size was small and severe BP patients might be
overrepresented in this sample.
DISCUSSION: Initial AM treatment of patients subsequently diagnosed as BP may
entrain a course characterized by higher proneness to switch and suicidal
behaviour. Accurate initial diagnosis of bipolar depression should prompt
combined treatment with antimanic drugs.

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J Affect Disord. 2011 Mar;129(1-3):14-26. Epub 2010 Jun 9.

New treatment guidelines for acute bipolar depression: a systematic review.

Nivoli AM, Colom F, Murru A, Pacchiarotti I, Castro-Loli P, González-Pinto A,
Fountoulakis KN, Vieta E.

Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, University
of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.

INTRODUCTION: Bipolar depression poses a great burden on patients and their
families due to its duration, associated functional impairment, and limited
treatment options. Given the complexity of the disorder and the advances in
treatment, a number of clinical guidelines, consensus statements and expert
opinions were developed with the aim to standardize treatment and provide
clinicians with treatment algorithms for every-day clinical practice.
Unfortunately, they often led to conflicting conclusions and recommendations due
to limitations of the available literature. As findings emerge from research
literature, guidelines quickly become obsolete and need to be updated or revised.
Many guidelines have been updated in the last 5 years, after the last review of
bipolar disorder (BD) treatment guidelines.
OBJECTIVE: The purpose of this work is to systematically review guidelines,
consensus meetings and treatment algorithms on the acute treatment of bipolar
depression updated or published since 2005, to critically underline common and
critical points, highlight limits and strengths, and provide a starting point for
future research
MATERIALS AND METHODS: The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT,
Excerpta Medica/EMBASE, databases were searched using “depression”, “bipolar”,
“manic-depression”, “manic-depressive” and “treatment guidelines” as key words
RESULTS: The search returned 204 articles. Amongst them, there were 28 papers
concerning structured treatment algorithms and/or guidelines suggested by
official panels. After excluding those guidelines that were not performed by
scientific societies or international groups and those published before 2005, the
final selection yielded 7 papers When looking into guidelines content, the
results indicate a trend to the gradual acceptance of the use of the atypical
antipsychotic quetiapine as monotherapy as first-line treatment. Antidepressant
monotherapy is discouraged in most of them, although some support the use of
antidepressants in combination with antimanic agents for a limited period of
time. Lamotrigine has become a highly controversial option.
CONCLUSION: The management of bipolar depression is complex and should be
differentiated from management of unipolar depression. Guidelines may be useful
instruments for helping clinicians to choose and plan bipolar depression
treatment by integrating the more updated scientific knowledge with every-day
clinical practice and patient-specific factors; however, a further effort is
needed in order to improve guidelines implementation in clinical practice. The
latest updates on treatment guidelines for bipolar depression give priority to
novel treatment approaches, such as quetiapine, over more traditional ones, such
as lithium or antidepressants. Lamotrigine is a controversial option.

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J Clin Psychiatry. 2011 Mar;72(3):356-66. Epub 2010 Aug 10.

Pharmacotherapy for the treatment of acute bipolar II depression: current
evidence.

Swartz HA, Thase ME.

Department of Psychiatry, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, USA. swartzha@upmc.edu

OBJECTIVE: Bipolar II disorder is a common, recurrent, and disabling psychiatric
illness, and yet little is known about how best to treat it. The pressing
clinical need for evidence-based approaches to the treatment of bipolar II
disorder, coupled with recent publication of pertinent studies, calls for an
updated review of this literature. This review focuses on a critical examination
of the evidence supporting the efficacy of treatments for acute depressive
episodes in bipolar II disorder.
DATA SOURCES: A MEDLINE (via Ovid) search of journals, covering the period from
January 1950 to January 2009, was performed to identify relevant studies.
Keywords used were bipolar II disorder, bipolar disorder, bipolar depression, and
pharmacotherapy. Studies were further limited to those that were in adult
samples, published in peer-reviewed journals, and written in English.
STUDY SELECTION: We examined all randomized trials evaluating the use of
pharmacotherapy in the treatment of acute bipolar II depression. Studies with
mixed samples of bipolar I and II or bipolar II and unipolar depression were
examined as well. Twenty-one randomized trials were identified and reviewed.
DATA EXTRACTION: Therapeutic agents were rated according to the quality of
evidence supporting their efficacy as treatments for bipolar II depression.
DATA SYNTHESIS: Ninety percent of relevant trials were published after 2005.
Quetiapine was judged as having compelling evidence supporting its efficacy.
Lithium, antidepressants, and pramipexole were judged as having preliminary
support for efficacy. Lamotrigine was considered to have mixed support.
CONCLUSIONS: Although progress has been made, further research on bipolar II
depression is warranted.

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J ECT. 2011 Mar;27(1):18-25.

Safety, tolerability, and effectiveness of high doses of adjunctive daily left
prefrontal repetitive transcranial magnetic stimulation for treatment-resistant
depression in a clinical setting.

Hadley D, Anderson BS, Borckardt JJ, Arana A, Li X, Nahas Z, George MS.

Brain Stimulation Laboratory, Psychiatry Department, Medical University of South
Carolina, USA. DakotaHadley88@gmail.com

OBJECTIVE: Daily left prefrontal repetitive transcranial magnetic stimulation
(rTMS) recently received Food and Drug Administration (FDA) approval for the
treatment of depression and offers an alternative to traditional approaches. This
approval was based on a study using 3000 stimuli per day (15,000 stimuli per
week) in adults with unipolar depression not taking antidepressant medications.
Several meta-analyses suggest a dose-response relationship with TMS. This study
was carried out before US FDA approval to test the safety, tolerability, and
effectiveness of adjunctive high-dose left prefrontal rTMS in a clinical setting
with particular attention to safety of higher doses and potential interactions
with antidepressant medications, speed of response, and effects on suicidality.
METHOD: We enrolled 19 patients who were in a current major depressive episode
with treatment-resistant unipolar or bipolar depression and treated them in their
acute episode and in a maintenance fashion for 18 months. The patients received
daily left prefrontal rTMS at 120% resting motor threshold, 10 Hz, 5 seconds on,
and 10 seconds off and for a mean of 6800 stimuli per session (34,000 stimuli per
week), more than twice the dose delivered in the pivotal FDA trial. All patients
continued antidepressant medication throughout the rTMS treatment; thus rTMS was
an adjunctive treatment. We measured adverse effects, depression, quality of
life, suicidal ideation, and social and physical functioning.
RESULTS: These higher rTMS doses were well tolerated without significant adverse
effects or adverse events. All measured dimensions showed improvement, with many
showing improvement in 1 to 2 weeks. Of perhaps most importance, suicidal
ideation diminished in 67% of the patients after just 1 week.
CONCLUSIONS: These uncontrolled data suggest that higher doses of daily left
prefrontal rTMS may safely be used in outpatients with major depressive episode
even as an adjunctive treatment.

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Rev Bras Psiquiatr. 2011 Mar;33(1):72-80.

[The pharmacological treatment of bipolar disorder: a systematic and critical
review of the methodological aspects of modern clinical trials].

[Article in Portuguese]

Cheniaux E.

Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
echeniaux@gmail.com

OBJECTIVE: To review systematically the main clinical trials on the
pharmacological treatment of bipolar disorder and to make a critical analysis of
their methodological aspects.
METHOD: A search in Medline, ISI and PsycINFO databases was conducted, using the
following search terms: “bipolar”, “randomized”, “placebo” e “controlled”.
Randomized, double-blind, placebo-controlled clinical trials on the
pharmacological treatment of bipolar disorder were selected. Besides, according
to our criteria, samples had to consist of at least 100 patients and experimental
drug had to be used as monotherapy.
RESULTS: 34 articles met our selection criteria. All drugs currently indicated
for mania, bipolar depression and maintenance treatment of bipolar disorder were
more effective than placebo in at least one clinical trial. However, these
studies had highly selected samples, high dropout rates and low response rates.
CONCLUSION: Modern clinical trials on pharmacological treatment of bipolar
disorder have important methodological limitations. So, their results should be
taken with caution.

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Ann Clin Psychiatry. 2011 Feb;23(1):17-24.

Lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar
depression.

Ahn YM, Nam JY, Culver JL, Marsh WK, Bonner JC, Ketter TA.

Department of Neuropsychiatry, Seoul National University Hospital, Department of
Psychiatry and Behavioral Science, Seoul National University College of Medicine,
Chongno-Gu, Seoul, Republic of Korea.

BACKGROUND: Lamotrigine and quetiapine are commonly used in bipolar disorder, but
there are no published systematic studies of their use in combination for
treatment-resistant bipolar depression.
METHODS: We studied 39 trials in outpatients (15 with bipolar I disorder, 22 with
bipolar II disorder, and 1 with bipolar disorder not otherwise specified; 1
patient had 2 trials) with depression resistant to quetiapine or lamotrigine who
were taking a mean of 1.7 other prescription psychotropic medications. Patients
were given either open-label lamotrigine or quetiapine naturalistically, for up
to 12 weeks of combination therapy.
RESULTS: Lamotrigine (mean dose, 204.2 mg/d) plus quetiapine (mean dose, 188.5
mg/d) increased the euthymia rate (0.0% to 46.2%), decreased syndromal (79.5% to
30.8%) and subsyndromal (20.5% to 15.4%) depression rates, and improved Clinical
Global Impression-Severity (mean change, -1.0) and Global Assessment of
Functioning (mean change, +5.9) scores. Approximately one-fifth of patients
discontinued therapy (20.5%) or required subsequent additional pharmacotherapy
(20.5%). Only 10.3% discontinued due to adverse effects, and there was no
significant change in mean body weight.
CONCLUSIONS: The findings of this uncontrolled open pilot study must be viewed
with caution. However, randomized, double-blind, placebo-controlled studies are
warranted to confirm the possibility that combination therapy with lamotrigine
and quetiapine is effective and well tolerated in patients with
treatment-resistant bipolar depression.

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Bipolar Disord. 2011 Feb;13(1):111-7. doi: 10.1111/j.1399-5618.2011.00887.x.

Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on
to lithium with the possibility of the addition of paroxetine in nonresponders: a
randomized, placebo-controlled trial with a novel design.

van der Loos ML, Mulder P, Hartong EG, Blom MB, Vergouwen AC, van Noorden MS,
Timmermans MA, Vieta E, Nolen WA; LamLit Study Group.

Collaborators: Baas RW, Bakker PR, Bloemkolk D, Blom MB, den Boer JA, Brouwer W,
van Dongen PH, Geling K, Glas G, Habekotté O, Hartong EG, van Hyfte DM, de Jong
E, Keegan A, de Keyser H, Knoppert-van der Klein EA, Kölling P, Koning D,
Kromdijk DH, Kruisdijk FR, Kunst AG, Kupka RW, Kuut G, van Leeuwen E, van
Lieshout JJ, van der Loos ML, Luteijn ML, de Maat M, Nolen WA, van Noorden M,
Notten PJ, Offermans JM, Ploeger RR, Postma DH, Scherders MJ, Schoof P, Segeren
J, Smit S, Vergouwen AC, Vos T, van Zaane J, Alvarez E, Arce R, González-Pinto A,
Livianos L, Vieta E.

Department of Psychiatry, Isala Klinieken Location Sophia, Zwolle, The
Netherlands. m.l.m.van.der.loos@isala.nl

OBJECTIVE: In two previous manuscripts, we described the efficacy of lamotrigine
versus placebo as add-on to lithium (followed by the addition of paroxetine in
nonresponders) in the short-term treatment of bipolar depression. In this paper
we describe the long-term (68 weeks) outcome of that study.
METHODS: A total of 124 bipolar depressed patients receiving lithium were
randomized to addition of lamotrigine or placebo. After eight weeks, paroxetine
was added to nonresponders for another eight weeks. Responders continued
medication and were followed for up to 68 weeks or until a relapse or recurrence
of a depressive or manic episode.
RESULTS: After eight weeks, the addition of lamotrigine to lithium was
significantly more efficacious than addition of placebo, while after addition of
paroxetine in nonresponders both groups further improved with no significant
difference between groups at week 16. During follow-up the efficacy of
lamotrigine was maintained: time to relapse or recurrence was longer for the
lamotrigine group [median time 10.0 months (confidence interval: 1.1-18.8)] versus the placebo group [3.5 months (confidence interval: 0.7-7.0)].
CONCLUSION: In patients with bipolar depression, despite continued use of
lithium, addition of lamotrigine revealed a continued benefit compared to placebo
throughout the entire study.

———

J Clin Psychiatry. 2011 Feb;72(2):156-67. Epub 2010 Oct 5.

Antidepressants for the acute treatment of bipolar depression: a systematic
review and meta-analysis.

Sidor MM, Macqueen GM.

Department of Psychiatry, University of Texas, Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 75390-9070, USA. michelle.sidor@utsouthwestern.edu

Comment in
J Clin Psychiatry. 2011 Mar;72(3):415-6; author reply 416.

OBJECTIVE: The role of antidepressants in the acute treatment of bipolar
depression remains a contentious issue. A previous meta-analysis of randomized
controlled trials (RCTs) concluded that antidepressants were effective and safe
for bipolar depression. Several trials published since then suggest that
antidepressants may not be as beneficial as previously concluded. The current
systematic review and meta-analyses reexamine the efficacy and safety of
antidepressant use for the acute treatment of bipolar depression.
DATA SOURCES: EMBASE, MEDLINE, CINAHL, PsycINFO, and the Cochrane Central
Register of Controlled Trials databases were searched for double-blind RCTs
published from 2003 to 2009 using the following diagnostic medical subject
heading (MESH) terms: bipolar disorder, bipolar depression, bipolar I disorder,
bipolar II disorder, bipolar III disorder, bipolar mania, cyclothymia, manic
depressive psychosis, mixed mania and depression, and rapid cycling and bipolar
disorder. Databases of trial registries were also searched for unpublished RCTs.
These searches were supplemented by hand searches of relevant articles and review
articles.
STUDY SELECTION: Trials that compared acute (< 16 wk) antidepressant treatment
with either an active drug or a placebo comparator in adult bipolar patients,
depressive phase were eligible for inclusion. Main outcome measures were clinical
response, remission, and affective switch.
DATA SYNTHESIS: Six RCTs (N = 1,034) were identified since publication in 2004 of
the first meta-analysis that assessed antidepressant use in the acute treatment
of bipolar depression. These studies were combined with earlier studies for a
total of 15 studies containing 2,373 patients. Antidepressants were not
statistically superior to placebo or other current standard treatment for bipolar
depression. Antidepressants were not associated with an increased risk of switch.
Studies that employed more sensitive criteria to define switch did report
elevated switch rates for antidepressants.
CONCLUSIONS: Although antidepressants were found to be safe for the acute
treatment of bipolar depression, their lack of efficacy may limit their clinical
utility. Further high-quality studies are required to address the existing
limitations in the literature.

———

Psychopharmacology (Berl). 2011 Feb;213(4):657-67. Epub 2010 Oct 31.

Number needed to treat analyses of drugs used for maintenance treatment of
bipolar disorder.

Popovic D, Reinares M, Amann B, Salamero M, Vieta E.

Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain.

RATIONALE: Due to the episodic and chronic nature of bipolar disorder (BD),
maintenance therapy represents a critical part of treatment; however, there is a
paucity of studies comparing effectiveness of available long-term treatments.
OBJECTIVE: The aim of this study is to determine and compare the efficacy of
pharmacological treatments for maintenance treatment of BD by means of the number
needed to treat (NNT).
METHODS: The efficacy of drugs used for maintenance treatment of BD, as emerging
from the results of randomized controlled trials, was assessed using the size
effect measure of NNT. PubMed searches were conducted on English-language
articles published until May 2010 using the search terms “bipolar disorder,”
“mania,” “mixed episode,” or “bipolar depression,” cross-referenced with trial
characteristic search phrases and generic names of medications. The search was
supplemented by manually reviewing reference lists from identified publications.
RESULTS: In 15 studies, aripiprazole, olanzapine, quetiapine, risperidone
long-acting injection, lithium, lamotrigine, and divalproex proved effectiveness
in terms of NNTs (? 10% advantage over placebo) for prevention of relapse into
any mood episode. Quetiapine, lithium, risperidone long-acting injection,
aripiprazole, and olanzapine are effective in manic recurrence prevention.
Lamotrigine, quetiapine, and lithium present significant NNTs for prevention of
depressive relapses.
CONCLUSIONS: All of the pharmacological agents assessed were effective in the
prevention of any kind of mood episode; however, different efficacy profiles were
found for prevention of manic and/or depressive relapses. The comparison of NNT
values of the available agents may represent a useful tool in clinical settings,
in order to facilitate implementation of long-term pharmacological interventions
in patients with BD.

———

J Affect Disord. 2011 Jan;128 Suppl 1:S21-8.

A clinical review of aripiprazole in bipolar depression and maintenance therapy
of bipolar disorder.

Yatham LN.

UBC Department of Psychiatry, The University of British Columbia, UBC Hospital,
Vancouver, BC, Canada. yatham@exchange.ubc.ca

BACKGROUND: Bipolar disorder is a chronic, recurrent disorder with a significant
negative impact on quality of life. Effective treatments are available for acute
mania. In contrast, there is a lack of consensus on the treatment of acute
bipolar depression and long treatment options for bipolar disorder require more
study. Aripiprazole is FDA approved for the treatment of acute mania. This paper
reviews current data on the efficacy of aripiprazole in the treatment of acute
bipolar depression and in maintenance therapy of bipolar disorder.
METHODS: PubMed and abstracts of recent conferences were searched for randomized,
double-blind studies that investigated the efficacy of aripiprazole in acute
bipolar depression or maintenance therapy of bipolar disorder.
RESULTS: Two studies assessed the efficacy of aripiprazole monotherapy in the
treatment of acute bipolar depression. These showed that although aripiprazole
significantly reduced depressive symptoms early in treatment, the results were
not significantly different from placebo at the primary end point of week 8. As
to long-term treatment, aripiprazole was superior to placebo in delaying time to
relapse for manic episodes, but not for depressive episodes after 26 and 100
weeks of maintenance therapy. Aripiprazole was as effective as lithium, and
adjunctive aripiprazole with lithium or valproate was more effective than placebo
plus lithium or valproate, in preventing a manic relapse. Reductions in manic and
mixed relapse rates compared to placebo were achieved in a study combining
aripiprazole with lamotrigine; however, the results were not statistically
significant. Similar to other maintenance studies, depressive relapse rates were
not significantly reduced compared to placebo.
LIMITATIONS: Negative findings for aripiprazole in the treatment of acute bipolar
depression have been attributed to high study doses, rapid titration, and high
placebo rates. A recent post-hoc analysis demonstrated that aripiprazole was more
effective in patients with severe depressive symptoms, particularly for patients
on a lower dose. Further research is needed to confirm this finding. The
inability of aripiprazole to reduce the time to depressive relapse during
maintenance therapy may be due to the recruitment of patients with an index manic
episode and a consequent lower incidence of depressive relapses. Therefore,
studies using a depression index episode are needed to appropriately evaluate
relapse prevention.
CONCLUSIONS: Although aripiprazole has proven efficacy for acute mania and the
prevention of mania, the evidence available thus far does not support the
efficacy of aripiprazole for the treatment of acute bipolar depression and
prevention of depressive relapse. Further studies with appropriate doses and a
depressive index episode are needed to clarify the role of aripiprazole in
bipolar disorder.

———

J Clin Psychiatry. 2011 Jan;72(1):e03.

Alternatives to antidepressants in treating acute bipolar depression.

Nierenberg AA.

Department of Psychiatry, Harvard Medical School and Massachusetts General
Hospital, Boston, MA, USA.

Major depressive episodes and subsyndromal depressive symptoms are associated
with significant psychosocial impairment for patients with bipolar disorder.
However, insufficient evidence exists to support the efficacy of antidepressants
for treating bipolar depression. Alternative pharmacotherapies have been approved
for the treatment of bipolar depressive episodes, and adjunctive psychosocial
interventions have proven efficacy when used with pharmacotherapy.

———

Neuropsychopharmacology. 2010 Dec;35(13):2545-52. Epub 2010 Sep 8.

Transition to mania during treatment of bipolar depression.

Perlis RH, Ostacher MJ, Goldberg JF, Miklowitz DJ, Friedman E, Calabrese J, Thase
ME, Sachs GS.

Department of Psychiatry, Bipolar Clinic and Research Program, Massachusetts
General Hospital and Harvard Medical School, Boston, MA 02114, USA.
rperlis@partners.org

Some individuals with bipolar disorder transition directly from major depressive
episodes to manic, hypomanic, or mixed states during treatment, even in the
absence of antidepressant treatment. Prevalence and risk factors associated with
such transitions in clinical populations are not well established, and were
examined in the Systematic Treatment Enhancement Program for Bipolar Disorder
study, a longitudinal cohort study. Survival analysis was used to examine time to
transition to mania, hypomania, or mixed state among 2166 bipolar I and II
individuals in a major depressive episode. Cox regression was used to examine
baseline clinical and sociodemographic features associated with hazard for such a
direct transition. These features were also examined for interactive effects with
antidepressant treatment. In total, 461/2166 subjects in a major depressive
episode (21.3%) transitioned to a manic/hypomanic or mixed state before
remission, including 289/1475 (19.6%) of those treated with antidepressants
during the episode. Among the clinical features associated with greatest
transition hazard were greater number of past depressive episodes, recent or
lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and
history of switch while treated with antidepressants. Greater manic symptom
severity was also associated with risk for manic transition among both
antidepressant-treated and antidepressant-untreated individuals. Three features,
history of suicide attempt, younger onset age, and bipolar subtype, exhibited
differential effects between individuals treated with antidepressants and those
who were not. These results indicate that certain clinical features may be
associated with greater risk of transition from depression to manic or mixed
states, but the majority of them are not specific to antidepressant-treated
patients.

———

Bipolar Disord. 2010 Nov;12(7):691-701. doi: 10.1111/j.1399-5618.2010.00868.x.

Neurosurgical treatment of bipolar depression: defining treatment resistance and
identifying surgical targets.

Lipsman N, McIntyre RS, Giacobbe P, Torres C, Kennedy SH, Lozano AM.

Division of Neurosurgery, University Health Network Department of Psychiatry,
University of Toronto, University Health Network, 399 Bathurst Street, Toronto,
Ontario, Canada. nir.lipsman@utoronto.ca

OBJECTIVES: Bipolar disorder (BD) is a complex psychiatric disorder that is often
underrecognized, misdiagnosed, and challenging to detect. During the past decade,
substantial progress has been made in the development of pharmacotherapeutic and
psychosocial interventions for various phases of BD. Notwithstanding these
developments, the majority of BD individuals, and particularly patients with
bipolar depression, receiving guideline concordant care do not experience
syndromal or functional recovery, underscoring the need for novel treatments.
Early success with deep brain stimulation (DBS) in the treatment of major
depressive episodes as part of major depressive disorder (MDD) has provided the
impetus to explore its application in other treatment-resistant psychiatric
disorders, notably BD. Herein, we provide the rationale for employing DBS as an
alternative treatment avenue in individuals with bipolar depression.
METHODS: We conducted a PubMed literature search, focusing on English language
articles beginning in 1950 to the present day, and employed the following search
terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and
circuitry. Search results were then manually reviewed and relevant articles
selected for analysis. Relevance was determined by author consensus and overall
manuscript quality. We also reviewed articles on currently available treatment
options for BD in order to develop a coherent and practical definition of
treatment resistance with a focus on surgical intervention.
RESULTS: Several lines of evidence indicate that although mania is the defining
feature of bipolar I disorder, depressive symptoms and episodes dominate the
longitudinal course, account for most of the illness burden including premature
mortality, and are least responsive to contemporary treatments. Disease models in
bipolar depression implicate abnormalities in the structure and function of
discrete neural circuits that subserve affective processing and cognitive
function with the subgenual cingulate cortex occupying a central role. Modulation
of the cingulate cortex with DBS in treatment-resistant MDD populations has
proven to offer acute and sustained antidepressant effects, suggesting possible
benefits for other mood disorder populations.
CONCLUSIONS: A surgical intervention for bipolar depression would not only be a
proof of concept regarding disease modeling but also an important and novel
treatment avenue for individuals affected by bipolar depression.

———

J Affect Disord. 2010 Nov;126(3):453-7. Epub 2010 Jun 12.

Comparison of paroxetine and amitriptyline as adjunct to lithium maintenance
therapy in bipolar depression: a reanalysis of a randomized, double-blind study.

Pilhatsch M, Wolf R, Winter C, Lewitzka U, Bauer M.

Dept. of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus,
Technische Universität, Dresden, Germany.

OBJECTIVE: To compare the efficacy and safety of adjunctive treatment with
paroxetine or amitriptyline in patients with bipolar disorder who relapsed into a
depressive episode during lithium maintenance therapy.
METHODS: Data from a randomized, double-blind trial comparing paroxetine (N=18)
or amitriptyline (N=22) as adjunctive treatment for an episode of depression
during lithium maintenance therapy were reanalyzed. Only patients with a
diagnosis of bipolar disorder were included. The primary endpoint was the change
in Hamilton Rating Scale for Depression (HAM-D21) from randomization to study end
(week 6).
RESULTS: There was a significant reduction of HAM-D21 total score from
randomization to study end in both treatment groups. The mean change in HAM-D21
score in the paroxetine and amitriptyline groups at study end was -14.9 and -15.5
(p=0.798), and the mean HAM-D21 at study end was 8.2 vs. 9.9 (p=0.420),
respectively. The patients treated with paroxetine showed a more rapid
improvement with lower HAM-D21 scores between weeks 3 and 5. Tolerability was
similar in both groups.
LIMITATIONS: No placebo comparator group and relatively small study sample size.
CONCLUSIONS: Adjunctive treatment with either paroxetine or amitriptyline is a
viable option for breakthrough depression during lithium maintenance therapy.

 

Harv Rev Psychiatry. 2010 Oct;18(5):266-78.

The pharmacological treatment of bipolar disorder: the question of modern
advances.

Hirschowitz J, Kolevzon A, Garakani A.

Department of Psychiatry, Mount Sinai School of Medicine, USA.
Jack.hirschowitz@mssm.edu

INTRODUCTION: Lithium has been the mainstay of treatment for patients with
bipolar disorder in the United States since 1970. Major treatment guidelines
recommend lithium as a first-line treatment for mania and maintenance treatment
of bipolar disorder, yet lithium has fallen out of favor while other agents have
grown in popularity. The purpose of this review is to examine the evidence for
treatments that were available in 1970 and to determine if the field has made any
significant advance in the treatment of mania, bipolar depression, and
maintenance.
METHODS: We conducted a MEDLINE search through 2009, and examined only
English-language, randomized/controlled, placebo, or comparison studies.
Tolerability as a factor was not considered for this review.
RESULTS: Lithium, valproate, benzodiazepines, and antipsychotics have been
reported effective for mania-which was essentially the state of the field in
1970. Despite an FDA indication for the use of lamotrigine for depression and
depression maintenance, the supporting evidence is conflicting. For bipolar
maintenance, the evidence is overwhelming in support of lithium and very thin for
valproate and carbamazepine. There is emerging evidence that several atypical
antipsychotics may have efficacy in prevention.
DISCUSSION: The gold standard for treating bipolar disorder in 1970 was lithium,
and the gold standard in 2009 remains lithium. Newer agents may increase our
armamentarium to some extent, but it is not clear if they represent a major
advance in treatment. They still need to be tested against the gold standard.

———

J Clin Psychiatry. 2010 Oct;71(10):1363-70. Epub 2010 Jul 27.

Adjunctive armodafinil for major depressive episodes associated with bipolar I
disorder: a randomized, multicenter, double-blind, placebo-controlled,
proof-of-concept study.

Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA.

Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
joseph.calabrese@UHhospitals.org

OBJECTIVE: To evaluate the efficacy and safety of armodafinil, the longer-lasting
isomer of modafinil, when used adjunctively in patients with bipolar depression.
METHOD: In this 8-week, multicenter, randomized, double-blind, placebo-controlled
study conducted between June 2007 and December 2008, patients who were
experiencing a major depressive episode associated with bipolar I disorder
(according to DSM-IV-TR criteria) despite treatment with lithium, olanzapine, or
valproic acid were randomly assigned to adjunctive armodafinil 150 mg/d (n = 128)
or placebo (n = 129) administered once daily in the morning. The primary outcome
measure was change from baseline in the total 30-item Inventory of Depressive
Symptomatology, Clinician-Rated (IDS-C??) score. Secondary outcomes included
changes from baseline in scores on the Montgomery-Ã…sberg Depression Rating Scale,
among other psychological symptom scales. Statistical analyses were performed
using analysis of covariance (ANCOVA), with study drug and concurrent mood
stabilizer treatment for bipolar disorder as factors and the corresponding
baseline value as a covariate. A prespecified sensitivity analysis was done using
analysis of variance (ANOVA) if a statistically significant treatment-by-baseline
interaction was found. Tolerability was also assessed.
RESULTS: A significant baseline-by-treatment interaction in the total IDS-C??
score (P = .08) was found. Patients administered adjunctive armodafinil showed
greater improvement in depressive symptoms as seen in the greater mean ± SD
change on the total IDS-C?? score (-15.8 ± 11.57) compared with the placebo group
(-12.8 ± 12.54) (ANOVA: P = .044; ANCOVA: P = .074). No differences between
treatment groups were observed in secondary outcomes. Adverse events reported
more frequently in patients receiving adjunctive armodafinil were headache,
diarrhea, and insomnia. Armodafinil was not associated with an increased
incidence and/or severity of suicidality, depression, or mania or with changes in
metabolic profile measurements.
CONCLUSIONS: In this proof-of-concept study, adjunctive armodafinil 150 mg/d
appeared to improve depressive symptoms according to some, but not all, measures
and was generally well tolerated in patients with bipolar depression.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00481195.

———

J Clin Psychopharmacol. 2010 Oct;30(5):579-90.

Treatment options for bipolar depression: a systematic review of randomized,
controlled trials.

Vieta E, Locklear J, Günther O, Ekman M, Miltenburger C, Chatterton ML, Aström M,
Paulsson B.

Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona,
Institut d’Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación
Biomédica en Red de Salud Mental, Barcelona, Spain. evieta@clinic.ub.es

This meta-analysis examined the effectiveness of treatments of bipolar
depression. Trials were identified using the MEDLINE, EMBASE,
http://www.clinicaltrials.gov, and Cochrane databases (1993 to July 2008). The
outcome measures included mean change in Montgomery-Asberg Depression Rating
Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D) total scores, and rates
of response and remission. Overall, 19 publications were included. Medications
included quetiapine, lamotrigine, paroxetine, lithium, olanzapine, aripiprazole,
phenelzine, and divalproex. The most trials were identified for quetiapine (5)
and lamotrigine (6). Not all medications were associated with symptomatic
improvement (significant reduction in MADRS/HAM-D total scores vs placebo), with
lamotrigine, paroxetine, aripiprazole, and lithium not being different from
placebo. Highest reductions in MADRS scores versus placebo were reported for the
olanzapine-fluoxetine combination (1 trial: -6.6; 95% confidence interval [CI],
-9.59 to -3.61; P = 0.000) and quetiapine monotherapy (5 trials: for 300 mg/d,
-4.8; 95% CI, -6.18 to -3.49; P = 0.000; for 600 mg/d, -4.8; 95% CI, -6.22 to
-3.28; P = 0.000), with quetiapine monotherapy also showing the highest reduction
in HAM-D scores (4 trials: -4.0; 95% CI, -5.0 to -2.9; P = 0.000). All
medications except paroxetine, lithium, aripiprazole, and phenelzine
significantly improved the ratio of probabilities of response (overall rate,
1.31; 95% CI, 1.22-1.40) and remission (1.32; 95% CI, 1.20-1.45) versus placebo.
Variability in efficacy exists between treatments of bipolar depression.
Quetiapine and the olanzapine-fluoxetine combination showed the greatest
symptomatic improvement. Efficacy considerations will need to be balanced against
safety and tolerability of the individual agents.

———

Clin Ter. 2010;161(4):321-7.

Duloxetine versus venlafaxine in the treatment of unipolar and bipolar
depression.

Serafini G, Pompili M, Del Casale A, Mancini M, Innamorati M, Lester D, Girardi
P, Tatarelli R.

Department of Neuroscience, Mental Health and Sensory Function, Sapienza
University of Rome, Italy. gianluca.serafi ni@uniroma1.it

OBJECTIVES: Both duloxetine and venlafaxine are efficacious in treating patients
with Major Depressive Disorder (MDD), even though the advantages in treatment
patients with bipolar disorder is unclear. This study aimed to evaluate the
efficacy of duloxetine vs venlafaxine in the acute treatment of unipolar and
bipolar depression.
MATERIALS AND METHODS: The study was a non randomized controlled trial. The
participants were 62 consecutive outpatients (41 men; 21 women) affected by
unipolar and bipolar depression treated either with duloxetine and venlafaxine.
RESULTS: More patients treated with duloxetine had a positive response to
treatment and remission both for depression (HAMD17 response: 90.3% vs 0.0%; p <
.001; HAM-D17 remission: 48.4% vs 0.0%; p < .001), and anxiety (HAM-A response:
90.3% vs 6.5%; p < .001; HAM-A remission: 71.0% vs 6.5%; p < .001) than controls.
Patients treated with duloxetine were also more likely to show a decrease in
HAM-D17 suicidality (100% vs 45.2%; p less than .001) and an increase in the
quality of life (SF-36 percentage of improvement: 6.35 [SD=9.66 vs -2.58 [9.98];
p less than .001) than controls.
CONCLUSIONS: Duloxetine is more effective in reducing anxiety and suicidal
ideation. Both treatments were safe and tolerated, and both may be successfully
used in unipolar and bipolar depression.

———

J Psychopharmacol. 2010 Sep 7. [Epub ahead of print]

Lamotrigine: when and where does it act in affective disorders? A systematic
review.

Amann B, Born C, Crespo JM, Pomarol-Clotet E, McKenna P.

Benito Menni, Complex Assistencial en Salut Mental, CIBERSAM, Research Unit, Sant
Boi de Llobregat, Barcelona, Spain.

Recent published data and treatment guidelines have created uncertainty about the
use of lamotrigine in affective disorders, especially in acute bipolar
depression. Furthermore, unpublished data on lamotrigine in mania, mixed
episodes, unipolar depression and rapid cycling are still waiting to be
integrated into the literature. Therefore, we critically reviewed the position of
lamotrigine in the acute and long-term treatment of affective disorders. Studies
were identified by searching English language articles published in MEDLINE using
the key words: lamotrigine, bipolar depression, unipolar depression, mania, mixed
episode, long-term treatment, rapid-cycling. Results of unpublished trials were
obtained from the GlaxoSmithKline website. Lamotrigine showed efficacy in the
prophylaxis of bipolar disorder, more so in depressive than manic episodes. There
was no evidence of effectiveness in the acute treatment of mania, mixed episodes,
unipolar depression or rapid-cycling bipolar I disorder. Its effect in the acute
treatment of bipolar depression is at most small. Based on current evidence,
lamotrigine is indicated for the prophylaxis of bipolar disorder with
predominantly depressive episodes. Its effectiveness in the acute treatment of
bipolar depression is open to debate, and practical considerations limit its
usefulness here. There are no grounds for recommending its use in manic or mixed
states, in rapidly-cycling bipolar I or in unipolar depression.

———

J Clin Psychiatry. 2010 May;71(5):e10.

Treatment strategies for bipolar depression.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center, and the
Center for Bipolar Illness Interventions in Hispanic Communities, San Antonio,
USA.

Resolving acute bipolar mood episodes is only one part of an overall strategy for
treating bipolar disorder. Successful prevention of mood episode relapse,
particularly bipolar depressive episodes, through effective continuation and
maintenance therapies can greatly improve patient functioning and outcomes.
Little evidence is available to guide decisions on the treatment of bipolar
depression, especially in the maintenance phase, and additional research into
effective options is urgently needed. General strategies for treating patients
with bipolar disorder include continuing the acute pharmacotherapeutic regimen
into the maintenance phase and considering tolerability.

———

J Clin Psychiatry. 2010 Oct;71(10):1363-70. Epub 2010 Jul 27.

Adjunctive armodafinil for major depressive episodes associated with bipolar I
disorder: a randomized, multicenter, double-blind, placebo-controlled,
proof-of-concept study.

Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA.

Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
joseph.calabrese@UHhospitals.org

OBJECTIVE: To evaluate the efficacy and safety of armodafinil, the longer-lasting
isomer of modafinil, when used adjunctively in patients with bipolar depression.
METHOD: In this 8-week, multicenter, randomized, double-blind, placebo-controlled
study conducted between June 2007 and December 2008, patients who were
experiencing a major depressive episode associated with bipolar I disorder
(according to DSM-IV-TR criteria) despite treatment with lithium, olanzapine, or
valproic acid were randomly assigned to adjunctive armodafinil 150 mg/d (n = 128)
or placebo (n = 129) administered once daily in the morning. The primary outcome
measure was change from baseline in the total 30-item Inventory of Depressive
Symptomatology, Clinician-Rated (IDS-C??) score. Secondary outcomes included
changes from baseline in scores on the Montgomery-Ã…sberg Depression Rating Scale,
among other psychological symptom scales. Statistical analyses were performed
using analysis of covariance (ANCOVA), with study drug and concurrent mood
stabilizer treatment for bipolar disorder as factors and the corresponding
baseline value as a covariate. A prespecified sensitivity analysis was done using
analysis of variance (ANOVA) if a statistically significant treatment-by-baseline
interaction was found. Tolerability was also assessed.
RESULTS: A significant baseline-by-treatment interaction in the total IDS-C??
score (P = .08) was found. Patients administered adjunctive armodafinil showed
greater improvement in depressive symptoms as seen in the greater mean ± SD
change on the total IDS-C?? score (-15.8 ± 11.57) compared with the placebo group
(-12.8 ± 12.54) (ANOVA: P = .044; ANCOVA: P = .074). No differences between
treatment groups were observed in secondary outcomes. Adverse events reported
more frequently in patients receiving adjunctive armodafinil were headache,
diarrhea, and insomnia. Armodafinil was not associated with an increased
incidence and/or severity of suicidality, depression, or mania or with changes in
metabolic profile measurements.
CONCLUSIONS: In this proof-of-concept study, adjunctive armodafinil 150 mg/d
appeared to improve depressive symptoms according to some, but not all, measures
and was generally well tolerated in patients with bipolar depression.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00481195.

———

J Nerv Ment Dis. 2010 Sep;198(9):679-81.

Clinical predictors associated with duration of repetitive transcranial magnetic
stimulation treatment for remission in bipolar depression: a naturalistic study.

Cohen RB, Brunoni AR, Boggio PS, Fregni F.

Centro Brasileiro de Estimulacao Magnetica Transcraniana, Sao Paulo, Brazil.

Repetitive transcranial magnetic stimulation (rTMS) has been widely tested and
shown to be effective for unipolar depression. Although it has also been
investigated for bipolar depression (BD), there are only few rTMS studies with
BD. Here, we investigated 56 patients with BD who received rTMS treatment until
remission (defined as Hamilton Depression Rating Scores < or =7). We used simple
and multiple logistic regressions to identify clinical and demographic predictors
associated with duration of treatment (defined as <15 vs. >15 rTMS sessions).
Age, refractoriness, number of prior depressive episodes, and severe depression
at baseline were associated with a longer rTMS treatment. In the multivariate
analysis, refractoriness (likelihood ratio (LR) = 4.33; p < 0.01) and baseline
severity (LR = 0.18, p < 0.01) remained significant predictors. Our preliminary
study showed that, in remitted patients, refractoriness and severity of index
episode are associated with the need of a longer rTMS treatment; providing
preliminary evidence of important factors associated with rTMS parameters
adjustment.

———

Adv Ther. 2010 Nov;27(11):774-84. Epub 2010 Sep 10.

The role of quetiapine extended release in the treatment of bipolar depression.

Cristancho MA, Thase ME.

University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.

Bipolar disorder is a common, recurrent, and chronic condition associated with
significant morbidity and reduced longevity mainly due to the depressive pole of
the illness. Despite the great need for effective therapies, relatively few
randomized controlled trials have been conducted and, to date, only two agents
have been approved by the United States Food and Drug Administration for
treatment of bipolar depression (olanzapine/fluoxetine combination and
quetiapine). Quetiapine is the first approved monotherapy for treatment of
bipolar depression, and an extended-release (XR) form of quetiapine is now
available. This once-daily, bioequivalent formulation represents a useful
alternative for patients who cannot tolerate twice-daily, immediate-release (IR)
quetiapine. Here, we summarize the evidence supporting the efficacy of quetiapine
for treatment of bipolar depression, and also review the similarities and
differences between the two formulations. Additional research on longer-term use
of quetiapine XR is needed to establish the durability of therapeutic effects and
tolerability over months or years of therapy, both alone and in combination with
other mood stabilizers. Studies on the potential utility of lower doses of
quetiapine XR and head-to-head studies to evaluate relative efficacy and
cost-effectiveness also are needed.

———

Psychiatr Q. 2010 Sep;81(3):207-13.

Long-term use of pramipexole in bipolar depression: a naturalistic retrospective
chart review.

El-Mallakh RS, Penagaluri P, Kantamneni A, Gao Y, Roberts RJ.

School of Medicine, University of Louisville, Louisville, KY, USA.
rselma01@louisville.edu

A naturalistic retrospective chart review of all patients given pramipexole for
bipolar depression in addition to their mood stabilizers was undertaken. Sixteen
patients were followed for an average of 6.7 +/- SD 9.0 months. Half of the
patients stopped the pramipexole an average of 2 months after starting it. For
all patients, depressed mood, and the total profile of depressive symptoms
improved significantly within 4 weeks and remained significantly improved for as
long as 36 weeks. Both global function (GAF), and global impression (CGI)
improved with pramipexole. Irritability and insomnia both increased slightly
initially, and then subsided. There were no changes in mania ratings for up to 36
months. Long-term outcome of adjunctive pramipexole appears to be adequate, with
apparent maintenance of effect for over 9 months.

———

J Clin Psychiatry. 2010 Oct 19. [Epub ahead of print]

Number needed to treat to harm for discontinuation due to adverse events in the
treatment of bipolar depression, major depressive disorder, and generalized
anxiety disorder with atypical antipsychotics.

Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, Calabrese JR.

10524 Euclid Ave, 12th Fl, Cleveland, OH 44106, USA. keming.gao@uhhospitals.org.

OBJECTIVE: To estimate the number needed to treat to harm (NNTH) for
discontinuation due to adverse events with atypical antipsychotics relative to
placebo during the treatment of bipolar depression, major depressive disorder
(MDD), and generalized anxiety disorder (GAD). DATA SOURCES: English-language
literature published and cited in MEDLINE from January 1966 to May 2009 was
searched with the terms antipsychotic, atypical antipsychotic, generic and brand
names of atypical antipsychotics, safety, tolerability, discontinuation due to
adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal
side effect; and bipolar depression, major depressive disorder, or generalized
anxiety disorder; and randomized, placebo-controlled clinical trial. This search
was augmented with a manual search. STUDY SELECTION: Studies with a cumulative
sample of ? 100 patients were included. DATA EXTRACTION: The NNTHs for
discontinuation due to adverse events, somnolence, sedation, ? 7% weight gain,
and akathisia relative to placebo were estimated with 95% confidence intervals to
reflect the magnitude of variance. DATA SYNTHESIS: Five studies in bipolar
depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole
and olanzapine have been studied in bipolar depression and refractory MDD. Only
quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric
conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH
for discontinuation due to adverse events was 14 in bipolar depression, but was
not significantly different from placebo in MDD. For olanzapine, the mean NNTHs
were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to
adverse events during quetiapine-XR treatment appeared to be associated with
dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse
events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for
GAD. CONCLUSIONS: At the same dose of quetiapine-XR, patients with GAD appeared
to have a lower tolerability than those with bipolar depression or MDD. Due to
flexible dosing, the risk for discontinuation due to adverse events in the
treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics
could not be compared.

———

World J Biol Psychiatry. 2010 Mar;11(2):81-109.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for
the Biological Treatment of Bipolar Disorders: Update 2010 on the treatment of
acute bipolar depression.

Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Möller HJ, Kasper S; WFSBP
Task Force On Treatment Guidelines For Bipolar Disorders.

Collaborators: Kasper S, Goodwin G, Bowden C, Grunze H, Möller HJ, Licht RW,
Vieta E, Akiskal H, Ayuso-Gutierrez JL, Bauer M, Bech P, Berk M, Bitter I,
Burrows G, Calabrese J, Cassano G, Cetkovich-Bakmas M, Cookson JC, Ferrier IN,
Gattaz WF, Goodwin FK, Heinze G, Higuchi T, Hirschfeld RM, Hoeschl C,
Holsboer-Trachsler E, Jamison KR, Katona C, Keller M, Kostukova E, Kruger H,
Kulhara P, Lecruibier Y, Larach V, Lingjaerde O, Lublin H, Maj M, Mendlewicz J,
Camacho RM, Mitchell P, Mosolov S, Montgomery S, Nemeroff C, Nolen W, Paykel ES,
Post RM, Puzynski S, Rihmer Z, Rybakowski JK, Vestergaard P, Whybrow PC, Yamada
K.

Newcastle University, RVI, Division of Psychiatry, Institute of Neuroscience,
Newcastle upon Tyne, UK. Heinz.Grunze@ncl.ac.uk

OBJECTIVES: These guidelines are based on a first edition that was published in
2002, and have been edited and updated with the available scientific evidence
until September 2009. Their purpose is to supply a systematic overview of all
scientific evidence pertaining to the treatment of acute bipolar depression in
adults.
METHODS: The data used for these guidelines have been extracted from a MEDLINE
and EMBASE search, from the clinical trial database clinicaltrials.gov, from
recent proceedings of key conferences, and from various national and
international treatment guidelines. Their scientific rigor was categorised into
six levels of evidence (A-F). As these guidelines are intended for clinical use,
the scientific evidence was finally assigned different grades of recommendation
to ensure practicability.
RESULTS: We identified 10 pharmacological monotherapies or combination treatments
with at least limited positive evidence for efficacy in bipolar depression,
several of them still experimental and backed up only by a single study. Only one
medication was considered to be sufficiently studied to merit full positive
evidence.
CONCLUSIONS: Although major advances have been made since the first edition of
this guideline in 2002, there are many areas which still need more intense
research to optimize treatment. The majority of treatment recommendations is
still based on limited data and leaves considerable areas of uncertainty.

———

World J Biol Psychiatry. 2010 Sep 21. [Epub ahead of print]

H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar
depression: an add-on, safety and feasibility study.

Harel EV, Zangen A, Roth Y, Reti I, Braw Y, Levkovitz Y.

The Emotion-Cognition Research Center, Shalvata Mental Health Care Center,
Hod-Hasharon, Israel (affiliated to the Sackler Faculty of Medicine, Tel-Aviv
University, Tel Aviv, Israel).

Abstract Objectives. The H1-Coil is a novel transcranial magnetic stimulation
(TMS) device capable of inducing a magnetic field with a deeper and wider
distribution than standard coils. This pilot study evaluated the safety and
feasibility of the H1-Coil as adjuvant treatment for bipolar depression (BPD).
Methods. Nineteen patients diagnosed as having BPD and under treatment with
psychotropic medication were enrolled in the study. They received daily
prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli)
every weekday for four consecutive weeks. The primary outcome measure was the
change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a
week after the last treatment session. Results. A significant mean decrease of
12.9 points in the HDRS-24 scale (P< 0.001) was found. Response rate was 63.2%
and remission rate was 52.6%. Treatment was well tolerated in terms of headache
and overall discomfort, and there were no significant change in cognitive
functioning or mood switches. One patient had a short induced generalized seizure
without complications. Conclusions. An add-on H-coil rTMS treatment protocol in
BPD subjects indicated improvement in bipolar depression symptoms. Sham-control
studies to further determine the efficacy and safety of the H-Coil for BPD are
warranted.

———

J Affect Disord. 2010 Sep 11. [Epub ahead of print]

Long-term naturalistic follow-up of lithium augmentation: Relevance to
bipolarity.

Inoue T, Abekawa T, Nakagawa S, Suzuki K, Tanaka T, Kitaichi Y, Boku S, Nakato Y,
Toda H, Koyama T.

BACKGROUND: Whether bipolarity (unrecognized bipolar disorder) is related to the
treatment response to lithium augmentation in antidepressant-refractory
depression remains unclear. This study of responders and non-responders to
lithium augmentation of 29 antidepressant-refractory patients with major
depression, whom we had studied during 1995-1997, compared the bipolar diagnosis
at the follow-up based on diagnostic confirmation after long-term follow-up.
METHODS: Before being classified as stage 2 treatment-resistant depression, these
patients had been treated adequately with at least two tricyclic or heterocyclic
antidepressants from different pharmacological classes (a minimum of the
equivalent of 150mg of imipramine for 4weeks). During 1995-1997, 29 patients
received lithium augmentation. Their treatment responses were recorded. Mean
follow-up was 8.0years (range, 1-13years). Bipolar conversion and full remission
were evaluated. RESULTS: After the long-term follow-up, diagnoses were changed to
bipolar depression in 3 of 4 lithium responders and 3 of 25 lithium
non-responders; lithium augmentation was more effective for unrecognized bipolar
patients. Only the family history of bipolar disorder predicted subsequent
bipolar conversion. LIMITATIONS: Treatment was not controlled in this
naturalistic study, which had a small sample size. CONCLUSIONS: Results of this
long-term follow-up study suggest that bipolarity is related to a positive
response to lithium augmentation in stage 2 treatment-resistant major depression.
The family history of bipolar disorder suggests false unipolar depression, and
therefore indicates lithium responders.

———

J Affect Disord. 2010 Nov 9. [Epub ahead of print]

Clinical value of early partial symptomatic improvement in the prediction of
response and remission during short-term treatment trials in 3369 subjects with
bipolar I or II depression.

Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, Evoniuk G,
Jansen W, Leon AC, Minkwitz M, Pikalov A, Stassen HH, Szegedi A, Tohen M, Van
Willigenburg AP, Calabrese JR.

Case Western Reserve University, University Hospitals Case Medical Center,
Cleveland, OH, USA.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic
improvement in predicting the probability of response during the short-term
treatment of bipolar depression. METHODS: Blinded data from 10 multicenter,
randomized, double-blind, placebo-controlled trials in bipolar I or II depression
were used to determine if early improvement (?20% reduction in depression symptom
severity after 14days of treatment) predicted later short-term response or
remission. Sensitivity, specificity, efficiency, and positive and negative
predictive values (PPV, NPV) were calculated using an intent to treat analysis of
individual and pooled study data. RESULTS: 1913 patients were randomized to
active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine,
and quetiapine), and 1456 to placebo. In the pooled positive studies, early
improvement predicted response and remission with high sensitivity (86% and 88%,
respectively), but rates of false positives were high (53% and 59%,
respectively). Pooled negative predictive values for response/remission (i.e.
confidence in knowing the drug will not result in response or remission) were 74%
and 82%, respectively, with low rates of false negatives (14% and 12%,
respectively). CONCLUSION: Early improvement in an individual patient does not
appear to be a reliable predictor of eventual response or remission due to an
unacceptably high false positive rate. However, the absence of early improvement
appears to be a highly reliable predictor of eventual non-response, suggesting
that clinicians can have confidence in knowing when a drug is not going to work
during short-term treatment. Patients who fail to demonstrate early improvement
within the first two weeks of treatment may benefit from a change in therapy.

———

Bipolar Disord. 2010 Nov;12(7):691-701. doi: 10.1111/j.1399-5618.2010.00868.x.

Neurosurgical treatment of bipolar depression: defining treatment resistance and
identifying surgical targets.

Lipsman N, McIntyre RS, Giacobbe P, Torres C, Kennedy SH, Lozano AM.

Division of Neurosurgery, University Health Network Department of Psychiatry,
University of Toronto, University Health Network, 399 Bathurst Street, Toronto,
Ontario, Canada. nir.lipsman@utoronto.ca

OBJECTIVES: Bipolar disorder (BD) is a complex psychiatric disorder that is often
underrecognized, misdiagnosed, and challenging to detect. During the past decade,
substantial progress has been made in the development of pharmacotherapeutic and
psychosocial interventions for various phases of BD. Notwithstanding these
developments, the majority of BD individuals, and particularly patients with
bipolar depression, receiving guideline concordant care do not experience
syndromal or functional recovery, underscoring the need for novel treatments.
Early success with deep brain stimulation (DBS) in the treatment of major
depressive episodes as part of major depressive disorder (MDD) has provided the
impetus to explore its application in other treatment-resistant psychiatric
disorders, notably BD. Herein, we provide the rationale for employing DBS as an
alternative treatment avenue in individuals with bipolar depression.
METHODS: We conducted a PubMed literature search, focusing on English language
articles beginning in 1950 to the present day, and employed the following search
terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and
circuitry. Search results were then manually reviewed and relevant articles
selected for analysis. Relevance was determined by author consensus and overall
manuscript quality. We also reviewed articles on currently available treatment
options for BD in order to develop a coherent and practical definition of
treatment resistance with a focus on surgical intervention.
RESULTS: Several lines of evidence indicate that although mania is the defining
feature of bipolar I disorder, depressive symptoms and episodes dominate the
longitudinal course, account for most of the illness burden including premature
mortality, and are least responsive to contemporary treatments. Disease models in
bipolar depression implicate abnormalities in the structure and function of
discrete neural circuits that subserve affective processing and cognitive
function with the subgenual cingulate cortex occupying a central role. Modulation
of the cingulate cortex with DBS in treatment-resistant MDD populations has
proven to offer acute and sustained antidepressant effects, suggesting possible
benefits for other mood disorder populations.
CONCLUSIONS: A surgical intervention for bipolar depression would not only be a
proof of concept regarding disease modeling but also an important and novel
treatment avenue for individuals affected by bipolar depression.

———

J Affect Disord. 2010 Sep 20. [Epub ahead of print]

Physical treatments for bipolar disorder: A review of electroconvulsive therapy,
stereotactic surgery and other brain stimulation techniques.

Loo C, Katalinic N, Mitchell PB, Greenberg B.

School of Psychiatry, University of New South Wales, Sydney, Australia; St.
George Hospital, Sydney, Australia; Bipolar Disorders Clinic, Black Dog
Institute, Sydney, Australia.

BACKGROUND: Despite pharmacological advances, bipolar disorder continues to be
difficult to treat. This article reviews the evidence base for the use of
electroconvulsive therapy (ECT) and other brain stimulation therapies in bipolar
disorder. METHODS: The evidence base for the efficacy of ECT and transcranial
magnetic stimulation in the treatment of mania, bipolar depression and mixed
affective states was reviewed. Reports on the use of vagus nerve stimulation,
stereotaxic surgery, deep brain stimulation, magnetic seizure therapy and
transcranial direct current stimulation in treating depression, as well as
bipolar disorder were also reviewed. Studies were identified from Medline and
Embase database searches. RESULTS: There are a few randomized controlled trials
of ECT in mania and bipolar depression, and none in mixed affective states.
Nevertheless, such studies consistently reported clinically meaningful efficacy,
with a majority of pharmacotherapy resistant patients responding to ECT. Evidence
for the use of other brain stimulation therapies in treating bipolar mood states
is preliminary and limited. CONCLUSIONS: ECT is an effective treatment for acute
mania, bipolar depression and mixed affective states and has useful efficacy even
in pharmacotherapy-resistant patients. Other brain stimulation techniques may
have potential for the treatment of bipolar disorder and should be further
researched.

———

Int J Neuropsychopharmacol. 2010 Oct 29:1-7. [Epub ahead of print]

Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist
pramipexole in treatment of bipolar depression.

Mah L, Zarate CA, Nugent AC, Singh JB, Manji HK, Drevets WC.

Kunin-Lunenfeld Applied Research Unit, Rotman Research Institute, Baycrest,
University of Toronto, Toronto, ON, Canada.

The D2/D3 receptor agonist pramipexole has clinical efficacy as an
antidepressant, but its neural mechanisms are unknown. We used 18FDG-PET to
investigate the cerebral metabolic effects of pramipexole augmentation of mood
stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on
mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7)
or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was
associated with reductions in normalized metabolism in bilateral orbitofrontal
cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC.
Voxel-wise analyses additionally showed decreased normalized metabolism in the
left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of
the anteromedial PFC following pramipexole treatment. These pramipexole-induced
effects on regional metabolism suggest a mechanism of antidepressant action
distinct from that previously reported under serotonin reuptake inhibitor
treatment and appear compatible with evidence that the central dopaminergic
system plays a role in the pathophysiology of bipolar depression.

———

Vertex. 2010 Mar-Apr;21(90):85-96.

[How do Argentinean psychiatrists treat bipolar depression?].

[Article in Spanish]

Mazaira S, Leiderman EA, Nemirovsky M, Vigo D, Wikinski S.

smazaira@arnet.com.ar

We show the results of a survey on bipolar depression treatment using a sample of
359 argentine psychiatrists in the context of The National Psychiatry Congress
that took place in the City of Buenos Aires, between September 26th and 29th,
2007. The objective was to study the attendant psychiatrists’ prescribing habits
in the treatment of bipolar depression. The discussion is based on the comparison
between the answers and the recommendations taken from the main consensus,
guidelines and from articles published by experts. The differences found point to
the distance often present between guidelines and expert consensus series (based
on patients meeting the strict criteria used in randomized controlled studies) on
one hand, and a clinician’s everyday real world practice, on the other hand.

———

Int Clin Psychopharmacol. 2010 Sep;25(5):297-301.

Identification of clinical factors associated with resistance to antidepressants
in bipolar depression: results from an European Multicentre Study.

Mendlewicz J, Massat I, Linotte S, Kasper S, Konstantinidis A, Lecrubier Y,
Montgomery S, Serretti A, Zohar J, Souery D; Group for the Study of Resistant
Depression (GSRD).

Free University of Brussels, School of Medicine, Brussels, Belgium.

This study is the first investigation to identify clinical factors associated
with treatment resistance in bipolar depression (TRBD). TRBD is defined as
failure to respond to at least two consecutive adequate antidepressant trials.
The primary objective of this European Multicenter Study was to identify specific
clinical and demographic factors associated with TRBD in a sample of bipolar
patients treated for a major depressive episode. A total of 261 bipolar patients
with major depressive episode were included in the analysis. Among them, 162
patients were considered as responders to treatment and the remaining 99 patients
were considered as treatment resistant with a 17-item Hamilton Rating Scale for
Depression Score remaining superior or equal to 17 after two consecutive adequate
antidepressant trials. Cox regression analysis was used to examine the
association between individual clinical variables and TRBD. We found four
clinical variables to be significantly associated with TRBD: melancholia [P=0.01,
odds ratio (OR)=2.4], comorbidity with social phobia (P=0.02, OR=2.3), current
suicidal risk (P=0.02, OR=1.8) and severe intensity of current depressive episode
(P=0.01, OR=1.8). Our findings identify four clinical variables associated with
TRBD, which could be further investigated in controlled prospective trials.

———

World J Biol Psychiatry. 2010 Mar;11(2 Pt 2):519-21.

Quetiapine monotherapy in bipolar I disorder: a 1-year stabilization in a woman
having undergone bone marrow transplantation.

Michopoulos I, Christodoulou C, Dervenoulas J, Soldatos CR, Lykouras L.

2nd Department of Psychiatry, Athens University Medical School, Attikon General
Hospital, Athens, Greece.

Queatiapine has been used in bipolar mania and most recently in bipolar
depression with good results; however, its use in maintenance treatment has not
been established yet. A case of a woman suffering from bipolar I disorder who
underwent bone marrow transplantation twice because of leukaemia is presented.
The use of quetiapine as a monotherapy was efficient and safe and proved to be a
good treatment in mood stabilization for 1 year.

———

J Affect Disord. 2010 Jun 8. [Epub ahead of print]

New treatment guidelines for acute bipolar depression: A systematic review.

Nivoli AM, Colom F, Murru A, Pacchiarotti I, Castro-Loli P, González-Pinto A,
Fountoulakis KN, Vieta E.

Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, University
of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; Department of
Psychiatry, Institute of Neuroscience, University of Sassari, Italy.

INTRODUCTION: Bipolar depression poses a great burden on patients and their
families due to its duration, associated functional impairment, and limited
treatment options. Given the complexity of the disorder and the advances in
treatment, a number of clinical guidelines, consensus statements and expert
opinions were developed with the aim to standardize treatment and provide
clinicians with treatment algorithms for every-day clinical practice.
Unfortunately, they often led to conflicting conclusions and recommendations due
to limitations of the available literature. As findings emerge from research
literature, guidelines quickly become obsolete and need to be updated or revised.
Many guidelines have been updated in the last 5years, after the last review of
bipolar disorder (BD) treatment guidelines. OBJECTIVE: The purpose of this work
is to systematically review guidelines, consensus meetings and treatment
algorithms on the acute treatment of bipolar depression updated or published
since 2005, to critically underline common and critical points, highlight limits
and strengths, and provide a starting point for future research MATERIALS AND
METHODS: The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta
Medica/EMBASE, databases were searched using “depression”, “bipolar”,
“manic-depression”, “manic-depressive” and “treatment guidelines” as key words
RESULTS: The search returned 204 articles. Amongst them, there were 28 papers
concerning structured treatment algorithms and/or guidelines suggested by
official panels. After excluding those guidelines that were not performed by
scientific societies or international groups and those published before 2005, the
final selection yielded 7 papers When looking into guidelines content, the
results indicate a trend to the gradual acceptance of the use of the atypical
antipsychotic quetiapine as monotherapy as first-line treatment. Antidepressant
monotherapy is discouraged in most of them, although some support the use of
antidepressants in combination with antimanic agents for a limited period of
time. Lamotrigine has become a highly controversial option. CONCLUSION: The
management of bipolar depression is complex and should be differentiated from
management of unipolar depression. Guidelines may be useful instruments for
helping clinicians to choose and plan bipolar depression treatment by integrating
the more updated scientific knowledge with every-day clinical practice and
patient-specific factors; however, a further effort is needed in order to improve
guidelines implementation in clinical practice. The latest updates on treatment
guidelines for bipolar depression give priority to novel treatment approaches,
such as quetiapine, over more traditional ones, such as lithium or
antidepressants. Lamotrigine is a controversial option.

———

Eur Neuropsychopharmacol. 2010 Nov 5. [Epub ahead of print]

Factors associated with initial treatment response with antidepressants in
bipolar disorder.

Pacchiarotti I, Valentí M, Bonnin CM, Rosa AR, Murru A, Kotzalidis GD, Nivoli AM,
Sánchez-Moreno J, Vieta E, Colom F.

INTRODUCTION: Controversy in antidepressant (AD) use in bipolar depression relies
in its potential induction of mood switches and ineffectiveness. Responders to
acute AD add-on treatment maintain response with continued treatment, whilst
partial/non-responders fail to reach remission despite continuation treatment. We
aimed to identify response predictors to acute AD addition in bipolar depression
in order to optimize treatment choice in bipolar depression and avoid unnecessary
AD exposure of people unlikely to respond. METHODS: Two hundred and twenty-one
DSM-IV-TR depressed bipolar – type I and II – patients were treated with AD on an
observational study. AD response was defined as an at least 50% drop from
baseline of their HDRS17 score after 8weeks of treatment. One hundred and
thirty-eight patients (138, 62.4%) fulfilled response criteria (RI) whilst 83
patients (37.6%) did not (NRI). In all cases AD therapy was on top of previously
prescribed stabilizers and/or atypical antipsychotics. RESULTS: RI patients were
more likely to have had previous response to ADs, whereas NRI had a higher number
of previous mood switches with ADs during past depressive episodes. Psychotic
symptoms were more frequent amongst RI, whilst lifetime history of atypical
depression was more frequent amongst NRI. NRI had more total, depressive, and
hypomanic, but not manic or mixed, episodes in the past than RI. Analyzed through
a logistic regression, higher previous response to ADs and lower rate of past
hypomanic episodes in RI were the variables explaining intergroups (RI vs. NRI)
differences. DISCUSSION: Taking into account the proper caution in the use of Ads
in bipolar disorder, there is a subgroup of bipolar patients who might benefit
from adjunctive Ads. Looking at specific clinical factors during the course of
the illness could help physicians in deciding whether to use an antidepressant in
a bipolar depressed patient already treated with mood stabilizers.
PMID: 21056928 [PubMed – as supplied by publisher] 21. J Affect Disord. 2010 Sep 2. [Epub ahead of print]

Differential outcome of bipolar patients receiving antidepressant monotherapy
versus combination with an antimanic drug.

Pacchiarotti I, Valentí M, Colom F, Rosa AR, Nivoli AM, Murru A, -Moreno JS,
Vieta E.

INTRODUCTION: Despite antidepressants are widely used in treating bipolar
depression, there is much debate about their utility and their potential dangers,
involving mood switches and suicidality. Our hypothesis was that the pattern of
initial antidepressant prescription, i.e., alone (AM) or in combination with
stabilizers (AC) might impact the long-term outcome of patients with bipolar
disorder (BP). We aimed to test this hypothesis and to identify outcome measures
that could be predicted by initial AM or AC treatment in patients with BP.
METHODS: We included 95 patients with DSM-IV BP from a pool of 138 patients
following a BP program. Patients were rated for initial AM vs. AC treatment when
they were first seen in primary care and subdivided into two groups accordingly.
Differences in their clinical course were sought investigating course both
retrospectively and prospectively (mean follow-up 10years). Primary outcome
measures comprised suicidality and switch rate. RESULTS: There were significantly
more patients who switched in the AM group than in the AC group. The number of
suicide attempts was higher in the AM group. Significance was retained after
performing logistic regression. LIMITATIONS: Sample size was small and severe BP
patients might be overrepresented in this sample. DISCUSSION: Initial AM
treatment of patients subsequently diagnosed as BP may entrain a course
characterized by higher proneness to switch and suicidal behaviour. Accurate
initial diagnosis of bipolar depression should prompt combined treatment with
antimanic drugs.

———

J Affect Disord. 2010 Nov;126(3):453-7. Epub 2010 Jun 12.

Comparison of paroxetine and amitriptyline as adjunct to lithium maintenance
therapy in bipolar depression: a reanalysis of a randomized, double-blind study.

Pilhatsch M, Wolf R, Winter C, Lewitzka U, Bauer M.

Dept. of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus,
Technische Universität, Dresden, Germany.

OBJECTIVE: To compare the efficacy and safety of adjunctive treatment with
paroxetine or amitriptyline in patients with bipolar disorder who relapsed into a
depressive episode during lithium maintenance therapy.
METHODS: Data from a randomized, double-blind trial comparing paroxetine (N=18)
or amitriptyline (N=22) as adjunctive treatment for an episode of depression
during lithium maintenance therapy were reanalyzed. Only patients with a
diagnosis of bipolar disorder were included. The primary endpoint was the change
in Hamilton Rating Scale for Depression (HAM-D21) from randomization to study end
(week 6).
RESULTS: There was a significant reduction of HAM-D21 total score from
randomization to study end in both treatment groups. The mean change in HAM-D21
score in the paroxetine and amitriptyline groups at study end was -14.9 and -15.5
(p=0.798), and the mean HAM-D21 at study end was 8.2 vs. 9.9 (p=0.420),
respectively. The patients treated with paroxetine showed a more rapid
improvement with lower HAM-D21 scores between weeks 3 and 5. Tolerability was
similar in both groups.
LIMITATIONS: No placebo comparator group and relatively small study sample size.
CONCLUSIONS: Adjunctive treatment with either paroxetine or amitriptyline is a
viable option for breakthrough depression during lithium maintenance therapy.

———

Psychopharmacology (Berl). 2010 Oct 31. [Epub ahead of print]

Number needed to treat analyses of drugs used for maintenance treatment of
bipolar disorder.

Popovic D, Reinares M, Amann B, Salamero M, Vieta E.

Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain.

RATIONALE: Due to the episodic and chronic nature of bipolar disorder (BD),
maintenance therapy represents a critical part of treatment; however, there is a
paucity of studies comparing effectiveness of available long-term treatments.
OBJECTIVE: The aim of this study is to determine and compare the efficacy of
pharmacological treatments for maintenance treatment of BD by means of the number
needed to treat (NNT). METHODS: The efficacy of drugs used for maintenance
treatment of BD, as emerging from the results of randomized controlled trials,
was assessed using the size effect measure of NNT. PubMed searches were conducted
on English-language articles published until May 2010 using the search terms
“bipolar disorder,” “mania,” “mixed episode,” or “bipolar depression,”
cross-referenced with trial characteristic search phrases and generic names of
medications. The search was supplemented by manually reviewing reference lists
from identified publications. RESULTS: In 15 studies, aripiprazole, olanzapine,
quetiapine, risperidone long-acting injection, lithium, lamotrigine, and
divalproex proved effectiveness in terms of NNTs (?10% advantage over placebo)
for prevention of relapse into any mood episode. Quetiapine, lithium, risperidone
long-acting injection, aripiprazole, and olanzapine are effective in manic
recurrence prevention. Lamotrigine, quetiapine, and lithium present significant
NNTs for prevention of depressive relapses. CONCLUSIONS: All of the
pharmacological agents assessed were effective in the prevention of any kind of
mood episode; however, different efficacy profiles were found for prevention of
manic and/or depressive relapses. The comparison of NNT values of the available
agents may represent a useful tool in clinical settings, in order to facilitate
implementation of long-term pharmacological interventions in patients with BD.

———

Hum Psychopharmacol. 2010 Mar;25(2):126-32.

Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar
depression: a randomized placebo-controlled pilot study.

Quante A, Zeugmann S, Luborzewski A, Schommer N, Langosch J, Born C, Anghelescu
I, Wolf J.

Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin,
Campus Benjamin Franklin, Berlin, Germany. arnim.quante@charite.de

OBJECTIVE: The use of atypical antipsychotics (AAPs) for the treatment of
unipolar and bipolar depression has been more and more frequently evaluated, and
aripiprazole showed positive effects in the treatment of unipolar depression.
However, no placebo-controlled studies of adjunctive aripiprazole for the
treatment of bipolar depression have been performed yet.
METHODS: In this prospective, double-blind, placebo-controlled, randomized trial,
23 inpatients with bipolar depression according to DSM-IV criteria were included.
Before randomization, patients had to be on a constant mood stabilizer treatment
with lithium or valproate for at least 1 week. After inclusion, all patients were
openly treated with additional citalopram and with additional aripiprazole or
placebo for 6 weeks. The primary outcome parameter was the reduction in
depressive symptoms according to the Hamilton Depression Rating Scale (HDRS)
within 6 weeks.
RESULTS: After 6 weeks of treatment, the HDRS score decreased in both groups.
There was no significant difference between both the groups at any point of time
with respect to the HDRS.
CONCLUSIONS: Derived from this small pilot study, adjunctive aripiprazole does
not seem to be a promising strategy for the acute treatment of bipolar
depression. However, this lack of additional benefit seems to stem from the
already good effectiveness of the control group, namely the treatment with
citalopram.

———

J Clin Psychiatry. 2010 Oct 19. [Epub ahead of print]

Lvetiracetam in the management of bipolar depression: a randomized, double-blind,
placebo-controlled trial.

Saricicek A, Maloney K, Muralidharan A, Ruf B, Blumberg HP, Sanacora G, Lorberg
B, Pittman B, Bhagwagar Z.

Department of Psychiatry, Yale University, New Haven, and Bristol-Myers Squibb,
Wallingford, Connecticut.

OBJECTIVE: To study the efficacy of adjunctive levetiracetam therapy compared
with placebo in the treatment of subjects with depression with bipolar disorder.
METHOD: This double-blind, placebo-controlled clinical trial randomly assigned
outpatients with bipolar disorder type I and type II who were experiencing a
major depressive episode (Structured Clinical Interview for DSM-IV Axis I
Disorders-Clinician Version criteria) to treatment with either placebo or
adjunctive levetiracetam (up to 2,500 mg/d flexibly dosed) for 6 weeks. The
subjects were recruited from October 2005 to June 2008. The primary efficacy
measure was mean change from baseline to week 6 in the Hamilton Depression Rating
Scale (21-item). Secondary efficacy assessments included the Montgomery-Ã…sberg
Depression Rating Scale, the Beck Depression Inventory, the Clinical Global
Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the
Young Mania Rating Scale. RESULTS: Of 42 subjects randomly assigned to placebo or
drug, 32 received at least 1 postbaseline assessment and thus were included in
the analysis. The mean (SD) levetiracetam daily dose at endpoint evaluation was
1,132 (425) mg/d. There was no significant difference in the mean change from
baseline to week 6 in the Hamilton Depression Rating Scale scores for
levetiracetam compared with placebo. There were no significant differences in any
of the secondary outcome measures. CONCLUSIONS: Levetiracetam adjunctive therapy
was not superior to placebo in the short-term treatment of subjects with
depression with bipolar disorder in the population studied. TRIAL REGISTRATION:
clinicaltrials.gov Identifier: NCT00566150.

———

J Clin Psychiatry. 2010 Oct 5. [Epub ahead of print]

Antidepressants for the acute treatment of bipolar depression: a systematic
review and meta-analysis.

Sidor MM, Macqueen GM.

Department of Psychiatry, University of Texas, Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 75390-9070, USA. michelle.sidor@utsouthwestern.edu.

OBJECTIVE: The role of antidepressants in the acute treatment of bipolar
depression remains a contentious issue. A previous meta-analysis of randomized
controlled trials (RCTs) concluded that antidepressants were effective and safe
for bipolar depression. Several trials published since then suggest that
antidepressants may not be as beneficial as previously concluded. The current
systematic review and meta-analyses reexamine the efficacy and safety of
antidepressant use for the acute treatment of bipolar depression. DATA SOURCES:
EMBASE, MEDLINE, CINAHL, PsycINFO, and the Cochrane Central Register of
Controlled Trials databases were searched for double-blind RCTs published from
2003 to 2009 using the following diagnostic medical subject heading (MESH) terms:
bipolar disorder, bipolar depression, bipolar I disorder, bipolar II disorder,
bipolar III disorder, bipolar mania, cyclothymia, manic depressive psychosis,
mixed mania and depression, and rapid cycling and bipolar disorder. Databases of
trial registries were also searched for unpublished RCTs. These searches were
supplemented by hand searches of relevant articles and review articles. STUDY
SELECTION: Trials that compared acute (< 16 wk) antidepressant treatment with
either an active drug or a placebo comparator in adult bipolar patients,
depressive phase were eligible for inclusion. Main outcome measures were clinical
response, remission, and affective switch. DATA SYNTHESIS: Six RCTs (N = 1,034)
were identified since publication in 2004 of the first meta-analysis that
assessed antidepressant use in the acute treatment of bipolar depression. These
studies were combined with earlier studies for a total of 15 studies containing
2,373 patients. Antidepressants were not statistically superior to placebo or
other current standard treatment for bipolar depression. Antidepressants were not
associated with an increased risk of switch. Studies that employed more sensitive
criteria to define switch did report elevated switch rates for antidepressants.
CONCLUSIONS: Although antidepressants were found to be safe for the acute
treatment of bipolar depression, their lack of efficacy may limit their clinical
utility. Further high-quality studies are required to address the existing
limitations in the literature.

———

Acta Psychiatr Scand. 2010 Sep;122(3):246-54. Epub 2010 Feb 5.

Efficacy and safety of two treatment algorithms in bipolar depression consisting
of a combination of lithium, lamotrigine or placebo and paroxetine.

van der Loos ML, Mulder P, Hartong EG, Blom MB, Vergouwen AC, van Noorden MS,
Timmermans MA, Vieta E, Nolen WA; LamLit Study Group.

Collaborators: Baas RW, Bakker PR, Blom MB, den Boer JA, Brouwer W, van Dongen
PH, van Hyfte DM, Geling K, Glas G, Hartong EG, Habekotté O, Keegan A, de Keyzer
H, de Jong E, Knoppert-van der Klein EA, Kölling P, Koning D, Kunst AG, Kupka RW,
Kuut G, van Lieshout JJ, Kromdijk DH, Kruisdijk FR, van Leeuwen E, van der Loos
ML, de Maat M, Nolen WA, van Noorden MS, Notten PJ, Luteijn ML, Schoof P,
Offermans JM, Bloemkolk D, Ploeger RR, Segeren J, Smit S, Postma DH, Scherders
MJ, Vergouwen AC, Vos T, van Zaane J, Vieta E, Arce R, Livianos L, González-Pinto
A, Alvarez E.

Department of Psychiatry, Isala Klinieken, Location Sophia, Zwolle, the
Netherlands. m.l.m.van.der.loos@isala.nl

OBJECTIVE: In a previous paper, we reported about the efficacy of the addition of
lamotrigine to lithium in patients with bipolar depression. In the second phase
of this study paroxetine was added to ongoing treatment in non-responders.
METHOD: Bipolar depressed patients (n = 124) treated with lithium were randomized
to addition of lamotrigine or placebo. In non-responders after 8 weeks,
paroxetine 20 mg was added for another 8 weeks to ongoing treatment.
RESULTS: After 8 weeks the improvement in patients treated with lamotrigine vs.
patients treated with placebo was significant. After addition of paroxetine this
difference disappeared as a result of greater further improvement in the
non-responders to placebo.
CONCLUSION: Addition of lamotrigine to lithium was found effective in bipolar
depressed patients. Further addition of paroxetine in non-responders to lithium
plus lamotrigine did not appear to provide additional benefit, while it appeared
to do so in non-responders to lithium plus placebo.

———

J Clin Psychopharmacol. 2010 Oct;30(5):579-90.

Treatment options for bipolar depression: a systematic review of randomized,
controlled trials.

Vieta E, Locklear J, Günther O, Ekman M, Miltenburger C, Chatterton ML, Aström M,
Paulsson B.

Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona,
Institut d’Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación
Biomédica en Red de Salud Mental, Barcelona, Spain. evieta@clinic.ub.es

This meta-analysis examined the effectiveness of treatments of bipolar
depression. Trials were identified using the MEDLINE, EMBASE,
http://www.clinicaltrials.gov, and Cochrane databases (1993 to July 2008). The
outcome measures included mean change in Montgomery-Asberg Depression Rating
Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D) total scores, and rates
of response and remission. Overall, 19 publications were included. Medications
included quetiapine, lamotrigine, paroxetine, lithium, olanzapine, aripiprazole,
phenelzine, and divalproex. The most trials were identified for quetiapine (5)
and lamotrigine (6). Not all medications were associated with symptomatic
improvement (significant reduction in MADRS/HAM-D total scores vs placebo), with
lamotrigine, paroxetine, aripiprazole, and lithium not being different from
placebo. Highest reductions in MADRS scores versus placebo were reported for the
olanzapine-fluoxetine combination (1 trial: -6.6; 95% confidence interval [CI],
-9.59 to -3.61; P = 0.000) and quetiapine monotherapy (5 trials: for 300 mg/d,
-4.8; 95% CI, -6.18 to -3.49; P = 0.000; for 600 mg/d, -4.8; 95% CI, -6.22 to
-3.28; P = 0.000), with quetiapine monotherapy also showing the highest reduction
in HAM-D scores (4 trials: -4.0; 95% CI, -5.0 to -2.9; P = 0.000). All
medications except paroxetine, lithium, aripiprazole, and phenelzine
significantly improved the ratio of probabilities of response (overall rate,
1.31; 95% CI, 1.22-1.40) and remission (1.32; 95% CI, 1.20-1.45) versus placebo.
Variability in efficacy exists between treatments of bipolar depression.
Quetiapine and the olanzapine-fluoxetine combination showed the greatest
symptomatic improvement. Efficacy considerations will need to be balanced against
safety and tolerability of the individual agents.

———

J Clin Psychiatry. 2010 Mar;71(3):e07.

Long-term treatment of bipolar depression and other issues.

Vieta E.

Department of Psychiatry, Bipolar Disorders Program, Hospital Clinic, University
of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.

Bipolar disorder is a highly episodic illness, and many patients require
long-term or lifelong treatment to maintain a stable mood. Because depression is
the dominant pole of both bipolar I and bipolar II disorder, maintenance therapy
must prevent depressive recurrence. Although numerous treatment options exist for
bipolar disorder, few have data supporting both short-term and long-term efficacy
for bipolar depression. When choosing among treatments, clinicians must consider
the existing evidence for the long-term effectiveness of various pharmacologic
and psychosocial interventions for controlling all types of mood events.

———

Int J Neuropsychopharmacol. 2011 Feb;14(1):131-42. Epub 2010 Sep 29.

Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute
treatment of schizophrenia, bipolar mania, bipolar depression, major depressive
disorder, and generalized anxiety disorder.

Wang Z, Kemp DE, Chan PK, Fang Y, Ganocy SJ, Calabrese JR, Gao K.

Department of Psychiatry, Division of Mood Disorders, Shanghai Mental Health
Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.

Quetiapine extended-release (quetiapine-XR) has been studied in patients with
schizophrenia, bipolar mania, bipolar depression, major depressive disorder
(MDD), and generalized anxiety disorder (GAD). The purpose of this study was to
compare the tolerability and sensitivity of quetiapine-XR among these psychiatric
conditions. The discontinuation due to adverse events (DAEs) and reported
somnolence in randomized, double-blind, placebo-controlled studies of
quetiapine-XR in these psychiatric conditions were examined. The absolute risk
reduction or increase and the number needed to treat to benefit (NNTB) or harm
(NNTH) for DAEs and reported somnolence of quetiapine-XR ? 300 mg/d relative to
placebo were estimated. Data from one study in schizophrenia (n=465), one in
mania (n=316), one in bipolar depression (n=280), two in refractory MDD (n=624),
two in MDD (n=669) and three in GAD (n=1109) were available. The risk for DAEs of
quetiapine-XR relative to placebo was significantly increased in bipolar
depression (NNTH=9), refractory MDD (NNTH=8), MDD (NNTH=9), and GAD (NNTH=5), but
not in schizophrenia and mania. The risk for reported somnolence of quetiapine-XR
relative to placebo was significantly increased in schizophrenia (600 mg/d
NNTH=15 and 800 mg/d NNTH=11), mania (NNTH=8), bipolar depression (NNTH=4),
refractory MDD (NNTH=5), MDD (NNTH=5) and GAD (NNTH=5). These results suggest
that patients with GAD had the poorest tolerability during treatment with
quetiapine-XR, but they had a similar sensitivity as those with bipolar
depression and MDD. Patients with schizophrenia or mania had a higher
tolerability and a lower sensitivity than those with bipolar depression, MDD, or
GAD.

———

Expert Rev Neurother. 2010 Jul;10(7):1045-51.

Diagnosis and treatment of postpartum bipolar depression.

Kelly E, Sharma V.

University of Western Ontario, Ontario, Canada.

The postpartum period is a time of increased risk of new-onset psychiatric
illness, hospital admissions and out-patient psychiatric care for new mothers.
Research into postpartum mood disorders has focused primarily on major depressive
disorder, and has overlooked the study of bipolar disorder, particularly bipolar
II disorder and bipolar disorder not otherwise specified. Failure to properly
diagnose postpartum bipolar disorder may delay the initiation of appropriate
treatment, lead to inappropriate treatment – thereby precipitating (hypo)mania,
rapid cycling or a mixed episode – or result in polypharmacy and treatment
refractoriness. The most serious consequence, however, is the high risk of
infanticide and suicide among women with postpartum bipolar disorder. While no
specific screening tools have been validated for postpartum mania or bipolar
depression, symptoms of hypomania, atypical depression, a family history of
bipolar disorder and a rapid onset of depressive symptoms following delivery may
suggest a bipolar diathesis. In the absence of any pharmacological or
psychotherapeutic treatments to guide clinical decision-making, it is recommended
that the treatment of postpartum bipolar depression follow the same guidelines as
the treatment of non-postpartum bipolar depression, using medications that are
compatible with lactation.

———

Harv Rev Psychiatry. 2010 Jun;18(3):143-57.

Bipolar depression: overview and commentary.

Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden CL.

Harvard Medical School, McLean Hospital, Belmont, MA, USA. rjb@mclean.org
Depressive phases are the most prevalent component of bipolar disorders, even
with modern treatment. Bipolar depressive morbidity is often misdiagnosed and is
limited in response to available treatments. These conditions are especially
debilitating and are associated with psychiatric comorbidity, substance abuse,
functional disability, and increased mortality owing to early suicide and
accidents, and later medical illnesses. There is growing awareness that bipolar
depression is one of the greatest challenges in modern psychiatry. It is
essential to differentiate various forms of depression, dysthymia, and dysphoric
mixed states of bipolar disorders from the clinical features of more common,
unipolar major depressive disorders. In bipolar depression, antidepressant
responses often are unsatisfactory, and these agents probably are overused.
Emerging treatments, including several anticonvulsant and modern antipsychotic
drugs, as well as lithium-alone or in selected combinations-are partially
effective for bipolar depression. Interest in recognizing bipolar depression and
seeking more effective, specific, and safer treatments for it are growing.

———

Br J Psychiatry. 2010 Apr;196:266-73.

Efficacy and acceptability of mood stabilisers in the treatment of acute bipolar
depression: systematic review.

Van Lieshout RJ, MacQueen GM.

Department of Psychiatry, Foothills Medical Centre, 1403-29th Street, NW,
Calgary, AB, Canada.

BACKGROUND: Although people with bipolar disorder spend more time in a depressed
than manic state, little evidence is available to guide the treatment of acute
bipolar depression. AIMS: To compare the efficacy, acceptability and safety of
mood stabiliser monotherapy with combination and antidepressant treatment in
adults with acute bipolar depression. METHOD: Systematic review and meta-analysis
of randomised, double-blind controlled trials. RESULTS: Eighteen studies with a
total 4105 participants were analysed. Mood stabiliser monotherapy was associated
with increased rates of response (relative risk (RR) = 1.30, 95% CI 1.16-1.44,
number needed to treat (NNT) = 10, 95% CI 7-18) and remission (RR = 1.51, 95% CI
1.27-1.79, NNT = 8, 95% CI 5-14) relative to placebo. Combination therapy was not
statistically superior to monotherapy. Weight gain, switching and suicide rates
did not differ between groups. No differences were found between individual
medications or drug classes for any outcome. CONCLUSIONS: Mood stabilisers are
moderately efficacious for acute bipolar depression. Extant studies are few and
limited by high rates of discontinuation and short duration. Further study of
existing and novel agents is required.

———

J Affect Disord. 2010 Apr;122(1-2):1-9. Epub 2009 Nov 18.

Valproate for the treatment of acute bipolar depression: systematic review and
meta-analysis.

Smith LA, Cornelius VR, Azorin JM, Perugi G, Vieta E, Young AH, Bowden CL.

Medical Research Matters, 77 Witney Road, Eynsham, OX29 4PN, UK.

BACKGROUND: Our aim was to analyse existing data on the efficacy and tolerability
of valproate for the treatment of acute bipolar depression. METHODS: Randomized
controlled trials comparing valproate with placebo were identified using searches
of electronic databases in October 2008. Outcomes investigated were depression,
anxiety, hypomania, attrition, and adverse events. Trial quality was assessed,
and data were summarized using meta-analyses. RESULTS: Four randomized,
controlled, doubleblind trials of 142 participants were included. Trial quality
was good, although individual study sample sizes were small. Study duration was
six weeks (2 studies) and eight weeks (2 studies). Meta-analysis showed a
significant difference in favour of valproate for reduction in depressive
symptoms, both on depression symptom scales (standardized mean difference (SMD)
-0.35 (95% confidence interval, -0.69, -0.02)), and participants with at least
50% improvement in symptoms – relative risk (RR) 2.00 (1.13, 3.53). Effects on
anxiety symptoms were small, SMD -0.32 (-0.72, 0.08) and inconclusive (p=0.12).
No evidence of a difference in mania symptoms, withdrawal for any reason, lack of
effectiveness or adverse events was detected. Nausea occurred more frequently
with valproate compared with placebo though the difference was not significant,
RR 2.01 (0.98, 4.11). Other adverse events occurring more frequently with
valproate (somnolence, fatigue/muscle weakness, headache, diarrhoea and dry
mouth) did not differ significantly between treatment groups. LIMITATIONS: Sample
sizes were small warranting a larger study to confirm or disprove these findings.
CONCLUSIONS: Valproate is effective for the reduction of depressive symptoms of
acute bipolar depression, and was well tolerated.

———

Int J Neuropsychopharmacol. 2010 Feb;13(1):5-14. Epub 2009 Jul 29.

Efficacy of modern antipsychotics in placebo-controlled trials in bipolar
depression: a meta-analysis.

Cruz N, Sanchez-Moreno J, Torres F, Goikolea JM, Valentí M, Vieta E.

Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Spain.

Comment in:
Int J Neuropsychopharmacol. 2010 Aug;13(7):967; author reply 969.

Randomized, controlled trials have demonstrated efficacy for second-generation
antipsychotics in the treatment of acute mania in bipolar disorder. Despite
depression being considered the hallmark of bipolar disorder, there are no
published systematic reviews or meta-analyses to evaluate the efficacy of modern
atypical antipsychotics in bipolar depression. We systematically reviewed
published or registered randomized, double-blind, placebo-controlled trials
(RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients
(DSM-IV criteria). Efficacy outcomes were assessed based on changes in the
Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data
were combined through meta-analysis using risk ratio as an effect size with a 95%
confidence interval (95% CI) and with a level of statistical significance of 5%
(p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and
one addressed both monotherapy and combination with an antidepressant. The two
quetiapine trials analysed the safety and efficacy of two doses: 300 and 600
mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of
5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and
6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed
doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated
superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials)
failed in the primary efficacy measure after the first 6 wk. Some modern
antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar
depressive patients from week 1 onwards. Rapid onset of action seems to be a
common feature of atypical antipsychotics in bipolar depression.

———

Curr Opin Psychiatry. 2010 Jan;23(1):19-24.

An update of evidence-based treatment of bipolar depression: where do we stand?

Fountoulakis KN.

3rd Department of Psychiatry, School of Medicine, Aristotle University of
Thessaloniki, 6 Odysseos Str. (Parodos Ampelonon Str.), Pylaia, Thessaloniki,
Greece. kfount@med.auth.gr

PURPOSE OF REVIEW: The current article attempts to summarize the current status
of our knowledge and practice in the treatment of bipolar depression and suggests
future directions. RECENT FINDINGS: Our knowledge about lithium solidly supports
its usefulness during all phases of bipolar illness and its specific
effectiveness on suicidal prevention. Specific second-generation antipsychotics
could constitute a promising option for treating bipolar depression, although
only limited data exist so far. Anticonvulsants appear to possess a broad
spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms.
Lamotrigine may be preferably effective in the treatment of depression but not
mania. The usefulness of antidepressants in bipolar depression is controversial.
The first line of psychosocial intervention in bipolar depression is
psychoeducation, family-focused psychoeducation and cognitive-behavioral therapy.
Electroconvulsive therapy and transcranial magnetic stimulation are options for
refractory patients. Accumulated knowledge so far indicates that bipolar patients
need continuous administration of an antimanic agent even during the acute
depressive phase. SUMMARY: The development of rationalized ‘combination
treatment’ guidelines is essential today, as it seems that the vast majority of
patients do poorly on monotherapy and need complex pharmacotherapies. Although
our knowledge is indeed limited, the development of some kind of guidelines for
polypharmacy is possible and should be done as soon as possible.

———

J Clin Psychiatry. 2010 Jan;71(1):e01.

Diagnosis, treatment, and recovery maintenance in bipolar depression.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center, and the
Center for Bipolar Illness Interventions in Hispanic Communities, San Antonio,
USA.

Misdiagnosis of bipolar disorder and inappropriate pharmacotherapeutic treatment
is common. Clinicians should screen for manic/hypomanic symptoms during
depressive episodes to differentiate bipolar depression from other depressive
disorders. Depression is the dominant pole of bipolar disorder, and effective
maintenance therapy must prevent depressive episode recurrence. Few pharmacologic
treatments have evidence supporting both short- and long-term efficacy for
bipolar depression. Clinicians must consider the existing evidence on the
long-term efficacy of various pharmacologic and psychosocial interventions for
preventing and treating bipolar mood episodes.

———

Ann Pharmacother. 2009 Nov;43(11):1848-56. Epub 2009 Oct 6.

Safety and efficacy of quetiapine in bipolar depression.

Bogart GT, Chavez B.

Englewood Hospital and Medical Center, Englewood, NJ, USA.

OBJECTIVE: To review the clinical data investigating the efficacy and safety of
quetiapine in bipolar depression. DATA SOURCES: Searches of MEDLINE and PubMed
(1977-July 2009) were conducted using the key words quetiapine and bipolar
depression. The references of literature found were cross-referenced. The
pharmaceutical company that produces quetiapine was contacted to obtain the
posters for the EMBOLDEN I and EMBOLDEN II trials. STUDY SELECTION AND DATA
EXTRACTION: Only double-blind, placebo-controlled trials were included for
review, as well as any subanalyses of the literature that matched this criterion.
DATA SYNTHESIS: There was a total of 5 double-blind, placebo-controlled trials
and 5 subanalyses reviewed. The results of these data demonstrated quetiapine’s
efficacy in the treatment of depressive phases of bipolar disorder, including
statistically significant improvement in the Montgomery-Asberg Depression Rating
Scale (MADRS). In the trials reviewed in this article, the change in MADRS scores
ranged from -15.4 to -16.94 within the quetiapine groups, and from -10.26 to
-11.93 in the placebo groups. There were also statistically significant
improvements in the Hamilton Anxiety Rating Scale, the Short Form of the Quality
of Life Enjoyment and Satisfaction Questionnaire, the Pittsburgh Sleep Quality
Index, and the Sheehan Disability Scale. All of these trials had a duration of 8
weeks and therefore cannot be applied to the long-term use of quetiapine in
bipolar depression. The most common adverse events were sedation, somnolence, and
dry mouth. The overall dropout rates for the trials reviewed ranged from 24% to
47%. CONCLUSIONS: Based on the literature reviewed here, quetiapine appears to be
a safe and efficacious short-term treatment option for bipolar depression.
Patients with bipolar type I showed greater improvement on the MADRS than those
with bipolar type II. Patients with a rapid-cycling disease course showed an
improvement in depressive symptoms, regardless of bipolar type.

———

Biochem Soc Trans. 2009 Oct;37(Pt 5):1080-4.

Neural network dysfunction in bipolar depression: clues from the efficacy of
lamotrigine.

Large CH, Di Daniel E, Li X, George MS.

Neurosciences Centre of Excellence for Drug Discovery, Medicines Research Centre,
GlaxoSmithKline S.p.A., Via Fleming 4, 37135, Verona, Italy.
charles.h.large@gsk.com

One strategy to understand bipolar disorder is to study the mechanism of action
of mood-stabilizing drugs, such as valproic acid and lithium. This approach has
implicated a number of intracellular signalling elements, such as GSK3beta
(glycogen synthase kinase 3beta), ERK (extracellular-signal-regulated
kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However,
lamotrigine does not seem to modulate any of these targets, which is intriguing
given that its profile in the clinic differs from that of valproic acid or
lithium, with greater efficacy to prevent episodes of depression than mania. The
primary target of lamotrigine is the voltage-gated sodium channel, but it is
unclear why inhibition of these channels might confer antidepressant efficacy. In
healthy volunteers, we found that lamotrigine had a facilitatory effect on the
BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic
stimulation) of the prefrontal cortex. This effect was in contrast with an
inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a
follow-up study, a similar prefrontal specific facilitatory effect was observed
in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and
prefrontal cortical TMS-induced BOLD response. In vitro, we found that
lamotrigine (3-10 microM) enhanced the power of gamma frequency network
oscillations induced by kainic acid in the rat hippocampus, an effect that was
not observed with valproic acid (100 microM). These data suggest that lamotrigine
has a positive effect on corticolimbic network function that may differentiate it
from other mood stabilizers. The results are also consistent with the notion of
corticolimbic network dysfunction in bipolar disorder.

———

Neurotoxicology. 2009 Jul;30(4):497-521. Epub 2009 Mar 24.

The effect of tumor necrosis factor antagonists on mood and mental
health-associated quality of life: novel hypothesis-driven treatments for bipolar
depression?

Soczynska JK, Kennedy SH, Goldstein BI, Lachowski A, Woldeyohannes HO, McIntyre
RS.

Institute of Medical Sciences, University of Toronto, Canada.

Bipolar disorder (BD) is associated with high rates of morbidity, comorbidity,
disability, economic and human capital costs as well as premature mortality.
Although, the past decade has witnessed substantial progress in the treatment of
BD, high rates of non-recovery, inter-episodic symptomatology, and episode
recurrence remain an ongoing deficiency. Conventional treatments for BD are
capable of alleviating ‘surface-based’ symptomatology yet no agent is
disease-modifying. Translational research initiatives provide evidence that mood
disorder symptomatology is subserved by disturbances in interacting
immuno-inflammatory, metabolic, and neuroendocrine networks. Numerous studies
document elevated pro-inflammatory circulating cytokines [e.g. interleukin-1
(IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)], in
individuals with BD as compared to healthy volunteers. Elevated peripheral levels
of TNF-alpha and its receptors (i.e. TNF-R1 and TNF-R2) are a frequent findings
across depressive and manic states and may persist into euthymia. As such,
TNF-alpha may constitute a trait marker of BD. Other markers of inflammation
including acute phase reactants (e.g. C-reactive protein) and vascular adhesion
molecules (e.g. intercellular adhesion molecule-1) are also altered in BD.
Herein, we review supporting evidence for the hypothesis that disturbances in
inflammatory homeostasis, as marked by elevated TNF-alpha levels, are salient to
the pathophysiology of BD and provide a platform for novel drug discovery. In
this review, we propose that TNF-alpha modulation is a target for
disease-modifying treatment of BD. To support this hypothesis, we review evidence
from clinical trials evaluating the efficacy of TNF-alpha antagonists (i.e.
adalimumab, etanercept, and infliximab) on depressive symptoms and mental
health-associated quality of life measures.

———

Bipolar Disord. 2009 Jun;11 Suppl 2:55-76.

Medicating mood with maintenance in mind: bipolar depression pharmacotherapy.

Malhi GS, Adams D, Berk M.

CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, Sydney,
Australia. gmalhi@med.usyd.edu.au

OBJECTIVES: Bipolar depression is a core feature of bipolar disorder, a phase in
which many patients spend the majority of time and one that confers a significant
degree of burden and risk. The purpose of this paper is to briefly review the
evidence base for the pharmacotherapy of bipolar depression and to discuss the
recommendations for its optimal management. METHODS: A detailed literature review
was undertaken with a particular emphasis on pharmacological treatment strategies
for bipolar depression across the acute and maintenance phases of the illness.
Electronic library and Web-based searches were performed using recognised tools
(MEDLINE, PubMED, EMBASE and PsychINFO) to identify the pertinent literature. A
summary of the evidence base is outlined and then distilled into broad clinical
recommendations to guide the pharmacological management of bipolar depression.
RESULTS: Partitioning treatment into acute and maintenance therapy is difficult
based on the paucity of current evidence. The evidence from treatment trials
favours the use of lithium and lamotrigine as first-line treatment in preference
to valproate, and indicates that, for acute episodes, quetiapine and olanzapine
have perhaps achieved equivalence at least in terms of efficacy. However, the
effectiveness of the atypical antipsychotics in maintenance therapy is
constrained by the potential for significant side effects of individual agents
and the lack of both long-term research data and clinical experience in treating
bipolar disorder as compared to other agents. Conversely, lithium and the
anticonvulsants are generally slower to effect symptomatic change, and this
limits their usefulness. CONCLUSIONS: There has been a tendency for research
trials of bipolar depression to differentiate the illness cross-sectionally into
the acute and maintenance phases of bipolar depression; however, in clinical
terms, bipolar depression invariably follows a longitudinal course in which the
phases of illness are inextricably linked, and useful acute treatments are
typically continued in maintenance. Therefore, when medicating mood in acute
bipolar depression it is imperative to keep maintenance in mind as it is this
aspect of treatment that determines long-term success.

———

Expert Opin Pharmacother. 2009 Feb;10(2):161-72.

An update on the treatment of bipolar depression.

Azorin JM, Kaladjian A.

Pôle Universitaire de Psychiatrie-Solaris, Hôpital Ste Marguerite, 13274
Marseille Cedex 9, France. jazorin@ap-hm.fr

BACKGROUND: Although depression accounts for a large part of the burden
associated with bipolar disorder, its drug treatment has been under-studied.
OBJECTIVE: To provide the best available evidence supporting the pharmacotherapy
of bipolar depression. METHODS: A systematic review was conducted, focusing on
randomized, controlled trials (RCTs) and meta-analyses. RESULTS/CONCLUSIONS:
Despite FDA approval of both the olanzapine-fluoxetine combination and quetiapine
for the treatment of acute bipolar depression, independent RCTs (i.e., not trials
conducted ‘under the umbrella’ of a drug company) have not found any drug to have
antidepressant effects similar to those seen in unipolar depression. A
practice-based suggestion, valuable for both short- and long-term treatment,
might be to have a background of mood stabilizers and to add drugs, following one
of several treatment options, trusting to find a drug with a degree of
effectiveness by trial and error. The list of drugs that could be used would
include all the current antidepressants, the olanzapine-fluoxetine combination
and probably quetiapine too. Special features and situations might also influence
treatment options.

———

Br J Psychiatry. 2009 Jan;194(1):4-9.

Lamotrigine for treatment of bipolar depression: independent meta-analysis and
meta-regression of individual patient data from five randomised trials.

Geddes JR, Calabrese JR, Goodwin GM.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
john.geddes@psych.ox.ac.uk

BACKGROUND: There is uncertainty about the efficacy of lamotrigine in bipolar
depressive episodes. AIMS: To synthesise the evidence for the efficacy of
lamotrigine in bipolar depressive episodes. METHOD: Systematic review and
meta-analysis of individual patient data from randomised controlled trials
comparing lamotrigine with placebo. RESULTS: Individual data from 1072
participants from five randomised controlled trials were obtained. More
individuals treated with lamotrigine than placebo responded to treatment on both
the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI
1.09-1.47, P=0.002) and Montgomery-Asberg Depression Rating Scale (MADRS)
(RR=1.22, 95% CI 1.06-1.41, P=0.005). There was an interaction (P=0.04) by
baseline severity of depression: lamotrigine was superior to placebo in people
with HRSD score >24 (RR=1.47, 95% CI 1.16-1.87, P=0.001) but not in people with
HRSD score < or =24 (RR=1.07, 95% CI 0.90-1.27, P=0.445). CONCLUSIONS: There is
consistent evidence that lamotrigine has a beneficial effect on depressive
symptoms in the depressed phase of bipolar disorder. The overall pool effect was
modest, although the advantage over placebo was larger in more severely depressed
participants.

———

Dialogues Clin Neurosci. 2009;11(1):73-80.

Challenges in the diagnosis and treatment of pediatric bipolar depression.

Chang K.

Pediatric Bipolar Disorders Program, Stanford University School of Medicine,
Stanford, California 94305-5540, USA. kchang88@stanford.edu

There has been great public and academic interest in the diagnosis and treatment
of bipolar disorders (BD) in children and adolescents over the past decade,
originally in the US, but now extending internationally. Much of the interest in
pediatric BD has focused on the unique manifestation of mania in younger
populations. Depression is often overlooked, both as a topic, and as a clinical
reality, in these children. While it is becoming clear that adults with BD spend
the majority of their symptomatic time in depressive rather than manic episodes,
less is known about the pediatric experience of bipolar depression. However,
children and adolescents with BD clearly do experience significant depressive
symptoms as well as depressive episodes, and therefore early recognition and
treatment is necessary. This review addresses what is known about the prevalence,
presentation, and treatment of depressive symptoms and episodes in youth with BD,
and includes a discussion about the recognition and treatment of bipolar
depressive episodes that occur before the first manic episode.

———

J Clin Psychiatry. 2008 Dec 3;69(10):e29.

Effective agents in treating bipolar depression.

Nierenberg AA.

Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital,
Boston, USA.

Individuals with bipolar disorder may spend about half of their time euthymic,
but recurring mood episodes are common and are predominated by depressive
symptoms. Despite the prevalence of depression in bipolar disorder, evidence
suggests that antidepressants are not likely to benefit most patients. Lithium
has long been the first-line treatment for bipolar disorder, but it is not the
most effective agent for treating bipolar depression. This activity reviews
multiple pharmacologic options that should be considered by clinicians treating
bipolar disorder.

———

Acta Psychiatr Scand. 2008 Nov;118(5):337-46. Epub 2008 Aug 26.

Are antidepressants safe in the treatment of bipolar depression? A critical
evaluation of their potential risk to induce switch into mania or cycle
acceleration.

Licht RW, Gijsman H, Nolen WA, Angst J.

Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark.
rl@psykiatri.aaa.dk

OBJECTIVE: To address whether switch of depression into hypomania or mania or
cycle acceleration in patients with bipolar disorder is caused by antidepressants
or whether this phenomenon is attributable to the natural history of bipolar
disorder itself. METHOD: A critical review of the literature, pointing at sources
of bias that have been previously overlooked. For examining the causation in
question, the Bradford-Hill criteria were applied, i.e. specificity of the
potential causative agent, strength of effect, consistency in findings,
dose-response relation, temporal relation with exposure to agent preceding effect
and biological plausibility. RESULTS: There is a scarcity of randomized studies
addressing the question, and the available studies all suffer from various forms
of bias. However, there is some evidence suggesting that antidepressants given in
addition to a mood stabilizer are not associated with an increased rate of switch
when compared with the rate associated with the mood stabilizer alone.
CONCLUSION: When combined with a mood stabilizer, antidepressants given for acute
bipolar depression seemingly do not induce a switch into hypomania or mania.
Whether antidepressants may accelerate episode frequency and/or may cause other
forms of destabilization in patients with bipolar disorder remain to be properly
studied.

———

18. J Fam Pract. 2008 Sep;57(9):606-8.

Clinical inquiries: what drugs are best for bipolar depression?

Ukaegbu C, Banks JB, Carter NJ, Goldman LS.

Department of Family Medicine, Quillen College of Medicine, East Tennessee State
University, Johnson City, TN, USA.

Antidepressants and lamotrigine are effective. Atypical antipsychotics, lithium,
and anticonvulsants also may help. Antidepressants, including tricyclics and
selective serotonin reuptake inhibitors (SSRIs), are useful adjuncts in
short-term treatment of bipolar depression and have low rates of inducing mania
(strength of recommendation [SOR]: 1 systematic review and randomized controlled
trials [RCTs]). Lamotrigine is beneficial for both acute treatment of bipolar
depression and prevention of recurrent episodes (SOR: 1 systematic review and 1
RCT). Some atypical antipsychotics alone (SOR: 2 RCTs) or in combination with
antidepressants (SOR: 1 multicenter RCT) effectively treat acute bipolar
depression. Lithium and anticonvulsants such as valproate also may be useful
(SOR: limited number of studies with small sample sizes).

———

Eur Neuropsychopharmacol. 2008 Jul;18(7):535-49. Epub 2008 May 23.

ECNP consensus meeting. Bipolar depression. Nice, March 2007.

Goodwin GM, Anderson I, Arango C, Bowden CL, Henry C, Mitchell PB, Nolen WA,
Vieta E, Wittchen HU.

University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK.
guy.goodwin@psych.ox.ac.uk

DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR,
remains the preferred diagnostic system. When employed in general population
samples, prevalence estimates of bipolar disorder are relatively consistent
across studies in Europe and USA. In community studies, first onset of bipolar
mood disorder is usually in the mid-teenage years and twenties, and the
occurrence of a major depressive episode or hypomania is usually its first
manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar
(BI) depression cross-sectionally are currently lacking, there is a longitudinal
risk – probably over 10% – that initial UP patients ultimately turn out as BP in
the longer run. Its early onset implies a severe potential burden of disease in
terms of impaired social and neuropsychological development, most of which is
attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is
rare in prepubertal children, when defined according to unmodified DSM-IV-TR
criteria. A broad diagnosis of bipolar disorder risks confounding with other
childhood psychopathology and has less predictive value for bipolar disorder in
adulthood than the conservative definition. Nevertheless, empirical studies of
drug and other treatments and longitudinal studies to assess validity of the
broadly defined phenotype in children and adolescents are desirable, rather than
extrapolation from adult bipolar practice. The need for an increased capacity to
conduct reliable trials in children and adolescents is a challenge to Europe,
whose healthcare system should allow greater participation and collaboration than
other regions, via clinical networks. ECNP will aspire to facilitate such
developments. BIPOLAR DEPRESSION IN ADULTS – UNIPOLAR/BIPOLAR CONTRAST: Despite
some differences in symptom profiles and severity measures, a cross-sectional
categorical distinction between bipolar (BP) and unipolar (UP) depression is
currently impossible. For regulatory purposes, a major depressive episode,
meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the
overall course of the disorder. However, in refining diagnosis in future studies
and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to
be informative as recommended by the International Society for Bipolar Disorders
(ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar
populations. Thus, RCT inclusion criteria for trials not targeting anxiety,
should accept co-morbid anxiety disorders as part of the history and even current
anxiety symptoms, where these are not dominating the mental state at recruitment
to a study. Rapid cycling patients defined as those suffering from 4 or more
episodes per year, may also be recruited into trials of bipolar depression
without impairing assay sensitivity. Illness severity critically affects assay
sensitivity. The minimum scores for entry into a bipolar depression trials should
be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients
with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There
is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome
for trials, although they probably capture global severity adequately. Secondary
measures to capture so-called atypical symptoms (such as hypersomnia or
hyperphagia), or specific psychopathology more common in bipolar participants
(such as lability of mood), could be informative as secondary measures. TREATMENT
STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the
gold-standard design for determining efficacy in bipolar depression. The
confounding effects of co-medication are emerging from the literature on
antidepressant studies in bipolar depression, often conducted in combination with
antimanic agents to avoid possible switch to mood elevation. Three arm trials,
including the compound to be tested, placebo, and a standard comparator, are
generally preferred in order to ensure assay sensitivity and a better picture of
benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials
may be enough. If efficacy happens to be proven as monotherapy, new compounds may
be tested in adjunctive-medication placebo-controlled designs. Younger adults,
without an established need for long-term medication, may be particularly
suitable for clinical trials requiring placebo controls. The conversion rate of
initial UP depression, converting to become BP in the long run is estimated to be
10%. Switch to mania or hypomania may be the consequence of active treatment for
bipolar depression. Some medicines such as the tricyclic antidepressants and
venlafaxine may be more likely to provoke switch than others, but this increased
rate of switch may not be seen until about 10 weeks of treatment. Twelve week
trials against placebo are necessary to determine the risk of switch and to
establish continuing effects. Careful assessment at 6-8 weeks is required to
ensure that patients who are failing to respond do not continue in a study for
unacceptable periods of time. To capture a switch event, studies should include
scales to define the phenomenology of the event (e.g. hypomania or mania) and its
severity. These may be best applied shortly after the clinical decision that
switch is occurring. Long-term treatment is commonly required in bipolar
disorder. Trials to detect maintenance of effect or continued response in bipolar
depression should follow a ‘relapse prevention’ design: i.e. patients are treated
in an index episode with the medicine of interest and then randomized to either
continue the active treatment or placebo. However, acute withdrawal of active
medication after treatment response might artificially enhance effect size due to
active drug withdrawal effects. A short taper is usually desirable. Longer
periods of stabilisation are also desirable for up to 3 months: protocol
compliance may then be difficult to achieve in practice and so will certainly
make studies more difficult and expensive to conduct. The addition of a medicine
to other agents during or after the resolution of a depressive or manic episode,
and its subsequent investigation as monotherapy against placebo to prevent
further relapse (as in the lamotrigine maintenance trials) is clinically
informative. Assay sensitivity and patient acceptability are enhanced if the
outcome in long-term studies is ‘time to intervention for a new episode’ for
discontinuation designs.

———

J Affect Disord. 2008 Jul;109(1-2):21-34. Epub 2007 Nov 26.

Treatment of bipolar depression: an update.

Fountoulakis KN, Grunze H, Panagiotidis P, Kaprinis G.

3rd Department of Psychiatry, Aristotle University of Thessaloniki, Greece.
kfount@med.auth.gr

This article attempts to summarize the current status of our knowledge and
practice in the acute treatment and prophylaxis of bipolar depression. For
prophylactic treatment, our knowledge about lithium firmly supports its
usefulness against bipolar depression and its specific effectiveness for suicidal
prevention. Valproic acid and carbamazepine could be effective, too, while
lamotrigine which seems to be preferably effective against depression but not
mania. The FDA has approved the olanzapine-fluoxetine combination and quetiapine
monotherapy for the treatment of acute bipolar depression. The usefulness of
antidepressants in bipolar depression is controversial both for acute and
prophylactic treatment; guidelines suggest their cautious use and always in
combination with an antimanic and mood stabilizer agent, because in some patients
they may induce switching to mania or hypomania, mixed episodes and rapid
cycling. Data on psychosocial intervention are restricted to the maintenance
phase. Electroconvulsive therapy and transcranial magnetic stimulation are
additional options for refractory patients. Bipolar depression seems to be a more
difficult condition to treat than mania. Most patients need complex combination
treatment although the published evidence on this type of treatment is limited.

———

Bipolar Disord. 2008 Feb;10(1 Pt 2):144-52.

Diagnostic guidelines for bipolar depression: a probabilistic approach.

Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM.

School of Psychiatry, University of New South Wales, Sydney, Australia.
phil.mitchell@unsw.edu.au

Comment in:
Bipolar Disord. 2009 May;11(3):337-8.

OBJECTIVES: There are currently no accepted diagnostic criteria for bipolar
depression for either research or clinical purposes. This paper aimed to develop
recommendations for diagnostic criteria for bipolar I depression. METHODS:
Studies on the clinical characteristics of bipolar and unipolar depression were
reviewed. To identify relevant papers, literature searches using PubMed and
Medline were undertaken. RESULTS: There are no pathognomonic characteristics of
bipolar I depression compared to unipolar depressive disorder. There are,
however, replicated findings of clinical characteristics that are more common in
both bipolar I depression and unipolar depressive disorder, respectively, or
which are observed in unipolar-depressed patients who ‘convert’ (i.e., who later
develop hypo/manic symptoms) to bipolar disorder over time. The following
features are more common in bipolar I depression (or in unipolar ‘converters’ to
bipolar disorder): ‘atypical’ depressive features such as hypersomnia,
hyperphagia, and leaden paralysis; psychomotor retardation; psychotic features,
and/or pathological guilt; and lability of mood. Furthermore, bipolar-depressed
patients are more likely to have an earlier age of onset of their first
depressive episode, to have more prior episodes of depression, to have shorter
depressive episodes, and to have a family history of bipolar disorder. The
following features are more common in unipolar depressive disorder: initial
insomnia/reduced sleep; appetite, and/or weight loss; normal or increased
activity levels; somatic complaints; later age of onset of first depressive
episode; prolonged episodes; and no family history of bipolar disorder.
CONCLUSIONS: Rather than proposing a categorical diagnostic distinction between
bipolar depression and major depressive disorder, we would recommend a
‘probabilistic’ (or likelihood) approach. While there is no ‘point of rarity’
between the two presentations, there is, rather, a differential likelihood of
experiencing the above symptoms and signs of depression. A table outlining draft
proposed operationalized criteria for such an approach is provided. The specific
details of such a probabilistic approach need to be further explored. For
example, to be useful, any diagnostic innovation should inform treatment choices.

———

Int J Neuropsychopharmacol. 2008 Feb;11(1):119-30. Epub 2007 Mar 5.

Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive
transcranial magnetic stimulation.

Xia G, Gajwani P, Muzina DJ, Kemp DE, Gao K, Ganocy SJ, Calabrese JR.

Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106,
USA. guohua.xia@case.edu

This review focused on the treatment-emergent mania/hypomania (TEM) associated
with repetitive transcranial magnetic stimulation (rTMS) treatment of depression.
English-language literature published from 1966-2006 and indexed in Medline was
searched. Ten of 53 randomized controlled trials on rTMS treatment of depression
specifically addressed TEM. The pooled TEM rate is 0.84% for the active treatment
group and 0.73% for the sham group. The difference is not statistically
significant. Along with case reports, a total of 13 cases of TEM associated with
rTMS treatment of depression have been published. Most of these patients were
diagnosed with bipolar disorder and the majority of patients experiencing TEM
took medication concurrent with rTMS. The parameters of rTMS used in these cases
were scattered over the spectrum of major parameters explored in previous
studies. Most train durations and intervals were within the published safety
guidelines of the field. Reducing the frequency of sessions from two per day to
one per day might be associated with a lower likelihood of TEM recurrence. The
severity of manic symptoms varied significantly, but all cases responded to
treatment that included a decrease or discontinuation of antidepressant and/or
rTMS treatment and/or use of anti-manic medication. Current data suggests that
rTMS treatment carries a slight risk of TEM that is not statistically higher than
that associated with sham treatment. More systematic studies are needed to better
understand TEM associated with rTMS. Special precautions and measures should be
adopted to prevent, monitor, and manage TEM in research and practice.

———

CNS Drugs. 2008;22(9):793-5.

Spotlight on olanzapine/fluoxetine in acute bipolar depression.

Deeks ED, Keating GM.

Wolters Kluwer Health | Adis, Auckland, New Zealand. demail@adis.co.nz

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of
the atypical antipsychotic olanzapine and the SSRI fluoxetine that is approved in
the US for the treatment of depressive episodes associated with bipolar disorder
in adults. Combination therapy with olanzapine plus fluoxetine is effective in
the treatment of patients with acute bipolar depression. The combination improves
depressive symptoms and symptom severity in this patient population, with an
efficacy greater than that of olanzapine alone or lamotrigine. Furthermore,
olanzapine plus fluoxetine is generally well tolerated. Although associated with
weight gain and potential elevations in glucose, lipid and prolactin levels, the
combination does not increase the risk of treatment-emergent mania. Additional
placebo- and active comparator-controlled studies are required in order to
confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar
depression and to definitively position olanzapine/fluoxetine with respect to
other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an
effective and generally well tolerated first-line option for the treatment of
acute bipolar depression.

———

CNS Drugs. 2008;22(5):389-406.

Burden of bipolar depression: impact of disorder and medications on quality of
life.

Michalak EE, Murray G, Young AH, Lam RW.

Division of Mood Disorders, Department of Psychiatry, University of British
Columbia, Vancouver, British Columbia, Canada. emichala@interchange.ubc.ca

Bipolar disorder is a complex, chronic psychiatric condition characterized by
recurring episodes of depressive illness and mania or hypomania. Although the
manic or hypomanic episodes define the disorder, recent research has shown that
depressive symptoms predominate over manic symptoms in the majority of patients,
and that bipolar depression accounts for much of the significant morbidity and
mortality associated with bipolar disorder. Given these findings, there has been
a recent upsurge of interest in furthering our understanding of the burden of
depression in bipolar disorder. At the same time, increasing scientific attention
is now being paid to expanding the measurement of outcome in bipolar disorder to
encompass broader indicators of response, one of which is the assessment of
quality of life (QOL). In this review, we provide a summary of the current
knowledge about QOL in the depressive phase of bipolar disorder, and the effects
of pharmacological treatment interventions for bipolar disorder upon QOL. It
appears that QOL is poorer in bipolar disorder than in other mood disorders and
anxiety disorders, but that schizophrenia might compromise QOL more severely than
bipolar disorder. Existing data also suggest that, for patients with bipolar
disorder, QOL is negatively associated with depression, both as a cross-sectional
mood state and perhaps also as a feature of the patient’s course. Despite its
clinical and public health importance, bipolar depression has only recently
started to receive the attention it warrants in clinical trials, and many
important questions about its optimal pharmacological management remain to be
answered. There is also a paucity of information about the impact of
pharmacological interventions on QOL in bipolar depression. To our knowledge,
only two clinical trials to date have specifically examined the impact of
medications on QOL in patients with bipolar depression. A small number of other
studies have examined the effects of depressive symptoms on QOL in patients who
are experiencing manic or mixed episodes. Nonetheless, QOL appears to be a
meaningful and important indicator of outcome and recovery in this patient
population, and one that warrants further scientific interest and energy.

———

Dialogues Clin Neurosci. 2008;10(2):181-92.

Bipolar depression: trial-based insights to guide patient care.

Kemp DE, Muzina DJ, McIntyre RS, Calabrese JR.

Case Western Reserve University, University Hospitals Case Medical Center,
Cleveland, Ohio, USA. kemp.david@gmail.com

For the majority of patients with bipolar disorder, major depressive episodes
represent the most debilitating and difficult-to-treat illness dimension.
Patients spend significantly more time depressed than manic or hypomanic, and
attempt suicide more frequently during this illness phase, yet the availability
of treatments remains limited. The discovery of more effective therapeutics for
managing depressive episodes is arguably the greatest unmet need in bipolar
disorder. This article provides an evidence-based summary of pharmacological
treatments for the acute and longitudinal management of bipolar depression.
Clinical trial results are reviewed for a diverse array of compounds, inclusive
of traditional mood stabilizers (eg, lithium and divalproex), atypical
antipsychotics, unimodal antidepressants, and modafinil. Where applicable,
differences in efficacy across compounds are examined through discussion of
number needed to treat and effect size determinations. A pragmatic clinical
approach is presented for management of the depressed phase of bipolar disorder.

———

Drugs. 2008;68(8):1115-37.

Olanzapine/fluoxetine: a review of its use in the treatment of acute bipolar
depression.

Deeks ED, Keating GM.

Wolters Kluwer Health, Adis, Auckland, New Zealand. demail@adis.co.nz

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of
the atypical antipsychotic olanzapine and the selective serotonin reuptake
inhibitor (SSRI) fluoxetine that is approved in the US for the treatment of
depressive episodes associated with bipolar disorder in adults. Combination
therapy with olanzapine plus fluoxetine is effective in the treatment of patients
with acute bipolar depression. The combination improves depressive symptoms and
symptom severity in this patient population, with an efficacy greater than that
of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is
generally well tolerated. Although associated with weight gain and potential
elevations in glucose, lipid and prolactin levels, the combination does not
increase the risk of treatment-emergent mania. Additional placebo- and active
comparator-controlled studies are required in order to confirm the efficacy of
olanzapine/fluoxetine in the treatment of bipolar depression and to definitively
position olanzapine/fluoxetine with respect to other agents. In the meantime,
fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated
first-line option for the treatment of acute bipolar depression.

———

Isr J Psychiatry Relat Sci. 2008;45(2):121-8.

Effectiveness and safety of adjunctive antidepressants in the treatment of
bipolar depression: a review.

Harel EV, Levkovitz Y.

Emotion-Cognition Research Center, The Shalvata Mental Health Care Center, Hod
Hasharon, Israel.

The treatment of the depressed phase of Bipolar Disorder (BPD) is understudied
and poses a widespread clinical dilemma. While the use of mood stabilizers in BPD
is a common practice, the role of antidepressants in the depressive phase of the
illness remains controversial. This paper reviews the available literature on the
subject and highlights the factors essential for making clinical decisions for
treating BPD. Most of the standard randomized controlled trials report the
efficacy of antidepressants in the acute phase of BPD, but the data also indicate
higher switch rates to mania and acceleration of mood cycle with their use.
Nevertheless, a recent large effectiveness study (STEP-BD) found no superiority
or risk of adjunct antidepressants to a mood stabilizer in the treatment of BPD.
In light of the available data, future large clinical studies are essential for
elucidating the role of antidepressants in the treatment of the depressed phase
of BPD. Until then, factors such as history of severe manias, past depression
severity and length and rapid cycling will continue to play a role in the
decision of clinicians in prescribing antidepressants for BPD in different phases
of the disorder.

———

J Clin Psychiatry. 2008;69 Suppl 5:4-8.

An analysis of the efficacy of treatments for bipolar depression.

Nierenberg AA.

Department of Psychiatry, Harvard Medical School and Depression Clinical and
Research Program and Bipolar Research Program, Massachusetts General Hospital,
Boston, MA 02114, USA. anierenberg@partners.org

Individuals with bipolar disorder are euthymic approximately half of the time,
but recurring mood episodes are common, and time spent ill is predominated by
depressive symptoms. Despite the prevalence of depression in bipolar disorder,
evidence suggests that antidepressants are not likely to benefit most patients.
Lithium, long considered a first-line treatment for bipolar disorder, is not the
most effective agent for preventing bipolar depression. This article reviews
multiple pharmacologic options that should be considered by clinicians treating
bipolar disorder in both acute and maintenance phases.

———

Curr Psychiatry Rep. 2007 Dec;9(6):497-503.

STEP-BD and bipolar depression: what have we learned?

Thase ME.

University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670,
Philadelphia, PA 19104, USA. thase@mail.med.upenn.edu

This article summarizes recent findings from the STEP-BD project pertaining to
bipolar depression treatment. Highlighted are four papers that report, in turn, a
large, randomized controlled trial of adjunctive antidepressants; a large,
randomized controlled trial of adjunctive psychosocial therapies
(cognitive-behavioral therapy, interpersonal social rhythms therapy, and
family-focused therapy); a small, randomized controlled trial contrasting
lamotrigine, risperidone, and inositol as add-on therapies for refractory bipolar
depression; and a naturalistic study of the risks of relapse during preventive
therapy. The STEP-BD results highlight the challenge of treating bipolar
depression to remission, illustrate the value of adjunctive psychotherapies, and
point to new directions for research.

———

Br J Hosp Med (Lond). 2007 Oct;68(10):530-1, 534-7.

Clinical challenges of bipolar depression.

Pandarakalam JP.

5 Boroughs Partnership NHS Trust, St. Helens North Community Mental Health Team,
St. Helens.

The observation that atypical antipsychotic drugs have some role in treating
bipolar disorders has revived interest in the management of bipolar disorder.
Given the prevalence of and the disability associated with bipolar depression,
current medication is inadequate and new research to help patients with this
condition is overdue.

———

Actas Esp Psiquiatr. 2007 May-Jun;35(3):199-207.

[Electroconvulsive therapy in the treatment of bipolar depression] [Article in Spanish]

Valentí M, Benabarre A, Bernardo M, García-Amador M, Amann B, Vieta E.

Programa de Trastornos Bipolares, Institut de Neurociències, Hospital Clínic i
Provincial de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona.

Since its introduction, electroconvulsive therapy is a treatment used in mood
disorders, especially in the depressive phases of bipolar disorder. The advance
of this technique has made it a useful and current option both in the treatment
of acute phases as in the prevention of recurrences. The objective of this
revision is to collect available data about the use of electroconvulsive therapy
in bipolar depression. Its indications, effectiveness, prediction and patterns of
response are included in this work, together with its complications, adverse
events and drug interactions. Differences in response between bipolar and
unipolar depression are also discussed.

———

J Am Acad Nurse Pract. 2007 Apr;19(4):172-8.

Unipolar or bipolar depression? Improving diagnostic confidence with the adult
patient.

Ramsley SE.

sueramsley@comcast.net

PURPOSE: The purpose of this article is to inform advanced practice nurses in
primary care about the differential diagnosis of bipolar disorder (BD), when
depression is identified in the adult patient. DATA SOURCES: Selected research
and clinical articles. CONCLUSIONS: Adult patients with BD are much more likely
to seek treatment for depression than for mania or hypomania. Recognition of BD
is improved when the primary care clinician is alerted to the factors indicating
bipolarity and utilizes available screening tools. IMPLICATIONS FOR PRACTICE:
Misdiagnosis of a bipolar spectrum disorder delays proper treatment and precludes
adequate management both pharmacologically and psychotherapeutically.

———

Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jan 30;31(1):275-82. Epub 2006
Jul 28.

Atypical antipsychotics in bipolar depression: neurobiological basis and clinical
implications.

Brugue E, Vieta E.

Bipolar Disorders Program, Hospital Clínic, University of Barcelona, IDIBAPS,
Spain.

The use of atypical antipsychotics is rapidly expanding in the management of
bipolar disorder. This therapeutic class appears to have benefits across the
spectrum of moods found in bipolar disorder, and a re-examination of the
monoamine hypothesis is required. This paper reviews the evidence for the role of
monoamines, and particularly dopamine, in bipolar depression and its implications
in the treatment of patients, focusing upon the response to atypical
antipsychotics. Relevant papers were identified undertaking a literature search
using PubMed: preclinical and clinical studies that incriminate the dopaminergic
system in bipolar depression, and recent controlled trials supporting the use of
atypical antipsychotics, are reviewed. There is substantial evidence indicating
that not only serotonin, but also dopamine may still play an important role as a
mediator of antidepressant response in bipolar depression. A regionally selective
balance between the dopamine and serotonin systems may account for the
mood-stabilizing properties of these drugs, and in fact, a low D(2) occupancy
might be more relevant to bipolar depression than greater 5-HT(2) action. This
mechanism might correlate with the ability to induce neurogenetic effects. Hence,
the greater the atypical profile, the more suitable for bipolar depression.
Further studies are needed to confirm this hypothesis.

———

CNS Drugs. 2007;21(8):695-7.

Spotlight on quetiapine in bipolar depression.

Keating GM, Robinson DM.

Wolters Kluwer Health/Adis, Auckland, New Zealand. demail@adis.co.nz

Quetiapine (Seroquel) is the only atypical antipsychotic approved in the US for
use as monotherapy in both bipolar mania and depression, offering potential
compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective
in the treatment of patients with bipolar I or II depression. Rapid and sustained
improvements in depressive and anxiety symptoms are seen with quetiapine, as well
as improvements in health-related quality of life. Quetiapine is generally well
tolerated in bipolar depression and is not associated with an increased risk of
treatment-emergent mania. Thus, despite the current lack of data from active
comparator trials, quetiapine monotherapy should be considered a first-line
option for the acute treatment of bipolar depression.

———

Drugs. 2007;67(7):1077-95.

Quetiapine: a review of its use in the treatment of bipolar depression.

Keating GM, Robinson DM.

Wolters Kluwer Health | Adis, Auckland, New Zealand. demail@adis.co.nz

Quetiapine (Seroquel) is the only atypical antipsychotic approved in the US for
use as monotherapy in both bipolar mania and depression, offering potential
compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective
in the treatment of patients with bipolar I or II depression. Rapid and sustained
improvements in depressive and anxiety symptoms are seen with quetiapine, as well
as improvements in health-related quality of life (HR-QOL). Quetiapine is
generally well tolerated in bipolar depression and is not associated with an
increased risk of treatment-emergent mania. Thus, despite the current lack of
data from active comparator trials, quetiapine monotherapy should be considered a
first-line option for the acute treatment of bipolar depression.

———

Expert Opin Pharmacother. 2007 Jan;8(1):111-3.

Zonisamide for bipolar depression.

Wilson MS, Findling RL.

Case Western Reserve University/University Hospitals Case Medical Center,
Division of Child & Adolescent Psychiatry, Department of Psychiatry, 11100 Euclid
Ave, Cleveland, OH 44106-5080, USA.

In recent years, research into bipolar depression has increased. Each year, more
studies are published using different agents to treat this condition. In addition
to effectiveness and tolerability, bipolar depression research has sought agents
that do not induce cycling or mania. This paper evaluates an open-label pilot
study on zonisamide for bipolar depression that examined the effectiveness and
tolerability of this agent while observing for any switch to mania. Zonisamide
was found to have a very low switch rate and modest effectiveness. However, a
high dropout rate was observed–mostly due to side effects. Until further
research is available, zonisamide is not recommended as a first-line treatment
for bipolar depression.

———

Expert Opin Pharmacother. 2007 Jan;8(1):13-21.

Bipolar depression: a review of randomised clinical trials.

Goodnick PJ.

Department of Psychiatry, University of Medicine and Dentistry of New Jersey,
Robert Wood Johnson Medical School, Carrier Clinic, POB 147, 252 CR 601, Belle
Mead, NJ 08502, USA. pgoodnick@aol.com

Randomised, controlled trials have been completed in the study of the response of
bipolar depression to lithium, antiepileptic drugs, antidepressants (particularly
the selective serotonin re-uptake inhibitors) and a few miscellaneous agents
including pramipexole. In most cases, only one randomised, controlled trial has
been completed, perhaps because that can be sufficient to gain US FDA approval
for an additional approved use for a medication already approved for another use
(usually mania). Despite numerous early studies of lithium, only one recent study
was completed with sufficient controls. In virtually all trials, the controlled
comparison has been with placebo. A review of risk factors, as well as adverse
events and kinetics based on these studies, focuses on net benefits, in
particular for quetiapine and lamotrigine. All antidepressants present with some
risk for induction of mania and/or cycle acceleration and are best used in
combination with mood stablisers; greatest risk for destabilisation seems to be
with venlafaxine.

———

Curr Psychiatry Rep. 2006 Dec;8(6):478-88.

Pharmacotherapy of bipolar depression: an update.

Thase ME.

University of Pittsburgh Medical Center, Western Psychiatric Institute and
Clinic, 3811 O’Hara St., Pittsburgh, PA 15213-2593, USA. thaseme@upmc.edu

Bipolar affective disorder is a virulent illness with high rates of recurrence,
disability, social impairment, and suicide. Although the manic or hypomanic
episodes define the disorder, the depressions are more numerous and less
responsive to treatment. As the initial depressive episodes are commonly
misdiagnosed, initiation of therapy with mood stabilizers is often delayed,
increasing the likelihood of treatment-emergent affective switches on
antidepressant monotherapy. The empirical basis for selecting treatments for
people with bipolar depression is weak, and only the combination of olanzapine
and fluoxetine has received US Food and Drug Administration (FDA) approval.
Conventional mood stabilizers are preferred for first-line therapies, although
atypical antipsychotics are increasingly used, and FDA approval of quetiapine is
pending. Antidepressants–particularly selective serotonin reuptake inhibitors
and bupropion–are indicated when mood stabilizers are ineffective and for
“breakthrough” depressions.

———

Dev Psychopathol. 2006 Fall;18(4):1213-30.

Bipolar depression: diagnostic and treatment considerations.

Thase ME.

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical
Center, PA 15123-2593, USA. thaseme@upmc.edu

Bipolar affective disorder is a recurrent, disabling, and potentially lethal
illness that typically begins early in life. Although the disorder is defined by
the manic and hypomanic episodes, for most people the depression episodes are the
more virulent aspect of the illness. Specifically, the depressive episodes are
more numerous, last longer, and are more difficult to treat than the manias, and
depression is the principal cause of the illness’s increased mortality due to
suicide. For people with early-onset depression, predictors of subsequent
bipolarity include a family history, psychotic features, and reverse
neurovegetative features. Initial episodes of depression are commonly
misdiagnosed, which often delays initiation of appropriate therapy and increases
the likelihood of treatment with antidepressants alone. Unfortunately, the
correct diagnosis is often not made until there has been a treatment-emergent
affective switch. There are no treatments specifically approved for bipolar
disorder in youth and, among antidepressants, only fluoxetine has received
approved. When bipolarity is suspected, treatment with mood stabilizers, both
conventional (i.e., lithium, valproate, and carbamazapine) and more recently
classified (lamotrigine) and atypical antipsychotics should be prioritized. When
antidepressants are indicated in combination with mood stabilizers, first choice
options include bupropion and the selective serotonin reuptake inhibitors.
Studies of adults indicate that several forms of focused psychotherapy may
improve longer term outcomes.

———

Drugs Today (Barc). 2006 Mar;42(3):185-92.

Olanzapine/fluoxetine combination for bipolar depression and other mood
disorders: a review.

Owen RT.

Medical Information Department, Prous Science, Barcelona, Spain.
journals@prous.com

Patients with bipolar disorder tend to experience most of their illness in the
depressed phase. Existing antidepressant therapies are effective in bipolar
depression but carry a risk of treatment-emergent mania or increased phase
cycling. Other therapies such as lithium may not be particularly effective, or
may not currently be licensed for the acute phase, such as lamotrigine. A
combination of the antipsychotic olanzapine and the serotonin reuptake inhibitor
fluoxetine has been investigated in both bipolar depression and other affective
disorders such as psychotic depression and treatment-refractory depression. The
combination’s possible mode of action, pharmacokinetics, drug interactions,
clinical efficacy and safety and tolerability have been reviewed.

———

Eur Arch Psychiatry Clin Neurosci. 2006 Feb;256(1):1-16. Epub 2005 Aug 4.

Do recent efficacy data on the drug treatment of acute bipolar depression support
the position that drugs other than antidepressants are the treatment of choice? A
conceptual review.

Möller HJ, Grunze H, Broich K.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7, 80336
Munich, Germany. hans-juergen.moeller@med.uni-muenchen.de

This conceptual review summarises the results of relevant studies on
antidepressants, mood stabilisers such as lithium and anticonvulsants, and second
generation antipsychotics in the indication of bipolar depression. Based on
methodological and clinical considerations, the position of antidepressants and
the possible alternatives in this indication are reviewed very carefully. In
addition the regulatory requirements for licensing a drug for the indication
“short-term treatment of bipolar depression” are described.

———

Expert Rev Neurother. 2006 Jan;6(1):33-9.

Olanzapine/fluoxetine combination for bipolar depression.

Shelton RC.

Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN
37212, USA. richard.shelton@vanderbilt.edu

Bipolar depression remains one of the most difficult to treat of all mental
disorders. Until recently, no treatments, including antidepressants, have
consistently shown to be effective in this condition. Olanzapine, an atypical
antipsychotic, has been approved by the US Food and Drug Administration for the
acute treatment of mania and maintenance prevention of relapse into depression or
mania. A clinical trial tested the relative effectiveness of the combination of
olanzapine and fluoxetine in bipolar type I depression, against olanzapine alone
or placebo. The combination produced a very robust clinical effect acutely and a
long-term follow-up study indicated that there was a low rate of induction of
mania or mixed states. Therefore, the olanzapine/fluoxetine combination
represents a viable alternative for bipolar depression. However, uptake of this
combined product in practice has been modest. This is likely to be the result of
several factors, including resistance to the use of fixed combination
preparations and, more recently, evidence of effectiveness of the atypical
quetiapine and the anticonvulsant lamotrigine. Perhaps the greatest resistance to
the use of olanzapine alone or in combination has been the problem of weight gain
and the attendant risk of type 2 diabetes and the metabolic syndrome. Vigorous
management of this problem has been shown to mitigate the potential for weight
gain and is required if this combination is to be used. However, many clinicians
find management of weight gain in olanzapine treated patients a challenge. In
addition, weight, waist circumference, lipids and glucose should be monitored.

———

J Clin Psychiatry. 2005 Nov;66(11):1376-85.

Typical and atypical antipsychotics in bipolar depression.

Gao K, Gajwani P, Elhaj O, Calabrese JR.

Mood Disorders Program, Department of Psychiatry, University Hospitals of
Cleveland, Case Western Reserve University School of Medicine, 11400 Euclid
Avenue, Cleveland, OH 44106, USA. keming.gao@uhhs.com

BACKGROUND: Symptomatic bipolar patients experience more depressive than manic
symptoms, but fewer studies have been designed for bipolar depression than for
bipolar mania. Since the antipsychotic agents have been shown to diminish
depressive symptoms during the treatment of mania, atypical agents are now being
studied for use in bipolar depression. DATA SOURCES: English-language articles
published from 1980 through July 2004 and cited in MEDLINE were searched using
the keywords antipsychotics, typical antipsychotics, atypical antipsychotics,
bipolar depression, bipolar disorder, manic-depressive illness, placebo, and
clinical trial. The generic and brand names of individual antipsychotics were
also entered as keywords. Peer-reviewed abstracts of placebo-controlled studies
assessing acute or long-term efficacy in bipolar depression presented at major
scientific meetings were also reviewed. STUDY SELECTION: Use of a depression
rating scale was required for inclusion of studies of the atypical antipsychotic
agents in our analysis. DATA SYNTHESIS: Twenty-one randomized trials and 13
nonrandomized prospective trials were identified. In the only 2 acute,
double-blind, placebo-controlled studies of antipsychotics in bipolar depression,
the effect size of olanzapine was small (0.32) compared with the effect sizes of
quetiapine (0.91-1.09, depending on dose). The effect size in acute mania of
olanzapine at week 4 and quetiapine at week 3 was 0.50 and 0.39, respectively.
Both olanzapine and quetiapine have been shown to be superior to placebo in the
acute treatment of bipolar I depression. In addition, olanzapine has been shown
to be more effective than placebo in delaying relapse into bipolar depression.
With the exception of a 6-month perphenazine study, there are no other randomized
studies of typical antipsychotics that support the conclusion that this class of
medication worsens bipolar depression. CONCLUSION: Emerging data suggest that the
atypical antipsychotic agents have a role in the acute and long-term treatment of
bipolar depression. No convincing data support the impression that the typical
antipsychotic agents worsen bipolar depression.

———

Harv Rev Psychiatry. 2005 Sep-Oct;13(5):257-71.

Bipolar depression: issues in diagnosis and treatment.

Thase ME.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA
15213, USA. thaseme@upmc.edu

Although bipolar affective disorder is defined by the history of manic or
hypomanic episodes, depression is arguably a more important facet of the illness.
Depressive episodes, on average, are more numerous and last longer than manic or
hypomanic episodes, and most suicides occur during these periods. Misdiagnosis of
major depressive disorder delays initiation of appropriate therapy, further
worsening prognosis. Distinguishing features of bipolar depression include
earlier age of onset, a family history of bipolar disorder, presence of psychotic
or reverse neurovegetative features, and antidepressant-induced switching.
Bipolar I depressions should initially be treated with a mood stabilizer
(carbamazapine, divalproex, lamotrigine, lithium, or an atypical antipsychotic);
antidepressant monotherapy is contraindicated. More severe or “breakthrough”
episodes often require a concomitant antidepressant, such as bupropion or a
selective serotonin reuptake inhibitor (SSRI). The first treatment specifically
approved for bipolar depression is a combination of the SSRI fluoxetine and the
atypical antipsychotic olanzapine. For refractory depressive episodes,
venlafaxine, the monoamine oxidase inhibitor tranylcypromine, and ECT are most
widely recommended. The optimal duration of maintenance antidepressant therapy
has not been established empirically and, until better evidence-based guidelines
are established, should be determined on a case-by-case basis.

———

Neuro Endocrinol Lett. 2005 Aug;26 Suppl 1:27-47.

Treatment of bipolar depression.

Svestka J.

Antidepressants have insufficient effect in 20-40% of patients treated for
depressive disorders. This is particularly true for psychotic and agitated
depression. When administered on a long-term basis, antidepressants cause a
switch into mania in 25-40% of patients and induce rapid cycling. Classical
antipsychotics have exhibited good therapeutic efficacy in the treatment of
various forms of depression, especially psychotic and agitated forms, albeit
burdened with many, above all extrapyramidal, side effects. When administered
over long periods of time, classical antipsychotics may have a depressogenic
effect. Second-generation antipsychotics have started to be increasingly used in
this indication for a variety of reasons including: their antidepressant effect
attributable to raised concentrations of catecholamines in the prefrontal cortex,
their impact on serotonin transmission, their antipsychotic effect due to their
mode of action including the mesolimbic blockade of dopamine D2 receptors, and
the low incidence of extrapyramidal and other side effects. The following text
encompasses the results of controlled trials using second-generation
antipsychotics in the treatment of acute depressive disorders.

———

J Affect Disord. 2005 Jul;87(1):115-9.

Is treatment-associated hypomania rare with duloxetine: secondary analysis of
controlled trials in non-bipolar depression.

Dunner DL, D’Souza DN, Kajdasz DK, Detke MJ, Russell JM.

Department of Psychiatry and Behavioral Sciences, University of Washington Center
for Anxiety and Depression, 4225 Roosevelt Way NE, Ste 306C, Seattle, WA 98105,
United States. ddunner@u.washington.edu

BACKGROUND: Selective serotonin (5-HT) and norepinephrine (NE) reuptake
inhibitors (SNRIs) like duloxetine have the efficacy of tricyclic antidepressants
(TCAs) with a more tolerable side-effect profile. Bipolar disorder is often
undetected, with the most common misdiagnosis being unipolar depression. Studies
have suggested that treatment of bipolar and unipolar depression with
heterocyclic TCAs may increase the risk of switch rate to mania. Studies of
antidepressants in unipolar major depression show a small risk of mania or
hypomania, presumably because some bipolar depressives were mistakenly studied.
This study investigated the rate of hypomania, mania, and hypomanic-like symptoms
observed during treatment with duloxetine in patients with major depression.
METHODS: This was a retrospective analysis of data from eight placebo-controlled,
double-blind, randomized clinical trials of duloxetine in patients with
non-bipolar major depression. LIMITATIONS: The studies were of limited duration.
Manic or hypomanic symptoms were not elicited using standardized mania rating
scale instruments. RESULTS: One case of mania occurred in the placebo group
(0.1%), and two cases of hypomania were observed in the duloxetine-treated group
(0.2%). Among hypomanic-like symptoms, only insomnia was significantly higher in
the duloxetine group than in the placebo group (p<0.05). CONCLUSIONS: Duloxetine
was associated with a low incidence of treatment-emergent hypomania, mania, or
hypomanic-like symptoms in patients with major depressive disorder (MDD). The low
incidence reported here may be due to greater diagnostic diligence on the part of
the investigators. It is possible that the cases reported likely reflect
inclusion of misdiagnosed bipolar II patients rather than true unipolar MDD
cases. The effect of duloxetine in patients with bipolar depression is not known.

———

Psychiatr Clin North Am. 2005 Jun;28(2):349-70, vii.

Treatment of bipolar depression.

Dubovsky SL.

Department of Psychiatry, State University of New York at Buffalo, 462 Grider
Street, Buffalo, NY 14215, USA. Dubovsky@buffalo.edu

This article discusses current practices in the treatment of bipolar depression.
In the absence of more definitive research, the treatment of bipolar depression
is guided by clinical experience and expert opinion, and sometimes by marketing
and popular trends, as much as it is by hard data. Considering the limitations of
current knowledge is an essential component of the scientific practice of
psychiatry.

———

Bipolar Disord. 2005;7 Suppl 5:13-23.

Newer treatment studies for bipolar depression.

Gao K, Calabrese JR.

NIMH Bipolar Research Center, Mood Disorders Program, University Hospitals of
Cleveland/Case Western Reserve University School of Medicine, Cleveland, OH, USA.
keming.gao@uhhs.com

OBJECTIVE: Depressive symptoms of bipolar disorder have more negative impact on a
patient’s life than manic symptoms. This review focused on the emerging efficacy
data for treatments in bipolar depression. METHODS: English-language literature
cited in Medline was searched with terms bipolar depression, clinical trial, and
trial. Randomized, placebo-controlled trials of newer studies with older agents
and all studies with newer or novel agents were prioritized. Open-label studies
of novel agents presented at major scientific meetings were also included.
RESULTS: Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were
superior to placebo in the acute treatment of bipolar depression. Lamotrigine
only significantly reduced core symptoms of depression compared with placebo.
Pramipexole, a dopamine D2/D3 receptor agonist and omega-3 fatty acids, a
polyunsaturated fatty acid, augmentation to mood stabilizer (MS) had superiority
to placebo in reducing depressive symptoms. Topiramate augmentation of an MS was
equally as effective as Bupropion-SR. Patients treated with an MS responded well
to the addition of agomelatine, a melatonin receptor agonist with 5-HT2C
antagonist properties. However, inositol and repetitive transcranial magnetic
stimulation did not separate from placebo. Lamotrigine and olanzapine, and to a
lesser extent, divalproex, are superior to placebo in preventing depressive
relapses. All agents were relatively well tolerated. CONCLUSIONS: Olanzapine,
OFC, and quetiapine are effective in the acute treatment of bipolar depression.
Compared with lithium and divalproex, lamotrigine is more effective in preventing
bipolar depression. Larger controlled studies of the other agents in the acute
and maintenance treatment of bipolar depression are warranted.

———

Bipolar Disord. 2005;7 Suppl 5:3-12.

Benefits and limitations of antidepressants and traditional mood stabilizers for
treatment of bipolar depression.

Goldberg JF, Nassir Ghaemi S.

Affective Disorders Program, Silver Hill Hospital, New Canaan, CT 06840, USA.
jgoldberg@silverhillhospital.org

OBJECTIVE: The aim of this paper was to review the rationales, risks, and
benefits for using standard antidepressants versus mood stabilizing agents and/or
atypical antipsychotics to treat bipolar depression. METHOD: A selective
literature review was conducted using key terms and by reference known to the
authors. Bibliographies of articles and book chapters were further scrutinized
for relevant literature. RESULTS: The strengths and limitations of current
studies are described and critically reviewed in order to present optimal
strategies for effective pharmacotherapy. Clinical factors that can mitigate or
confound simple bivariate relationships between antidepressant use and outcome
have seldom been examined using multivariate statistical techniques. For many of
the key questions there is a paucity of informative literature and randomized
clinical trials are of limited value in addressing some of the issues.
CONCLUSIONS: Clinicians and investigators should be aware of the methodological
shortcomings of existing studies. Decisions about the relative merits versus
contraindications for antidepressant use should be made via more individualized,
case-by-case profiling rather than by rigid prescribing practices.

———

Bipolar Disord. 2005;7 Suppl 4:34-40.

Bipolar depression: a new role for atypical antipsychotics?

Keck PE Jr.

Psychopharmacology Research Program, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA. paul.keck@uc.edu

Bipolar depression, the most common phase of bipolar disorder, causes significant
morbidity and mortality. Traditional drugs such as lithium, lamotrigine or
antidepressants each offer some clinical efficacy; however, efficacy can be
limited and side effects are sometimes problematic. Thus there is a major unmet
need for effective, well-tolerated agents for the treatment of bipolar
depression. The atypical antipsychotics, with their proven efficacy against manic
symptoms, are emerging as candidates for use against the depressive phase of
bipolar disorder. Several studies have shown that some atypicals improve
depressive symptoms in mixed episodes in patients with bipolar disorder; however,
few studies have been performed in patients specifically with bipolar depressive
episodes. In a randomized, placebo-controlled trial in patients with acute
bipolar I depression, olanzapine monotherapy and an olanzapine-fluoxetine
combination significantly improved Montgomery-Asberg Depression Rating Scale
(MADRS) total scores compared with placebo (p < 0.001) with corresponding effect
sizes (improvement of active treatment over placebo divided by pooled standard
deviation) of 0.32 and 0.68, respectively. Importantly, there were no significant
differences in rates of switch into mania among the three groups. Recent results
from an 8-week, randomized placebo-controlled trial in patients with bipolar I
and II disorder who were experiencing a bipolar depressive episode showed that
quetiapine (300 and 600 mg/day) had significantly greater efficacy compared with
placebo in improving the core symptoms of depression, including suicidal
thoughts. Quetiapine significantly improved MADRS total scores compared with
placebo (p < 0.001); effect sizes (improvement of quetiapine over placebo divided
by pooled standard deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine,
respectively, were observed. Both doses of quetiapine significantly improved
symptoms of anxiety, sleep quality and global quality of life (all, p < 0.001
versus placebo). These initial findings suggest that atypical antipsychotics may
prove to be important future treatments for patients with bipolar depression.

———

Expert Rev Neurother. 2005 Jan;5(1):69-78.

Treatment of bipolar depression: focus on pharmacologic therapies.

Mitchell PB, Malhi GS.

University of New South Wales, School of Psychiatry, Prince of Wales Hospital,
Randwick, New South Wales 2031, Australia. phil.mitchell@unsw.edu.au

Recent studies have highlighted significant limitations in our capacity to
effectively treat bipolar depression. This article reviews the present status of
treatments for this condition, highlighting emerging new pharmacotherapies such
as lamotrigine, olanzapine and quetiapine, while also addressing modern
psychologic interventions such as cognitive behavioral therapy and
psychoeducation. The role of older treatments such as lithium and the
antidepressants is also discussed, particularly as a recent meta-analysis has
thrown into question current heightened concern over antidepressant-induced
mania. The advent of new pharmacologic and psychologic treatments provides
optimism for improved outcomes for this highly disabling condition.

———

J Clin Psychiatry. 2005;66 Suppl 5:34-9.

The package of care for patients with bipolar depression.

Vieta E.

Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona,
IDIBAPS, Barcelona, Spain. evieta@clinic.ub.es

Although pharmacotherapy is the mainstay of the comprehensive program of medical
care for the management of patients with bipolar disorder, the additional
benefits of psychosocial interventions for the patient, family, and caregivers
are now being recognized and increasingly adopted. Several facets of bipolar
disorder can be addressed more effectively by instituting adjunctive psychosocial
interventions. Recent clinical evidence indicates that combining pharmacotherapy
with psychosocial interventions, which are tailored to patients’ individual
needs, may decrease the risk of relapse, improve patient adherence, and decrease
the number and length of hospitalizations. A multidisciplinary approach may also
enhance long-term patient outcomes such as mood stability, enhanced occupational
and/or social functioning, and overall quality of life. Psychoeducation helps
individuals become active and informed participants in the management of their
illness, promoting a collaborative relationship between patients and their
caregivers. However, psychosocial interventions are not useful for all patients
with bipolar illness and may be more useful in addressing some problems than
others. Evidence would suggest that psychosocial interventions, with continuing
pharmacotherapy, are best used as prophylaxis and during periods of remission to
prevent further episodes. Further randomized, clinical trials will help to define
which components of psychosocial intervention are most effective in patients with
bipolar disorder.

———

J Clin Psychiatry. 2005;66 Suppl 5:26-33.

Clinical highlights in bipolar depression: focus on atypical antipsychotics.

Calabrese JR, Elhaj O, Gajwani P, Gao K.

University Hospitals of Cleveland/Case Western Reserve University School of
Medicine, Cleveland, Ohio, USA. joseph.calabrese@uhhs.com

Despite the considerable burden of bipolar depression, the treatment of this
debilitating phase of bipolar disorder is suboptimally addressed by currently
available pharmacologic options. Consequently, there is a need for the
development of new treatment options with enhanced efficacy and tolerability.
Evidence of antidepressant efficacy for some of the atypical antipsychotics in
the treatment of bipolar depression has recently emerged. The findings of a
large-scale, placebo-controlled, double-blind, randomized clinical study of
olanzapine alone and in combination with fluoxetine, and a similar study of
quetiapine monotherapy, suggest that some of the atypical antipsychotics may be
efficacious in treating depressive symptoms in patients with bipolar I disorder.
Subpopulation analyses suggest that quetiapine monotherapy and the olanzapine
plus fluoxetine combination appear to be effective in treating depression in
patients with a rapid-cycling course. The magnitude of improvement in depressive
symptoms in the bipolar I population appears to be larger for quetiapine
monotherapy compared with either olanzapine or olanzapine plus fluoxetine;
however, the limitations of such a cross-study comparison are acknowledged. Both
olanzapine monotherapy and combination therapy, as well as quetiapine
monotherapy, were well tolerated. The overall incidence of treatment-emergent
mania was low and comparable with placebo in both studies. Somnolence, weight
gain, increased appetite and nonfasting glucose and cholesterol levels were more
commonly reported in patients treated with olanzapine monotherapy or combination
therapy compared with placebo. Dry mouth, sedation/somnolence, dizziness, and
constipation were more commonly associated with quetiapine treatment. Large,
controlled studies are needed to determine whether other psychotropic agents have
antidepressant properties that would make them suitable for use in patients with
bipolar depression. In addition, direct comparison of the regimens used in the
current study should determine whether the differences evident between them can
be confirmed.

———

J Clin Psychiatry. 2005;66 Suppl 5:17-25.

Reevaluating therapies for bipolar depression.

Grunze H.

Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany.
Heinz.Grunze@med.uni-muenchen.de

The most commonly employed pharmacotherapies for bipolar depression include
antidepressants, lithium, and anticonvulsants, such as lamotrigine, valproate,
and carbamazepine. A combination of these agents, usually an antidepressant and a
mood stabilizer, is often required to achieve an optimal response. However, some
treatment guidelines still caution that antidepressant exposure should be
minimized in patients with bipolar depression, due to concern that they may
trigger treatment-emergent mania or cycle acceleration. This advice prevails
despite data showing that antidepressants are effective in treating bipolar
depression and evidence that coadministration of a mood-stabilizing medication,
at least with modern antidepressants, such as the selective serotonin reuptake
inhibitors, can reduce the risk of treatment-emergent mania to levels comparable
with those observed with mood stabilizer monotherapy. Although the antidepressant
efficacy of most mood stabilizers has not been satisfactorily proven, first-line
therapy with 1 mood stabilizer alone or a combination of 2 mood stabilizers is
still recommended by many guidelines. Inappropriate treatment of bipolar
depression may leave patients at high risk of suicide and increased chronicity of
symptoms; effective therapy should, therefore, be provided as early as possible.
The efficacy and safety of antidepressants for bipolar depression both as
monotherapy and when combined with a mood stabilizer should be studied in
adequately powered trials in order to revise treatment guidelines.
Electroconvulsive therapy remains an option for treatment-refractory patients and
those intolerant to pharmacologic treatment, as well as patients who are pregnant
or at high risk of suicide.

———

J Clin Psychiatry. 2005;66 Suppl 5:11-6.

Challenges in the management of bipolar depression.

Suppes T, Kelly DI, Perla JM.

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas
75390-9121, USA. trisha.suppes@utsouthwestern.edu

Bipolar depression has started to receive more attention in clinical trials only
relatively recently, despite the fact that patients spend more time in the
depressed phase than in the manic phase of bipolar disorder. The diagnosis and
management of bipolar depression are challenging, and many patients are
undiagnosed or misdiagnosed due to symptom similarities with unipolar depression
or other illnesses and/or comorbidities. Untreated or inappropriately treated
bipolar depression adds to the burden of illness and is associated with a greater
risk of suicide. Treatment options include lithium, lamotrigine, atypical
antipsychotics, and traditional antidepressants, such as the selective serotonin
reuptake inhibitors. However, traditional antidepressants are recommended with
caution due to their potential risk of switching patients into mania. Some
atypical antipsychotics have shown efficacy in bipolar depression, although
longer-term studies are warranted. The choice of treatment for different
subgroups of patients with bipolar depression, including those with comorbid
anxiety, may vary and also needs further study. Other important issues that
require further investigation include the recognition of the core features of
bipolar depression and the threshold symptoms for treatment, as well as the
optimal treatment choices for monotherapy or combination therapy, and acute
versus long-term management of bipolar depression.

———

J Clin Psychiatry. 2005;66 Suppl 1:3-6.

Treatment options for bipolar depression.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center, San Antonio,
TX 78229-3900, USA. bowdenc@uthscsa.edu

Bipolar disorder is often misdiagnosed as major depressive disorder because of
the high frequency of depressive symptomatology in many patients with bipolar
disorder. Depressive episodes that are resistant to treatment may also be
associated with a worse course of illness in bipolar disorder, but we do not yet
understand all the factors in the connection between bipolar disorder and
depression. The data on the effectiveness of antidepressants in the treatment of
depression in bipolar disorder vary greatly, and there have been few prospective,
randomized studies on the subject. From the data so far, the rates of induction
of mania for selective serotonin reuptake inhibitors and lamotrigine seem similar
to those seen with placebo. The optimal length of time to continue antidepressant
treatment in patients with bipolar disorder has not yet been determined; however,
research tends to indicate that a longer term of treatment (6 months or more) may
aid in the prevention of relapse. Newer U.S. Food and Drug
Administration-approved treatments for depression in bipolar disorder include a
combination of olanzapine and fluoxetine, which is used for depressive episodes
in bipolar disorder, and lamotrigine, which is used for maintenance treatment of
bipolar I disorder. Psychoeducation has also been examined as a possible
treatment for depression in bipolar disorder, and a study has shown that patients
receiving psychoeducation plus medication may have a lower rate of relapse than
patients who receive medication alone.

———

Bipolar Disord. 2004 Dec;6(6):530-9.

Bipolar depression: phenomenological overview and clinical characteristics.

Mitchell PB, Malhi GS.

School of Psychiatry, University of New South Wales and Mood Disorders Unit,
Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
phil.mitchell@unsw.edu.au

OBJECTIVES: There has been increasing interest in the depressed phase of bipolar
disorder (bipolar depression). This paper aims to review the clinical
characteristics of bipolar depression, focusing upon its prevalence and
phenomenology, related neuropsychological dysfunction, suicidal behaviour,
disability and treatment responsiveness. METHODS: Studies on the prevalence of
depression in bipolar disorder, the comparative phenomenology of bipolar and
unipolar depression, as well as neuropsychology and brain imaging studies, are
reviewed. To identify relevant papers, a literature search using MEDLINE and
PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance in
bipolar disorder, and most frequently presents as subsyndromal, minor or
dysthymic depression. Compared with major depressive disorder (unipolar
depression), bipolar depression is more likely to manifest with psychosis,
melancholic symptoms, psychomotor retardation (in bipolar I disorder) and
‘atypical’ symptoms. The few neuropsychological studies undertaken indicate
greater impairment in bipolar depression. Suicide rates are high in bipolar
disorder, with suicidal ideation, suicide attempts and completed suicides all
occurring predominantly in the depressed phase of this condition. Furthermore,
the depressed phase (even subsyndromal) appears to be the major contributant to
the disability related to this condition. CONCLUSIONS: The significance of the
depressed phase of bipolar disorder has been markedly underestimated. Bipolar
depression accounts for most of the morbidity and mortality due to this illness.
Current treatments have significant limitations.

———

Am J Psychiatry. 2004 Sep;161(9):1537-47.

Antidepressants for bipolar depression: a systematic review of randomized,
controlled trials.

Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM.

Department of Psychiatry, Warneford Hospital, Oxford, UK.
harm.gijsman@doctors.net.uk

Comment in:
Evid Based Ment Health. 2005 May;8(2):35.
Am J Psychiatry. 2005 Aug;162(8):1546-7; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1546; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1545-6; author reply 1547-8.

OBJECTIVE: This study reviewed the evidence from randomized, controlled trials on
the efficacy and safety of antidepressants in the short-term treatment of bipolar
depression. METHOD: The authors performed a systematic review and meta-analysis
of randomized, controlled trials. They searched the Cochrane Collaboration
Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating
results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The
main outcome measures were the proportion of patients who clinically responded to
treatment and the rate of switching to mania. RESULTS: Twelve randomized trials
were included, with a total of 1,088 randomly assigned patients. Five trials
compared one or more antidepressants with placebo: 75% of these patients were
receiving a concurrent mood stabilizer or an atypical antipsychotic.
Antidepressants were more effective than placebo. Antidepressants did not induce
more switching to mania (the event rate for antidepressants was 3.8% and for
placebo, it was 4.7%). Six trials allowed comparison between two antidepressants.
The rate of switching for tricyclic antidepressants was 10%, and for all other
antidepressants combined, it was 3.2%. CONCLUSIONS: Antidepressants are effective
in the short-term treatment of bipolar depression. The trial data do not suggest
that switching is a common early complication of treatment with antidepressants.
It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine
oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment.
Given the limited evidence, there is a compelling need for further studies with
longer follow-up periods and careful definition and follow-up of emerging mania
and partial remission.
PMID: 15337640 [PubMed – indexed for MEDLINE] CNS Spectr. 2004 Sep;9(9 Suppl 9):11-8.

Rethinking the treatment paradigm for bipolar depression: the importance of
long-term management.

Baldassano CF, Ballas CA, O’Reardon JP.

Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, PA 19104, USA. cfb@mail.med.upenn.edu

The need for long-term management of bipolar disorder is evident. Bipolar
patients spend more time depressed than manic; however, few agents used for
maintenance therapy of bipolar disorder have demonstrated good efficacy in
delaying relapse into depression. This article provides a comprehensive review of
open-label and randomized, controlled studies examining prophylactic efficacy in
bipolar disorder, especially bipolar depression. Lithium, considered the gold
standard for bipolar disorder maintenance therapy may be more effective in
delaying manic relapse than in delaying depressive relapse. Evidence for the
efficacy of divalproex and carbamazepine in delaying depressive relapse is yet to
be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time to
depressive relapse. Unpublished studies show olanzapine’s efficacy in preventing
manic recurrence, while its efficacy in preventing depressive recurrence is yet
to be proven. As patients with bipolar disorder are prone to experiencing
depressive episodes, more attention needs to be focused on preventing depressive
relapse. To date, three agents–lithium, lamotrigine, and olanzapine–have been
shown to have prophylactic benefits in treating this highly recurrent disorder.
PMID: 15361807 [PubMed – indexed for MEDLINE] IDrugs. 2004 Sep;7(9):846-50.

Bipolar depression: an overview.

Oral ET, Vahip S.

Mood Disorders Outpatient Program, Bakirköy State Hospital for Research and
Training in Neurology & Psychiatry, Istanbul 34747, Turkey.
etoral@superonline.com

Depressive episodes are significant in bipolar illness since patients can spend
up to one-third of their lives in depression. Although the treatment of bipolar
depression remains an understudied area, new data from randomized, controlled
trials and naturalistic studies have expanded the range of treatments available.
The main aim in the treatment of bipolar depression is the prevention of the
patient switching to mania and cycle acceleration, and antidepressant therapy may
be contraindicated because of the risk for switching. Guidelines for the acute
treatment of bipolar depression emphasize treatment with a mood stabilizer, of
which lithium has been the most thoroughly studied in randomized, controlled
trials in acute bipolar depression. Lamotrigine has also demonstrated significant
efficacy in recent studies and has been approved by the FDA.

———

Int Clin Psychopharmacol. 2004 May;19(3):113-24.

A review of acute treatments for bipolar depression.

Silverstone PH, Silverstone T.

Departments of Psychiatry and Neuroscience, University of Alberta, Edmonton,
Alberta, Canada. peter.silverstone@ualberta.ca

Bipolar patients generally spend much more time in the depressed phase of their
illness than the manic phase, and there are many more bipolar type II and bipolar
spectrum disorder patients than there are bipolar type I. Additionally, there is
a significant risk of suicide in bipolar patients when depressed. The treatment
of the depressed phase of bipolar disorder is therefore a matter of some
priority. Here, we review current evidence supporting the use of five groups of
treatments: anti-depressants; lithium; anti-convulsants (valproate, and
carbamazepine, lamotrigine, gabapentin); anti-psychotics; and other treatments
(electroconvulsive therapy, benzodiazepines, sleep-deprivation, and dopamine
agonists). From this review, it is apparent that the literature regarding the
treatment of bipolar depression is significantly limited in several key areas.
Nonetheless, from the evidence currently available, the treatments with the best
evidence for efficacy are selective serotonin reuptake inhibitors (SSRIs) and
lamotrigine. There is also some evidence in favour of bupropion and moclobemide.
Although lithium and olanzapine monotherapies can also be beneficial, they appear
less efficacious than antidepressants. One of the major concerns about treatment
with antidepressants has been the risk of precipitating a switch into mania.
However, recent studies suggest that, if a mood stabilizer and antidepressant are
given concurrently, then the risk of switching is minimized. There is also recent
evidence for an independent antidepressant action for at least one atypical
antipsychotic. Therefore, the conclusion from this review, in contrast to
previous suggestions, is that a combination of an atypical antipsychotic and
either an SSRI or lamotrigine may provide a useful first-line treatment for
depressed bipolar disorder patients. Further research is clearly required to
examine this approach and compare it with other possible treatment options.

———

Bipolar Disord. 2003 Dec;5(6):396-406.

A re-evaluation of the role of antidepressants in the treatment of bipolar
depression: data from the Stanley Foundation Bipolar Network.

Post RM, Leverich GS, Nolen WA, Kupka RW, Altshuler LL, Frye MA, Suppes T,
McElroy S, Keck P, Grunze H, Walden J; Stanley Foundation Bipolar Network.

Department of Health and Human Services, National Institutes of Health, National
Institute of Mental Health, Biological Psychiatry Branch, Bethesda, MD
20892-1272, USA. postr@intra.nimh.nih.gov

OBJECTIVES: The risk-to-benefit ratio of the use of unimodal antidepressants
(ADs) as adjuncts to mood stabilizers continues to be an area of controversy and
disagreement among experts in the field. This paper reviews new data on: (1)
depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD
discontinuation that are pertinent to the ongoing discussion and recommendations.
METHODS: In the first study reviewed, 258 outpatients with bipolar illness were
assessed prospectively on a daily basis using the National Institute of Mental
Health-Life Chart Method (NIMH-LCM) for 1 year. In the second study, 127 bipolar
depressed patients were randomized to 10 weeks of sertraline, bupropion, or
venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized
and responders were offered a year of continuation treatment. In the final study,
Altshuler et al. retrospectively and prospectively assessed the risk of
depressive relapses in patients who remained on ADs after 2 months of euthymia
compared with those who discontinued ADs. RESULTS: Despite intensive naturalistic
treatment, the 258 outpatients with bipolar illness followed prospectively for 1
year showed three times as many days depressed as days manic, re-emphasizing the
considerable depressive morbidity that remains in bipolar disorder despite the
number of treatment options available. In the study of bipolar depressed patients
randomized to one of three ADs, a range of severities and durations of hypomanic
to manic switches were discerned following 175 trials of AD augmentation of
treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were
associated with switches into hypomania or mania and another 9.1% with a week or
more of hypomania alone (with no to minimal dysfunction). In 73 continuation
phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic
and hypomanic switches, respectively. In the Altshuler et al. studies, those who
remained well on any AD for more than 2 months (only 15-20% of those initially
treated) and who continued on ADs showed a lesser rate of relapse into depression
over 1 year (35 and 36% in the first and second study, respectively) compared
with those who discontinued their ADs (68 and 70% relapsing into depression).
Surprisingly, this continuation of ADs was associated with no increase in the
rate of switching into mania compared with those stopping ADs. CONCLUSIONS: These
data reveal that depression and depressive cycling remain a substantial problem
in some two-thirds of intensively treated bipolar outpatients. Acute AD
augmentation was associated with a modest response rate and 18.2% switched into a
hypomanic to manic episode, and 35.6% of the continuation trials showed these two
types of switches. Two separate studies suggest that in the very small subgroup
who remain well on ADs for at least 2 months, one should consider continuation of
this AD augmentation treatment, because AD discontinuation appears associated
with a substantially increased risk of depression relapse over the subsequent
year with no reduced risk of switching into mania.

———

Ann Clin Psychiatry. 2003 Sep-Dec;15(3-4):225-32.

What drugs are best for bipolar depression?

Baldassano CF, Datto SM, Littman L, Lipari MA.

Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104, USA. cfb@mail.med.upenn.edu

Bipolar depression is a severe, potentially lethal disorder for which there are
no specific, FDA-indicated pharmacotherapies. Research in this area has been
limited, and most treatments are based on unsupported extrapolation from the
treatment of unipolar depression, or follow guidelines derived largely from the
clinical practice experience of experts in this field. There is clearly a medical
need for new and more effective treatments for bipolar depression. Recently, the
newer antiepileptic drugs, and atypical antipsychotics, have been studied to
evaluate their role in bridging this gap in the psychopharmacologic
armamentarium. Drugs in these classes will be reviewed, in addition to serotonin
reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive therapy.
In this paper, current trends in the acute and long-term medication treatment of
bipolar depression will be described, with particular focus on evidence from the
existing literature. Additional factors, such as side effects, risk/benefit
issues, and drug-drug interactions, will be considered in an attempt to make
overall recommendations for medication selection.

———

Int J Neuropsychopharmacol. 2003 Sep;6(3):285-91.

Recent placebo-controlled acute trials in bipolar depression: focus on
methodology.

Muzina DJ, Calabrese JR.

Cleveland Clinic Foundation, Cleveland, Ohio, USA. muzinad@ccf.org

Comment in:
Int J Neuropsychopharmacol. 2004 Mar;7(1):105-6; author reply 107.

The completion of three recent large-scale, double-blind controlled acute trials
in bipolar I depression has improved our understanding of the management of major
depressive episodes associated with bipolar disorder. In contrast to the
cross-over designs used in the early studies of lithium in bipolar depression,
the designs utilized in these recent studies have employed random assignment to
parallel arms including the use of placebo as a monotherapy in one study. The
analyses of recent studies have all been conducted on intent-to-treat data, and
included two types, change from baseline analyses and responder analyses.
Lamotrigine monotherapy was shown to be superior to placebo with both types of
analyses on the Montgomery-Asberg Depression Rating Scale (MADRS) and the
Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton Depression
Rating Scale (HAMD) (n=195). The percentage of patients responding to placebo as
a monotherapy were 29, 26 and 37%, respectively; there were no differences in
switch rates (5% vs. 5%). Paroxetine augmentation was no better than placebo
augmentation overall with both types analyses on the CGI and HAMD (n=117); the
MADRS was not used. In patients with lithium levels < or =0.8 mequiv./l, the
change from baseline analysis showed paroxetine to be superior to placebo, but
responder analyses were negative; switch rates with paroxetine, imipramine, and
placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in efficacy to
imipramine (n=156), but had a lower rate of switching (4% vs. 11%).

———

Psychiatr Clin North Am. 2003 Jun;26(2):495-518.

Treatment of bipolar depression: current status, continued challenges, and the
STEP-BD approach.

Thase ME, Bhargava M, Sachs GS.

Department of Psychiatry, University of Pittsburgh Medical Center, Western
Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213-2593,
USA. thaseme@msx.upmc.edu

Even though at least 10% (if not 20%) of those who experience a first lifetime
episode of depression will subsequently develop bipolar disorder, the alliance of
academic and industry research agendas that leads to developing and testing new
antidepressants has failed to produce a sufficient knowledge base. It is
therefore impossible to apply a truly empirical approach to guide the treatment
of people with bipolar depression. Consequently, there are holes in contemporary
evidenced-based practice guidelines large enough to drive a truck through;
furthermore, there are some recommendations that have no factual basis other than
expert opinion. However, with new research emerging on lamotrigine and
olanzapine, in addition to the pending results of larger studies supported by the
National Institute of Mental Health and the Stanley Foundation, there is evidence
that some progress is being made.

———

Biol Psychiatry. 2003 Apr 15;53(8):691-700.

Acceleration and augmentation strategies for treating bipolar depression.

Altshuler LL, Frye MA, Gitlin MJ.

Department of Psychiatry and Biobehavioral Sciences, University of California,
Los Angeles, Los Angeles, California 90095, USA.

Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.

Despite the prevalence and morbidity of bipolar depression, few randomized
treatment trials have been conducted to assess clinical efficacy. Even fewer
studies have assessed approaches that optimize treatment response for bipolar
depression. This review will define three types of common combination
strategies–adjunctive, acceleration and augmentation–and discuss the limited
literature of controlled studies reported on acceleration and augmentation
approaches.

———

Biol Psychiatry. 2003 Apr 15;53(8):671-9.

Advances in the pharmacologic treatment of bipolar depression.

Keck PE Jr, Nelson EB, McElroy SL.

Division of Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.

Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.

The pharmacologic treatment of bipolar depression has not been well studied in
randomized, controlled trials. Thus important clinical questions regarding the
efficacy in bipolar depression of mood stabilizers, antidepressants, and new
antiepileptic and atypical antipsychotic agents have been relatively unaddressed.
Until recently there were few data regarding the degree to which mood stabilizers
reduce the risk of switching associated with antidepressant treatment. Likewise,
although treatment guidelines have often recommended limiting antidepressant
exposure in the maintenance treatment of bipolar depression, the potential risks
of depressive relapse after antidepressant discontinuation were largely unknown.
We review here data from new randomized, controlled trials published or presented
during the past 5 years regarding the efficacy of antidepressants, mood
stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment
of bipolar depression. We also review new studies clarifying the protective
effect of coadministration of mood stabilizers from antidepressant-associated
switching and the risk of depressive relapse when antidepressants are
discontinued during maintenance treatment.
PMID: 12706953 [PubMed – indexed for MEDLINE] Bipolar Disord. 2003 Apr;5(2):85-97.

Bipolar depression: criteria for treatment selection, definition of
refractoriness, and treatment options.

Yatham LN, Calabrese JR, Kusumakar V.

Department of Psychiatry, The University of British Columbia, Vancouver, British
Columbia, Canada. yatham@interchange.ubc.ca

OBJECTIVE: This paper reviews controlled studies of bipolar depression, outlines
criteria for choosing treatment, defines refractoriness in bipolar depression,
and provides options for treatment of refractory bipolar depression. METHODS:
Controlled studies that examined the efficacy of treatments for acute and
long-term treatment of bipolar depression were located through electronic
searches of several databases and by manual crosssearch of references and
proceedings of international meetings. RESULTS: Lithium comes close to fulfilling
the proposed criteria for first-line treatment for bipolar depression, and those
not responding to lithium should be considered to have refractory bipolar
depression. Options for such patients include addition of lamotrigine or a second
mood stabilizer, or a newer-generation antidepressant such as a serotonin
re-uptake inhibitor or bupropion, or the atypical antipsychotic olanzapine.
CONCLUSIONS: Although there is a paucity of research in the treatment of
refractory bipolar depression, available data could be used for providing
rational treatment options for such patients. However, further studies are
urgently needed to determine which options are most appropriate for which type of
patients.

———

J Fam Pract. 2003 Mar;Suppl:S14-7.

Treating bipolar depression.

Shelton RC.

Vanderbilt University School of Medicine, Nashville, TN, USA.

PMID: 12676079 [PubMed – indexed for MEDLINE] Bipolar Disord. 2003;5 Suppl 2:20-35.

The role of atypical antipsychotics in bipolar depression and anxiety disorders.

McIntyre R, Katzman M.

Mood Disorder Psychopharmacology Unit, University of Toronto, University Health
Network, Toronto Western Hospital, 399 Bathurst Street, ECW-3D-003, Toronto,
Ontario, M5T 2S9, Canada. rmcintyr@uhnres.utoronto.ca

Bipolar disorder is a complex condition that includes symptoms of mania,
depression, and often anxiety. Diagnosing and treating bipolar depression is
challenging, with the disorder often being diagnosed as unipolar depression. In
addition, comorbid anxiety can be a significant detractor to successful outcomes,
increasing symptom severity, frequency of episodes and suicide rates, and
decreasing response to antidepressant therapy. Anxiety often precedes and hastens
the onset of bipolar disorder, and a shared genetic etiology has been suggested.
Studies have demonstrated the efficacy of atypical antipsychotics for the acute
and maintenance treatment of mania. Evidence from studies in patients with
treatment-resistant major depressive disorder and bipolar depression indicate
that these agents may also have antidepressant effects. In open trials in
patients with bipolar mania, risperidone therapy has led to significant
reductions in depression scores compared with baseline. Reductions in depression
scores in patients with bipolar mania have been significantly greater with
olanzapine compared with placebo. In patients with bipolar depression, the
combination of olanzapine and fluoxetine resulted in significant improvement in
depression compared with olanzapine alone or placebo. Although little data are
available on the effects of these agents on comorbid anxiety in patients with
bipolar disorder, some atypical antipsychotics have demonstrated efficacy in
patients with anxiety disorders, including obsessive-compulsive disorder,
post-traumatic stress disorder, and generalized anxiety disorder. Thus, atypical
antipsychotics represent an important therapeutic option for the treatment of
bipolar disorder, providing improvements in manic, depressive, and anxiety
symptoms.

———

Drug Saf. 2003;26(5):337-51.

Avoiding drug-induced switching in patients with bipolar depression.

Henry C, Demotes-Mainard J.

Service Universitaire de Psychiatrie, CH Charles Perrens, Bordeaux, France.
chantal.henry@bordeaux.inserm.fr

Antidepressant-induced switching is a major risk during the treatment of bipolar
depression. Despite several clinical studies, questions remain regarding both the
definition of these mood switches and the most appropriate therapeutic strategy
to avoid this adverse effect. This review will first briefly consider the current
guidelines for the acute treatment of bipolar depression. We will then review the
mechanisms of action of antidepressant and mood stabilisers, and the switches
induced by various types of antidepressant treatments, or triggered by
antidepressant withdrawal, as well as by atypical antipsychotics. We then will
address the risk of mood switch according to the type of mood stabiliser used.
The propensity to mood switches in bipolar patients is subject to individual
differences. Therefore we will describe both the clinical and biological
characteristics of patients prone to mood switches under antidepressant
treatment. However, the clinical characteristics of the depressive syndrome may
also be a key determinant for mood switches. Various data help identify the most
appropriate drug management strategies for avoiding mood switches during the
treatment of bipolar depression. Selective serotonin reuptake inhibitors appear
to be the drugs of first-choice because of the low associated risk of mood
switching. Antidepressants must be associated with a mood stabiliser and the most
effective in the prevention of switches seems to be lithium. Whatever the mood
stabiliser used, effective plasma levels must be ensured. The optimal duration of
antidepressant treatment for bipolar depression is still an open issue –
prolonged treatments after recovery may be unnecessary and may facilitate mood
elation. Moreover, some mood episodes with mixed symptoms can be worsened by
antidepressants pointing to the need for a better delineation of the categories
of symptoms requiring antidepressant treatment. Finally, as a result of this
review, we suggest some propositions to define drug-induced switches in bipolar
patients, and to try to delineate which strategies should be recommended in
clinical practice to reduce as far as possible the risk of mood switch during the
treatment of bipolar depression.

———

J Clin Psychiatry. 2003;64 Suppl 1:13-8.

New approaches in managing bipolar depression.

Keck PE Jr, McElroy SL.

Program Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.
paul.keck@uc.edu

Historically, the pharmacologic treatment of bipolar depression has not been well
studied. New data are beginning to emerge regarding the efficacy of new
medications and the use of combinations of mood stabilizers and antidepressants
in acute and long-term treatment of bipolar depression. We reviewed data from
recent randomized, controlled trials of mood stabilizers and antidepressants in
the treatment of bipolar depression and naturalistic studies examining the risk
of switching and depressive relapse with ongoing antidepressant treatment.
PMID: 12625800 [PubMed – indexed for MEDLINE] 74. Bipolar Disord. 2001 Feb;3(1):11-22.

Psychotherapy for bipolar depression: a phase-specific treatment strategy?

Swartz HA, Frank E.

Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute
and Clinic, PA, USA. swartzha@msx.upmc.edu

OBJECTIVES: The depressive phase of bipolar disorder is particularly difficult to
treat. Pharmacologic strategies for bipolar depression are often inadequate. We
therefore review the literature on the role of psychotherapy as an adjunct to
medication in the treatment of bipolar depression. METHODS: With one exception,
there are no descriptions of psychotherapies employed specifically for the
treatment of bipolar depression. We therefore reviewed published reports of
psychotherapy for bipolar disorder in general and extracted from these reports
relevant data or impressions about the specific effects of the therapies on the
depressive phase of the disorder. RESULTS: Described psychosocial approaches to
bipolar disorder include psychoeducation, group therapy, cognitive-behavioral
therapy, couples therapy, family therapy, and interpersonal psychotherapy. Only
cognitive-behavioral therapy has been tested in a pilot study for the treatment
of bipolar depression specifically. Results from randomized controlled trials of
family therapy and interpersonal and social rhythm therapy suggest that these
treatments may be more efficacious in the treatment and prevention of depression
relative to mania. CONCLUSIONS: A limited number of well-designed studies and
preponderance of case reports limit definitive conclusions about the role of
psychotherapy in the treatment of bipolar depression. However, converging reports
suggest that cognitive-behavioral therapy, family therapy, and interpersonal and
social rhythm therapy may be particularly useful for bipolar depression. We
propose a novel approach to the treatment of bipolar disorder that includes the
use of phase-specific sequenced psychotherapies delivered in variable patterns
and linked to fluctuating mood states.

———

Biol Psychiatry. 2000 Sep 15;48(6):558-72.

Bipolar depression: pharmacotherapy and related therapeutic strategies.

Thase ME, Sachs GS.

Department of Psychiatry, University of Pittsburgh School of Medicine, Western
Psychiatric Institute and Clinic, Pennsylvania 15213, USA.

The depressed phase of bipolar affective disorder is a significant cause of
suffering, disability, and mortality and represents a major challenge to treating
clinicians. This article first briefly reviews the phenomenology and clinical
correlates of bipolar depression and then focuses on the major pharmacological
treatment options. We strongly recommend use of mood stabilizers as the
first-line treatment for the type I form of bipolar depression, largely because
longer-term preventative therapy with these agents almost certainly will be
indicated. Depressive episodes that do not respond to lithium, divalproex, or
another mood stabilizer, or episodes that “breakthrough” despite preventive
treatment, often warrant treatment with an antidepressant or electroconvulsive
therapy. The necessity of mood stabilizers in the type II form of bipolar
depression is less certain, aside from the rapid cycling presentation. Both
experts and practicing clinicians recommend bupropion and the selective serotonin
reuptake inhibitors as coequal initial choices, with venlafaxine and monoamine
oxidase inhibitors, such as tranylcypromine, preferred for more resistant cases.
The risk of antidepressant-induced hypomania or mania with concomitant mood
stabilizer therapy is low, on the order of 5% to 10% during acute phase therapy.
Additional therapeutic options and optimal durations of therapy also are
discussed.

———

76. Bipolar Disord. 2000 Sep;2(3 Pt 2):256-60.

The treatment of bipolar depression.

Sachs GS, Koslow CL, Ghaemi SN.

Massachusetts General Hospital, Consolidated Department of Psychiatry, Harvard
Medical School, Boston 02114, USA. sachsg@aol.com

OBJECTIVES: The treatment of the depressed phase of bipolar disorder is
understudied and remains a common clinical dilemma for clinicians. Compared to
the manic phases, episodes of bipolar depression are more frequent and of longer
duration, yet the literature on this problem is minimal. The few methodologically
sound studies find that treatment effective for unipolar depression are also
efficacious for bipolar depression. However, standard antidepressant agents may
cause acute mania or a long-term worsening of bipolar illness. This paper reviews
the available literature on the treatment of bipolar depression and offers
recommendations for clinical management. METHODS: A literature search was
conducted using keywords ‘bipolar disorder’, ‘depression’, ‘drug therapy’,
‘antidepressants’, ‘lithium’, and ‘anticonvulsants’. RESULTS: If effectively
treated by lithium, patients are spared the risk of antidepressant-induced mania.
If lithium is not sufficient treatment for acute depression, the combination of
lithium and a standard antidepressant appears to reduce the risk of affective
switch, as well as the induction of a long-term rapid-cycling course.
Additionally, tapering antidepressant medication after periods of sustained
remission can be beneficial in limiting the risk of affective switch and
acceleration of the cycle rate. CONCLUSIONS: Doctors must be cautious in
prescribing antidepressants for bipolar depression. Use of antidepressants alone
should be avoided.
PMID: 11249803 [PubMed – indexed for MEDLINE] Eur Arch Psychiatry Clin Neurosci. 2000;250(2):57-68.

Have some guidelines for the treatment of acute bipolar depression gone too far
in the restriction of antidepressants?

Möller HJ, Grunze H.

Psychiatrische Klinik der Ludwig-Maximilian-Universität, Munich, Germany.

This paper gives a critical review of recommendations concerning the drug
treatment of acute bipolar depression. The suggestions of different guidelines
and consensus papers, especially in US-American and Canadian psychiatry, have a
strong tendency against antidepressants in bipolar depression; they prefer
mono-therapy with mood stabilizers and, in the case of co-medication with mood
stabilizers and antidepressants in severe depression, to withdraw the
antidepressant as early as possible. The intention of this restrictive use is to
avoid the risk of mania and the risk of rapid cycling induced by antidepressants.
However, apparently the risk of suicidal acts, which is as prominent in bipolar
depression as in unipolar depression, has been totally neglected. Furthermore,
the fact that none of the mood stabilizers have proven their antidepressive
efficacy leads not only to the risk of depression-related suicidal behavior but
also to the risk of chronicity of depressive symptoms due to undertreatment.
Altogether the view expressed in some guidelines and consensus papers appears not
well balanced. Furthermore, the fact that apparently the selective serotonin
re-uptake inhibitors and possibly some other modern antidepressants have only a
low risk of inducing a switch to mania should stimulate a rewriting of the
guidelines on drug treatment in acute bipolar depression in a less restrictive
way concerning the use of antidepressants.

———

Eur Neuropsychopharmacol. 1999 Aug;9 Suppl 4:S113-7.

Lamotrigine in the treatment of bipolar depression.

Bowden CL, Mitchell P, Suppes T.

Department of Psychiatry, University of Texas, Health Science Center at San
Antonio, 78284-7792, USA.

Several case reports and open studies have reported the efficacy of lamotrigine
in bipolar depression. A randomised placebo-controlled 7-week study comparing two
doses of lamotrigine with placebo in 195 patients with moderate to severe bipolar
depression has now been completed. Lamotrigine was superior to placebo after 3
weeks as assessed by changes in the Montgomery-Asberg Depression Rating Scale
(MADRS). A response, defined as more than 50% improvement on the MADRS occurred
in 56 and 48% of the lamotrigine 200 and 50 mg/day groups, respectively, compared
with 29% for placebo (P<0.05). There was no evidence that lamotrigine
destabilised mood or precipitated mania. Tolerability was good and there were no
cases of serious rashes. Preliminary results from an ongoing study also indicate
that lamotrigine is more effective than gabapentin in bipolar depression. In
conclusion, lamotrigine is effective in alleviating bipolar depression, without
causing mood destabilisation. Slow dosage escalation yields good tolerability.

———

J Clin Psychiatry. 1998;59 Suppl 18:30-6.

Bipolar depression: specific treatments.

Potter WZ.

Nervous System Disorders, Clinical Research, Lilly Research Laboratories,
Indianapolis, Ind 46285, USA.

From the perspective of pharmacologic treatment, bipolar depression is considered
in this article as belonging to a spectrum of affective disorders. Insufficient
controlled data permit only general recommendations for treatment of the spectrum
of affective disorders, except perhaps for the classic form of bipolar I
disorder. While the field waits for prospective controlled trials, a wide range
of drugs is currently available for the treatment of bipolar depression. The
potential advantages of having an increasing number of agents with different
mechanisms of actions are suggested by the many small studies claiming some
degree of advantage in one or another subgroup of patients with bipolar
depression. Several antidepressants and one anticonvulsant have the virtue of
clinical experience that contributes to a body of information about side effects
and the potential for producing benefit in at least some bipolar depressed
patients. By default, and because they appear to have less chance of
precipitating mania and are otherwise safe, selective serotonin reuptake
inhibitors are probably the most comfortable first-line treatment for bipolar
depression.

PMID: 9840196 [PubMed – indexed for MEDLINE] Can J Psychiatry. 1997 Aug;42 Suppl 2:87S-91S.

Bipolar depression: treatment options.

Yatham LN, Kusumakar V, Parikh SV, Haslam DR, Matte R, Sharma V, Kennedy S.

Department of Psychiatry, University of British Columbia, Vancouver.
yatham@unixg.ubc.ca

OBJECTIVE: To review studies on treatments for bipolar depression and make
recommendations for practising clinicians treating patients with bipolar
depression. METHOD: Studies that examined various treatments for bipolar
depression were evaluated and rated for evidence of efficacy using Periodic
Health Examination criteria. The rating for classification of recommendation for
an intervention was made taking both the efficacy and the side effects into
consideration. RESULTS: Mood stabilizers, cyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) are all effective
in treating bipolar depression. Almost all antidepressant treatments with the
exception of mood stabilizers have been reported to induce a manic-hypomanic
switch and rapid cycling. CONCLUSIONS: Mood stabilizers, lithium in particular,
are recommended as the first-line treatment. Addition of a second mood stabilizer
or a cyclic antidepressant would be an appropriate next step. Newer agents such
as lamotrigine offer considerable promise in treating bipolar depressed patients.

———

Can J Psychiatry. 1995 Nov;40(9):533-44.

Treatment of acute bipolar depression: a review of the literature.

Srisurapanont M, Yatham LN, Zis AP.

Department of Psychiatry, University of British Columbia, Vancouver.

OBJECTIVE: Our goal was to ascertain the efficacy of various antidepressant
treatments for acute bipolar depression. METHOD: English articles that reported
on the efficacy of antidepressant treatments in bipolar depression were located
by computerized Medline and manual search. These studies were systematically
reviewed and response rates for each treatment were computed. RESULTS: The
available data suggest that mood stabilizers, MAOIs, cyclic antidepressants, and
ECT are all effective in treating bipolar depression. All antidepressant
treatments with the exception of mood stabilizers have been reported to induce a
manic/hypomanic switch. CONCLUSIONS: It is recommended that mood stabilizers may
be the first step of treatment, followed by the addition of an antidepressant,
especially a cyclic antidepressant. The specific symptoms profile of individual
patients, such as anergic or psychotic features, may indicate more specific
treatment options. ECT is an important measure for those who are
pharmacotherapy-resistant or psychotic.

———

Br J Psychiatry. 2006 Jan;188:46-50.

Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised
double-blind placebo-controlled study.

Frangou S, Lewis M, McCrone P.

Section of Neurobiology of Psychosis, PO66, Institute of Psychiatry, De
Crespigny Park, London SE5 8AF, UK. s.frangou@iop.kcl.ac.uk

BACKGROUND: Epidemiological and clinical studies suggest that increased intake
of eicosapentaenoic acid (EPA) alleviates unipolar depression. AIMS: To examine
the efficacy of EPA in treating depression in bipolar disorder. METHOD: In
a12-week, double-blind study individuals with bipolar depression were randomly
assigned to adjunctive treatment with placebo (n=26) or with 1 g/day (n=24) or 2
g/day (n=25) of ethyl-EPA. Primary efficacy was assessed by the Hamilton Rating
Scale for Depression (HRSD), with changes in the Young Mania Rating Scale and
Clinical Global Impression Scale (CGI) as secondary outcome measures. RESULTS:
There was no apparent benefit of 2 g over 1 g ethyl-EPA daily. Significant
improvement was noted with ethyl-EPA treatment compared with placebo in the HRSD
(P=0.04) and the CGI (P=0.004) scores. Both doses were well tolerated.
CONCLUSIONS: Adjunctive ethyl-EPA is an effective and well-tolerated
intervention in bipolar depression.

———-

Clin Psychol Rev. 2005 Dec;25(8):1076-100. Epub 2005 Sep 2.

The nature and treatment of depression in bipolar disorder: a review and
implications for future psychological investigation.

Mansell W, Colom F, Scott J.

Psychological Treatments PO96, Department of Psychological Medicine, Institute
of Psychiatry, London SE5 8AF, UK. warren.mansell@manchester.ac.uk

Bipolar depression is poorly understood and researched, yet it is has a huge
impact on functioning in bipolar disorder. This review explores the current
status of research regarding the phenomenology, natural history,
neuropsychology, psychosocial predictors and cognitive style of bipolar
depression. The current status of pharmacotherapy and psychological treatment of
bipolar depression is also described. In particular, the manner in which
cognitive behaviour therapy for bipolar depression has been adapted from CBT for
unipolar depression is critically evaluated. It is concluded that there appears
to be a considerable overlap between the features of unipolar and bipolar
depression, yet there is also emerging evidence for specific elements. The
ability of current psychological theories of bipolar disorder to account for the
findings are compared, and as a consequence, a new preliminary integrative model
is proposed to direct future hypothesis-led research, which will need to
incorporate more suitable populations and utilise more objective methods of
assessment.

———-

J Clin Psychiatry. 2005 Dec;66(12):1535-1540.

Combined Total Sleep Deprivation and Light Therapy in the Treatment of
Drug-Resistant Bipolar Depression: Acute Response and Long-Term Remission Rates.

Benedetti F, Barbini B, Cigala Fulgosi M, Colombo C, Dallaspezia S, Pontiggia A,
Smeraldi E.

From the Department of Neuropsychiatric Sciences, Scientific Institute and
University Vita-Salute San Raffaele (all authors), and CERMAC (Centro di
Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San
Raffaele (Drs. Benedetti, Colombo, and Smeraldi), Milan, Italy.

BACKGROUND: Drug resistance remains a persistent source of morbidity and
mortality for patients with bipolar depression. A growing number of clinical
studies support the usefulness of chronotherapeutic interventions, such as total
sleep deprivation (TSD) and light therapy (LT), in the treatment of nonresistant
bipolar depression. METHOD: To investigate the clinical usefulness of TSD plus
LT in the treatment of drug-resistant bipolar depression, we treated 60
inpatients for 1 week with repeated TSD and LT combined with ongoing
antidepressants and lithium salts. All patients had a DSM-IV diagnosis of
bipolar I disorder. Drug resistance was rated according to Thase and Rush
criteria. The pattern of relapses and recurrences was assessed during a
prospective 9-month follow-up. Data were gathered from September 2002 to July
2004. RESULTS: A 2-way repeated-measures analysis of variance with changes in
self-rated perceived mood scores as dependent variable and with time and group
(history of drug resistance) as independent factors confirmed significant
time-by-group interaction (p = .0339). A logistic regression on rates of
achievement of response (50% reduction in Hamilton Rating Scale for Depression
ratings) confirmed the significance of observed differences: overall, 70%
(23/33) of nonresistant versus 44% (12/27) of drug-resistant patients achieved
response (p = .045). A survival time analysis (Cox proportional hazards model)
showed that history of drug resistance significantly influenced the pattern of
relapses and recurrences, with 57% (13/23) of nonresistant responders and 17%
(2/12) of drug-resistant responders being euthymic after 9 months (p = .0212).
DISCUSSION: The combination of repeated TSD and LT in drug-resistant patients
was useful in triggering an acute response. Further clinical research is needed
to optimize this treatment option for drug-resistant patients in the long term.

———

Am J Psychiatry. 2005 Nov;162(11):2146-51.

Bipolar depression in a low-income primary care clinic.

Olfson M, Das AK, Gameroff MJ, Pilowsky D, Feder A, Gross R, Lantigua R, Shea S,
Weissman MM.

New York State Psychiatric Institute, Department of Psychiatry, Columbia
University, 1051 Riverside Dr., Unit 24, New York, NY 10032, USA.
mo49@columbia.edu

OBJECTIVE: This study estimated the proportion of patients attending an urban
general medical practice with current major depression and a history of bipolar
disorder and compared the history, presentation, and treatment of patients with
unipolar and bipolar depression. METHOD: A group of 1,143 patients was assessed
with measures of past and current mental health and treatment. Patients were
partitioned into bipolar and unipolar groups based on a predefined cutoff on the
Mood Disorder Questionnaire. The groups were compared on sociodemographic
characteristics, depressive symptoms, comorbid mental disorders, and mental
health treatment. RESULTS: Approximately one-quarter of the patients with major
depression had lifetime bipolar depression. Patients with unipolar and bipolar
depression did not significantly differ on background or health characteristics.
Patients with bipolar depression were significantly more likely to report
hallucinations, current suicidal ideation, and low self-esteem than patients
with unipolar depression but less likely to report disturbed appetite. Patients
with bipolar depression were significantly more likely to have an alcohol use
disorder and to report inpatient psychiatric care and antipsychotic treatment
during the past month than patients with unipolar depression. Nearly one-half of
the patients with bipolar depression had taken an antidepressant in the last
month, but most were not also being treated with an antipsychotic or mood
stabilizer. CONCLUSIONS: Bipolar depression is common in urban general medicine
practice. When patients took antidepressants, they seldom received concurrent
antimanic medications. Because of the risks of treating bipolar disorder with
antidepressant monotherapy, physicians should assess their depressed patients
for mania before prescribing antidepressants.

———-

J Clin Psychiatry. 2005 Nov;66(11):1376-85.

Typical and atypical antipsychotics in bipolar depression.

Gao K, Gajwani P, Elhaj O, Calabrese JR.

Mood Disorders Program, Department of Psychiatry, University Hospitals of
Cleveland, Case Western Reserve University School of Medicine, 11400 Euclid
Avenue, Cleveland, OH 44106, USA. keming.gao@uhhs.com

BACKGROUND: Symptomatic bipolar patients experience more depressive than manic
symptoms, but fewer studies have been designed for bipolar depression than for
bipolar mania. Since the antipsychotic agents have been shown to diminish
depressive symptoms during the treatment of mania, atypical agents are now being
studied for use in bipolar depression. DATA SOURCES: English-language articles
published from 1980 through July 2004 and cited in MEDLINE were searched using
the keywords antipsychotics, typical antipsychotics, atypical antipsychotics,
bipolar depression, bipolar disorder, manic-depressive illness, placebo, and
clinical trial. The generic and brand names of individual antipsychotics were
also entered as keywords. Peer-reviewed abstracts of placebo-controlled studies
assessing acute or long-term efficacy in bipolar depression presented at major
scientific meetings were also reviewed. STUDY SELECTION: Use of a depression
rating scale was required for inclusion of studies of the atypical antipsychotic
agents in our analysis. DATA SYNTHESIS: Twenty-one randomized trials and 13
nonrandomized prospective trials were identified. In the only 2 acute,
double-blind, placebo-controlled studies of antipsychotics in bipolar
depression, the effect size of olanzapine was small (0.32) compared with the
effect sizes of quetiapine (0.91-1.09, depending on dose). The effect size in
acute mania of olanzapine at week 4 and quetiapine at week 3 was 0.50 and 0.39,
respectively. Both olanzapine and quetiapine have been shown to be superior to
placebo in the acute treatment of bipolar I depression. In addition, olanzapine
has been shown to be more effective than placebo in delaying relapse into
bipolar depression. With the exception of a 6-month perphenazine study, there
are no other randomized studies of typical antipsychotics that support the
conclusion that this class of medication worsens bipolar depression. CONCLUSION:
Emerging data suggest that the atypical antipsychotic agents have a role in the
acute and long-term treatment of bipolar depression. No convincing data support
the impression that the typical antipsychotic agents worsen bipolar depression.

———

Harv Rev Psychiatry. 2005 Sep-Oct;13(5):257-71.

Bipolar depression: issues in diagnosis and treatment.

Thase ME.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh,
PA 15213, USA. thaseme@upmc.edu

Although bipolar affective disorder is defined by the history of manic or
hypomanic episodes, depression is arguably a more important facet of the
illness. Depressive episodes, on average, are more numerous and last longer than
manic or hypomanic episodes, and most suicides occur during these periods.
Misdiagnosis of major depressive disorder delays initiation of appropriate
therapy, further worsening prognosis. Distinguishing features of bipolar
depression include earlier age of onset, a family history of bipolar disorder,
presence of psychotic or reverse neurovegetative features, and
antidepressant-induced switching. Bipolar I depressions should initially be
treated with a mood stabilizer (carbamazapine, divalproex, lamotrigine, lithium,
or an atypical antipsychotic); antidepressant monotherapy is contraindicated.
More severe or “breakthrough” episodes often require a concomitant
antidepressant, such as bupropion or a selective serotonin reuptake inhibitor
(SSRI). The first treatment specifically approved for bipolar depression is a
combination of the SSRI fluoxetine and the atypical antipsychotic olanzapine.
For refractory depressive episodes, venlafaxine, the monoamine oxidase inhibitor
tranylcypromine, and ECT are most widely recommended. The optimal duration of
maintenance antidepressant therapy has not been established empirically and,
until better evidence-based guidelines are established, should be determined on
a case-by-case basis.

———-

Eur Arch Psychiatry Clin Neurosci. 2005 Aug 4; [Epub ahead of print]

Do recent efficacy data on the drug treatment of acute bipolar depression
support the position that drugs other than antidepressants are the treatment of
choice? A conceptual review.

Moller HJ, Grunze H, Broich K.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7,
80336, Munich, Germany, hans-juergen.moeller@med.uni-muenchen.de.

This conceptual review summarises the results of relevant studies on
antidepressants, mood stabilisers such as lithium and anticonvulsants, and
second generation antipsychotics in the indication of bipolar depression. Based
on methodological and clinical considerations, the position of antidepressants
and the possible alternatives in this indication are reviewed very carefully. In
addition the regulatory requirements for licensing a drug for the indication
‘short-term treatment of bipolar depression’ are described.

PMID: 16078087 [PubMed – as supplied by publisher]

9: Acta Psychiatr Scand. 2005 Aug;112(2):105-9.

One-year outcome with antidepressant–treatment of bipolar depression.

Joffe RT, MacQueen GM, Marriott M, Young LT.

Department of Psychiatry, UMDNJ-New Jersey Medical School, Newark, NJ 07101,
USA. Joffe@umdnj.edu

OBJECTIVE: To examine the risk of relapse into mania or depression with varying
duration of antidepressant treatment in a cohort of 59 patients with bipolar
disorder. METHOD: An open naturalistic evaluation using life charting methods of
patients with 1 year follow-up, who responded to antidepressant treatment and
who then less or more than 6 months of antidepressant treatment. RESULTS:
Patients who received more than 6 months of antidepressant treatment were less
likely to relapse into depression at follow-up of 1 year. There was no
difference in relapse rates for mania in the different antidepressant treatment
duration groups. Gender and bipolar subtype did not significantly affect relapse
rates for depression or mania. CONCLUSION: Our data, taken with other studies,
suggest that the duration of optimal antidepressant treatment in bipolar
disorder must be further evaluated. Copyright 2005 Blackwell Munksgaard.

———-

Neuro Endocrinol Lett. 2005 Aug;26 Suppl 1:27-47.

Treatment of bipolar depression.

Svestka J.

Antidepressants have insufficient effect in 20-40% of patients treated for
depressive disorders. This is particularly true for psychotic and agitated
depression. When administered on a long-term basis, antidepressants cause a
switch into mania in 25-40% of patients and induce rapid cycling (Wehr et al.,
1979, 1987; Goldberg et al., 2001). Classical antipsychotics have exhibited good
therapeutic efficacy in the treatment of various forms of depression, especially
psychotic and agitated forms, albeit burdened with many, above all
extrapyramidal, side effects (for review see Thase, 2002). When administered
over long periods of time, classical antipsychotics may have a depressogenic
effect. Second-generation antipsychotics have started to be increasingly used in
this indication for a variety of reasons including: their antidepressant effect
attributable to raised concentrations of catecholamines in the prefrontal
cortex, their impact on serotonin transmission, their antipsychotic effect due
to their mode of action including the mesolimbic blockade of dopamine D2
receptors, and the low incidence of extrapyramidal and other side effects. The
following text encompasses the results of controlled trials using
second-generation antipsychotics in the treatment of acute depressive disorders.

———-

Am J Psychiatry. 2005 Jul;162(7):1351-60.

A randomized, double-blind, placebo-controlled trial of quetiapine in the
treatment of bipolar I or II depression.

Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler
AJ, McCoy R, Wilson E, Mullen J.

University Hospitals of Cleveland and Case University School of Medicine, 11400
Euclid Ave., Suite 200, Cleveland, OH 44106, USA. joseph.calabrese@uhhs.com

OBJECTIVE: There is a major unmet need for effective options in the treatment of
bipolar depression. METHOD: Five hundred forty-two outpatients with bipolar I
(N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV)
were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo.
The primary efficacy measure was mean change from baseline to week 8 in the
Montgomery-Asberg Depression Rating Scale total score. Additional efficacy
assessments included the Hamilton Depression Rating Scale, Clinical Global
Impression of severity and improvement, Hamilton Anxiety Rating Scale,
Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction
Questionnaire. RESULTS: Quetiapine at either dose demonstrated statistically
significant improvement in Montgomery-Asberg Depression Rating Scale total
scores compared with placebo from week 1 onward. The proportions of patients
meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale
score improvement) at the final assessment in the groups taking 600 and 300
mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for
placebo. The proportions of patients meeting remission criteria
(Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups
taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at
600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg
Depression Rating Scale items, respectively, compared to placebo, including the
core symptoms of depression. Treatment-emergent mania rates were low and similar
for the quetiapine and placebo groups (3.2% and 3.9%, respectively).
CONCLUSIONS: Quetiapine monotherapy is efficacious and well tolerated for the
treatment of bipolar depression.

———-

J Am Board Fam Pract. 2005 Jul-Aug;18(4):271-81.

Is your depressed patient bipolar?

Kaye NS.

Department of Psychiatry and Family Medicine, Jefferson Medical College,
Wilmington, Delaware 19808, USA. nskaye@aol.com

Accurate diagnosis of mood disorders is critical for treatment to be effective.
Distinguishing between major depression and bipolar disorders, especially the
depressed phase of a bipolar disorder, is essential, because they differ
substantially in their genetics, clinical course, outcomes, prognosis, and
treatment. In current practice, bipolar disorders, especially bipolar II
disorder, are underdiagnosed. Misdiagnosing bipolar disorders deprives patients
of timely and potentially lifesaving treatment, particularly considering the
development of newer and possibly more effective medications for both depressive
features and the maintenance treatment (prevention of recurrence/relapse). This
article focuses specifically on how to recognize the identifying features
suggestive of a bipolar disorder in patients who present with depressive
symptoms or who have previously been diagnosed with major depression or
dysthymia. This task is not especially time-consuming, and the interested
primary care or family physician can easily perform this assessment. Tools to
assist the physician in daily practice with the evaluation and recognition of
bipolar disorders and bipolar depression are presented and discussed.

———-

J Clin Psychiatry. 2005 Jun;66(6):726-9.

Omega-3 eicosapentaenoic acid in bipolar depression: report of a small
open-label study.

Osher Y, Bersudsky Y, Belmaker RH.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion
University of the Negev, Beer Sheva, Israel. yamy@bgumail.bgu.ac.il

INTRODUCTION: Epidemiologic studies have suggested that consumption of cold
water fish oils may have some protective function against depression. This
proposition is supported by a series of biochemical and pharmacologic studies
that have suggested that fatty acids may modulate neurotransmitter metabolism
and cell signal trans-duction in humans and that abnormalities in fatty acid and
eicosanoid metabolism may play a causal role in depression. Aware of the
critical need for antidepression treatments that might not carry the risk of
precipitating a manic episode in bipolar patients, we decided to conduct an
open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression.
METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by
DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to
6 months. The study was conducted between September 2001 and January 2003.
RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up
achieved a 50% or greater reduction in Hamilton Rating Scale for Depression
scores within 1 month. No patients developed hypomania or manic symptoms. No
significant side effects were reported. LIMITATIONS: This study is limited both
by the open-label design and by the small sample size. As in all previous
reported studies, patients in this study were treated in an outpatient setting,
so that the most severely depressed bipolar patients (requiring hospitalization)
are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty
acids in bipolar depression is still an open question, we believe that these
initial results are encouraging, especially for mild to moderate bipolar
depression, and justify the continuing exploration of its use.

———-

Psychiatr Clin North Am. 2005 Jun;28(2):349-70, vii.

Treatment of bipolar depression.

Dubovsky SL.

Department of Psychiatry, State University of New York at Buffalo, 462 Grider
Street, Buffalo, NY 14215, USA. Dubovsky@buffalo.edu

This article discusses current practices in the treatment of bipolar depression.
In the absence of more definitive research, the treatment of bipolar depression
is guided by clinical experience and expert opinion, and sometimes by marketing
and popular trends, as much as it is by hard data. Considering the limitations
of current knowledge is an essential component of the scientific practice of
psychiatry.

———-

J Clin Psychiatry. 2005 May;66(5):611-6.

Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in
the treatment of bipolar depression.

Keck PE Jr, Corya SA, Altshuler LL, Ketter TA, McElroy SL, Case M, Briggs SD,
Tohen M.

Psychopharmacology Research Program, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, OH 45267, USA. paul.keck@ic.edu

BACKGROUND: Treatment-emergent mania is a potential risk when patients with
bipolar disorder are treated with antidepressant agents. These subanalyses
compare treatment-emergent mania rates in bipolar I depressed patients treated
with olanzapine, placebo, or olanzapine/fluoxetine combination. METHOD: In this
8-week, double-blind investigation, patients with bipolar I depression (DSM-IV
criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total
score > or = 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370),
placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50
mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania
Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP)
Severity of Mania scale, and adverse events records. RESULTS: Overall rates of
study discontinuation due to mania were low and not significantly different
among the therapy groups (p = .358). Incidence of treatment-emergent mania
(defined as a YMRS score < 15 at baseline and > or = 15 at any subsequent visit)
did not differ significantly among therapy groups (olanzapine 5.7%, placebo
6.7%, olanzapine/fluoxetine combination 6.4%; p = .861). Subjects receiving
olanzapine or olanzapine/fluoxetine combination had greater mean decreases in
YMRS scores than those receiving placebo (p < .001 for both). Subjects receiving
olanzapine or olanzapine/fluoxetine combination also had greater mean decreases
in CGI-BP scores than those receiving placebo (p = .040 and p = .003,
respectively). CONCLUSION: These results suggest that olanzapine/fluoxetine
combination does not present a greater risk of treatment-emergent mania compared
to olanzapine or placebo over 8 weeks of acute treatment for bipolar I
depression. Due to the cyclical nature of bipolar disorder, patients taking
olanzapine/fluoxetine combination for bipolar depression should still be
monitored for signs or symptoms of emerging mania.

———-

J Affect Disord. 2005 Apr;85(3):259-66.

Divalproex in the treatment of bipolar depression: a placebo-controlled study.

Davis LL, Bartolucci A, Petty F.

Veteran’s Affairs Medical Center (151), 3701 Loop Road East, Tuscaloosa, AL
35404, USA. lori.davis@med.va.gov

BACKGROUND: The treatment of bipolar disorder in the depressed phase is
complicated by a tendency for conventional antidepressant drugs to worsen the
course of the illness by precipitating a manic episode or increasing cycle
frequency. Thus, the potential antidepressant efficacy of mood stabilizers, such
as divalproex, which is an effective treatment for the manic phase of bipolar
disorder, is of considerable interest. METHODS: The clinical efficacy of
divalproex (valproate, Depakote) was tested in an 8-week, double-blind,
placebo-controlled, randomized clinical trial in 25 outpatients with bipolar I
depression. The primary outcome measure was the 17-item Hamilton Rating Scale
for Depression, and secondary measures included the Hamilton Rating Scale for
Anxiety, the Clinician Administered Rating Scale for Mania, and the Clinical
Global Impression scale. RESULTS: Using repeated measures ANOVA with last
observation carried forward, divalproex was more effective than placebo in
improving symptoms of depression (p = 0.0002) and symptoms of anxiety (p =
0.0001) than placebo. LIMITATIONS: The sample size was small, and most patients
were male. CONCLUSIONS: These pilot results indicate that divalproex is
effective in reducing the symptoms of depression and anxiety in bipolar I,
depressed phase. These positive results support the need to perform a larger,
multisite study of divalproex treatment for bipolar depression.

———

J ECT. 2005 Mar;21(1):31-4.

Efficacy of electroconvulsive therapy in treatment-resistant bipolar disorder: a
case series.

Macedo-Soares MB, Moreno RA, Rigonatti SP, Lafer B.

Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo,
Brazil. marciabms@uol.com.br

The response to electroconvulsive therapy for six bipolar patients after
pharmacotherapy failure is discussed. METHODS: Inclusion criteria were as
follows: (1) bipolar mood disorder, manic, depressive or mixed episode (DSM-IV);
(2) failure of pharmacotherapy, that is, for mania, manic episode unresponsive
to at least 2 adequate antimanic trials for 6 weeks; and for bipolar depression,
bipolar depressive episode unresponsive to at least 2 adequate antidepressant
trials for 8 weeks. The patients underwent 12 bilateral sessions of ECT 3 times
per week. Clinical response was considered a reduction of 50% or greater in the
Young Mania Rating Scale (YMRS) and in the Hamilton Rating Scale for
Depression-21 items (HAMD-21). Final YMRS <6 and HAMD-21 <8 defined remission.
RESULTS: Six of the 9 referred patients consented to be submitted to ECT. Four
were male, with ages ranging from 29 to 61 years, and their age at onset ranged
from 19 to 49 years. Four showed psychotic features. All responded to ECT.

———-

J Affect Disord. 2005 Feb;84(2-3):117-25.

A different depression: clinical distinctions between bipolar and unipolar
depression.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd
Curl Drive, 7th Floor (Mail Code 7792), San Antonio, TX 78229-3900, USA.
bowdenc@uthscsa.edu

Delayed diagnosis or misdiagnosis can prolong the suffering of patients with
bipolar disorder. Accurate early diagnosis is sometimes difficult, however,
particularly because patients often present in the depressive phase, which can
easily be mistaken for unipolar depression. Unfortunately, therapy appropriate
for unipolar depression can increase the risk of manic switch or cycle
acceleration in bipolar disorder, especially in those with a family history of
bipolarity and suicide, although some antidepressants may be useful in some
bipolar patients. In addition, most currently available mood stabilizers, though
effective in managing mania, do not effectively resolve depression. In contrast,
lamotrigine has shown activity in bipolar depression and has a very low risk of
manic switch. Bipolar depression, compared with unipolar depression, is more
likely to be associated with hypersomnia, motor retardation, mood lability,
early onset, and a family history of bipolar disorder. Awareness of these
distinctions can greatly improve diagnosis of bipolar disorder and provide an
opportunity for effective therapeutic intervention.

———

J Clin Psychiatry. 2005 Feb;66(2):195-8.

A preliminary open-label study of zonisamide treatment for bipolar depression in
10 patients.

Anand A, Bukhari L, Jennings SA, Lee C, Kamat M, Shekhar A, Nurnberger JI Jr,
Lightfoot J.

Department of Psychiatry, Indiana University School of Medicine, IN 46202, USA.
aanand@iupui.edu

OBJECTIVE: The purpose of this study was to investigate the effectiveness of
zonisamide in the treatment of bipolar depression. METHOD: Ten patients with
DSM-IV bipolar disorder, depressed phase, who had either not tolerated or not
responded to previous treatments were given zonisamide in this add-on open-label
study. Zonisamide treatment was started at 100 mg/day and increased by 100 mg
every 2 weeks to a maximum of 300 mg/day in divided doses (b.i.d. or t.i.d.).
Subjects underwent weekly visits at which they were administered the 17-item
Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS),
and Clinical Global Impressions scale (CGI). Every 2 weeks, subjects also
underwent laboratory tests, a urine examination, and a verbal memory test.
Outcome measures were analyzed with repeated-measures analysis of variance.
RESULTS: Eight subjects completed all 8 weeks of the study. Two subjects
completed more than 4 weeks of the study, and their data were analyzed using the
last observation carried forward. Bipolar depression subjects had a significant
reduction in HAM-D scores (p < .001) and in CGI-Improvement (CGI-I) scores (p <
.001). Five of 8 subjects who completed all 8 weeks of the study had more than a
50% decrease in HAM-D scores and were rated much improved on the CGI-I at the
end of 8 weeks of treatment. There was no significant drug effect on YMRS
scores, weight, or verbal memory. CONCLUSION: Zonisamide may be a useful drug in
the treatment of bipolar depression. Further controlled clinical trials are
needed.

———-

Bipolar Disord. 2005;7 Suppl 5:13-23.

Newer treatment studies for bipolar depression.

Gao K, Calabrese JR.

NIMH Bipolar Research Center, Mood Disorders Program, University Hospitals of
Cleveland/Case Western Reserve University School of Medicine, Cleveland, OH,
USA. keming.gao@uhhs.com

OBJECTIVE: Depressive symptoms of bipolar disorder have more negative impact on
a patient’s life than manic symptoms. This review focused on the emerging
efficacy data for treatments in bipolar depression. METHODS: English-language
literature cited in Medline was searched with terms bipolar depression, clinical
trial, and trial. Randomized, placebo-controlled trials of newer studies with
older agents and all studies with newer or novel agents were prioritized.
Open-label studies of novel agents presented at major scientific meetings were
also included. RESULTS: Olanzapine, olanzapine-fluoxetine combination (OFC), and
quetiapine were superior to placebo in the acute treatment of bipolar
depression. Lamotrigine only significantly reduced core symptoms of depression
compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and
omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood
stabilizer (MS) had superiority to placebo in reducing depressive symptoms.
Topiramate augmentation of an MS was equally as effective as Bupropion-SR.
Patients treated with an MS responded well to the addition of agomelatine, a
melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol
and repetitive transcranial magnetic stimulation did not separate from placebo.
Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to
placebo in preventing depressive relapses. All agents were relatively well
tolerated. CONCLUSIONS: Olanzapine, OFC, and quetiapine are effective in the
acute treatment of bipolar depression. Compared with lithium and divalproex,
lamotrigine is more effective in preventing bipolar depression. Larger
controlled studies of the other agents in the acute and maintenance treatment of
bipolar depression are warranted.

———-

Bipolar Disord. 2005;7 Suppl 5:3-12.

Benefits and limitations of antidepressants and traditional mood stabilizers for
treatment of bipolar depression.

Goldberg JF, Nassir Ghaemi S.

Affective Disorders Program, Silver Hill Hospital, New Canaan, CT 06840, USA.
jgoldberg@silverhillhospital.org

OBJECTIVE: The aim of this paper was to review the rationales, risks, and
benefits for using standard antidepressants versus mood stabilizing agents
and/or atypical antipsychotics to treat bipolar depression. METHOD: A selective
literature review was conducted using key terms and by reference known to the
authors. Bibliographies of articles and book chapters were further scrutinized
for relevant literature. RESULTS: The strengths and limitations of current
studies are described and critically reviewed in order to present optimal
strategies for effective pharmacotherapy. Clinical factors that can mitigate or
confound simple bivariate relationships between antidepressant use and outcome
have seldom been examined using multivariate statistical techniques. For many of
the key questions there is a paucity of informative literature and randomized
clinical trials are of limited value in addressing some of the issues.
CONCLUSIONS: Clinicians and investigators should be aware of the methodological
shortcomings of existing studies. Decisions about the relative merits versus
contraindications for antidepressant use should be made via more individualized,
case-by-case profiling rather than by rigid prescribing practices.

———-

Bipolar Disord. 2005;7 Suppl 4:34-40.

Bipolar depression: a new role for atypical antipsychotics?

Keck PE Jr.

Psychopharmacology Research Program, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA. paul.keck@uc.edu

Bipolar depression, the most common phase of bipolar disorder, causes
significant morbidity and mortality. Traditional drugs such as lithium,
lamotrigine or antidepressants each offer some clinical efficacy; however,
efficacy can be limited and side effects are sometimes problematic. Thus there
is a major unmet need for effective, well-tolerated agents for the treatment of
bipolar depression. The atypical antipsychotics, with their proven efficacy
against manic symptoms, are emerging as candidates for use against the
depressive phase of bipolar disorder. Several studies have shown that some
atypicals improve depressive symptoms in mixed episodes in patients with bipolar
disorder; however, few studies have been performed in patients specifically with
bipolar depressive episodes. In a randomized, placebo-controlled trial in
patients with acute bipolar I depression, olanzapine monotherapy and an
olanzapine-fluoxetine combination significantly improved Montgomery-Asberg
Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001)
with corresponding effect sizes (improvement of active treatment over placebo
divided by pooled standard deviation) of 0.32 and 0.68, respectively.
Importantly, there were no significant differences in rates of switch into mania
among the three groups. Recent results from an 8-week, randomized
placebo-controlled trial in patients with bipolar I and II disorder who were
experiencing a bipolar depressive episode showed that quetiapine (300 and 600
mg/day) had significantly greater efficacy compared with placebo in improving
the core symptoms of depression, including suicidal thoughts. Quetiapine
significantly improved MADRS total scores compared with placebo (p < 0.001);
effect sizes (improvement of quetiapine over placebo divided by pooled standard
deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively,
were observed. Both doses of quetiapine significantly improved symptoms of
anxiety, sleep quality and global quality of life (all, p < 0.001 versus
placebo). These initial findings suggest that atypical antipsychotics may prove
to be important future treatments for patients with bipolar depression.

———-

Drugs. 2005;65(17):2533-51.

Quetiapine: a review of its use in acute mania and depression associated with
bipolar disorder.

Dando TM, Keating GM.

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in
the treatment of schizophrenia, shows efficacy in the treatment of acute mania
and depression associated with bipolar disorder.Quetiapine, either as
monotherapy or in combination with lithium or divalproex sodium (valproate
semisodium), is generally well tolerated and effective in reducing manic
symptoms in adult and adolescent patients with acute bipolar mania, and is
approved for use in adults for this indication. As monotherapy, the drug is also
effective in reducing depressive symptoms in patients with bipolar depression.
It is associated with a low incidence of extrapyramidal symptom (EPS)-related
adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows
potential in the treatment of bipolar depression, and represents a useful agent
for the treatment of acute bipolar mania.

———-

Expert Rev Neurother. 2005 Jan;5(1):69-78.

Treatment of bipolar depression: focus on pharmacologic therapies.

Mitchell PB, Malhi GS.

University of New South Wales, School of Psychiatry, Prince of Wales Hospital,
Randwick, New South Wales 2031, Australia. phil.mitchell@unsw.edu.au

Recent studies have highlighted significant limitations in our capacity to
effectively treat bipolar depression. This article reviews the present status of
treatments for this condition, highlighting emerging new pharmacotherapies such
as lamotrigine, olanzapine and quetiapine, while also addressing modern
psychologic interventions such as cognitive behavioral therapy and
psychoeducation. The role of older treatments such as lithium and the
antidepressants is also discussed, particularly as a recent meta-analysis has
thrown into question current heightened concern over antidepressant-induced
mania. The advent of new pharmacologic and psychologic treatments provides
optimism for improved outcomes for this highly disabling condition.

———-

J Clin Psychiatry. 2005;66 Suppl 5:40-8.

Atypical antipsychotics in bipolar depression: potential mechanisms of action.

Yatham LN, Goldstein JM, Vieta E, Bowden CL, Grunze H, Post RM, Suppes T,
Calabrese JR.

Department of Psychiatry, The University of British Columbia, UBC Hospital,
Vancouver, Canada. Yatham@interchange.ubc.ca

“Conventional” antidepressants, such as the selective serotonin reuptake
inhibitors (SSRIs), bupropion, or serotonin-norepinephrine reuptake inhibitors,
are not recommended as monotherapy for bipolar depression. Although they are
likely to provide effective symptom relief in combination with mood stabilizers,
the risk of precipitating a switch to mania often complicates their use even as
combination therapy. Recently, 2 psychotropic medications approved for treating
acute mania, olanzapine and quetiapine, have also been shown to possess
antidepressant activity without destabilizing mood and, as such, are potential
mood stabilizers. This article aims to review the mechanism of action of
conventional antidepressants and newer agents that are effective in the
treatment of bipolar depression. A number of mechanisms have been postulated to
play a role in the effective treatment of bipolar depression, including targets
as diverse as serotonin (5-HT), norepinephrine, dopamine, gamma-aminobutyric
acid (GABA), glutamate, and various second messenger signaling pathways. A
review of the data reveals an important point of commonality among the
antidepressant treatments, olanzapine, and quetiapine. Antidepressant
treatments, such as norepinephrine reuptake inhibitors, SSRIs, and
electroconvulsive therapy, induce a reduction of 5-HT(2A) receptors. Both
olanzapine and quetiapine not only are antagonists at this receptor but also
induce downregulation of 5-HT(2A) receptors. It is possible that the
antidepressant efficacy of these agents is mediated by this receptor, while the
additional benefit of olanzapine and quetiapine over unimodal antidepressant
treatments, in terms of stabilizing mood, may be provided by their concomitant
dopamine D(2) antagonism. Further studies should be conducted to examine these
hypotheses.

———

J Clin Psychiatry. 2005;66 Suppl 5:26-33.

Clinical highlights in bipolar depression: focus on atypical antipsychotics.

Calabrese JR, Elhaj O, Gajwani P, Gao K.

University Hospitals of Cleveland/Case Western Reserve University School of
Medicine, Cleveland, Ohio, USA. joseph.calabrese@uhhs.com

Despite the considerable burden of bipolar depression, the treatment of this
debilitating phase of bipolar disorder is suboptimally addressed by currently
available pharmacologic options. Consequently, there is a need for the
development of new treatment options with enhanced efficacy and tolerability.
Evidence of antidepressant efficacy for some of the atypical antipsychotics in
the treatment of bipolar depression has recently emerged. The findings of a
large-scale, placebo-controlled, double-blind, randomized clinical study of
olanzapine alone and in combination with fluoxetine, and a similar study of
quetiapine monotherapy, suggest that some of the atypical antipsychotics may be
efficacious in treating depressive symptoms in patients with bipolar I disorder.
Subpopulation analyses suggest that quetiapine monotherapy and the olanzapine
plus fluoxetine combination appear to be effective in treating depression in
patients with a rapid-cycling course. The magnitude of improvement in depressive
symptoms in the bipolar I population appears to be larger for quetiapine
monotherapy compared with either olanzapine or olanzapine plus fluoxetine;
however, the limitations of such a cross-study comparison are acknowledged. Both
olanzapine monotherapy and combination therapy, as well as quetiapine
monotherapy, were well tolerated. The overall incidence of treatment-emergent
mania was low and comparable with placebo in both studies. Somnolence, weight
gain, increased appetite and nonfasting glucose and cholesterol levels were more
commonly reported in patients treated with olanzapine monotherapy or combination
therapy compared with placebo. Dry mouth, sedation/somnolence, dizziness, and
constipation were more commonly associated with quetiapine treatment. Large,
controlled studies are needed to determine whether other psychotropic agents
have antidepressant properties that would make them suitable for use in patients
with bipolar depression. In addition, direct comparison of the regimens used in
the current study should determine whether the differences evident between them
can be confirmed.

———-

J Clin Psychiatry. 2005;66 Suppl 5:11-6.

Challenges in the management of bipolar depression.

Suppes T, Kelly DI, Perla JM.

Department of Psychiatry, University of Texas Southwestern Medical Center,
Dallas 75390-9121, USA. trisha.suppes@utsouthwestern.edu

Bipolar depression has started to receive more attention in clinical trials only
relatively recently, despite the fact that patients spend more time in the
depressed phase than in the manic phase of bipolar disorder. The diagnosis and
management of bipolar depression are challenging, and many patients are
undiagnosed or misdiagnosed due to symptom similarities with unipolar depression
or other illnesses and/or comorbidities. Untreated or inappropriately treated
bipolar depression adds to the burden of illness and is associated with a
greater risk of suicide. Treatment options include lithium, lamotrigine,
atypical antipsychotics, and traditional antidepressants, such as the selective
serotonin reuptake inhibitors. However, traditional antidepressants are
recommended with caution due to their potential risk of switching patients into
mania. Some atypical antipsychotics have shown efficacy in bipolar depression,
although longer-term studies are warranted. The choice of treatment for
different subgroups of patients with bipolar depression, including those with
comorbid anxiety, may vary and also needs further study. Other important issues
that require further investigation include the recognition of the core features
of bipolar depression and the threshold symptoms for treatment, as well as the
optimal treatment choices for monotherapy or combination therapy, and acute
versus long-term management of bipolar depression.

———-

J Clin Psychiatry. 2005;66 Suppl 5:5-10.

The impact of bipolar depression.

Post RM.

Bipolar Collaborative Network, Chevy Chase, MD, USA. robert.post@nih.gov

Bipolar disorder is a chronic, intermittent illness that is associated with high
morbidity and mortality. In addition, patients with bipolar disorder often have
comorbid psychiatric conditions (such as anxiety disorders, alcohol or substance
abuse, and eating disorders) or medical disorders (such as obesity), which
result in increased burden of illness for the patients, family members, and
treating clinicians. Although bipolar disorder consists of recurring episodes of
mania and depression, patients spend more time depressed than manic. Bipolar
depression is associated with a greater risk of suicide and of impairment in
work, social, or family life than mania. This health burden also results in
direct and indirect economic costs to the individual and society at large.
Bipolar depression is often undiagnosed or misdiagnosed as unipolar depression,
resulting in incorrect or inadequate treatment. Available treatments for bipolar
depression include medications such as lithium, selected anticonvulsants, and
the atypical antipsychotics. Traditional antidepressants are not recommended as
monotherapy for bipolar depression as they can induce switching to mania. Early
and accurate diagnosis, aggressive management, and earlier prophylactic
treatment regimens are needed to overcome the impact of depressive episodes in
patients with bipolar disorder.

———-

J Clin Psychiatry. 2005;66 Suppl 1:3-6.

Treatment options for bipolar depression.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center, San
Antonio, TX 78229-3900, USA. bowdenc@uthscsa.edu

Bipolar disorder is often misdiagnosed as major depressive disorder because of
the high frequency of depressive symptomatology in many patients with bipolar
disorder. Depressive episodes that are resistant to treatment may also be
associated with a worse course of illness in bipolar disorder, but we do not yet
understand all the factors in the connection between bipolar disorder and
depression. The data on the effectiveness of antidepressants in the treatment of
depression in bipolar disorder vary greatly, and there have been few
prospective, randomized studies on the subject. From the data so far, the rates
of induction of mania for selective serotonin reuptake inhibitors and
lamotrigine seem similar to those seen with placebo. The optimal length of time
to continue antidepressant treatment in patients with bipolar disorder has not
yet been determined; however, research tends to indicate that a longer term of
treatment (6 months or more) may aid in the prevention of relapse. Newer U.S.
Food and Drug Administration-approved treatments for depression in bipolar
disorder include a combination of olanzapine and fluoxetine, which is used for
depressive episodes in bipolar disorder, and lamotrigine, which is used for
maintenance treatment of bipolar I disorder. Psychoeducation has also been
examined as a possible treatment for depression in bipolar disorder, and a study
has shown that patients receiving psychoeducation plus medication may have a
lower rate of relapse than patients who receive medication alone.

———-

World J Biol Psychiatry. 2005;6(4):231-41.

Bipolar disorder, antidepressants and induction of hypomania or mania. A
systematic review.

Visser HM, Van Der Mast RC.

De Geestgronden, Institute for Mental Health Care, Hoofddorp, The Netherlands.

OBJECTIVE: The literature cautions against the induction of (hypo)mania owing to
the use of antidepressants in bipolar disorder. Objectives of this review are to
examine: (1) the evidence for this assumption; (2) underlying risk factors; and
(3) the extent to which a mood stabilizer may be protective. METHOD: A
systematic literature review was conducted. RESULTS: Thirteen relevant studies
were included. All of them had methodological shortcomings. Overall, there is no
strong evidence that use of antidepressants in bipolar disorder increases the
risk of (hypo)mania. Possible, although unreplicated, risk factors are: a short
allele of the promoter region of the serotonin transporter gene SCL6A4,
substance abuse or dependence, multiple antidepressant trials, lower number of
previous manias, less delusions during illness, depressive polarity at illness
onset, and rapid cycling that has, however, been contradicted by another study.
Subtype of bipolar disorder (I or II) has been considered in four studies, with
conflicting results. Mood stabilizers are possibly protective. CONCLUSION: There
is an urgent need for adequate studies of sufficient size. For the time being,
treatment of bipolar depression may best be based on the results of the life
chart of the individual patient keeping in mind the risk factors found until
now.

———-

Biol Psychiatry. 2004 Dec 15;56(12):957-63.

Mood state at study entry as predictor of the polarity of relapse in bipolar
disorder.

Calabrese JR, Vieta E, El-Mallakh R, Findling RL, Youngstrom EA, Elhaj O,
Gajwani P, Pies R.

Case University School of Medicine, University Hospitals of Cleveland, 11400
Euclid Avenue, Suite #200, Cleveland, OH 44106, USA. joseph.calabrese@uhhs.com

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few
have enrolled patients who present depressed. In fact, only lithium and
lamotrigine have been studied over the long term with placebo-controlled designs
in recently manic and recently depressed bipolar patients. Given the magnitude
of the unmet medical need and the data suggesting that symptomatic patients with
bipolar disorder spend the majority of their time depressed, this is
unfortunate. Our review of the pre-lithium literature and more recent
publications suggests that mood state at study entry predicts the polarity of
relapse and the response to treatment. Accordingly, a need exists to enroll
recently depressed patients in maintenance studies to elucidate the complete
spectrum of efficacy of putative mood stabilizers and improve the long-term
treatment of bipolar depression. Patients presenting depressed for a maintenance
study tend to relapse into depression; those presenting manic, into
hypomania/mania/mixed states. This is particularly true during the first several
months of the randomized treatment. The polarity of the index episode tends to
predict the polarity of relapse into a subsequent episode in a ratio of about
2:1 to 3:1. We conclude that putative mood stabilizers must be tested in
recently manic and recently depressed patients to determine their spectrum of
prophylactic efficacy.

———-

Bipolar Disord. 2004 Dec;6(6):530-9.

Bipolar depression: phenomenological overview and clinical characteristics.

Mitchell PB, Malhi GS.

School of Psychiatry, University of New South Wales and Mood Disorders Unit,
Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
phil.mitchell@unsw.edu.au

OBJECTIVES: There has been increasing interest in the depressed phase of bipolar
disorder (bipolar depression). This paper aims to review the clinical
characteristics of bipolar depression, focusing upon its prevalence and
phenomenology, related neuropsychological dysfunction, suicidal behaviour,
disability and treatment responsiveness. METHODS: Studies on the prevalence of
depression in bipolar disorder, the comparative phenomenology of bipolar and
unipolar depression, as well as neuropsychology and brain imaging studies, are
reviewed. To identify relevant papers, a literature search using MEDLINE and
PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance
in bipolar disorder, and most frequently presents as subsyndromal, minor or
dysthymic depression. Compared with major depressive disorder (unipolar
depression), bipolar depression is more likely to manifest with psychosis,
melancholic symptoms, psychomotor retardation (in bipolar I disorder) and
‘atypical’ symptoms. The few neuropsychological studies undertaken indicate
greater impairment in bipolar depression. Suicide rates are high in bipolar
disorder, with suicidal ideation, suicide attempts and completed suicides all
occurring predominantly in the depressed phase of this condition. Furthermore,
the depressed phase (even subsyndromal) appears to be the major contributant to
the disability related to this condition. CONCLUSIONS: The significance of the
depressed phase of bipolar disorder has been markedly underestimated. Bipolar
depression accounts for most of the morbidity and mortality due to this illness.
Current treatments have significant limitations. Blackwell Munksgaard, 2004

———-

Curr Psychiatry Rep. 2004 Dec;6(6):459-65.

Separate and concomitant use of lamotrigine, lithium, and divalproex in bipolar
disorders.

Lieberman DZ, Goodwin FK.

Department of Psychiatry and Behavioral Sciences, George Washington University,
2150 Pennsylvania Ave, NW, Washington, DC 20037, USA.

Expert consensus emphasizes the need for better recognition and accurate
diagnosis of bipolar disorder. Current research on lithium, divalproex, and
lamotrigine provides new insight into the effective management of this illness.
Advances in identifying the mechanism of action of mood stabilization has
focused on signaling pathways within the cell that are associated with
neurotrophic effects. Clinical research has led to confirmatory evidence of the
efficacy of lithium in all phases of bipolar disorder, with the greatest effects
seen in the treatment and prevention of mania. Compared to divalproex, lithium
also has been found to have greater efficacy in the prevention of suicide.
Lamotrigine has emerged as a first line treatment for bipolar depression, which
is an area of weakness for other mood stabilizers. Oral loading of divalproex
leads to rapid stabilization of mania without imposing a greater adverse effect
burden than conventional dosing. Because no agent is universally effective in
all phases of the illness, combination therapy with two or more agents often is
the best option.

———-

Expert Rev Neurother. 2004 Nov;4(6 Suppl 2):S27-33.

Bipolar depression: the role of atypical antipsychotics.

Post RM, Calabrese JR.

robert.post@nih.gov

Acute manic episodes in bipolar disorder require rapid and effective relief.
Bipolar depression is a major component of the bipolar disorder spectrum.
Existing treatment options for bipolar depression include lithium, lamotrigine
and conventional antidepressants. However, lithium is more effective in treating
mania or hypomania than depression, both acutely and prophylactically,
lamotrigine has only been demonstrated to be effective in one adequately powered
study in acute bipolar I depression, and conventional antidepressants have been
associated with emergent mania and cycle acceleration. Symptomatic outpatients
can expect to spend, on average, 33% of their time in the depressive phase
compared with 11% in the manic phase. Consequently, there is a need for
additional agents to effectively treat bipolar depression. The atypical agents
olanzapine, risperidone and quetiapine have demonstrated efficacy against the
manic phase of bipolar disorder and appear also to have potential in the
depressive phase. Olanzapine monotherapy significantly improved depressive
symptoms compared with placebo in patients with bipolar disorder in an 8-week
randomized, controlled clinical study, but the magnitude of the clinical effect
was small. The observed improvement in depressive symptoms became moderately
large when olanzapine was combined with the antidepressant fluoxetine.
Quetiapine monotherapy also resulted in significant improvements compared with
placebo in patients with either bipolar I or bipolar II disorder in another
8-week randomized, controlled clinical study, but the effect size was large. A
6-month open-label study of risperidone added to ongoing therapy demonstrated
improvements in depressive symptoms in patients with bipolar and schizoaffective
disorders experiencing a manic, hypomanic, mixed or depressive episode. The
receptor-binding profile of these agents supports a role in the treatment of
depressive symptoms and clinical data are beginning to emerge of their efficacy
in both the acute and maintenance setting.

———

Bipolar Disord. 2004 Oct;6(5):432-4.

Acute treatment of bipolar depression with adjunctive zonisamide: a
retrospective chart review.

Baldassano CF, Ghaemi SN, Chang A, Lyman A, Lipari M.

Bipolar Outpatient Program, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104-3309, USA. cfb@mail.med.upenn.edu

BACKGROUND: This retrospective chart review evaluated the use of zonisamide as
adjunctive treatment in patients with bipolar depression. METHOD: The charts of
outpatients with bipolar I or II disorder treated with adjunctive zonisamide
were reviewed. The efficacy of zonisamide was assessed via comparison of
physician-rated Global Assessment of Functioning (GAF) and Clinical Global
Impression of Severity (CGI-S) Scale scores at baseline and after 6 weeks of
therapy using paired t-tests. Patients who scored < or = 2 on the CGI-S after 6
weeks of zonisamide therapy were considered good responders to zonisamide.
RESULTS: Charts for 12 patients (four men and eight women) with a mean (+/- SD)
age of 39.6 (+/- 7.6) years were evaluated. Patients received a mean (+/- SD)
zonisamide dosage of 236 (+/- 68) mg/day. Mean GAF scores significantly improved
from 44.0 at baseline to 59.3 at week 6 (P = 0.05). Mean CGI-S scores improved
from 4.54 at baseline to 3.42 at week 6, but the change was not statistically
significant. Six patients (50.0%) were considered responders to zonisamide. Four
patients discontinued zonisamide therapy, two for an adverse event (sedation)
and two for lack of efficacy. CONCLUSIONS: Zonisamide may be a useful adjunctive
treatment for some patients with bipolar depression. Conclusions from this study
are limited due to its retrospective design. Further investigation of zonisamide
in the treatment of bipolar depression is warranted.

———-

Bipolar Disord. 2004 Oct;6(5):416-20.

Adjunctive stimulant use in patients with bipolar disorder: treatment of
residual depression and sedation.

Carlson PJ, Merlock MC, Suppes T.

Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9121,
USA.

BACKGROUND: Residual depression and medication-induced sedation remain
significant problems for many patients with bipolar disorder (BD). Some evidence
indicates that bipolar depression may be more responsive to dopaminergic agents,
suggesting that adjunctive stimulant medication may be an effective treatment
for bipolar depression as well as for medication-induced sedation. However,
there are few data regarding the use of these medications in BD, likely due in
part to concerns regarding potential stimulant-induced switching and stimulant
abuse. METHODS: In order to evaluate the effectiveness and safety of
psychostimulants in BD, we retrospectively reviewed the cases of eight
consecutive individuals from our clinic (five with bipolar I and three with
bipolar II) who received adjunctive stimulants (either methylphenidate or
amphetamine) within the last 2 years. Primary target symptoms of stimulant
therapy included residual depression and medication-induced sedation. The degree
of clinical change in target symptoms was estimated, and the Clinical Global
Impression-BP Version scale (CGI-BP) was used to evaluate the overall severity
of illness at baseline, 6 months after stimulant initiation, and at last visit.
RESULTS: The eight patients generally showed moderate clinical improvement in
their target symptoms and substantial improvement of overall bipolar illness
(mean change in CGI-BP overall score 2.9). There was no evidence of
stimulant-induced switching or abuse. The stimulants were well tolerated.
CONCLUSION: The present case series suggests that adjunctive stimulants may be a
reasonable therapeutic option for treating residual depression and
medication-induced sedation in some patients. Controlled trials are needed to
assess the safety and effectiveness of stimulant augmentation in BD.

———-

Am J Psychiatry. 2004 Sep;161(9):1537-47.

Comment in:
Am J Psychiatry. 2005 Aug;162(8):1545-6; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1546-7; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1546; author reply 1547-8.
Evid Based Ment Health. 2005 May;8(2):35.

Antidepressants for bipolar depression: a systematic review of randomized,
controlled trials.

Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM.

Department of Psychiatry, Warneford Hospital, Oxford, UK.
harm.gijsman@doctors.net.uk

OBJECTIVE: This study reviewed the evidence from randomized, controlled trials
on the efficacy and safety of antidepressants in the short-term treatment of
bipolar depression. METHOD: The authors performed a systematic review and
meta-analysis of randomized, controlled trials. They searched the Cochrane
Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register,
incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX,
and LILACS. The main outcome measures were the proportion of patients who
clinically responded to treatment and the rate of switching to mania. RESULTS:
Twelve randomized trials were included, with a total of 1,088 randomly assigned
patients. Five trials compared one or more antidepressants with placebo: 75% of
these patients were receiving a concurrent mood stabilizer or an atypical
antipsychotic. Antidepressants were more effective than placebo. Antidepressants
did not induce more switching to mania (the event rate for antidepressants was
3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two
antidepressants. The rate of switching for tricyclic antidepressants was 10%,
and for all other antidepressants combined, it was 3.2%. CONCLUSIONS:
Antidepressants are effective in the short-term treatment of bipolar depression.
The trial data do not suggest that switching is a common early complication of
treatment with antidepressants. It may be prudent to use a selective serotonin
reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic
antidepressant as first-line treatment. Given the limited evidence, there is a
compelling need for further studies with longer follow-up periods and careful
definition and follow-up of emerging mania and partial remission.

———-

CNS Spectr. 2004 Sep;9(9 Suppl 9):11-8.

Rethinking the treatment paradigm for bipolar depression: the importance of
long-term management.

Baldassano CF, Ballas CA, O’Reardon JP.

Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, PA 19104, USA. cfb@mail.med.upenn.edu

The need for long-term management of bipolar disorder is evident. Bipolar
patients spend more time depressed than manic; however, few agents used for
maintenance therapy of bipolar disorder have demonstrated good efficacy in
delaying relapse into depression. This article provides a comprehensive review
of open-label and randomized, controlled studies examining prophylactic efficacy
in bipolar disorder, especially bipolar depression. Lithium, considered the gold
standard for bipolar disorder maintenance therapy may be more effective in
delaying manic relapse than in delaying depressive relapse. Evidence for the
efficacy of divalproex and carbamazepine in delaying depressive relapse is yet
to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time
to depressive relapse. Unpublished studies show olanzapine’s efficacy in
preventing manic recurrence, while its efficacy in preventing depressive
recurrence is yet to be proven. As patients with bipolar disorder are prone to
experiencing depressive episodes, more attention needs to be focused on
preventing depressive relapse. To date, three agents–lithium, lamotrigine, and
olanzapine–have been shown to have prophylactic benefits in treating this
highly recurrent disorder.

———-

IDrugs. 2004 Sep;7(9):846-50.

Bipolar depression: an overview.

Oral ET, Vahip S.

Mood Disorders Outpatient Program, Bakirkoy State Hospital for Research and
Training in Neurology & Psychiatry, Istanbul 34747, Turkey.
etoral@superonline.com

Depressive episodes are significant in bipolar illness since patients can spend
up to one-third of their lives in depression. Although the treatment of bipolar
depression remains an understudied area, new data from randomized, controlled
trials and naturalistic studies have expanded the range of treatments available.
The main aim in the treatment of bipolar depression is the prevention of the
patient switching to mania and cycle acceleration, and antidepressant therapy
may be contraindicated because of the risk for switching. Guidelines for the
acute treatment of bipolar depression emphasize treatment with a mood
stabilizer, of which lithium has been the most thoroughly studied in randomized,
controlled trials in acute bipolar depression. Lamotrigine has also demonstrated
significant efficacy in recent studies and has been approved by the FDA.

———-

J Am Osteopath Assoc. 2004 Jun;104(6 Suppl 6):S9-14.

Comment in:
J Am Osteopath Assoc. 2004 Dec;104(12):516; discussion 517; author reply
517.

Bipolar depression in primary care: a hidden threat.

Lewis FT.

CNS Clinical Research Group, 8100 Royal Palm Blvd, Coral Springs, FL 33065-5733,
USA. flewisdo@bellsouth.net

With the recent awareness of the bipolar spectrum, the interest and concern of
physicians regarding the depressive side of bipolar disorder has emerged.
Depression is the modal phase of bipolar disorder, as well as the phase that
imparts the greatest risk for suicide. Despite these realities, little is known
about the management of bipolar depression and much of what is known is
complicated by conflicting reports regarding the use of antidepressants as
either short- or long-term treatment modalities. This fear among physicians of
complicating a patient’s course secondary to antidepressant use combined with
the fact that presently available mood stabilizers are less than reliable
antidepressants has resulted in far more questions about management than
answers. This article explores the clinical issues involving the depressive
states, reviews some of the emerging data, and, it is hoped, lends some guidance
regarding treatment options.

———-

Eur Neuropsychopharmacol. 2004 May;14 Suppl 2:S89-93.

Lamotrigine: a depression mood stabiliser.

Herman E.

Psychiatric Clinic, Psychiatric Office, Charles University, Na Markvartce 8, 160
00 Praha, Prague 6, Czech Republic. aapsych@mbox.vol.cz

Depression mood stabilisers, which stabilise mood from below the mood baseline
(euthymia) without inducing switch into mania or episode acceleration, are
urgently needed for the effective treatment of bipolar depression. The
anticonvulsant lamotrigine, recently approved as maintenance therapy for bipolar
depression, has undergone evaluation as acute and maintenance therapy for
bipolar disorder in several controlled clinical trials. Data from these trials
suggest that lamotrigine is effective in the treatment and prevention of bipolar
depression without destabilising mood. Although the majority of evidence comes
from studies in patients with bipolar I disorder, a recent naturalistic study
suggests that these observations may also extend to patients with bipolar II
disorder. Lamotrigine may therefore fulfil the unmet need for an effective
depression mood stabiliser.

———-

Expert Opin Pharmacother. 2004 May;5(5):1101-7.

Pharmacotherapy for bipolar depression: an economic assessment.

Bowden CL, Krishnan AA.

Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 78229-3900, USA. bowden@uthscsa.edu

Bipolar disorder (BPD) is a common, severe and recurrent mood disorder
associated with high rates of comorbidities, suicide, dysfunction and a high
socioeconomic burden. Although the management of BPD has traditionally focused
on the acute treatment of mania, the chronic nature of BPD necessitates
long-term maintenance treatment. Bipolar depression is the predominant abnormal
affective pole and causes greater disability and economic burden than mania.
Maintenance pharmacotherapy can reduce rates of future episodes, and
subsequently, the associated risks, functional disability and economic burden of
bipolar illness.

———-

J Clin Psychiatry. 2004 May;65(5):627-33.

Comment in:
J Clin Psychiatry. 2004 Nov;65(11):1578-9; author reply 1579.

Anger attacks in bipolar depression: predictors and response to citalopram added
to mood stabilizers.

Mammen OK, Pilkonis PA, Chengappa KN, Kupfer DJ.

Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. msmmenok@msx.upmc.edu

BACKGROUND: Of the 2 reports in the literature on anger attacks in bipolar
depression, one found them to be uncommon (12%) compared with the rate in
bipolar mixed states and unipolar depression (40%-60%), whereas the other found
them to be common (62%). We examined anger attacks among participants in an
8-week trial of open-label citalopram added to mood stabilizer for the treatment
of bipolar depression. We also examined trait anger, hypomanic symptoms, and
depressive symptoms as predictors of anger attacks. We hypothesized that if
anger attacks were related to hypomanic symptoms they would respond unfavorably
to citalopram, whereas if they were related to trait anger or depressive
symptoms they would respond favorably. METHOD: In 45 participants with a DSM-IV
diagnosis of bipolar I or II depression, anger attacks, hypomanic symptoms, and
depressive symptoms were assessed using a modified Anger Attacks Questionnaire,
Young Mania Rating Scale, and Hamilton Rating Scale for Depression,
respectively. Trait anger was measured using the State-Trait Anger Inventory.
Posttreatment data were collected at the end of 8 weeks of treatment with
citalopram or at dropout from the trial. The first participant study visit was
in November 1998, and the final participant study visit was in December 2000.
RESULTS: Before treatment with citalopram, 17 (38.6%) of 44 participants
reported anger attacks (data on anger attacks were missing for 1 participant
before treatment and 4 after treatment). Significantly fewer participants
reported anger attacks after treatment (6 of 41, 14.6%; McNemar test, p <.05,
2-tailed). At pretreatment and post-treatment, trait anger was the only
significant predictor of anger attacks (p <.05). CONCLUSIONS: These findings
suggest that in bipolar depression anger attacks are common, may respond
favorably to acute treatment with citalopram added to mood stabilizer, and are
better predicted by trait anger than hypomanic or depressive symptoms. Further
studies are needed to clarify the diagnostic and treatment implications of anger
attacks in bipolar depression.

———-

Am J Psychiatry. 2004 Mar;161(3):564-6.

Preliminary randomized, double-blind, placebo-controlled trial of pramipexole
added to mood stabilizers for treatment-resistant bipolar depression.

Goldberg JF, Burdick KE, Endick CJ.

Department of Psychiatry, Weill Medical College of Cornell University, New York,
NY, USA. jgoldber1@lij.edu

OBJECTIVE: Previous studies suggest that the dopamine agonist pramipexole may
possess antidepressant properties. The authors conducted a preliminary
randomized, placebo-controlled trial to determine the safety and antidepressant
efficacy of pramipexole in treatment-resistant bipolar depression. METHOD:
Twenty-two depressed outpatients with DSM-IV nonpsychotic bipolar disorder were
randomly assigned to receive placebo or flexibly dosed pramipexole (mean maximum
dose=1.7 mg/day, SD=1.3) added to existing mood stabilizers for 6 weeks. The
primary outcome measure was response, defined as improvement in Hamilton
Depression Rating Scale score of 50% or more over the baseline score; secondary
analyses involved changes in Clinical Global Impression (CGI) severity scores.
RESULTS: More patients given pramipexole (10 [83%] of 12) than patients given
placebo (six [60%] of 10) completed the study. Eight (67%) of 12 patients taking
pramipexole and two (20%) of 10 taking placebo had an improvement of at least
50% in their Hamilton depression scale scores. The mean percentage of
improvement from baseline Hamilton depression scale scores was greater for
patients taking pramipexole (48%) than for those taking placebo (21%). Mean
improvements in CGI severity were also greater with pramipexole than placebo. No
patients discontinued the study because of adverse events except for one patient
who became hypomanic while taking pramipexole. CONCLUSIONS: Pramipexole was a
safe and effective antidepressant among patients with bipolar depression. Larger
randomized, controlled trials are needed to affirm these initial observations.

———-

J Clin Psychiatry. 2004 Feb;65(2):204-10.

A 52-week, open-label continuation study of lamotrigine in the treatment of
bipolar depression.

McElroy SL, Zarate CA, Cookson J, Suppes T, Huffman RF, Greene P, Ascher J.

Psychopharmacology Research Program, University of Cincinnati College of
Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0559, USA.
susan.mcelroy@uc.edu

BACKGROUND: Lamotrigine has demonstrated efficacy for the acute treatment of
depression in bipolar I patients in a placebo-controlled, monotherapy study. We
describe the results of a 52-week, open-label continuation of that trial.
METHOD: Patients meeting DSM-IV criteria for bipolar I disorder with a current
major depressive episode who completed a 7-week, double-blind study of bipolar
depression were offered 1 year of open-label lamotrigine therapy (flexible doses
of 100-500 mg/day) in a continuation study. To maintain the acute study blind,
the first 3 weeks of the continuation study remained blinded while patients
previously randomly assigned to placebo were titrated to a lamotrigine dose of
50 mg/day. Patients who had been randomly assigned to lamotrigine continued at
their fixed doses. Beginning at week 4, all patients received open-label
lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications
were permitted during the open-label phase. Effectiveness (Montgomery-Asberg
Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale)
and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The
study was conducted from June 1996 to December 1998. RESULTS: Of 135 patients
completing the acute study, 124 (92%) entered the continuation study: 77 had
received lamotrigine and 47 had received placebo in the acute study. The mean
duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187
mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and
sustained improvement from baseline was seen in mean observed MADRS scores (p
<.05). The proportion of patients achieving remission (MADRS score < or = 11) by
week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less
frequently than in the preceding year. Headache was the most common drug-related
adverse event. CONCLUSION: During 1 year of open-label therapy with lamotrigine
as adjunctive therapy or monotherapy, bipolar I patients experienced sustained
improvement in depressive symptoms without evidence of mood destabilization.

———-

Am J Psychiatry. 2004 Jan;161(1):163-5.

Antidepressant treatment in bipolar versus unipolar depression.

Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ.

Department of Psychiatry, Cambridge Hospital, MA 02139, USA.
ghaemi@hms.harvard.edu

OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar
depression. METHOD: The authors analyzed clinical records for outcomes of
antidepressant trials for 41 patients with bipolar depression and 37 with
unipolar depression, similar in age and sex distribution. RESULTS: Short-term
nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%)
depression. Manic switching occurred only in bipolar depression but happened
less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle
acceleration occurred only in bipolar depression (25.6%), with new rapid cycling
in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and
withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in
unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid
cycling, or response loss. Modern antidepressants, in general, did not have
lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS:
The findings suggest an unfavorable cost/benefit ratio for antidepressant
treatment of bipolar depression.

———-

Am J Psychiatry. 2004 Jan;161(1):93-8.

Low-field magnetic stimulation in bipolar depression using an MRI-based
stimulator.

Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen
BM, Renshaw PF.

Brain Imaging Center, McLean Hospital, Belmont, MA 02478, USA.
mrohan@mclean.harvard.edu

OBJECTIVE: Anecdotal reports have suggested mood improvement in patients with
bipolar disorder immediately after they underwent an echo-planar magnetic
resonance spectroscopic imaging (EP-MRSI) procedure that can be performed within
clinical MR system limits. This study evaluated possible mood improvement
associated with this procedure. METHOD: The mood states of subjects in an
ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief
Affect Scale, a structured mood rating scale, immediately before and after an
EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects
with bipolar disorder, and actual EP-MRSI was administered to a comparison group
of healthy subjects. The characteristics of the electric fields generated by the
EP-MRSI scan were analyzed. RESULTS: Mood improvement was reported by 23 of 30
bipolar disorder subjects who received the actual EP-MRSI examination, by three
of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14
healthy comparison subjects who received actual EP-MRSI. Significant differences
in mood improvement were found between the bipolar disorder subjects who
received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects
who received actual EP-MRSI, between the healthy subjects and the bipolar
disorder subjects and to a lesser extent between the unmedicated bipolar
disorder subjects and the bipolar disorder subjects who were taking medication.
The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than
fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of
depression (1-500 V/m) and also extended uniformly throughout the head, unlike
the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train
of monophasic trapezoidal gradient pulses, differed from that used in rTMS.
CONCLUSIONS: These preliminary data suggest that the EP-MRSI scan induces
electric fields that are associated with reported mood improvement in subjects
with bipolar disorder. The findings are similar to those for rTMS depression
treatments, although the waveform used in EP-MRSI differs from that used in
rTMS. Further investigation of the mechanism of EP-MRSI is warranted.

———-

CNS Drugs. 2004;18(1):63-7.

Spotlight on lamotrigine in bipolar disorder.

Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established
anticonvulsant agent that has shown efficacy in the prevention of mood episodes
in adult patients with bipolar I disorder. The mechanism of action of the drug
in patients with bipolar disorder may be related to the inhibition of sodium and
calcium channels in presynaptic neurons and subsequent stabilisation of the
neuronal membrane. Lamotrigine monotherapy significantly delayed time to
intervention with additional pharmacotherapy or electroconvulsive therapy for
any new mood episode (mania, hypomania, depression and mixed episodes), compared
with placebo, in two large, randomised, double-blind trials of 18 months’
duration. Additionally, lamotrigine was significantly superior to placebo at
prolonging time to intervention for depression. These effects of lamotrigine
were demonstrated in both recently manic/hypomanic and recently depressed
patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in
pooled data only, although lithium was superior to lamotrigine on this measure.
Two of four double-blind, short-term studies have shown lamotrigine to be more
effective than placebo in the treatment of patients with treatment-refractory
bipolar disorder or those with bipolar depression. Lamotrigine has not
demonstrated efficacy in the treatment of acute mania. Lamotrigine was generally
well tolerated in maintenance studies with the most common adverse events being
headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor
were significantly lower in lamotrigine- than in lithium-treated patients. The
incidence of serious rash with lamotrigine treatment was 0.1% in all studies of
bipolar disorder and included one case of mild Stevens-Johnson syndrome.
Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine
is titrated over a 6-week period to 200 mg/day to minimise the incidence of
serious rash. Adjustments to the initial and target dosages are required if
coadministered with valproate semisodium or carbamazepine. CONCLUSION:
Lamotrigine has been shown to be an effective maintenance therapy for patients
with bipolar I disorder, significantly delaying time to intervention for any
mood episode. Additionally, lamotrigine significantly delayed time to
intervention for a depressive episode and showed limited efficacy in delaying
time to intervention for a manic/hypomanic episode, compared with placebo.
Although not approved for the short-term treatment of mood episodes, lamotrigine
has shown efficacy in the acute treatment of patients with bipolar depression
but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine
is generally well tolerated, does not appear to cause bodyweight gain and,
unlike lithium, generally does not require monitoring of serum levels.

———-

Depress Anxiety. 2004;20(3):131-8.

Pramipexole in treatment-resistant depression: an extended follow-up.

Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano
GB.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology,
University of Pisa, Pisa, Italy. pcassano@partners.org

We evaluated the long-term antidepressant safety and response of adjunctive
pramipexole, a D2-D3 dopamine agonist, in the course of drug-resistant
depression. Twenty-three patients with treatment-resistant major depressive
episode (MDE) were followed up after a 16-week pramipexole add-on trial.
Pramipexole was added to current treatment with TCA or SSRI, at increasing doses
from 0.375-1.500 mg/day. The LIFE scale was administered at baseline of the
acute trial, at Weeks 16, 32, and 48. Patients were analyzed for sustained
remission (score= <2 at LIFE for at least 8 weeks) and recurrence (after
remission score > =3 at LIFE for at least 2 weeks) of depression. Of 23
patients, 12 had major depression and 11 had bipolar depression (16 women; mean
age=52.8 years). Mean age of onset and median duration of current MDE were 35.1
years and 6 months, respectively; all subjects had at least two prior MDEs. Mean
pramipexole dose was 0.990 mg/day. Median duration of follow-up was 28 weeks.
Mean baseline MADRS and CGI-S scores were 33.7+/-8.4 (sd) and 4.6+/-0.8,
respectively. Median time to sustained remission from baseline was 10 weeks and
overall 60.9% (14/23) of subjects recovered within Week 22. Recurrence of
depression occurred in 35.7% (5/14) of remitters after Week 24 and within Week
28 from remission. Although there were no sleep attacks, two cases of hypomania
and one case of psychotic mania occurred at Weeks 22, 24, and 30, respectively.
Pramipexole augmentation of antidepressant treatment was relatively safe and
presumably effective in the long-term course of treatment resistant depression.
(c) 2004 Wiley-Liss, Inc.

———-

Depress Anxiety. 2004;19(4):199-208.

Unmet needs in bipolar depression.

Frye MA, Gitlin MJ, Altshuler LL.

UCLA Bipolar Disorder Research Program, David Geffen School of Medicine,
University of California, Los Angeles, CA 90095, USA. MFrye@mednet.ucla.edu

Bipolar disorders, particularly bipolar spectrum disorders, frequently go
unrecognized and undiagnosed by clinicians and thus remain untreated or
inappropriately treated. Although the symptoms of bipolar I disorder are widely
acknowledged and recognized among clinicians, epidemiology sampling studies over
the past several years have found that bipolar II disorder and bipolar spectrum
disorders are likely to be more prevalent and more challenging to diagnose,
particularly as depressive presentations are far more common in these groups.
Bipolar disorder is associated with increased morbidity and mortality, as well
as higher healthcare costs, but it is unclear how much of the consequences of
bipolar disorder are unrecognized in the face of poor recognition of bipolar II
and bipolar spectrum disorders. This article addresses challenges in diagnosing
and treating bipolar disorder in the face of a depressive episode, and offers
guidelines for recognizing and appropriately managing these patients. Studies
with the newer anticonvulsant mood stabilizer lamotrigine have shown
antidepressant effects in bipolar disorder, and may fill an unmet need for
treatment options in patients who present with depression in the context of
bipolar disorder.

———-

Drug Saf. 2004;27(3):173-84.

Safety and tolerability of lamotrigine for bipolar disorder.

Bowden CL, Asnis GM, Ginsberg LD, Bentley B, Leadbetter R, White R.

Department of Psychiatry, University of Texas Health Science Center at San
Antonio, San Antonio, Texas 78229-3900, USA. bowdenc@uthscsa.edu

Tolerability and safety are important considerations in optimising
pharmacotherapy for bipolar disorder. This paper reviews the tolerability and
safety of lamotrigine, an anticonvulsant recommended in the 2002 American
Psychiatric Association guidelines as a first-line treatment for acute
depression in bipolar disorder and one of several options for maintenance
therapy. This paper reviews the tolerability and safety of lamotrigine using
data available from a large programme of eight placebo-controlled clinical
trials of lamotrigine enrolling a total of nearly 1800 patients with bipolar
disorder. This review is the first to collate all the safety information from
these clinical trials, including data from four unpublished studies. The results
these trials in which 827 patients with bipolar disorder were given lamotrigine
as monotherapy or adjunctive therapy for up to 18 months for a total of 280
patient-years of exposure demonstrated that lamotrigine is well-tolerated with
an adverse-event profile generally comparable with that of placebo. The most
common adverse event with lamotrigine was headache. Lamotrigine did not appear
to destabilise mood and was not associated with sexual adverse effects, weight
gain, or withdrawal symptoms. Few patients experienced serious adverse events
with lamotrigine, and the incidence of withdrawals because of adverse events was
low. Serious rash occurred rarely (0.1% incidence) in the clinical development
programme including both controlled and uncontrolled clinical trials. These
findings – considered in the context of data showing lamotrigine to be effective
for bipolar depression – establish lamotrigine as a well-tolerated addition to
the psychotropic armamentarium.

———-

Ann Pharmacother. 2003 Dec;37(12):1807-9.

Modafinil for remitted bipolar depression with hypersomnia.

Fernandes PP, Petty F.

Omaha Veterans Affairs Medical Center and Creighton University School of
Medicine, Omaha, NE. Praveen.Fernandes@med.va.gov

OBJECTIVE: To report 2 cases of bipolar disorder with recent depression in
remission with prominent residual hypersomnia, responding well to the addition
of the psychostimulant modafinil.CASE SUMMARIES: Two patients with bipolar
disorder with recent depressive episodes in remission are presented. Despite the
absence of prominent depressive symptoms, both patients had significant
hypersomnia, with scores ranging from 15 to 20 (maximum 24) on the Epworth
Sleepiness Scale. The addition of modafinil to their medication regimen resulted
in a decrease in hypersomnia and improvement in their level of
functioning.DISCUSSION: This is the first report (MEDLINE search, October 7,
2003) demonstrating the use of modafinil in the treatment of hypersomnia in
bipolar disorder while mood symptoms were in remission. Hypersomnia frequently
occurs in depressive episodes and can be disabling when severe. The patients had
optimal mood stabilization with mood stabilizers and antidepressants, but
continued to experience excessive daytime sleepiness. Conventional stimulants
were not considered because of the risk of triggering mania. The addition of the
selective psychostimulant modafinil resulted in significant improvement in the
hypersomnia, with improvement in functioning. No adverse effects or mood changes
were noted.CONCLUSIONS: Modafinil may be a well-tolerated and effective
alternative to conventional stimulants in the treatment of hypersomnia,
especially in bipolar disorder, where there is considerable risk of switch to
mania with stimulant medications. Modafinil may be useful even when depressive
symptoms are not prominent.

———-

Bipolar Disord. 2003 Dec;5(6):456-63.

Clinical consequences of under-recognized bipolar spectrum disorder.

Dunner DL.

Department of Psychiatry and Behavioral Sciences, Center for Anxiety and
Depression, University of Washington School of Medicine, Seattle, WA 98105, USA.
ddunner@uwashington.edu

The prevalence of bipolar disorder is higher than previously believed,
especially when bipolar spectrum disorders (BSD) are taken into account, and may
approach rates as high as 5%. Difficulties in diagnosing bipolar II and BSD
arise from complexities associated with defining and diagnosing hypomania.
Additionally, bipolar disorder and BSD are often misdiagnosed because of
symptoms that overlap with other psychiatric disorders, particularly unipolar
depression. Recognition of the broader spectrum of bipolar disorders and their
adequate treatment is paramount because bipolar disorder exacts such a high
personal and societal toll, with high rates of suicide and interpersonal
problems and a substantial economic burden. Recognition can be improved with
active screening, and screening tools such as the Mood Disorders Questionnaire
can be easily included in the initial assessment of patients who present with
depressive symptoms. Depressive episodes are common in patients who experience
BSDs, and increasingly treatment approaches designed specifically for bipolar
depression are being studied.

———-

Bipolar Disord. 2003 Dec;5(6):421-33.

Comment in:
Bipolar Disord. 2003 Dec;5(6):434-5.

Antidepressants in bipolar disorder: the case for caution.

Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK.

Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA and Harvard
Medical School, Boston, MA 02139, USA. ghaemi@hms.harvard.edu

The 2002 American Psychiatric Association (APA) guidelines for the treatment of
bipolar disorder recommended more conservative use of antidepressants. This
change in comparison with previous APA guidelines has been criticized,
especially from some groups in Europe. The Munich group in particular has
published a critique of assumptions underlying the conservative recommendations
of the recent APA treatment guidelines. In this paper, we re-examine the
argument put forward by the Munich group, and we demonstrate that indeed,
conceptually and empirically, there is a strong rationale for a cautious
approach to antidepressant use in bipolar disorder, consistent with, and perhaps
even more strongly than, the APA guidelines. This rationale is based on support
for the following four propositions: (i) The risk of antidepressant induced
mood-cycling is high, (ii) Antidepressants have not been shown to definitively
prevent completed suicides and reduce mortality, whereas lithium has, (iii)
Antidepressants have not been shown to be more effective than mood stabilizers
in acute bipolar depression and have been shown to be less effective than mood
stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood
stabilizers, especially lithium and lamotrigine, have been shown to be effective
in acute and prophylactic treatment of bipolar depressive episodes. We therefore
draw three conclusions from this interpretation of the evidence: (i) There are
significant risks of mania and long-term worsening of bipolar illness with
antidepressants, (ii) Antidepressants should generally be reserved for severe
cases of acute bipolar depression and not routinely used in mild to moderate
cases and (iii) Antidepressants should be discontinued after recovery from the
depressive episode, and maintained only in those who repeatedly relapse after
antidepressant discontinuation (a minority we judge to represent only about
15-20% of bipolar depressed patients).

———-

Bipolar Disord. 2003 Dec;5(6):396-406.

A re-evaluation of the role of antidepressants in the treatment of bipolar
depression: data from the Stanley Foundation Bipolar Network.

Post RM, Leverich GS, Nolen WA, Kupka RW, Altshuler LL, Frye MA, Suppes T,
McElroy S, Keck P, Grunze H, Walden J; Stanley Foundation Bipolar Network.

Department of Health and Human Services, National Institutes of Health, National
Institute of Mental Health, Biological Psychiatry Branch, Bethesda, MD
20892-1272, USA. postr@intra.nimh.nih.gov

OBJECTIVES: The risk-to-benefit ratio of the use of unimodal antidepressants
(ADs) as adjuncts to mood stabilizers continues to be an area of controversy and
disagreement among experts in the field. This paper reviews new data on: (1)
depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD
discontinuation that are pertinent to the ongoing discussion and
recommendations. METHODS: In the first study reviewed, 258 outpatients with
bipolar illness were assessed prospectively on a daily basis using the National
Institute of Mental Health-Life Chart Method (NIMH-LCM) for 1 year. In the
second study, 127 bipolar depressed patients were randomized to 10 weeks of
sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers;
non-responders were re-randomized and responders were offered a year of
continuation treatment. In the final study, Altshuler et al. retrospectively and
prospectively assessed the risk of depressive relapses in patients who remained
on ADs after 2 months of euthymia compared with those who discontinued ADs.
RESULTS: Despite intensive naturalistic treatment, the 258 outpatients with
bipolar illness followed prospectively for 1 year showed three times as many
days depressed as days manic, re-emphasizing the considerable depressive
morbidity that remains in bipolar disorder despite the number of treatment
options available. In the study of bipolar depressed patients randomized to one
of three ADs, a range of severities and durations of hypomanic to manic switches
were discerned following 175 trials of AD augmentation of treatment with a mood
stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into
hypomania or mania and another 9.1% with a week or more of hypomania alone (with
no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2%
were similarly associated with hypomanic to manic and hypomanic switches,
respectively. In the Altshuler et al. studies, those who remained well on any AD
for more than 2 months (only 15-20% of those initially treated) and who
continued on ADs showed a lesser rate of relapse into depression over 1 year (35
and 36% in the first and second study, respectively) compared with those who
discontinued their ADs (68 and 70% relapsing into depression). Surprisingly,
this continuation of ADs was associated with no increase in the rate of
switching into mania compared with those stopping ADs. CONCLUSIONS: These data
reveal that depression and depressive cycling remain a substantial problem in
some two-thirds of intensively treated bipolar outpatients. Acute AD
augmentation was associated with a modest response rate and 18.2% switched into
a hypomanic to manic episode, and 35.6% of the continuation trials showed these
two types of switches. Two separate studies suggest that in the very small
subgroup who remain well on ADs for at least 2 months, one should consider
continuation of this AD augmentation treatment, because AD discontinuation
appears associated with a substantially increased risk of depression relapse
over the subsequent year with no reduced risk of switching into mania.

———-

CNS Spectr. 2003 Dec;8(12):1-10; quiz 11.

Treatment of bipolar depression.

Post RM, Baldassano CF, Perlis RH, Ginsberg DL.

Bipolar Collaborative Network, Chevy Chase, Maryland, USA.

Bipolar disorder is underdiagnosed and often mistaken for unipolar depression.
Bipolar patients spend 33% of their time in a state of depression compared to
11% of time spent in a manic state. Duration of time depressed and severity of
depression are associated with increased risk for suicide, which occurs in 10%
to 20% of bipolar patients. Antidepressants are increasingly being used as
adjuncts in the depressed phase of bipolar disorder, although they provide a
moderate risk for switch into mania. Lithium and some antiepileptics and
atypical antipsychotics have shown antidepressant effects in the treatment of
bipolar disorder. Other adjuncts for treatment-refractory patients include
monoamine oxidase inhibitors and electroconvulsive therapy.

———-

Ann Clin Psychiatry. 2003 Sep-Dec;15(3-4):225-32.

What drugs are best for bipolar depression?

Baldassano CF, Datto SM, Littman L, Lipari MA.

Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104, USA. cfb@mail.med.upenn.edu

Bipolar depression is a severe, potentially lethal disorder for which there are
no specific, FDA-indicated pharmacotherapies. Research in this area has been
limited, and most treatments are based on unsupported extrapolation from the
treatment of unipolar depression, or follow guidelines derived largely from the
clinical practice experience of experts in this field. There is clearly a
medical need for new and more effective treatments for bipolar depression.
Recently, the newer antiepileptic drugs, and atypical antipsychotics, have been
studied to evaluate their role in bridging this gap in the psychopharmacologic
armamentarium. Drugs in these classes will be reviewed, in addition to serotonin
reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive
therapy. In this paper, current trends in the acute and long-term medication
treatment of bipolar depression will be described, with particular focus on
evidence from the existing literature. Additional factors, such as side effects,
risk/benefit issues, and drug-drug interactions, will be considered in an
attempt to make overall recommendations for medication selection.

———-

Int J Neuropsychopharmacol. 2003 Sep;6(3):285-91.

Comment in:
Int J Neuropsychopharmacol. 2004 Mar;7(1):105-6; author reply 107.

Recent placebo-controlled acute trials in bipolar depression: focus on
methodology.

Muzina DJ, Calabrese JR.

Cleveland Clinic Foundation, Cleveland, Ohio, USA. muzinad@ccf.org

The completion of three recent large-scale, double-blind controlled acute trials
in bipolar I depression has improved our understanding of the management of
major depressive episodes associated with bipolar disorder. In contrast to the
cross-over designs used in the early studies of lithium in bipolar depression,
the designs utilized in these recent studies have employed random assignment to
parallel arms including the use of placebo as a monotherapy in one study. The
analyses of recent studies have all been conducted on intent-to-treat data, and
included two types, change from baseline analyses and responder analyses.
Lamotrigine monotherapy was shown to be superior to placebo with both types of
analyses on the Montgomery-Asberg Depression Rating Scale (MADRS) and the
Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton
Depression Rating Scale (HAMD) (n=195). The percentage of patients responding to
placebo as a monotherapy were 29, 26 and 37%, respectively; there were no
differences in switch rates (5% vs. 5%). Paroxetine augmentation was no better
than placebo augmentation overall with both types analyses on the CGI and HAMD
(n=117); the MADRS was not used. In patients with lithium levels < or =0.8
mequiv./l, the change from baseline analysis showed paroxetine to be superior to
placebo, but responder analyses were negative; switch rates with paroxetine,
imipramine, and placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in
efficacy to imipramine (n=156), but had a lower rate of switching (4% vs. 11%).

———-

J Clin Psychiatry. 2003 Jul;64(7):825-33.

A computer algorithm for calculating the adequacy of antidepressant treatment in
unipolar and bipolar depression.

Oquendo MA, Baca-Garcia E, Kartachov A, Khait V, Campbell CE, Richards M,
Sackeim HA, Prudic J, Mann JJ.

Silvio O. Conte Centers for the Neuroscience of Mental Disorders for the Study
of the Neurobiology of Suicidal Behavior, New York, USA.
moquendo@neuron.cpmc.columbia.edu

BACKGROUND: Major depression is often treated with medications in doses that are
too low or too short in duration. We published an early version of the
Antidepressant Treatment History Form (ATHF) that rates the adequacy of
antidepressant treatment. The updated ATHF presented here includes newer
medications and a computer algorithm to automate the evaluation of the adequacy
of pharmacotherapy or electroconvulsive therapy for depression. METHOD: The
computer algorithm was written in MS-DOS Q-BASIC and in Visual Basic 5.0.
Treatment data from 47 depressed (Structured Clinical Interview for DSM-III-R)
patients were scored by the computer algorithm and assigned a number from 0 to 5
for the adequacy of antidepressant treatment. A psychiatrist blinded to the
computer ratings manually rated the treatment using the ATHF. RESULTS: The
computer algorithm, based on an updated version of the ATHF, estimates the
adequacy of treatment of unipolar and bipolar depression. Computer algorithm
results agreed with those generated by a clinician completing the form manually
(kappa = 0.88 to 1.00). CONCLUSION: The computer algorithm can be used to
analyze large databases and may help reduce the morbidity and mortality
associated with major depression by improving the assessment of adequacy of
pharmacologic treatments for research and quality assurance purposes. The
availability of the updated ATHF on the Internet for downloading allows for
modifications according to the user’s purposes.

———-

Psychopharmacol Bull. 2003 Summer;37(3):118-26.

Effects of tranylcypromine on the sleep of patients with anergic bipolar
depression.

Jindal RD, Fasiczka AL, Himmelhoch JM, Mallinger AG, Thase ME.

Department of Psychiatry, University of Pittsburgh School of Medicine, Western
Psychiatric Institute and Clinic, Pittsburgh, PA 15313, USA.
jindalr@msx.upmc.edu

A significant proportion of patients with bipolar disorder are hypersomnolent.
It is not clear if this affects response to treatment because few studies have
systematically examined treatment effects on sleep in patients with bipolar
depression. Reported herein are the results of what we believe to be the first
study of the effects of the monoamine oxidase inhibitor tranylcypromine (average
dose=37 mg/day) on the sleep of patients with bipolar depression.Twenty-three
patients with anergic bipolar depression completed sleep studies before and
after pharmacotherapy. Changes in polysomnographic variables were examined using
paired t tests. The patients experienced a 40% reduction in rapid eye movement
(REM) sleep time, as well as significant decreases in REM percentage,REM
activity, number of REM periods, and REM intensity.REM latency was prolonged by
nearly 3-fold.The decrease in REM sleep was accompanied by a modest (8%)
reduction in total sleep time and increased “light” sleep. There was no change
in sleep continuity indices or slow wave sleep. Correlational analyses suggested
that antidepressant response was only weakly associated with changes in REM
sleep. These findings indicate that tranylcypromine’s effects on REM sleep
greatly surpass effects on sleep architecture or sleep maintenance. Moreover,
effective treatment of bipolar depression did not “normalize” the
hypersomnolence associated with bipolar depression.

———-

J Psychiatr Pract. 2003 May;9(3):181-94.

When do antidepressants worsen the course of bipolar disorder?

Goldberg JF.

Zucker Hillside Hospital/North Shore Long Island Jewish Health System, Glen
Oaks, NY 11002, USA.

Bipolar disorder may be more prevalent than previously believed. Because a
substantial number of patients with bipolar disorder present with an index
depressive episode, it is likely that many are misdiagnosed with unipolar major
depression. Even if a correct diagnosis is made, depressive symptoms in bipolar
disorder are notoriously difficult to treat. Patients are often treated with
antidepressants, which, if used improperly, are known to induce mania and
provoke rapid cycling. This article explores diagnostic conundrums in bipolar
depression and their possible solutions, based on current research evidence. It
also elucidates current evidence regarding the risks and benefits associated
with antidepressant use and evaluates alternative treatment regimens for the
depressed bipolar population, including the use of traditional mood stabilizers
such as lithium, novel anticonvulsants such as lamotrigine, and atypical
antipsychotics.

———-

Drugs. 2003;63(19):2029-50.

Lamotrigine: a review of its use in bipolar disorder.

Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.

Adis International Limited, Mairangi Bay, Auckland, New Zealand.
demail@adis.co.nz

Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established
anticonvulsant agent that has shown efficacy in the prevention of mood episodes
in adult patients with bipolar I disorder. The mechanism of action of the drug
in patients with bipolar disorder may be related to the inhibition of sodium and
calcium channels in presynaptic neurons and subsequent stabilisation of the
neuronal membrane. Lamotrigine monotherapy significantly delayed time to
intervention with additional pharmacotherapy or electroconvulsive therapy for
any new mood episode (mania, hypomania, depression and mixed episodes), compared
with placebo, in two large, randomised, double-blind trials of 18 months’
duration. Additionally, lamotrigine was significantly superior to placebo at
prolonging time to intervention for depression. These effects of lamotrigine
were demonstrated in both recently manic/hypomanic and recently depressed
patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in
pooled data only, although lithium was superior to lamotrigine on this measure.
Two of four double-blind, short-term studies have shown lamotrigine to be more
effective than placebo in the treatment of patients with treatment-refractory
bipolar disorder or those with bipolar depression. Lamotrigine has not
demonstrated efficacy in the treatment of acute mania.Lamotrigine was generally
well tolerated in maintenance studies with the most common adverse events being
headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor
were significantly lower in lamotrigine- than in lithium-treated patients. The
incidence of serious rash with lamotrigine treatment was 0.1% in all studies of
bipolar disorder and included one case of mild Stevens-Johnson syndrome.
Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine
is titrated over a 6-week period to 200 mg/day to minimise the incidence of
serious rash. Adjustments to the initial and target dosages are required if
coadministered with valproate semisodium or carbamazepine. CONCLUSION:
Lamotrigine has been shown to be an effective maintenance therapy for patients
with bipolar I disorder, significantly delaying time to intervention for any
mood episode. Additionally, lamotrigine significantly delayed time to
intervention for a depressive episode and showed limited efficacy in delaying
time to intervention for a manic/hypomanic episode, compared with placebo.
Although not approved for the short-term treatment of mood episodes, lamotrigine
has shown efficacy in the acute treatment of patients with bipolar depression
but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine
is generally well tolerated, does not appear to cause bodyweight gain and,
unlike lithium, generally does not require monitoring of serum levels.

———-

Am J Psychiatry. 2003 Jul;160(7):1252-62.

Impact of antidepressant discontinuation after acute bipolar depression
remission on rates of depressive relapse at 1-year follow-up.

Altshuler L, Suppes T, Black D, Nolen WA, Keck PE Jr, Frye MA, McElroy S, Kupka
R, Grunze H, Walden J, Leverich G, Denicoff K, Luckenbaugh D, Post R.

Stanley Bipolar Treatment Network, USA. laltshuler@mednet.ucla.edu

OBJECTIVE: While guidelines for treating patients with bipolar depression
recommend discontinuing antidepressants within 6 months after remission, few
studies have assessed the implications of this strategy on the risk for
depressive relapse. This study examined the effect of antidepressant
discontinuation or continuation on depressive relapse risk among bipolar
subjects successfully treated for an acute depressive episode. METHOD:
Eighty-four subjects with bipolar disorder who achieved remission from a
depressive episode with the addition of an antidepressant to an ongoing mood
stabilizer regimen were followed prospectively for 1 year. The risk of
depressive relapse among 43 subjects who stopped antidepressant treatment within
6 months after remission (“discontinuation group”) was compared with the risk
among 41 subjects who continued taking antidepressants beyond 6 months
(“continuation group”). RESULTS: A Cox proportional hazards regression analysis
indicated that shorter antidepressant exposure time following successful
treatment was associated with a significantly shorter time to depressive
relapse. Furthermore, patients who discontinued antidepressant treatment within
the first 6 months after remission experienced a significantly shorter period of
euthymia before depressive relapse over the length of 1-year follow-up. One year
after successful antidepressant response, 70% of the antidepressant
discontinuation group experienced a depressive relapse compared with 36% of the
continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84
subjects had experienced a manic relapse; only six of these subjects were taking
an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of
depressive relapse in patients with bipolar illness was significantly associated
with discontinuing antidepressants soon after remission. The risk of manic
relapse was not significantly associated with continuing use of antidepressant
medication and, overall, was substantially less than the risk of depressive
relapse. Maintenance of antidepressant treatment in combination with a mood
stabilizer may be warranted in some patients with bipolar disorder.

———-

Neuropsychopharmacology. 2003 Jul;28(7):1374-82. Epub 2003 May 28.

Maintenance efficacy of divalproex in the prevention of bipolar depression.

Gyulai L, Bowden CL, McElroy SL, Calabrese JR, Petty F, Swann AC, Chou JC,
Wassef A, Risch CS, Hirschfeld RM, Nemeroff CB, Keck PE Jr, Evans DL, Wozniak
PJ.

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104,
USA. gyulai@mail.med.upenn.edu

Breakthrough depression is a common problem in the treatment of bipolar
disorder. Only one, recently published, double-blind, placebo-controlled trial
has examined the efficacy of divalproex in the prevention of depressive episodes
in bipolar patients. This report describes, in further detail, the findings from
that trial of the effect of divalproex on multiple dimensions of depressive
morbidity in bipolar disorder. A randomized, double-blind, parallel-group,
multicenter study was conducted over a 52-week maintenance period. Bipolar I
patients, who may have been treated with open-label lithium or divalproex and
who met recovery criteria within 3 months of onset of an index manic episode,
were randomized to maintenance treatment with divalproex, lithium, or placebo in
a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough
depression was allowed in maintenance phase. Outcome measures were the rate of
early discontinuation for depression, time to depressive relapse, proportion of
patients with depressive relapse, mean change in Depressive Syndrome Scale
score, proportion of patients receiving antidepressants, and time in the study.
Among patients taking an antidepressant, a higher percentage of patients on
placebo than divalproex discontinued early for depression. Patients who were
previously hospitalized for affective episodes or took divalproex in the open
period relapsed later on divalproex than on lithium during the maintenance
period. Divalproex-treated patients had less worsening of depressive symptoms
than lithium-treated patients during maintenance. Indices of severity of
prestudy illness course predicted worse outcome in all treatment groups.
Divalproex improved several dimensions of depressive morbidity and reduced the
probability of depressive relapse in bipolar disorder, particularly in patients
who had responded to divalproex when manic, and among patients with a more
severe course of illness.

———-

Psychiatr Clin North Am. 2003 Jun;26(2):495-518.

Treatment of bipolar depression: current status, continued challenges, and the
STEP-BD approach.

Thase ME, Bhargava M, Sachs GS.

Department of Psychiatry, University of Pittsburgh Medical Center, Western
Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213-2593,
USA. thaseme@msx.upmc.edu

Even though at least 10% (if not 20%) of those who experience a first lifetime
episode of depression will subsequently develop bipolar disorder, the alliance
of academic and industry research agendas that leads to developing and testing
new antidepressants has failed to produce a sufficient knowledge base. It is
therefore impossible to apply a truly empirical approach to guide the treatment
of people with bipolar depression. Consequently, there are holes in contemporary
evidenced-based practice guidelines large enough to drive a truck through;
furthermore, there are some recommendations that have no factual basis other
than expert opinion. However, with new research emerging on lamotrigine and
olanzapine, in addition to the pending results of larger studies supported by
the National Institute of Mental Health and the Stanley Foundation, there is
evidence that some progress is being made.

———-

J Clin Psychiatry. 2003;64 Suppl 5:32-7.

Lithium combinations in acute and maintenance treatment of unipolar and bipolar
depression.

Fawcett JA.

Department of Psychiatry, University of New Mexico School of Medicine,
Albuquerque 87131, USA. jfawcett@salud.unm.edu

Bipolar illness and unipolar depression are both affective disorders associated
with high lifetime morbidity and premature mortality due to suicide. Numerous
double-blind, placebo-controlled trials have shown that lithium augmentation
therapy is effective in treating acute episodes of bipolar depression,
refractory major depression, and delusional depression as well as in reducing
recurrences of these illnesses. Lithium is the only agent approved by the U.S.
Food and Drug Administration for maintenance treatment of bipolar disorder.
Further research is needed to specifically address whether the antidepressant
effect of adding lithium is greater in bipolar disorder or in unipolar
depressions. This article will summarize available evidence and clinical
considerations regarding the use of lithium augmentation in acute and
maintenance treatment of unipolar and bipolar depressions.

———-

Biol Psychiatry. 2003 Apr 15;53(8):691-700.

Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.

Acceleration and augmentation strategies for treating bipolar depression.

Altshuler LL, Frye MA, Gitlin MJ.

Department of Psychiatry and Biobehavioral Sciences, University of California,
Los Angeles, Los Angeles, California 90095, USA.

Despite the prevalence and morbidity of bipolar depression, few randomized
treatment trials have been conducted to assess clinical efficacy. Even fewer
studies have assessed approaches that optimize treatment response for bipolar
depression. This review will define three types of common combination
strategies–adjunctive, acceleration and augmentation–and discuss the limited
literature of controlled studies reported on acceleration and augmentation
approaches. Copyright 2003 Society of Biological Psychiatry

———-

Biol Psychiatry. 2003 Apr 15;53(8):671-9.

Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.

Advances in the pharmacologic treatment of bipolar depression.

Keck PE Jr, Nelson EB, McElroy SL.

Division of Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.

The pharmacologic treatment of bipolar depression has not been well studied in
randomized, controlled trials. Thus important clinical questions regarding the
efficacy in bipolar depression of mood stabilizers, antidepressants, and new
antiepileptic and atypical antipsychotic agents have been relatively
unaddressed. Until recently there were few data regarding the degree to which
mood stabilizers reduce the risk of switching associated with antidepressant
treatment. Likewise, although treatment guidelines have often recommended
limiting antidepressant exposure in the maintenance treatment of bipolar
depression, the potential risks of depressive relapse after antidepressant
discontinuation were largely unknown. We review here data from new randomized,
controlled trials published or presented during the past 5 years regarding the
efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in
the acute and maintenance treatment of bipolar depression. We also review new
studies clarifying the protective effect of coadministration of mood stabilizers
from antidepressant-associated switching and the risk of depressive relapse when
antidepressants are discontinued during maintenance treatment. Copyright 2003
Society of Biological Psychiatry

———-

Arch Gen Psychiatry. 2003 Apr;60(4):392-400.

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance
treatment in recently manic or hypomanic patients with bipolar I disorder.

Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery
P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group.

Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 78229, USA. bowdenc@uthscsa.edu

BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar
depression and rapid cycling in placebo-controlled clinical trials. This
double-blind, placebo-controlled study was conducted to assess the efficacy and
tolerability of lamotrigine and lithium compared with placebo for the prevention
of relapse or recurrence of mood episodes in recently manic or hypomanic
patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label
phase during which treatment with lamotrigine was initiated and other
psychotropic drug regimens were discontinued, patients were randomized to
lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as
double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349
patients who met screening criteria and entered the open-label phase, 175 met
stabilization criteria and were randomized to double-blind maintenance treatment
(lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both
lamotrigine and lithium were superior to placebo at prolonging the time to
intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs
placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to
a depressive episode (P =.02). Lithium was superior to placebo at prolonging the
time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse
event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and
lithium were superior to placebo for the prevention of relapse or recurrence of
mood episodes in patients with bipolar I disorder who had recently experienced a
manic or hypomanic episode. The results indicate that lamotrigine is an
effective, well-tolerated maintenance treatment for bipolar disorder,
particularly for prophylaxis of depression.

———-

Bipolar Disord. 2003 Apr;5(2):85-97.

Bipolar depression: criteria for treatment selection, definition of
refractoriness, and treatment options.

Yatham LN, Calabrese JR, Kusumakar V.

Department of Psychiatry, The University of British Columbia, Vancouver, British
Columbia, Canada. yatham@interchange.ubc.ca

OBJECTIVE: This paper reviews controlled studies of bipolar depression, outlines
criteria for choosing treatment, defines refractoriness in bipolar depression,
and provides options for treatment of refractory bipolar depression. METHODS:
Controlled studies that examined the efficacy of treatments for acute and
long-term treatment of bipolar depression were located through electronic
searches of several databases and by manual crosssearch of references and
proceedings of international meetings. RESULTS: Lithium comes close to
fulfilling the proposed criteria for first-line treatment for bipolar
depression, and those not responding to lithium should be considered to have
refractory bipolar depression. Options for such patients include addition of
lamotrigine or a second mood stabilizer, or a newer-generation antidepressant
such as a serotonin re-uptake inhibitor or bupropion, or the atypical
antipsychotic olanzapine. CONCLUSIONS: Although there is a paucity of research
in the treatment of refractory bipolar depression, available data could be used
for providing rational treatment options for such patients. However, further
studies are urgently needed to determine which options are most appropriate for
which type of patients.

———-

Drug Saf. 2003;26(5):337-51.

Avoiding drug-induced switching in patients with bipolar depression.

Henry C, Demotes-Mainard J.

Service Universitaire de Psychiatrie, CH Charles Perrens, Bordeaux, France.
chantal.henry@bordeaux.inserm.fr

Antidepressant-induced switching is a major risk during the treatment of bipolar
depression. Despite several clinical studies, questions remain regarding both
the definition of these mood switches and the most appropriate therapeutic
strategy to avoid this adverse effect.This review will first briefly consider
the current guidelines for the acute treatment of bipolar depression. We will
then review the mechanisms of action of antidepressant and mood stabilisers, and
the switches induced by various types of antidepressant treatments, or triggered
by antidepressant withdrawal, as well as by atypical antipsychotics. We then
will address the risk of mood switch according to the type of mood stabiliser
used. The propensity to mood switches in bipolar patients is subject to
individual differences. Therefore we will describe both the clinical and
biological characteristics of patients prone to mood switches under
antidepressant treatment. However, the clinical characteristics of the
depressive syndrome may also be a key determinant for mood switches. Various
data help identify the most appropriate drug management strategies for avoiding
mood switches during the treatment of bipolar depression. Selective serotonin
reuptake inhibitors appear to be the drugs of first-choice because of the low
associated risk of mood switching. Antidepressants must be associated with a
mood stabiliser and the most effective in the prevention of switches seems to be
lithium. Whatever the mood stabiliser used, effective plasma levels must be
ensured. The optimal duration of antidepressant treatment for bipolar depression
is still an open issue – prolonged treatments after recovery may be unnecessary
and may facilitate mood elation. Moreover, some mood episodes with mixed
symptoms can be worsened by antidepressants pointing to the need for a better
delineation of the categories of symptoms requiring antidepressant treatment.
Finally, as a result of this review, we suggest some propositions to define
drug-induced switches in bipolar patients, and to try to delineate which
strategies should be recommended in clinical practice to reduce as far as
possible the risk of mood switch during the treatment of bipolar depression.

———-

Ann Clin Psychiatry. 2002 Dec;14(4):223-32.

Combining lithium and anticonvulsants in bipolar disorder: a review.

Pies R.

Tufts University School of Medicine, Boston, Massachusetts, USA.
ronpies@massmed.org

While the benefits of lithium in bipolar disorder are evident, its limitations
as monotherapy are well recognized, particularly in bipolar depression. This has
propelled trials of combined lithium-anticonvulsant therapy in many bipolar
patients. The present review of the English-language literature examines both
controlled and open studies of such combination therapy, including the risk of
drug-drug interactions. Trials of lithium plus either carbamazepine or
divalproex have generally produced favorable results, although increased rates
of adverse effects may reduce treatment adherence. More recent reports suggest
that lithium may be safely and effectively combined with lamotrigine, and
perhaps with topiramate, although controlled studies are required. The combined
use of lithium with newer, putative mood stabilizers, such as zonisamide or
levetiracetam, cannot yet be recommended, but is an important area for future
research. Provisional recommendations for combined treatment are provided.

———-

J Clin Psychiatry. 2003;64 Suppl 1:13-8.

New approaches in managing bipolar depression.

Keck PE Jr, McElroy SL.

Program Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.
paul.keck@uc.edu

Historically, the pharmacologic treatment of bipolar depression has not been
well studied. New data are beginning to emerge regarding the efficacy of new
medications and the use of combinations of mood stabilizers and antidepressants
in acute and long-term treatment of bipolar depression. We reviewed data from
recent randomized, controlled trials of mood stabilizers and antidepressants in
the treatment of bipolar depression and naturalistic studies examining the risk
of switching and depressive relapse with ongoing antidepressant treatment.

———

World J Biol Psychiatry. 2000 Jul;1(3):129-36.

New perspectives in the acute treatment of bipolar depression.

Grunze H, Schlosser S, Walden J.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7,
80336 Munich, Germany.

In contrast to mania, bipolar depression is usually characterised by
longer-lasting episodes and a higher incidence of treatment refractoriness.
Additionally, the risks of antidepressive standard treatment regimens are
increasingly recognised, especially the risk of a switch into mania or induction
of a rapid cycling course. Mood stabilisers, e.g. lithium, and some
anticonvulsants, appear to have at least some antidepressant efficacy, which,
however, may not be sufficient for treating severe depression. Currently, their
use as a monotherapy of mild depression and at the start as a co-medication to
antidepressants in severe depression is under consideration. The potential
usefulness and risks of currently applied antidepressive treatment strategies as
well as potential future developments will be reviewed in this article. At this
stage, at least in severe depression, the use of true antidepressants still
appears to be mandatory, especially because of the risk of suicide. However,
initial combination with a mood stabiliser can be recommended. The treatment of
depressive episodes only responsive to ECT should include combination with a
mood stabiliser, in this case lithium, right from the start. In patients with
lithium refractoriness, mood stabilising anticonvulsants should be initiated
directly after the end of the ECT cycle. In order to reach sufficient plasma
levels and thus reduce the risk of a switch, a loading therapy is recommended.

———-

Bipolar Disord. 2002 Oct;4(5):315-22.

Insight into illness in patients with mania, mixed mania, bipolar depression and
major depression with psychotic features.

Dell’Osso L, Pini S, Cassano GB, Mastrocinque C, Seckinger RA, Saettoni M,
Papasogli A, Yale SA, Amador XF.

Department of Psychiatry, Pharmacology, Neurobiology and, Biotechnology,
University of Pisa, Pisa, Italy. ldellosso@psico.med.unipi.it

BACKGROUND: Poor insight into illness is a common feature of bipolar disorder
and one that is associated with poor clinical outcome. Empirical studies of
illness awareness in this population are relatively scarce with the majority of
studies being published over the previous decade. The study reported here sought
to replicate previous report findings that bipolar patients frequently show high
levels of poor insight into having an illness. We also wanted to examine whether
group differences in insight exist among bipolar manic, mixed and unipolar
depressed patients with psychotic features. METHODS: A cohort of 147 inpatients
with DSM-III-R bipolar disorder and 30 with unipolar depression with psychotic
features, were evaluated in the week prior to discharge using the Structured
Clinical Interview for DSM-III-R-Patient Edition (SCID-P), the Brief Psychiatric
Rating Scale (BPRS) and the Scale to assess Unawareness of Mental Disorder
(SUMD). RESULTS: Insight into specific aspects of the illness was related to the
polarity of mood episode: patients with mania showed significantly poorer
insight compared with those with mixed mania, bipolar depression and unipolar
depression. A linear regression analysis using SUMD score as the dependent
variable and symptoms of mania as the independent variable found that specific
manic symptoms did not account for level of insight. Similar results were
obtained when the mean insight scores of patients with and without grandiosity
were contrasted. CONCLUSIONS: We hypothesize that the lack of association
between level of insight and total number of manic symptoms or with specific
manic symptoms may be related to the persistence of subsyndromal symptoms in
patients remitting from a manic episode.

———

Bipolar Disord. 2002 Oct;4(5):307-14.

Pramipexole in treatment-resistant depression: a 16-week naturalistic study.

Lattanzi L, Dell’Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A,
Battistini G, Bassi A, Abelli M, Cassano GB.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies,
University of Pisa, Italy. paolo.cassano@psico.med.unipi.it

OBJECTIVE: To assess the antidepressant efficacy and tolerability of adjunctive
pramipexole, a D2-D3 dopamine agonist, in patients with drug-resistant
depression. METHODS: The study sample consisted of in-patients with major
depressive episode, according to the DSM-IV, and drug resistance. Pramipexole
was added to antidepressant treatment with TCA or SSRI, at increasing doses from
0.375 to 1.0 mg/day. Two independent response criteria were adopted: a > 50%
reduction of the Montgomery-Asberg Depressive Rating Scale (MADRS) total score
and a score of I or 2 on the Clinical Global Impression scale (CGI-1) at
endpoint. Side-effects were assessed by the Dosage Record Treatment Emergent
Symptom Scale (DOTES). RESULTS: Thirty-seven patients were enrolled. Of these.
16 had unipolar depression and 21 had bipolar depression. Six patients dropped
out in the first week. Of the 31 patients included in the analyses. 19 completed
the 16-week follow-up. Mean maximal dose of pramipexole was 0.95 mg/day. Mean
scores on MADRS decreased from 33.3 +/- 8.4 at baseline to 13.9 +/- 11.5 at
endpoint (p < 0.001) and the CGI-S decreased from 4.6 +/- 0.8 at baseline to 2.8
+/- 1.3 at endpoint (p < 0.001). At endpoint, 67.7% (21/31) of patients were
responders on MADRS and 74.2% on CGI-I. Of the 37 patients enrolled, 10
discontinued pramipexole because of adverse events. CONCLUSIONS: These
preliminary data suggest that pramipexole adjunction to antidepressant treatment
may be effective and well tolerated in patients with resistant major depression.

———

Bipolar Disord. 2002 Oct;4(5):296-301.

Gabapentin augmentation therapy in bipolar depression.

Wang PW, Santosa C, Schumacher M, Winsberg ME, Strong C, Ketter TA.

Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, CA 94305-5723, USA. wangp0@stanford.edu

BACKGROUND: Gabapentin (GBP) may be useful in bipolar disorders, including as
adjunctive therapy for bipolar depression, although controlled studies suggest
inefficacy as primary treatment for mania or treatment-resistant rapid cycling.
METHODS: We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added
to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women,
mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS)
> 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness
duration was 18.6 years, current depressive episode duration was 18.0 weeks.
Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global
Impression-Severity (CGI-S) ratings were obtained. RESULTS: Overall, HDRS
ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12
(p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement
(HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5
(p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In
non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005).
Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35)
patients responded, while only two of nine patients (22%) with severe depression
(HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar,
statistically significant HDRS decreases. GBP was well tolerated. CONCLUSION:
Open adjunctive GBP was effective and well tolerated in patients with mild to
moderate bipolar depression. This open pilot study must be viewed with caution,
and randomized controlled studies are warranted.

———-

16: World J Biol Psychiatry. 2002 Jul;3(3):115-24.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for
biological treatment of bipolar disorders. Part I: Treatment of bipolar
depression.

Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D, Licht R, Vieta E, Moller HJ;
World Federation of Societies of Biological Psychiatry Task Force on Treatment
Guidelines for Bipolar Disorders.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7,
80336 Munich, Germany. grunze@psy.med.uni-muenchen.de

These practice guidelines for the biological, mainly pharmacological treatment
of bipolar depression were developed by an international task force of the World
Federation of Societies of Biological Psychiatry (WFSBP). Their purpose is to
supply a systematic overview of all scientific evidence pertaining to the
treatment of bipolar depression. The data used for these guidelines have been
extracted from a MEDLINE and EMBASE search, and from recent proceedings of key
conferences and various national and international treatment guidelines. Their
scientific rigor was categorised into four levels of evidence (A-D). As these
guidelines are intended for clinical use, the scientific evidence was not only
graded, but also commented on by the experts of the task force to ensure
practicability.

———-

CNS Drugs. 2003;17(1):9-25.

Bipolar depression: management options.

Malhi GS, Mitchell PB, Salim S.

School of Psychiatry, University of New South Wales, Randwick, Sydney, New South
Wales, Australia.

Bipolar depression is the predominant abnormal mood state in bipolar disorder.
However, despite the key pertinence of this phase of the condition, the focus of
research and indeed of clinical interest in the management of bipolar disorder
has been mainly on mania. Bipolar depression has been largely neglected, and
early studies often failed to distinguish depression due to major unipolar
depression from that due to bipolar disorder. Consequently, many treatments used
in the management of major depression have been adopted for use in bipolar
depression without any robust evidence of efficacy. The selective serotonin
reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine
oxidase inhibitors are all effective antidepressants in the management of
bipolar depression. They are all associated with a small risk of
antidepressant-induced mood instability. The mood stabilisers lithium,
carbamazepine and valproate semisodium (divalproex sodium) all appear to have
modest acute antidepressant properties. Among these, lithium is supported by the
strongest data, but the use of lithium in the treatment of bipolar depression as
a monotherapeutic agent is limited by its slow onset of action. Recently, there
has been a growing body of evidence suggesting that lamotrigine may have
particular effectiveness in both the acute and prophylactic management of
bipolar depression. Clinical management of bipolar depression involves various
combinations of antidepressants and mood stabilisers and is partly determined by
the context in which the depressive episode occurs. In general, ‘de novo’ and
‘breakthrough’ (where the patient is already receiving medication) bipolar
depression may be successfully managed by initiating mood stabiliser
monotherapy, to which an antidepressant or second mood stabiliser may be added
at a later date, if necessary. Breakthrough episodes of bipolar depression
occurring in patients receiving combination therapy (two mood stabilisers or a
mood stabiliser plus an antidepressant) require either switching of ongoing
medications or further augmentation. If this fails, then novel strategies or ECT
should be considered. Bipolar depression is a disabling illness and the
predominant mood state for the vast majority of those with bipolar disorder. It
therefore warrants prompt management once suitably diagnosed, especially as it
is associated with a considerable risk of suicide and in the majority of
instances is eminently treatable.

———

Psychol Med. 2002 Nov;32(8):1417-23.

Bipolar depression: relationship between episode length and antidepressant
treatment.

Frankle WG, Perlis RH, Deckersbach T, Grandin LD, Gray SM, Sachs GS, Nierenberg
AA.

BACKGROUND: The role of antidepressant medications in bipolar depression remains
controversial, mainly due to a lack of research in this area. In this study the
authors examined the episode length in bipolar depression and the relationship
between antidepressant therapy and episode length. METHOD: A retrospective chart
review of 165 subjects identified 50 (30%) with bipolar illness who experienced
a major depressive episode between 1 January 1998 and 15 December 2000. Data
gathered utilized a structured instrument completed by the clinician at each
visit. This instrument includes modified SCID mood modules as well as continuous
ratings for each associated symptom of depression and mood elevation. Survival
analysis was employed to calculate the median length of the depressive episodes
for the entire group. Further survival analysis compared the episode length for
subjects treated with antidepressants during the depression (N = 33) with those
who did not receive antidepressants (N = 17). The rate of switch into elevated
mood states was compared for the two groups. RESULTS: The survival analysis for
the entire sample demonstrated 25%, 50% and 75% probability of recovery at 33
(S.E. 8.7), 66 (S.E. 17.9) and 215 (S.E. 109.9) days, respectively. Comparing
those who received (N = 33) and those who did not receive (N = 17)
antidepressants during the episode did not reveal any difference in the length
of the depressive episode. Switch rates were not significantly different between
those receiving antidepressants and those not taking these medications (15.2% v.
17.6%, respectively). CONCLUSIONS: Over the past 20 years little progress has
been made in reducing the length of depressive episodes in those with bipolar
illness. This is despite increasing pharmacological options available for
treating depression. Clinicians treating bipolar depression should discuss with
their patients the likelihood that the episode will last between 2-3 months. Our
results also suggest that antidepressant treatment may not reduce the length of
depressive episodes, neither did it appear to contribute to affective switch in
our sample.

———

J Clin Psychiatry. 2002 Nov;63(11):1012-9.

Comment in:
J Clin Psychiatry. 2002 Nov;63(11):1010-1.

Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance
and management.

Calabrese JR, Sullivan JR, Bowden CL, Suppes T, Goldberg JF, Sachs GS, Shelton
MD, Goodwin FK, Frye MA, Kusumakar V.

Department of Psychiatry, Case Western Reserve University/University Hospitals
of Cleveland, Cleveland, Ohio, USA. jrc8@po.cwru.edu

BACKGROUND: The rate of lamotrigine-associated rash in patients with mood
disorders has not been well characterized. The objective of this report was to
determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar
depression or bipolar disorder. METHOD: A retrospective analysis was conducted
of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open
study, 7 randomized controlled acute trials, and 4 randomized controlled
maintenance trials from 1996 to 2001. RESULTS: A total of 1955 patients were
treated with lamotrigine in open-label settings (open-label phases preceding or
following randomization and 1 stand-alone open-label study); 1198 patients
received lamotrigine in controlled settings, and 1056 patients received placebo.
In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine-
and placebo-treated patients, respectively. Rates of serious rash were 0% with
lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the
open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257)
and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not
requiring hospitalization occurred in a patient treated with lamotrigine. There
were no cases of toxic epidermal necrolysis in any setting. CONCLUSION: Serious
drug eruptions associated with lamotrigine were rare. Although rash is a
potentially life-threatening reaction, the risk of serious rash due to
lamotrigine should be weighed against more common risks associated with
untreated or undertreated bipolar depression.

———-

J Clin Psychiatry. 2002 Nov;63(11):963-71.

The impact of treatment-resistant depression on health care utilization and
costs.

Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, Russell JM.

MEDSTAT Group, Cambridge, Mass, USA.

BACKGROUND: Approximately 50% of patients diagnosed with major depressive
disorder will experience a recurrent or chronic course of illness for which
long-term treatment is recommended. Moreover, at least 20% of patients diagnosed
with depression do not respond satisfactorily to several traditional
antidepressant medication treatment trials. Very little is known about the
health care costs of patients with treatment-resistant depression. METHOD: Based
on medical claims data (MarketScan Research Database, The MEDSTAT Group,
Cambridge, Mass.) from January 1, 1995, to June 30, 2000, a naturalistic,
retrospective analysis was conducted to study the characteristics and health
care utilization of patients with treatment-resistant depression. All patients
having an International Classification of Diseases, Ninth Revision (ICD-9),
diagnosis code for unipolar or bipolar depression with specified antidepressant
dosing and treatment durations were initially selected. Patients were then
classified as “treatment resistant” if either they switched from or augmented
initial antidepressant medication with other antidepressants at least twice
(outpatient treatment-resistant group) or they switched from or augmented their
initial antidepressant medication and also had a claim for either a
depression-related hospitalization or suicide attempt (hospitalized
treatment-resistant group). Those meeting the initial medication and diagnosis
selection criteria but not meeting the treatment-resistance criteria constituted
the comparison group. Members of the comparison group had comparatively stable
antidepressant medication use patterns, consistent with an acceptable response
to treatment. Patients were followed for a minimum of 9 months. Resource
utilization was calculated from index date to last available claims data point
and then annualized. RESULTS: Treatment-resistant patients were more likely to
be diagnosed with bipolar disorder or concurrent substance abuse or anxiety
disorders than the comparison group (p <.001). Treatment-resistant patients were
at least twice as likely to be hospitalized (general medical and depression
related) and had at least 12% more outpatient visits (p <.02). Treatment
resistance was also associated with use of 1.4 to 3 times more psychotropic
medications (including antidepressants) (p <.001). Patients in the hospitalized
treatment-resistant group had over 6 times the mean total medical costs of
non-treatment-resistant depressed patients ($42,344 vs. $6512) (p <.001) and
their total depression-related costs were 19 times greater than those of
patients in the comparison group ($28,001 vs. $1455) (p <.001). CONCLUSION:
Treatment-resistant depression is costly and associated with extensive use of
depression-related and general medical services. These findings underscore the
need for early identification and effective long-term maintenance treatment for
treatment-resistant depression.

———-

Can J Psychiatry. 2002 Oct;47(8):767-70.

Lamotrigine use in geriatric patients with bipolar depression.

Robillard M, Conn DK.

Baycrest Centre for Geriatric Care, Department of Psychiatry, 3560 Bathurst
Street, Toronto, ON M6A 2E1. mrobillard@baycrest.org

OBJECTIVE: To study the effectiveness of adding lamotrigine to the treatment of
inpatient geriatric patients with bipolar disorder (BD) who were in the
depressed phase and had been on lithium and valproate for at least 3 months.
METHOD: Lamotrigine was started at 25 mg given at bedtime, with weekly
incremental increases of 12.5 mg daily until a total dosage of either 75 mg or
100 mg was obtained. Improvement was measured by clinical interview and Hamilton
Depression Rating Scale (HDRS) scores. Patients were reassessed at 6 weeks, and
if their HDRS score had decreased by at least 50%, they were considered to have
improved. RESULTS: The study group comprised 5 women with an average age of 71.5
years (range 65 to 85). Four had rapid-cycling BD, and 1 had mixed BD. All
patients had early age of onset, as judged by their first contact with a
psychiatrist or their first hospitalization. The average initial HDRS score was
27 (range 20 to 35). Of the patients, 3 out of the 5 had remission of symptoms,
as judged by clinical interview and reduction of their HDRS score by 50%. At 3
months follow-up, these 3 patients had not required rehospitalization and were
doing well. Lamotrigine was well tolerated, and none of the patients developed a
rash. One patient did develop coarse hand tremor that improved when the
lamotrigine dosage was decreased. CONCLUSIONS: Lamotrigine in conjunction with
lithium and valproate may be effective in treating geriatric patients with BD
and depression.

———

J Clin Psychiatry. 2002;63 Suppl 10:18-22.

Long-term treatment of bipolar disorder with lamotrigine.

Calabrese JR, Shelton MD, Rapport DJ, Kimmel SE, Elhaj O.

jrc8@po.cwru.edu

Bipolar depression is as debilitating as mania in bipolar disorder, but the
treatment of bipolar depression has historically received less attention. To
date, there is no mood stabilizer (liberally defined as a medication that
decreases episode severity, duration, or frequency in one phase of bipolar
illness without producing a negative effect in other phases) that demonstrates
similar efficacy in both the depressive and the manic phases of bipolar
disorder. However, bipolar depression–which is prevalent, sometimes chronic,
and associated with a low quality of life and a high risk of suicide–must be
addressed as energetically as mania. Recent research into the long-term
treatment of bipolar disorder has raised several questions about the
generalizability of early lithium studies, as a result of these studies’
designs. Researchers conducting more recent studies of mood stabilizers in the
long-term treatment of bipolar disorder have attempted to clarify their results
by, for example, performing survival analyses of the data. Until pharmacotherapy
has been found that is equally efficacious in the treatment of both manic and
depressive episodes in bipolar disorder, the use of combination therapy to
manage bipolar disorder is advised. Lithium and divalproex sodium remain the
first-line treatments for mania. Lamotrigine has been found to have acute
efficacy in treating episodes of bipolar depression without increasing cycling
or provoking a switch into mania, as well as a long-term role in delaying
relapse and recurrence of depressive episodes.

———-

Expert Opin Pharmacother. 2002 Oct;3(10):1513-9.

Erratum in:
Expert Opin Pharmacother. 2002 Nov;3(11):1683..

Lamotrigine in the treatment of bipolar disorder.

Bowden CL.

Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

Lamotrigine has undergone a remarkable series of systematic studies since 1994
that now establish it as an efficacious, well-tolerated treatment in bipolar
disorder. Its efficacy principally addresses both acute and maintenance phase
benefits on depressive symptomatology. These benefits have been demonstrated in
placebo-controlled studies, rapid cycling patients, bipolar I and II patients
and monotherapy as well as in combination therapy, although this has been less
well studied. The drug is exceptionally well-tolerated in long-term treatment,
although initial dosing requires gradual dosage escalation to avoid the risk of
inducing serious rashes with features within the spectrum of Stevens-Johnson
syndrome. Administration with valproate requires a slower dosage titration,
whereas, as with many drugs, administration with carbamazepine requires a more
rapid dosage increase. In contrast to marketed antidepressants, lamotrigine
appears not to induce manic or hypo-manic episodes, nor to increase cycling
frequency. This combination of properties makes it a first-choice treatment for
acute bipolar depression and continuation treatment, especially, but not limited
to, prophylaxis against recurrent depression and depressive symptoms.
Lamotrigine appears not to have acute antimanic properties. A small number of
studies suggest a broader spectrum of efficacy, including in some axis I
disorders that are comorbidly associated with bipolar disorder.

———-

Bipolar Disord. 2002 Jun;4(3):207-13.

Topiramate versus bupropion SR when added to mood stabilizer therapy for the
depressive phase of bipolar disorder: a preliminary single-blind study.

McIntyre RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH.

Department of Psychiatry, University of Toronto, Mood and Anxiety Disorders
Program, Center for Addiction and Mental Health, Clarke Site, Ontario, Canada.
roger_mcintyre@camh.net

OBJECTIVE: Antiepileptic drugs (AEDs) are commonly employed in the treatment of
bipolar disorder. The efficacy and tolerability of topiramate, a novel
anticonvulsant, and bupropion SR when added to mood stabilizer therapy were
compared under single-blind conditions (rater-blinded) in patients meeting
DSM-IV criteria for bipolar I/II depression. METHODS: A total of 36 out-patients
with Hamilton Depression Rating Scale (HDRS-17) scores > or = 16 were randomized
to receive escalating doses of either topiramate (50-300 mg/day) or bupropion SR
(100-400 mg/day) for 8 weeks. Data were analyzed on an intent-to-treat basis
using the last observation carried forward method. RESULTS: The percentage of
patients meeting a priori response criteria (> or = 50% decrease from baseline
in mean HDRS-17 total score) was significant for both topiramate (56%) and
bupropion SR (59%) [t(17) = 2.542, p = 0.04 and t(17) = 2.661, p = 0.03,
respectively]. Baseline demographic and clinical parameters were comparable
between the two treatment groups. The mean doses of study medication were 176
mg/day (SD = 102 mg/day) for the topiramate-treated group and 250 mg/day (SD =
133 mg/day) for the bupropion SR-treated group. A significant and comparable
reduction in depressive symptoms was observed from baseline to endpoint
following topiramate and bupropion SR treatment, according to a > or = 50%
reduction in the HDRS-17. Total mean HDRS-17 scores significantly decreased from
baseline to endpoint in both groups (p = 0.001), however, differences between
the topiramate-treated group and the bupropion SR-treated group were not
significant [t(36) = 1.754, p = 0.097]. Both topiramate and bupropion SR were
generally well tolerated. Thirteen patients discontinued the study: 2 because of
lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects
(six in the topiramate and four in the bupropion SR-treated group). There were
no cases of affective switch in either arm. Weight loss was experienced by
patients in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR
and 5.8 kg in topiramate) [t(17) = 2.325, p = 0.061 and t(17) = 2.481, p =
0.043, respectively]. CONCLUSIONS: These preliminary data suggest that
adjunctive topiramate may reduce depressive symptom severity in acute bipolar
depression. The antidepressant efficacy of this compound requires confirmation
via double-blind placebo controlled investigation.

———

Acta Psychiatr Scand. 2002 Jun;105(6):414-8.

Previous mood state predicts response and switch rates in patients with bipolar
depression.

MacQueen GM, Trevor Young L, Marriott M, Robb J, Begin H, Joffe RT.

Mood Disorders Program, McMaster University, Hamilton, Ont., Canada.

OBJECTIVE: The treatment of bipolar depression is a significant clinical problem
that remains understudied. The role for antidepressant (AD) agents vs. mood
stabilizers has been particularly problematic to ascertain. METHOD: Detailed
life charting data from 42 patients with 67 depressive episodes were reviewed.
Response rates and rates of switch into mania were compared based on the
preceding mood state and on whether an AD or mood stabilizing (MS) agent was
added following onset of depression. RESULTS: Patients who became depressed
following a period of euthymia were more likely to respond to treatment (62.5%)
than patients who became depressed following a period of mania or hypomania
(27.9%). The ratio of response to switch for previously euthymic patients was
particularly favorable. CONCLUSION: Mood state prior to onset of depression in
bipolar disorder appears to be an important clinical variable that may guide
both choice of treatment administered and expectation of outcome to treatment.

———

Psychiatr Serv. 2002 May;53(5):580-4.

Comment in:
Psychiatr Serv. 2002 Oct;53(10):1331.

Use of antidepressants to treat depression in bipolar disorder.

El-Mallakh RS, Karippot A.

Department of Psychiatry and Behavioral Sciences, University of Louisville
School of Medicine, Kentucky 40292, USA. rselma01@louisville.edu

For decades, clinicians and researchers did not distinguish between bipolar and
unipolar depression. The safety and efficacy of antidepressants for the
treatment of unipolar depression were studied, and the data were applied to the
treatment of bipolar depression without validation. As evidence has accumulated
that antidepressants may adversely affect the course of bipolar illness, more
research has been focused on that problem. Current evidence suggests that
although antidepressants are clearly effective in the acute treatment of type I
and type II bipolar depression, they are also associated with a variety of
adverse outcomes. They may induce a switch to mania or hypomania at a rate two
or three times the spontaneous rate. Long-term use may destabilize the illness,
leading to an increase in the number of both manic and depressed episodes;
induce rapid cycling (at least four episodes a year); and increase the
likelihood of a mixed state. Antidepressants should be used with caution in the
treatment of bipolar depression.

———

Biol Psychiatry. 2002 Mar 1;51(5):387-99.

Principal components of the Beck Depression Inventory and regional cerebral
metabolism in unipolar and bipolar depression.

Dunn RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, Post RM.

Biological Psychiatry Branch, NIMH, NIH, Bethesda, Maryland 20892-1272, USA.

BACKGROUND: We determined clustering of depressive symptoms in a combined group
of unipolar and patients with bipolar disorder using Principle Components
Analysis of the Beck Depression Inventory. Then, comparing unipolars and
bipolars, these symptom clusters were examined for interrelationships, and for
relationships to regional cerebral metabolism for glucose measured by positron
emission tomography. METHODS: [18F]-fluoro-deoxyglucose positron emission
tomography scans and Beck Depression Inventory administered to 31 unipolars and
27 bipolars, all medication-free, mildly-to-severely depressed. BDI component
and total scores were correlated with global cerebral metabolism for glucose,
and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple
comparisons. RESULTS: In both unipolars and bipolars, the psychomotor-anhedonia
symptom cluster correlated with lower absolute metabolism in right insula,
claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher
normalized metabolism in anterior cingulate. In unipolars, the negative
cognitions cluster correlated with lower absolute metabolism bilaterally in
frontal poles, and in right dorsolateral frontal cortex and supracallosal
cingulate. CONCLUSIONS: Psychomotor-anhedonia symptoms in unipolar and bipolar
depression appear to have common, largely right-sided neural substrates, and
these may be fundamental to the depressive syndrome in bipolars. In unipolars,
but not bipolars, negative cognitions are associated with decreased frontal
metabolism. Thus, different depressive symptom clusters may have different
neural substrates in unipolars, but clusters and their substrates are convergent
in bipolars.

———

J Clin Psychiatry. 2001 Aug;62(8):612-6.

The impact of antidepressant discontinuation versus antidepressant continuation
on 1-year risk for relapse of bipolar depression: a retrospective chart review.

Altshuler L, Kiriakos L, Calcagno J, Goodman R, Gitlin M, Frye M, Mintz J.

Department of Psychiatry and Biobehavioral Sciences, University of California,
Los Angeles, USA. LAltshuler@mednet.ucla.edu

BACKGROUND: Current treatment guidelines recommend discontinuation of an
antidepressant within 3 to 6 months after remission of depression in patients
with bipolar illness. Yet few studies directly compare the impact of
antidepressant discontinuation versus antidepressant continuation on the risk
for depressive relapse in patients with bipolar disorder who have been
successfully treated for a depressive episode. METHOD: In a retrospective chart
review, patients with DSM-IV bipolar disorder who were treated for an index
episode of depression by adding antidepressant medication to ongoing mood
stabilizer medications were identified. The risk of depressive relapse in 25
subjects who stopped antidepressant medications after improvement was compared
with the risk of depressive relapse in 19 subjects who continued antidepressants
after improvement. RESULTS: Termination of antidepressant medication
significantly increased the risk of a depressive relapse. Antidepressant
continuation was not significantly associated with an increased risk of mania.
CONCLUSION: While this study may have been limited by the retrospective nature
of the chart review, nonrandomized assignment of treatment, and reliance on
unstructured progress notes, it suggests that antidepressant discontinuation may
increase the risk of depressive relapse in some patients with bipolar disorder.
Further research is needed to clarify whether maintenance antidepressant
treatment may be warranted in some patients with bipolar disorder, especially in
those with frequent recurrent depressive episodes.

———-

J Clin Psychiatry. 2001 Jul;62(7):565-9.

Effectiveness and safety of long-term antidepressant treatment in bipolar
disorder.

Ghaemi SN, Lenox MS, Baldessarini RJ.

Consolidated Department of Psychiatry, Harvard Medical School, Boston, Mass,
USA. nassir_ghaemi@hms.harvard.edu

OBJECTIVE: We sought to review research on use of antidepressants for long-term
treatment of bipolar depression. METHOD: We conducted a computerized literature
search of the MEDLINE, HealthStar, Current Contents, PsychInfo, and National
Library of Medicine databases to identify studies involving antidepressant,
anticonvulsant, or lithium use in bipolar disorder or manic-depressive illness
published from 1966 through 2000. RESULTS: Only 7 blinded, controlled trials of
long-term antidepressant treatment in bipolar disorders were found. The
available information is not adequate to support the safety or effectiveness of
long-term antidepressant treatment for bipolar depression, with or without
mood-stabilizing cotherapy. CONCLUSION: Antidepressant treatment of bipolar
depression is extraordinarily understudied. Controlled trials comparing specific
antidepressants, particularly to compare mood-stabilizing agents given alone and
combined with an antidepressant, are needed.

———

J Clin Psychiatry. 2001 Jul;62(7):552-5.

Electroconvulsive therapy in medication-nonresponsive patients with mixed mania
and bipolar depression.

Ciapparelli A, Dell’Osso L, Tundo A, Pini S, Chiavacci MC, Di Sacco I, Cassano
GB.

Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology,
University of Pisa, Italy.

BACKGROUND: The aim of this study was to investigate the effectiveness of
electroconvulsive therapy (ECT) in medication-nonresponsive patients with mixed
mania and bipolar depression. METHOD: Forty-one patients with mixed mania
(DSM-IV diagnosis of bipolar I disorder, most recent episode mixed) and 23
patients with bipolar depression (DSM-IV diagnosis of bipolar I disorder, most
recent episode depressed) consecutively assigned to ECT treatment were included
in this study. Subjects were evaluated using the Montgomery-Asberg Depression
Rating Scale (MADRS), the Brief Psychiatric Rating Scale (BPRS), and the
Clinical Global Impressions-Severity of Illness scale (CGI-S). Assessments were
carried out the day before starting ECT, 48 hours after completion of the third
session (T1), and a week after the last session of ECT (T2). RESULTS: Both
groups received an equal number of ECT sessions (mean +/- SD = 7.2 +/- 1.7 vs.
7.3 +/- 1.6). In both groups, within-group comparisons showed that there was a
significant reduction in CGI-S score (mixed mania, p <.0001 at T1 and T2;
bipolar depression, p < .01 at T1, p < .0001 at T2), MADRS total score (both
groups, p < .0001 at T1 and T2), BPRS total score (mixed mania, p < .0001 at T1
and T2; bipolar depression, p < .001 at T1, p < .0001 at T2), and BPRS
activation factor score (mixed mania, p < .0001 at T1 and T2; bipolar
depression, NS at T1, p < .01 at T2). Between-group comparisons revealed that
patients with mixed mania showed significantly greater decrease in MADRS score
(p < .001) and a greater proportion of responders (CGI-S) than patients with
bipolar depression at endpoint (56% [N = 23] vs. 26% [N = 6], p = .02). Patients
with mixed mania showed a greater reduction in suicidality, as measured by MADRS
score, than patients with bipolar depression (p < .02). CONCLUSION: In our
study, ECT was associated with a substantial reduction in symptomatology, in
both patients with mixed mania and those with bipolar depression. However, the
mixed mania group exhibited a more rapid and marked response as well as a
greater reduction in suicidal ideation. Response to ECT was not influenced by
the presence of delusions.

———-

Ann N Y Acad Sci. 2001 Apr;932:24-38; discussion 39-43.

Treating the suicidal patient with bipolar disorder. Reducing suicide risk with
lithium.

Baldessarini RJ, Tondo L, Hennen J.

Department of Psychiatry & Neuroscience Program, Harvard Medical School, and
Bipolar & Psychotic Disorders Program, Mailman Research Center, McLean Division
of Massachusetts General Hospital, Belmont, Massachusetts 02478, USA.
rjb@mclean.org

Bipolar disorder is associated with increased mortality because of complications
of commonly comorbid substance use and stress-sensitive medical disorders as
well as accidents and very high rates of suicide. Long-term lithium treatment
may be associated with reduced suicidal risk. We review and summarize findings
that help to quantify relationships between the presence versus the absence of
lithium maintenance and suicides or attempts in patients with bipolar or other
major affective disorders. Results from 33 studies (1970-2000) yielded 13-fold
lower rates of suicide and reported attempts during long-term lithium treatment
than without it or after it was discontinued. Although greatly reduced, these
rates remain above those estimated for the general population. Evidence for
substantial, if incomplete, protection against suicide with lithium is supported
by more compelling evidence than that for any other treatment provided for
patients with mood disorders. Studies of commonly used, but incompletely
evaluated, alternative treatments are required, and further protection against
premature mortality can be anticipated with better protection against bipolar
depression.

———

J Clin Psychiatry. 2001 Apr;62(4):249-55.

Antidepressant-induced mania in bipolar patients: identification of risk
factors.

Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M.

Service Universitaire de Psychiatrie, Centre Hospitalier Charles-Perrens,
France. chantal.henry@bordeaux.inserm.fr

BACKGROUND: Concerns about possible risks of switching to mania associated with
antidepressants continue to interfere with the establishment of an optimal
treatment paradigm for bipolar depression. METHOD: The response of 44 patients
meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was
assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating
Scale and the Bech-Rafaelson Mania Rating Scale. Patients who experienced a
manic or hypomanic switch were compared with those who did not on several
variables including age, sex, diagnosis (DSM-IV bipolar I vs. bipolar II),
number of previous manic episodes, type of antidepressant therapy used
(electroconvulsive therapy vs. antidepressant drugs and, more particularly,
selective serotonin reuptake inhibitors [SSRIs]), use and type of mood
stabilizers (lithium vs. anticonvulsants), and temperament of the patient,
assessed during a normothymic period using the hyperthymia component of the
Semi-structured Affective Temperament Interview. RESULTS: Switches to hypomania
or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of
patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and
11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs.
bipolar II), and additional treatment did not affect the risk of switching. The
incidence of mood switches seemed not to differ between patients receiving an
anticonvulsant and those receiving no mood stabilizer. In contrast, mood
switches were less frequent in patients receiving lithium (15%, 4/26) than in
patients not treated with lithium (44%, 8/18; p = .04). The number of previous
manic episodes did not affect the probability of switching, whereas a high score
on the hyperthymia component of the Semistructured Affective Temperament
Interview was associated with a greater risk of switching (p = .008).
CONCLUSION: The frequency of mood switching associated with acute antidepressant
therapy may be reduced by lithium treatment. Particular attention should be paid
to patients with a hyperthymic temperament, who have a greater risk of mood
switches.

———

33: J Clin Psychiatry. 2001 Mar;62(3):212-6; quiz 217.

Comment in:
J Clin Psychiatry. 2002 Jan;63(1):77-8.

The clinical features of bipolar depression: a comparison with matched major
depressive disorder patients.

Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS.

School of Psychiatry, University of New South Wales, Australia.
phil.mitchell@unsw.edu.au

BACKGROUND: Despite a resurgence of interest in the treatment of bipolar
depression, there have been few controlled studies of the clinical
characteristics of this condition. Identification of any distinctive clinical
“signatures” of bipolar depression would be helpful in determining treatment
options in the clinical setting. METHOD: From a cohort of 270 inpatients and
outpatients assessed in detail during a DSM-IV major depressive episode, 39
bipolar I disorder patients were identified and closely matched with 39 major
depressive disorder patients for gender, age, and the presence or absence of
DSM-IV melancholic subtype. Patients were compared on a broad range of
parameters including the Hamilton Rating Scale for Depression (depression
severity), 54 depressive symptoms, the Newcastle Endogenous Depression
Diagnostic Index, 3 family history items, 2 physical health items, the CORE
scale (psychomotor disturbance), and 5 history items. RESULTS: Although the
bipolar patients were no more severely depressed than the major depressive
disorder controls, they were more likely to demonstrate psychomotor-retarded
melancholic and atypical depressive features and to have had previous episodes
of psychotic depression. These findings were largely duplicated even when the
population was confined to those with DSM-IV melancholia. CONCLUSION: The
clinical admixture of psychomotor-retarded melancholic signs and symptoms,
“atypical” features, and (less frequently) psychosis may provide a “bipolar
signature” in clinical scenarios when there is uncertainty concerning the
polarity of a depressive presentation.

———

Bipolar Disord. 2001 Feb;3(1):23-9.

Ketoconazole in bipolar patients with depressive symptoms: a case series and
literature review.

Brown ES, Bobadilla L, Rush AJ.

Department of Psychiatry, University of Texas Southwestern Medical Center,
Dallas 75390-9070, USA. sherwood.brown@utsouthwestern.edu

BACKGROUND: Data from several studies suggest that medications, such as
ketoconazole, which lower cortisol levels, may be effective for major depressive
disorder (MDD). As with MDD, the manic, depressive, and mixed phases of bipolar
disorder are frequently associated with elevated cortisol levels. The literature
on the use of cortisol-lowering strategies in mood disorders is reviewed, and a
case series illustrating the use of ketoconazole in bipolar depression is
presented. METHODS: For the review, the MEDLINE and PSYCHINFO databases were
searched, as were the bibliographies of pertinent articles to find papers on the
use of cortisol-lowering agents in patients with mood disorders. In our
open-label case series (n = 6), ketoconazole (up to 800 mg/day) as an add-on
therapy was given to patients with treatment-resistant or intolerant bipolar I
or II disorders with current symptoms of depression. RESULTS: Several case
reports and small open studies suggest that cortisol-lowering agents may be
useful for patients with depression. Two recent placebo-controlled trials of
ketoconazole on patients with MDD report conflicting results. In our case
series, all three patients who received a dose of at least 400 mg/day had
substantial reductions in depressive symptoms. None had significant increases in
mania. However, cortisol levels were not lowered in any of the subjects.
CONCLUSIONS: The literature suggests that cortisol-lowering medications may be
effective for a subset of depressed patients. Our preliminary findings suggest
that ketoconazole may be useful in some patients with bipolar depression. Larger
clinical trials are needed to confirm our observations.

———

Bipolar Disord. 2000 Mar;2(1):56-9.

An open study of methylphenidate in bipolar depression.

El-Mallakh RS.

Department of Psychiatry and Behavioral Sciences, University of Louisville
School of Medicine, KY 40292, USA. rselma01@athena.louisville.edu

BACKGROUND: The treatment of bipolar depression is problematic. Mood stabilizing
agents are often inadequate, while antidepressants may induce mania or mood
destabilization. Methylphenidate has been advocated as an effective
antidepressant agent in unipolar depression, and depression secondary to medical
illness. Amphetamine administration has been shown to reduce manic behavior.
These independent observations suggest that methylphenidate may be a safe and
effective agent in bipolar depression. METHODS: Fourteen depressed subjects with
DSM-IV bipolar illness and a Hamilton-depression (HAM-D) scale score of at least
15 had methylphenidate added to a stable mood stabilizer regiment. Patients were
followed weekly for 4 weeks and then biweekly for an additional 8 weeks.
RESULTS: HAM-D scores dropped from 16.9 +/- 1.79 SD at baseline to 9.4 +/- 9.73
on week 12 (p = 0.12, t = 1.84, df= 6) and 9.8 +/- 7.56 on last observation
carried forward (LOCF) (p = 0.019, t = 2.8, df = 10). Psychiatric symptom
assessment scale (PSAS) scores dropped from 17.9 +/- 5.63 at baseline to 4.8 +/-
7.47 at week 12 (p = 0.016, t = 4.02, df= 4) and 6.3 +/- 6.75 on LOCF (p =
0.007, t = 3.74, df = 7). Three individuals stopped secondary to anxiety,
agitation, and hypomania, respectively. CONCLUSION: In this brief, open study,
methylphenidate was effective and relatively safe in depressed bipolar subjects.

———

Neuropsychopharmacology 1999 Apr;20(4):380-5

Sustained antidepressant effect of sleep deprivation combined with pindolol in
bipolar depression. A placebo-controlled trial.

Smeraldi E, Benedetti F, Barbini B, Campori E, Colombo C

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Italy.

Total sleep deprivation (TSD) shows powerful but transient clinical effects in
patients affected by bipolar depression. Pindolol blocks the serotonergic
5-HT1A autoreceptor, thus improving the antidepressant effect of selective
serotonin reuptake inhibitors. We evaluated the interaction of TSD and pindolol
in the treatment of acute episodes of bipolar depression. Forty bipolar
depressed inpatients were randomized to receive pindolol 7.5 mg/day or placebo
for nine days in combination with three consecutive TSD cycles. Pindolol
significantly improved the antidepressant effect of TSD, and prevented the
short-term relapse after treatment. The response rate (HDRS scores < 8) at the
end of treatment was 15/20 for pindolol, and 3/20 for placebo. Coadministration
of pindolol and TSD resulted in a complete response, which could be sustained
for six months with lithium salts alone, in 65% of cases. This results suggest
a major role for serotonergic transmission in the mechanism of action of TSD,
and makes TSD treatment more effective in the treatment of bipolar depression.

———-

J Clin Psychiatry 1999 Feb;60(2):79-88

A double-blind placebo-controlled study of lamotrigine monotherapy in
outpatients with bipolar I depression. Lamictal 602 Study Group.

Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD

Case Western Reserve University, Cleveland, Ohio, USA.

BACKGROUND: More treatment options for bipolar depression are needed. Currently
available antidepressants may increase the risk of mania and rapid cycling, and
mood stabilizers appear to be less effective in treating depression than mania.
Preliminary data suggest that lamotrigine, an established antiepileptic drug,
may be effective for both the depression and mania associated with bipolar
disorder. This is the first controlled multicenter study evaluating lamotrigine
monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with
bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195)
received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks.
Psychiatric evaluations, including the Hamilton Rating Scale for Depression
(HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating
Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and
Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine
200 mg/day demonstrated significant antidepressant efficacy on the 17-item
HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo.
Improvements were seen as early as week 3. Lamotrigine 50 mg/day also
demonstrated efficacy compared with placebo on several measures. The
proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26%
for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups,
respectively. Adverse events and other safety results were similar across
treatment groups, except for a higher rate of headache in the lamotrigine
groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated
treatment for bipolar depression.

———-

J Clin Psychiatry 1999;60 Suppl 2:77-84; discussion 111-6

Effects of lithium treatment and its discontinuation on suicidal behavior in
bipolar manic-depressive disorders.

Baldessarini RJ, Tondo L, Hennen J

International Consortium for Research on Bipolar Disorders; the Department of
Psychiatry, Harvard Medical School, Boston, Mass, USA.

BACKGROUND: Whether mood-altering treatments reduce risk of suicidal behavior
remains largely unproved. METHOD: We compared suicidal rates in published
studies of patients treated with lithium with those who were not, and in a mood
disorders clinic before, during, and after discontinuing lithium. RESULTS:
Published reports indicate a 7.0-fold lower rate of suicidal acts with lithium
treatment of manic-depressive patients. In new findings in over 300 bipolar
patients, latency from illness onset to lithium maintenance averaged 8.3 years
(from 11.0 years in women with bipolar II disorder to 6.9 years in men with
bipolar I disorder), but half of all suicidal acts occurred in the first 7.5 of
18.3 years at risk. Most acts (89%) occurred during depressive (73%) or
dysphoric-mixed (16%) mood states and were associated with previous severe
depression, prior attempts, and lower age at onset. Morbidity was reduced
2.7-fold and suicidal acts per year 6.5-fold during lithium treatment, with
8.3-fold cumulative sparing of risk by 15 years on lithium. In the first year
off lithium, affective illness recurred in 67% of patients, and suicidal rates
rose 20-fold but were much lower thereafter; fatalities were 14 times more
frequent after discontinuation of lithium. Early morbidity was 2.5-fold lower,
and suicidal risk was 2.0-fold lower after slow versus rapid discontinuation.
CONCLUSION: Lithium maintenance is associated with sustained reduction of
suicidal acts in manic-depressive disorders. Treatment discontinuation,
particularly abruptly, led to early affective morbidity and suicidal behavior.
Improved diagnosis and treatment as well as earlier intervention for
potentially lethal bipolar depression are urgently needed, as are studies of
all mood-altering agents for effects on suicidal behavior.

———-

Am J Psychiatry 1999 May;156(5):798

Pramipexole in refractory bipolar depression.

Goldberg JF, Frye MA, Dunn RT

———-

Eur Arch Psychiatry Clin Neurosci 1998;248(6):296-300

Antidepressant-associated maniform states in acute treatment of patients with
bipolar-I depression.

Bottlender R, Rudolf D, Strauss A, Moller HJ

Psychiatrische Klinik der Ludwig-Maximilians-Universitat, Munich, Germany.
bottlend@psy.med.uni-muechen.de

Medical records of 158 patients with bipolar depression were analysed for the
incidence of a switch from depression to maniform states (mania and hypomania).
Relation to psychopharmacological treatment was investigated. Thirty-nine (25%)
patients of the total sample had switched to a maniform state during the
treatment period in the hospital. Among that group the phenomenon occurred in
23 patients (15%) as a hypomania and in 16 patients (10%) as a mania. Patients
with a switch were significantly more often treated with tricyclic
antidepressants (TCA) than patients without switch (79.5% vs 51.3%). Mood
stabilising medication might reduce the risk for switching, especially in
patients treated with TCA; however, it seems not totally sufficient, since 59%
of the switched patients received mood stabilisers. The switch phenomenon was
not associated with sociodemographic or clinical data.

———-

Psychiatry Clin Neurosci 1998 Dec;52 Suppl:S212-4

Brain imaging of affective disorders and schizophrenia.

Kishimoto H, Yamada K, Iseki E, Kosaka K, Okoshi T

Kanagawa Psychiatric Center Serigaya Hospital, Japan.

We review recent findings in human brain imaging, for example, which brain
areas are used during perception of colors, moving objects, human faces, facial
expressions, sadness and happiness etc. One study used fluorine-18-labeled
deoxyglucose positron emission tomography (PET) in patients with unipolar
depression and bipolar depression, and found hypometabolism in the left
anterolateral prefrontal cortex. Another study reported increased regional
cerebral blood flow in the amygdala in familial pure depressive disease. Using
11C-glucose PET, we reported that the glutamic acid pool was reduced in
cortical areas of the brain in patients with major depression. We also found
that the thalamic and cingulate areas were hyperactive in drug-naive (never
medicated) acute schizophrenics, while the associative frontal, parietal,
temporal gyri were hypoactive in drug-naive chronic schizophrenics. Brain
biochemical disturbances of schizophrenic patients involved glutamic acid,
N-acetyl aspartic acid, phosphatidylcholine and sphingomyelin which are
important chemical substances in the working brain. The areas of the thalamus
and the cingulate which become hyperactive in acute schizophrenic patients are
important brain areas for perception and communication. The association areas
of the cortex which become disturbed in chronic schizophrenia are essential
brain areas in human creativity (language, concepts, formation of cultures and
societies) and exist only in human beings.

———-

J Affect Disord 1998 Sep;50(2-3):203-13

Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical
issues.

Himmelhoch JM

Department of Psychiatry, University of Pittsburgh School of Medicine,
Pennsylvania, USA.

Reports in the literature indicate a subtle but consistent relationship between
panic and bipolar II disorder. The possible connection between social phobia
and bipolarity is less investigated. When we studied the treatment outcome of
32 social phobic patients administered either the reversible monoamine oxidase
inhibitor (RIMA) meclobomide or the irreversible inhibitor MAOI phenelzine, we
found that eighteen had remission > 50% of their socially anxious symptoms.
Moreover, 14/18 of those improved became hypomanic, according to the Raskin
Mania Scale (RMS) and the Young Mania Scale (YMS) coupled with expert clinical
diagnosis. These findings possibly allude to a relationship of social phobia to
bipolarity. Treatment with RIMA or MAOI exposed these subjects as having an
atypical bipolar syndrome which is part of the bipolar spectrum. We then
compared this special subset of subjects to the 18 socially phobic patients who
failed to respond to RIMA’s or MAOI’s and to 26 patients with generalized
anxiety disorder (GAD). Eleven of the 14 hypomanic responders gave histories of
serious developmental deprivation (anaclisis); only 5/18 social phobics and
3/26 GADs without hypomanic responses had anaclitic histories. The author
raises the possibility that anaclisis may have interacted with the impediment
of volition of uncomplicated bipolar depression to produce social inhibition
and anxiety. Finally, the author upholds the central role of depressive
inhibition in bipolar disorder, which during antidepressant therapy often
overshoots in a hypomanic direction; even in the absence of prior spontaneous
hypomania, such disinhibition should classify this special subset of social
phobic patients within the bipolar spectrum.

———-

J Clin Psychiatry 1998;59 Suppl 18:30-6

Bipolar depression: specific treatments.

Potter WZ

Nervous System Disorders, Clinical Research, Lilly Research Laboratories,
Indianapolis, Ind 46285, USA.

From the perspective of pharmacologic treatment, bipolar depression is
considered in this article as belonging to a spectrum of affective disorders.
Insufficient controlled data permit only general recommendations for treatment
of the spectrum of affective disorders, except perhaps for the classic form of
bipolar I disorder. While the field waits for prospective controlled trials, a
wide range of drugs is currently available for the treatment of bipolar
depression. The potential advantages of having an increasing number of agents
with different mechanisms of actions are suggested by the many small studies
claiming some degree of advantage in one or another subgroup of patients with
bipolar depression. Several antidepressants and one anticonvulsant have the
virtue of clinical experience that contributes to a body of information about
side effects and the potential for producing benefit in at least some bipolar
depressed patients. By default, and because they appear to have less chance of
precipitating mania and are otherwise safe, selective serotonin reuptake
inhibitors are probably the most comfortable first-line treatment for bipolar
depression.

———-

Neurosci Lett 1998 Oct 23;255(3):143-6

Serotonin transporter gene polymorphisms in patients with unipolar or bipolar
depression.

Bellivier F, Henry C, Szoke A, Schurhoff F, Nosten-Bertrand M, Feingold J,
Launay JM, Leboyer M, Laplanche JL

Laboratoire de recherche sur les personnalites et conduites adaptatives, CNRS
UMR 7593 Pavillon Clerambault, Hopital Pitie-Salpetriere, Paris, France.
fbell@ext.jussieu.fr

To explore the involvement of serotonin transporter (5HTT) in mood disorder, we
studied two polymorphisms of the 5HTT gene (a variable number of tandem repeats
in the second intron (VNTR) and a 44 bp insertion/deletion in the 5HTT linked
polymorphic region (5-HTTLPR)) in a sample of unipolar and bipolar patients and
controls. Homozygosity for the short variant of the 5-HTTLPR was significantly
more frequent in bipolar patients than in controls (chi2 = 4.68, d.f. = 1, P =
0.03) whereas there was no difference between bipolar patients and controls for
allele distribution, suggesting a recessive effect. The interaction between the
two markers suggests that the two polymorphisms probably have independent
effects to determine the susceptibility to affective disorder. Further studies
are required to identify the precise phenotype associated with 5HTT
polymorphisms in depressed patients.

———-

Med Pregl 1998 Jul-Aug;51(7-8):329-32

[Clinical characteristics of unipolar and bipolar depression].
[Article in Serbo-Croatian (Roman)]

Cvjetkovic-Bosnjak M

Institut za neurologiju, psihijatriju i mentalno zdravlje, Medicinski fakultet,
Novi Sad.

INTRODUCTION: In the last decades affective disorders were divided into
unipolar and bipolar and this division has been generally accepted. The bipolar
type is manifested by mania or by both mania and depression. On the other hand,
unipolar affective disorders are manifested only by depression. In numerous
investigations authors have noticed that there are very distinctive differences
between these two types of depressive disorders such as: course of illness,
personality disorders, sex, family history etc. Nevertheless, in practice it is
often very difficult to make the right diagnosis. The bipolar type often starts
with a few pure depressive episodes and sometimes mania occurs a few years
later so only at that point the psychiatrist can make the right diagnosis and
treat the patient correctly. MATERIAL AND METHODS: This investigation comprised
50 patients hospitalized at the Psychiatric Clinic in Novi Sad during
1992-1995. The experimental group consisted of 20 patients with a bipolar
affective disorder (according to ICD-X), while the control group consisted of
30 patients with clinical diagnosis of unipolar depression (intensive, without
psychiatric features). Both groups of patients were weekly evaluated by
Hamilton Depression Rating Scale (HDRS), whereas the initial score for all
patients had to be higher than 16. RESULTS: Patients suffering from unipolar
depression were older than patients with bipolar depression and there were more
females in this group. There were no differences in demographic characteristics
(level of education, migration, etc.), but the experimental group had a greater
genetic loading for affective disorders. Unipolar depressive patients had more
agitation and they were more anxious than patients with bipolar depression.
DISCUSSION AND CONCLUSION: The fact that unipolar depressive patients were
older than bipolar is similar to most of the results gained in this kind of
investigation. On the other hand, we did not find statistical differences in
the intensity of disorders, and in the literature these results are
contraindicating. Numerous investigators report that bipolar depressives had a
stronger genetic loading for affective disorders and our study confirms the
same. All these results can help us to make the right diagnosis of unipolar and
bipolar affective disorders.

———-

J Clin Psychiatry 1998 Aug;59(8):405-14

Lithium treatment and risk of suicidal behavior in bipolar disorder patients.

Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M

International Consortium for Research on Bipolar Disorders, Department of
Psychiatry, University of Cagliari and Lucio Bini Psychiatric Center, Sardinia.

BACKGROUND: Lithium may exert an antisuicidal effect in bipolar disorder
patients, but this hypothesis requires further testing by direct comparison of
patients with and without lithium treatment. METHOD: Risk of life-threatening
suicidal acts over time and associated factors were analyzed in 310 patients
with DSM-IV bipolar I (N = 186) or II (N = 124) disorder evaluated for a mean
of 8.3 years before, and prospectively during, a mean of 6.4 years of lithium
maintenance in a mood disorder clinic; 185 were also followed for a mean of 3.7
years after clinically discontinuing lithium. RESULTS: In 5233 patient-years of
observation, 58 patients made 90 suicide attempts (8 were fatal). Survival
analyses with Weibull modeling with adjustments for covariates indicated a
highly significant 6.4-fold adjusted hazard ratio during versus before and
7.5-fold ratio after versus during lithium maintenance. Suicidal acts were more
common early in the course of illness before lithium and were associated with
prior suicide attempts, greater proportion of time depressed, and younger age.
After the discontinuation of lithium, suicidal acts were more frequent in the
first year than at later times or before start of lithium treatment. Fatalities
were 9 times more frequent after versus during treatment. CONCLUSION: Lithium
maintenance was associated with marked reduction of life-threatening suicidal
acts, the number of which sharply increased after discontinuing lithium.
Suicidal behavior was strongly associated with prior suicide attempts, more
time depressed, and younger age or recent onset. Greater attention to suicidal
risk in patients with bipolar depression and assessment of all proposed
mood-stabilizing agents for antisuicidal effects are strongly encouraged.

———-

J Clin Psychiatry 1998 Jul;59(7):383-4

Bipolar depression associated with fenfluramine and phentermine.

Zimmer JE, Gregory RJ

———-

J Clin Psychiatry 1998 Jul;59(7):374-9

Bipolar depression and antidepressant-induced mania: a naturalistic study.

Boerlin HL, Gitlin MJ, Zoellner LA, Hammen CL

Department of Psychiatry, University of California, Los Angeles School of
Medicine, UCLA Neuropsychiatric Institute and Hospital, USA.

BACKGROUND: The likelihood and character of antidepressant-induced mania remain
important but poorly understood factors in the treatment of bipolar depression.
METHOD: We examined the response to naturalistic treatment of 29 bipolar I
patients who experienced a total of 79 depressive episodes. Treatment consisted
primarily of mood stabilizers used alone (N = 31) or in combination with
antidepressants (N = 48). Intensity of baseline mood stabilizer therapy,
adequacy of added antidepressant therapy, intensity of ensuing mania or
hypomania, and course of illness prior to study were measured, and selected
comparisons were made between treatment groups. RESULTS: Postdepressive mood
elevations (i.e., switches) that occurred during or up to 2 months after each
depressive episode were present in 28% (22/79) and judged to be severely
disruptive in only 10% (8/79) of episodes. Examining only the first episode per
patient, a history of a greater number of past manic episodes was associated
with a higher risk of switching (p < .023). Antidepressant treatment combined
with mood stabilizer therapy was not associated with higher rates of
postdepressive mood elevation than mood stabilizer therapy alone. At a
descriptive level, subjects treated with tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs) were associated with a higher switch rate
than those treated with fluoxetine; TCAs were also associated with more intense
switches. CONCLUSION: The frequency and severity of postdepressive mood
elevation associated with acute or continuation antidepressant therapy may be
reduced by mood stabilizers. Such elevations may be more likely in patients
with a strong history of mania.

———-

Neuropsychobiology 1998;38(1):6-12

Cortisol, hypothermic, and behavioral responses to ipsapirone in patients with
bipolar depression and normal controls.

Shiah IS, Yatham LN, Lam RW, Tam EM, Zis AP

Division of Mood Disorders, Department of Psychiatry, The University of British
Columbia, Vancouver, B.C., Canada.

To examine if 5-HT1A receptor function is involved in the pathophysiology of
bipolar depression, we measured the cortisol, hypothermic and behavioral
responses to ipsapirone, a 5-HT1A receptor agonist, in 8 patients with bipolar
depression and 26 normal controls. After obtaining blood samples for baseline
cortisol levels and measuring baseline body temperature, a single dose of 0.3
mg/kg of ipsapirone was administered orally to all the subjects, and further
blood and temperature readings were obtained every 30 min for 3 h. The results
showed that the administration of ipsapirone led to a significant increase in
cortisol release and a significant decrease in body temperature both in bipolar
depressed patients and normal controls. There was no significant difference in
the cortisol or hypothermic responses to ipsapirone between groups. However,
there was a significant positive correlation between the Hamilton Depression
Rating (HAMD) scores and the hypothermic response in the depressed patients,
while the HAMD scores were not significantly correlated with the cortisol
response. Comparing our findings with those of previous studies, we suggest
that the alterations in 5-HT1A receptor sensitivity in depressed patients may
be related to the severity of depression, and they may only occur in more
severely depressed patients.

———-

J Clin Psychiatry 1998;59 Suppl 6:74-81; discussion 82

Anticonvulsants and antipsychotics in the treatment of bipolar disorder.

Keck PE Jr, McElroy SL, Strakowski SM

Department of Psychiatry, University of Cincinnati College of Medicine, Ohio
45267-0559, USA.

A number of recent advances in clinical psychopharmacology regarding
anticonvulsant and new antipsychotic medications have important implications
with respect to the treatment of patients who have bipolar disorder. The
authors reviewed the available literature on the efficacy of the
anticonvulsants valproate, carbamazepine, gabapentin, and lamotrigine for the
treatment of bipolar disorder. They also reviewed the use of standard and new
antipsychotic medications for the treatment of various aspects of the illness.
Valproate and carbamazepine have been shown to be effective in the treatment of
acute mania in controlled trials. Preliminary data suggest that these agents
may differ in their time course of antimanic activity and predictors of
response. Neither agent has been extensively studied in controlled trials in
bipolar depression or as maintenance therapy, although carbamazepine has
received the most systematic study in these areas. Gabapentin and lamotrigine
are only now being evaluated in controlled trials in patients who have bipolar
disorder. Antipsychotics are commonly used in the treatment of patients with
acute mania and as maintenance treatment. However, the use of standard
antipsychotics in acute mania is associated with a number of limitations. New
antipsychotic agents may possess thymoleptic as well as antipsychotic activity,
but they have not been studied in controlled trials in bipolar disorder.

———-

J Clin Psychiatry 1998 Jul;59(7):374-9

Bipolar depression and antidepressant-induced mania: a naturalistic study.

Boerlin HL, Gitlin MJ, Zoellner LA, Hammen CL

Department of Psychiatry, University of California, Los Angeles School of
Medicine, UCLA Neuropsychiatric Institute and Hospital, USA.

BACKGROUND: The likelihood and character of antidepressant-induced mania remain
important but poorly understood factors in the treatment of bipolar depression.
METHOD: We examined the response to naturalistic treatment of 29 bipolar I
patients who experienced a total of 79 depressive episodes. Treatment consisted
primarily of mood stabilizers used alone (N = 31) or in combination with
antidepressants (N = 48). Intensity of baseline mood stabilizer therapy,
adequacy of added antidepressant therapy, intensity of ensuing mania or
hypomania, and course of illness prior to study were measured, and selected
comparisons were made between treatment groups. RESULTS: Postdepressive mood
elevations (i.e., switches) that occurred during or up to 2 months after each
depressive episode were present in 28% (22/79) and judged to be severely
disruptive in only 10% (8/79) of episodes. Examining only the first episode per
patient, a history of a greater number of past manic episodes was associated
with a higher risk of switching (p < .023). Antidepressant treatment combined
with mood stabilizer therapy was not associated with higher rates of
postdepressive mood elevation than mood stabilizer therapy alone. At a
descriptive level, subjects treated with tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs) were associated with a higher switch rate
than those treated with fluoxetine; TCAs were also associated with more intense
switches. CONCLUSION: The frequency and severity of postdepressive mood
elevation associated with acute or continuation antidepressant therapy may be
reduced by mood stabilizers. Such elevations may be more likely in patients
with a strong history of mania.

———-

Ann N Y Acad Sci 1997 Dec 29;836:339-51

Effect of lithium maintenance on suicidal behavior in major mood disorders.

Tondo L, Jamison KR, Baldessarini RJ

Department of Psychology, University of Cagliari, Sardinia, Italy.

We reviewed evidence of a possible antisuicide action of lithium maintenance
treatment in mood disorders. Of 28 published studies involving over 17,000
patients with major affective illnesses, most yielded supportive evidence: risk
of suicides and attempts averaged 3.2 versus 0.37 per 100 patient-years without
versus with lithium (8.6-fold difference). In a new study of 284 bipolar I- and
II-disordered patients, corresponding rates (2.2 vs. 0.39/100 patient-years)
differed by 5.6-fold (p < 0.001); moreover, after discontinuing lithium, rates
of suicidal acts rose by 7-fold (16-fold within the first year), and fatalities
increased by nearly 9-fold. Lithium maintenance treatment in recurring major
mood disorders has strong evidence of antisuicide effects not demonstrated with
any other mood stabilizer. Close association of suicide and depression in
bipolar disorder emphasizes the need for improved identification and treatment
of bipolar depression.

———-

J Child Adolesc Psychopharmacol 1998;8(3):181-5

Mixed mania associated with tricyclic antidepressant therapy in prepubertal
delusional depression: three cases.

Strober M

Division of Child and Adolescent Psychiatry, Neuropsychiatric Institute and
Hospital, School of Medicine, University of California at Los Angeles,
90024-1759, USA.

This report describes the sudden appearance of mixed mania in three children
with delusional depression soon after the commencement of tricyclic
antidepressant therapy. The observation is consistent with reports linking
psychomotor abnormalities and psychosis in severely depressed juveniles to an
increased propensity for manic switching, as well as adult studies that report
a greater risk of antidepressant-induced cycling in bipolar compared with
unipolar affective illness. The cases described suggest the need for caution
when considering tricyclic pharmacotherapy in juveniles with severe depressive
disease.

———-

J Clin Psychiatry 1998;59 Suppl 4:73-9

The Expert Consensus Guidelines for treating depression in bipolar disorder.

Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL

Department of Psychiatry, Duke University Medical Center, Durham, NC 27710,
USA.

We present expert consensus guideline recommendations for the treatment of
bipolar depression. These were arrived at through the statistical aggregation
of the survey responses of 61 leading clinical researchers to eight questions
about the key decision points in the management of bipolar depression. The
experts’ first-line recommendation for treating psychotic depression in bipolar
disorder is to provide a combination of mood stabilizer, antidepressant, and
neuroleptic medication. For severe, but nonpsychotic bipolar depression, the
experts recommend the combination of a mood stabilizer and an antidepressant.
For milder bipolar depression, a mood stabilizer and an antidepressant together
or a mood stabilizer alone would be first line. The experts’ antidepressant
dose and dosing schedule recommendations are equivalent for unipolar and
bipolar depression, but the experts recommend a faster discontinuation of
antidepressants during the maintenance phase in bipolar patients–probably to
reduce the risk of rapid cycling. Among the antidepressants, the experts prefer
bupropion and the serotonin reuptake inhibitors as first line. They also
believe that bupropion is least likely among antidepressants to cause switches
to mania. Among mood stabilizers, the experts rate lithium as most likely to
have a direct antidepressant effect.

———-

Ann Clin Psychiatry 1997 Dec;9(4):199-202

Pharmacotherapy of inpatients with bipolar depression.

Howland RH

Western Psychiatric Institute and Clinic, and Department of Psychiatry,
University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.

The pharmacotherapy of bipolar depression has not been well studied. Controlled
studies support the efficacy of some antimanic and antidepressant drugs, but
these studies usually exclude patients typically seen in nonresearch settings.
The purpose of this study was to examine the pharmacotherapy of 69 inpatients
with bipolar depression. More than 90% of the patients received at least one
antimanic drug, and lithium was used most frequently. Only one-half of the
patients received antidepressants. Three-quarters of antidepressant-treated
patients received serotonin reuptake inhibitors or other nontricyclic drugs.
There were few differences between antidepressant- and
non-antidepressant-treated patients. Psychotic patients were more likely to
receive lithium, neuroleptics, and anticholinergics, whereas nonpsychotic
patients tended to receive anticonvulsants more often. Psychotic patients were
also more likely to receive polypharmacy. These results suggest that
polypharmacy of inpatients with bipolar depression is common, and that
psychosis is an important variable in the choice of pharmacotherapy.

PMID: 9511942, UI: 98170893

———-

Psychiatry Res 1997 Nov 14;73(1-2):47-56

Suicidality, panic disorder and psychosis in bipolar depression,
depressive-mania and pure-mania.

Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Tsai-Dilsaver Y, Krajewski KJ

Harris County Psychiatric Center, University of Texas, Houston, USA.

This study was undertaken to assess links between suicidality, panic disorder,
psychosis, bipolar depression, depressive-mania and pure-mania. The subjects
are a consecutive series of 129 persons with bipolar disorder who were admitted
to a university teaching hospital; 53 had bipolar depression, 32 had
depressive-mania and 44 had pure-mania. They met the Research Diagnostic
Criteria (RDC) for major depressive disorder (bipolar depression), primary
mania (pure-mania) or both disorders (depressive-mania) at entry into the
study. Suicidality, intra-episode panic disorder (IEPD) and psychotic features
were ascertained using structured interviews. Sources of data included a
routine clinical interview, serial clinical assessments, the Schedule for
Affective Disorders and Schizophrenia (SADS), the Structured Clinical Interview
for DSM-III-R and reviews of charts. Multivariate logistic regression analysis
was used to determine the strength of the relationships between suicidality,
IEPD, psychotic features and the phase of illness. The rates of suicidality
(79.3%, 56.3% and 2.3%), IEPD (62.3%, 62.5% and 2.3%) and psychotic features
(52.8%, 96.9% and 88.6%) differed significantly between the groups with bipolar
depression, depressive-mania and pure-mania. Subjects with bipolar depression
and depressive-mania resembled one another with respect to the severity, but
not rate of suicidality. They had identical rates of IEPD. Subjects with
bipolar depression had a higher probability of being suicidal and a lower
probability of being psychotic than persons with either subtype of mania.
Pure-mania was distinguished by low rates of suicidality and IEPD. The authors
describe directions for prospective studies of the relationships between phase
of illness and phenomena in groups of bipolar persons.

———-

Life Sci 1997;61(15):1445-55

Comparative studies of the biological distinction between unipolar and bipolar
depressions.

Yatham LN, Srisurapanont M, Zis AP, Kusumakar V

Department of Psychiatry, University of British Columbia, Vancouver, Canada.

Although unipolar depression and bipolar depression are considered distinct
entities both by clinicians and researchers, it is not clear whether a
pathophysiological distinction, which is the bridge between etiology and
treatment, exists between these two conditions. The objective of this paper was
to systematically review the studies that examined the biological differences
between unipolar and bipolar depression. Using computerized Medline and manual
searches, we located and reviewed studies that directly compared patients with
unipolar depression with bipolar depressed patients on at least one biological
variable. The results showed that patients with bipolar depression had lower
levels of urinary NE and its metabolites and lower platelet MAO activity, and
higher platelet free and stimulated intracellular calcium levels compared with
unipolar depressed patients, but none of the variables examined appeared to
differentiate the two groups consistently. We discuss some of the
methodological flaws that might have contributed to this, and suggest that
further studies should control for such confounding variables.

———-

Depress Anxiety 1997;5(4):175-89

Alternative approaches to refractory depression in bipolar illness.

Post RM, Leverich GS, Denicoff KD, Frye MA, Kimbrell TA, Dunn R

Biological Psychiatry Branch, National Institute of Mental Health, NIH,
Bethesda, MD 20892-1272, USA.

Thus, there appears to be a large variety of approaches to refractory bipolar
depression. In contrast to several decades ago, wherein augmentation of lithium
with antidepressants and neuroleptics was essentially the only treatment mode
available, a panoply of treatment options now exist. However, their relative
efficacy in different illness subtypes and stages remains to be better
delineated, as do their optimal sequencing and use in combination in individual
patients. It is the opinion of these authors and many of our colleagues in the
field that initial use of several mood stabilizer drugs in combination may have
a preferable long-term outcome in some rapid cycling patients, compared with
the immediate use of a unimodal antidepressant with an inadequate single mood
stabilizer, although this remains to be systematically studied. The use of
thyroid augmentation strategies would appear to have merit in relationship to
not only the potential treatment of lithium-related hypothyroidism, but also in
augmenting antimanic and antidepressant effects. As one moves toward some of
the complex combination treatment strategies discussed in this chapter, one has
to be particularly careful about drug interactions and their potential for
toxicity as well as therapeutic effects. Perhaps a prevailing guideline would
be to use these agents more carefully in combination therapy than in
monotherapy, with slow upward titration of dose to individual patients’ side
effects thresholds, even in preference to targeting of conventional blood level
windows. In this way, side effects can be avoided during the assessment of
complex combination regimens. In addition, one should be aware of potential
pharmacokinetic interactions. For example, with the addition of valproate to
carbamazepine, one should reduce the dose of carbamazepine, as valproate will
not only increase the free fraction of carbamazepine based on displacement of
protein binding, but will lead to increased accumulation of
carbamazepine-10,11-epoxide. This epoxide is not measured in conventional
assays but could contribute to the side effects profile (Ketter and Post,
1994). Similarly, valproate will markedly increase blood levels of lamotrigine;
the starting dose of this agent should be substantially lower than conventional
dosage when these two drugs are used in combination. We suggest the utility of
detailed mapping with a formal system-such as the Life Chart Methodology (LCM)
(Leverich and Post, 1996)-of mood fluctuation vs. medications in order to
optimize and rationalize complex combination therapy. In this way, not only can
the nuances of partial response be better defined, but also basic decisions
about the therapeutic index and relative likelihood of response can be more
readily assessed. We have discussed the other merits of the life chart method
as an important clinical treatment tool as well as a research tool in other
venues, but reemphasize its potential great importance in the treatment of
refractory cyclic bipolar patients, in whom an initial period of remission of
depression may, in many instances, be as likely attributable to the natural
course of illness as the current intervention being offered. As such, it
behooves the clinician to have a systematic database for the more subtle issues
of dose titration and sequential addition of medications in complex combination
regimens. In the face of inefficiency to one combination strategy, how one
moves to the next strategy remains a highly individualized, clinically-based
algorithm. We suggest the potential utility of moving towards a new set of mood
stabilizers and then repeating some of the unimodal antidepressant additions
and augmentation trials in an attempt to overcome refractory depression.
Refractory depression in bipolar patients should be viewed as a medical
emergency in light of the high potential for suicide in the illness in general
(Chen and Dilsaver, 1996) and in patients who have either sustained or episodic
refractoriness.

———-

Psychiatry Res 1997 Sep 19;72(2):145-8

An open study of lamotrigine in refractory bipolar depression.

Kusumakar V, Yatham LN

Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.

Bipolar depressed patients (n = 22) who were refractory to treatment with a
combination of divalproex sodium (DVP) and another mood stabilizer or DVP and
an antidepressant for 6 weeks were treated in an open naturalistic study with
an addition of lamotrigine to DVP. Sixteen out of 22 (72%) responded by the end
of week 4 and none developed rash or switched to mania. The results of this
preliminary study suggest that lamotrigine may be useful in bipolar depression.

———-

Can J Psychiatry 1997 Aug;42 Suppl 2:87S-91S

Bipolar depression: treatment options.

Yatham LN, Kusumakar V, Parikh SV, Haslam DR, Matte R, Sharma V, Kennedy S

Department of Psychiatry, University of British Columbia, Vancouver.
yatham@unixg.ubc.ca

OBJECTIVE: To review studies on treatments for bipolar depression and make
recommendations for practicing clinicians treating patients with bipolar
depression. METHOD: Studies that examined various treatments for bipolar
depression were evaluated and rated for evidence of efficacy using Periodic
Health Examination criteria. The rating for classification of recommendation
for an intervention was made taking both the efficacy and the side effects into
consideration. RESULTS: Mood stabilizers, cyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) are all
effective in treating bipolar depression. Almost all antidepressant treatments
with the exception of mood stabilizers have been reported to induce a
manic-hypomanic switch and rapid cycling. CONCLUSIONS: Mood stabilizers,
lithium in particular, are recommended as the first-line treatment. Addition of
a second mood stabilizer or a cyclic antidepressant would be an appropriate
next step. Newer agents such as lamotrigine offer considerable promise in
treating bipolar depressed patients.

———-

Can J Psychiatry 1997 Apr;42(3):298-302

Treatment of bipolar depression: a survey of Canadian psychiatrists.

Sharma V, Mazmanian DS, Persad E, Kueneman KM

Mood Disorders Unit, London Psychiatric Hospital, Ontario.

OBJECTIVE: This study was conducted to examine how Canadian psychiatrists
manage bipolar depression. METHOD: A questionnaire specific to the treatment of
bipolar depression was mailed to 1639 active members of the Canadian
Psychiatric Association. RESULTS: Seven hundred and sixty-six completed
questionnaires were returned (46.7%). Most psychiatrists indicated that a
combination of psychotherapy and somatic therapy was their preferred approach.
For bipolar disorder, depressed, lithium carbonate and selective serotonin
reuptake inhibitors (SSRIs) were the preferred treatment strategies. For
substitution, tricyclic antidepressants (TCAs) were the favored choice.
Lithium carbonate was the preferred choice for augmentation and, addition.
CONCLUSION: These findings indicate that a combination of psychotherapy and
somatic therapy is the preferred treatment approach for bipolar depression.
Lithium carbonate and SSRIs are the favored somatic therapies.

———-

J Clin Psychopharmacol 1997 Dec;17(6):460-6

General principles in the pharmacotherapy of antidepressant-induced rapid
cycling: a case series.

Simpson HB, Hurowitz GI, Liebowitz MR

Department of Psychiatry, College of Physicians and Surgeons, Columbia
University, New York, New York, USA.

The treatment of depression in patients who rapidly cycle once they receive
antidepressant medication is a difficult clinical problem. Hurowitz and
Liebowitz presented six patients with antidepressant-induced rapid cycling and
proposed guidelines for how to manage medications in these patients. In this
article, we present six new cases of antidepressant-induced rapid cycling as
well as follow-up from four of the previous cases. We conclude that DSM-IV
criteria are not sufficiently sensitive to diagnose antidepressant-induced
rapid cycling and that the treatment guidelines of Hurowitz and Liebowitz,
although not foolproof, are useful. General recommendations for treating
patients with antidepressant-induced rapid cycling are discussed.

———-

Psychiatry Res 1997 Sep 19;72(2):145-8

An open study of lamotrigine in refractory bipolar depression.

Kusumakar V, Yatham LN

Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.

Bipolar depressed patients (n = 22) who were refractory to treatment with a
combination of divalproex sodium (DVP) and another mood stabilizer or DVP and
an antidepressant for 6 weeks were treated in an open naturalistic study with
an addition of lamotrigine to DVP. Sixteen out of 22 (72%) responded by the end
of week 4 and none developed rash or switched to mania. The results of this
preliminary study suggest that lamotrigine may be useful in bipolar depression.

———-

Can J Psychiatry 1997 Aug;42 Suppl 2:87S-91S

Bipolar depression: treatment options.

Yatham LN, Kusumakar V, Parikh SV, Haslam DR, Matte R, Sharma V, Kennedy S

Department of Psychiatry, University of British Columbia, Vancouver.
yatham@unixg.ubc.ca

OBJECTIVE: To review studies on treatments for bipolar depression and make
recommendations for practising clinicians treating patients with bipolar
depression. METHOD: Studies that examined various treatments for bipolar
depression were evaluated and rated for evidence of efficacy using Periodic
Health Examination criteria. The rating for classification of recommendation
for an intervention was made taking both the efficacy and the side effects into
consideration. RESULTS: Mood stabilizers, cyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) are all
effective in treating bipolar depression. Almost all antidepressant treatments
with the exception of mood stabilizers have been reported to induce a
manic-hypomanic switch and rapid cycling. CONCLUSIONS: Mood stabilizers,
lithium in particular, are recommended as the first-line treatment. Addition of
a second mood stabilizer or a cyclic antidepressant would be an appropriate
next step. Newer agents such as lamotrigine offer considerable promise in
treating bipolar depressed patients.

———-

J Affect Disord 1997 Feb;42(2-3):145-53

Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar
depression and dysthymia.

Pini S, Cassano GB, Simonini E, Savino M, Russo A, Montgomery SA

Institute of Psychiatry, University of Verona, Ospedale Policlinico, Italy.

Eighty-seven patients with current episode of depression were assessed by the
SCID-P and subdivided in bipolar depressives (N = 24), unipolar depressives (n
= 38) and dysthymics (n = 25). Anxiety disorders comorbidity in these three
groups was investigated by means of the SCID-P. Panic disorder comorbidity was
found in 36.8% of bipolar depressives, 31.4% of unipolar depressives and 13% of
dysthymics. Prevalence of obsessive-compulsive disorder was 21.1% in bipolars,
14.3% in unipolars and 8.7% in dysthymics. Generalized anxiety disorder
resulted in being much more associated with dysthymia (65.2%) than with bipolar
(31.6%) or unipolar depression (37.1%). Social phobia comorbidity was exhibited
mainly by unipolars (11.4%), while no cases were detected in the bipolar group.
Odds ratios revealed that generalized anxiety disorder is significantly more
likely to co-occur with dysthymia. Panic disorder showed a higher trend to be
associated with bipolar and unipolar depression. Social phobia was more
frequent among unipolar depression.

———-

Lancet 1997 Jan 18;349(9046):178-9

Amantadine and human Borna disease virus in vitro and in vivo in an infected
patient with bipolar depression.

Bode L, Dietrich DE, Stoyloff R, Emrich HM, Ludwig H
———

Depress Anxiety 1997;5(2):73-83

Bipolar depression: an underestimated treatment challenge.

Hlastala SA, Frank E, Mallinger AG, Thase ME, Ritenour AM, Kupfer DJ

Department of Psychiatry, University of Pittsburgh School of Medicine, Western
Psychiatric Institute and Clinic, PA 15213, USA.

We sought to determine whether depressive and mixed/cycling episodes were as
responsive to standardized pharmacotherapeutic interventions as were manic
episodes in bipolar 1 patients. As part of the Maintenance Therapies in Bipolar
Disorder (MH29618, E. Frank, PI) study, forty-two acutely ill bipolar 1
patients who had been randomly assigned to one of two preliminary phase
non-pharmacologic treatment strategies (interpersonal and social rhythm therapy
[IPSRT] or a standard medication clinic approach) were treated according to a
standardized pharmacotherapeutic protocol. Symptom severity was measured weekly
with the Hamilton Depression Rating Scale and the Bech-Rafaelsen Mania Scale in
order to assess symptomatic remission. Survival analysis with the proportional
hazards model was performed on time to remission. Manic patients were
significantly more likely to achieve clinical remission than the depressed
patients (100 vs. 59%) and did so significantly more rapidly. The difference in
proportion remitting and time to remission between the depressed and
mixed/cycling groups was not statistically significant. No significant effect
for non-pharmacologic treatment assignment was found. These results point to
the need to develop more effective treatments for bipolar depression. They also
suggest that psychotherapy has a limited impact in the acute phase treatment of
bipolar episodes.

———-

Depress Anxiety 1996-97;4(4):190-8

Management of the depressive component of bipolar disorder.

Kalin NH

Department of Psychiatry, University of Wisconsin, Madison 53719, USA.

Acute bipolar depression (ABD) and breakthrough depression occurring during
maintenance therapy of bipolar disorder are associated with significant
morbidity and an increased risk of suicide. Lithium is an effective mood
stabilizer for ABD, but its onset of antidepressant action is slow and
additional antidepressant therapy is often prescribed. The extent to which
other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant
activity is unclear. Preliminary initial research suggests three potential
advantages that selective serotonin reuptake inhibitors have over tricyclic
antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a
lower frequency of antidepressant-induced mania. Bupropion may also have
significant advantages. However, further research is needed to confirm these
findings. Monoamine oxidase inhibitors are the antidepressant of choice for
atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest
response rate of all treatments for ABD. Further research is needed to explore
combination treatments with mood stabilizers and antidepressants for the
effective treatment of ABD.

———-

Encephale 1996 Dec;22 Spec No 7:52-6

[Treatment of bipolar depression].
[Article in French]

Krebs MO

Chargee de Recherche INSERM, Service hospitalo-universitaire de Sante Mentale
et de Therapeutique, CH Sainte-Anne, Faculte Cochin Port-Royal, Paris.

———-

Acta Psychiatr Scand 1996 Dec;94(6):421-7

Atypical depressive symptoms and clusters in unipolar and bipolar depression.

Robertson HA, Lam RW, Stewart JN, Yatham LN, Tam EM, Zis AP

Department of Psychiatry, University of British Columbia, Vancouver, Canada.

In order to examine differences in the atypical symptoms of depression between
unipolar and bipolar patients, we studied 109 depressed patients (79 unipolar
and 30 bipolar subjects) diagnosed with DSM-IV criteria. Patients were assessed
using the Atypical Depression Diagnostic Scale (ADDS), a semi-structured
interview that rates mood reactivity and other atypical depressive symptoms.
Although atypical depression was common in this sample (28% of cases with
definite atypical depression), no differences were found between the unipolar
and bipolar patients in either the atypical symptom profile or the prevalence
of an atypical depression diagnosis. The interrelationships between the
atypical symptoms were also examined using a hierarchical cluster analysis. A
five-cluster solution maximized differences between groups, with results
suggesting that atypical depression may be a heterogeneous diagnosis.

———-

Psychiatr Clin North Am 1996 Jun;19(2):371-86

Treatment algorithms in treatment-resistant depression.

Amsterdam JD, Hornig-Rohan M

Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, USA.

When faced with a patient having treatment-resistant depression, it is
essential to maintain a systematic approach to diagnosis and treatment: 1.
Consider the presence of comorbid medical or psychiatric illness that may
contribute to or cause the refractory state 2. Determine the affective subtype
of depression (e.g., unipolar vs. phenotypic variant of bipolar depression) 3.
Ensure the presence of adequate antidepressant dosage, plasma concentrations
(where applicable), and duration of treatment 4. Apply systematic treatment
algorithms, which means (1) initiate the most efficacious “first-line” therapy
for a specific depressive subtype (even if that is an MAOI) and (2) initiate
augmentation strategies in a systematic fashion. Augmentation strategies should
be initiated only after first reviewing prior therapy, considering available
treatment alternatives, and examining the relative risk:benefit ratio for each
treatment option in the current clinical context. Following these guidelines
should prevent the development of “therapeutic nihilism” in both the patient
and physician, as well as enhance the ultimate treatment outcome for patients
with treatment-resistant depression.

———-

Am J Psychiatry 1996 Oct;153(10):1370

Antidepressant-induced manic switches.

Furukawa T

———-

J Clin Psychopharmacol 1996 Dec;16(6):425-7

Induction of mania with serotonin reuptake inhibitors.

Howland RH

Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, PA 15213, USA.

Serotonin reuptake inhibitors (SRIs) are now considered the first-line
treatment for depression, but they have not been well studied in bipolar
disorder. Recently, some authors have recommended that patients at risk for
antidepressant-induced mania be treated with SRIs rather than tricyclic
antidepressants (TCAs). Clinical information about 11 patients who developed
mania during treatment with SRIs is described. These patients were found to
have personal or family histories of hypomania or mania, but these disorders
were not usually recognized at the time of the patients’ initial treatment for
depression. The SRI-induced manic episodes were also quite severe, having
psychotic features or requiring patients to be secluded for extreme agitation,
but patients responded completely to antimanic treatment. The risk of
treatment-emergent mania with SRIs is not trivial, especially among patients at
risk for bipolar disorder. Additional research is needed to compare the actual
rate of drug-induced mania with SRIs and TCAs in patients with different
bipolar subtypes, while controlling for concurrent antimanic drug use.

———-

Am J Psychiatry 1996 Sep;153(9):1239

Antidepressant-induced cycle acceleration in bipolar disorder.

Simpson HB, Liebowitz MR

Comments:
Comment on: Am J Psychiatry 1995 Aug;152(8):1130-8

———-

Psychiatr Clin North Am 1996 Jun;19(2):215-36

Treatment-resistant bipolar depression.

Sachs GS

Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston, USA.

Patients with treatment-resistant bipolar depression require careful
management, which takes into account the life-threatening potential of their
depression and the risk of iatrogenic mania. Because there are few data
specific to treatment of bipolar depression, much of the approach to bipolar
depression is derived from experience with unipolar depression. There are,
however, important differences between these two illnesses. Compared with
patients with unipolar illness, patients with bipolar depression more likely
experience antidepressant benefit from mood-stabilizing medication and,
therefore, avoid the risks of antidepressant medication. Treatment of comorbid
anxiety and substance abuse improves response. The risk of treating bipolar
patients can be reduced but not avoided. Improved outcome may be achieved by
careful assessment, prospective mood charting, and attempts to taper
antidepressant medications after an appropriate continuation phase.

———-

J Clin Psychopharmacol 1996 Apr;16(2 Suppl 1):15S-23S

Outcome in the pharmacologic treatment of bipolar disorder.

Keck PE Jr, McElroy SL

Department of Psychiatry, University of Cincinnati College of Medicine, Ohio,
USA.

Outcome studies of bipolar disorder, the majority of which were conducted
before the use of lithium, divalproex, and carbamazepine, generally found that
only 50 to 60% of patients achieved good recovery 6 to 12 months after a manic
episode. Over the past decade, a number of new pharmacologic studies have
provided further information regarding the acute and long-term outcome of
patients with bipolar disorder treated with these medications. In addition,
better operational criteria to define outcome have been advanced, allowing for
easier extrapolation of the results of clinical trials to clinical practice. We
review the outcome of studies of lithium, divalproex, and carbamazepine in the
acute treatment of episodes of mania and bipolar depression and in the
maintenance treatment of bipolar disorder and the implications of these studies
to clinical practice.

———-

Depress Anxiety 1996-97;4(4):190-8

Management of the depressive component of bipolar disorder.

Kalin NH

Department of Psychiatry, University of Wisconsin, Madison 53719, USA.

Acute bipolar depression (ABD) and breakthrough depression occurring during
maintenance therapy of bipolar disorder are associated with significant
morbidity and an increased risk of suicide. Lithium is an effective mood
stabilizer for ABD, but its onset of antidepressant action is slow and
additional antidepressant therapy is often prescribed. The extent to which
other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant
activity is unclear. Preliminary initial research suggests three potential
advantages that selective serotonin reuptake inhibitors have over tricyclic
antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a
lower frequency of antidepressant-induced mania. Bupropion may also have
significant advantages. However, further research is needed to confirm these
findings. Monoamine oxidase inhibitors are the antidepressant of choice for
atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest
response rate of all treatments for ABD. Further research is needed to explore
combination treatments with mood stabilizers and antidepressants for the
effective treatment of ABD.

———-

Am J Psychiatry 1995 Aug;152(8):1130-8

Antidepressant-induced mania and cycle acceleration: a controversy revisited.

Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L

Brentwood VA Medical Center, Los Angeles, USA.

OBJECTIVE: The longitudinal course of 51 patients with treatment-refractory
bipolar disorder was examined to assess possible effects of heterocyclic
antidepressants on occurrence of manic episodes and cycle acceleration. METHOD:
Using criteria established from life charts, investigators rated the patients’
episodes of mania or cycle acceleration as likely or unlikely to have been
induced by antidepressant therapy. Discriminant function analyses were
performed to assess predictors of vulnerability to antidepressant-induced mania
or cycle acceleration. Further, the likelihood of future antidepressant-induced
episodes in persons who had had one such episode was assessed. RESULTS:
Thirty-five percent of the patients had a manic episode rated as likely to have
been antidepressant-induced. No variable was a predictor of vulnerability to
antidepressant-induced mania. Cycle acceleration was likely to be associated
with antidepressant treatment in 26% of the patients assessed. Younger age at
first treatment was a predictor of vulnerability to antidepressant-induced
cycle acceleration. Forty-six percent of patients with antidepressant-induced
mania, but only 14% of those without, also showed antidepressant-induced cycle
acceleration at some point in their illness. CONCLUSIONS: Mania is likely to be
antidepressant-induced and not attributable to the expected course of illness
in one-third of treatment-refractory bipolar patients, and rapid cycling is
induced in one-fourth. Antidepressant-induced mania may be a marker for
increased vulnerability to antidepressant-induced cycle acceleration.
Antidepressant-induced cycle acceleration (but not antidepressant-induced
mania) is associated with younger age at first treatment and may be more likely
to occur in women and in bipolar II patients.

Comments:
Comment in: Am J Psychiatry 1996 Sep;153(9):1239

———-

Can J Psychiatry 1995 Nov;40(9):533-44

Treatment of acute bipolar depression: a review of the literature.

Srisurapanont M, Yatham LN, Zis AP

Department of Psychiatry, University of British Columbia, Vancouver.

OBJECTIVE: Our goal was to ascertain the efficacy of various antidepressant
treatments for acute bipolar depression. METHOD: English articles that reported
on the efficacy of antidepressant treatments in bipolar depression were located
by computerized Medline and manual search. These studies were systematically
reviewed and response rates for each treatment were computed. RESULTS: The
available data suggest that mood stabilizers, MAOIs, cyclic antidepressants,
and ECT are all effective in treating bipolar depression. All antidepressant
treatments with the exception of mood stabilizers have been reported to induce
a manic/hypomanic switch. CONCLUSIONS: It is recommended that mood stabilizers
may be the first step of treatment, followed by the addition of an
antidepressant, especially a cyclic antidepressant. The specific symptoms
profile of individual patients, such as anergic or psychotic features, may
indicate more specific treatment options. ECT is an important measure for those
who are pharmacotherapy-resistant or psychotic.

———-

J Clin Psychiatry 1995 Jun;56(6):260-4

Prescribing trends of antidepressants in bipolar depression.

Zarate CA Jr, Tohen M, Baraibar G, Kando JC, Mirin J

Pharmacoepidemiology Center, McLean Hospital, Belmont, Mass. 02178, USA.

BACKGROUND: This study utilizing pharmacoepidemiologic methods was undertaken
to determine the prescribing patterns of antidepressants particularly in
bipolar depression. METHOD: From pharmacy records of the McLean Hospital, the
number of patients receiving antidepressants and given electroconvulsive
therapy (ECT) from June 1, 1987, to May 8, 1993, was determined. We later
linked these data bases with patients who were diagnosed with DSM-III-R bipolar
depression (296.5) during the same period of time. RESULTS: During the 6-year
period, it was determined that 3829 inpatients had received tricyclic
antidepressants (TCAs), 2981 fluoxetine, 2603 trazodone, 809 bupropion, 743
monoamine oxidase inhibitors (MAOIs), 592 stimulants, 588 sertraline, 48
paroxetine, and 894 ECT. There were significant increases over time in
prescriptions of MAOIs compared with fluoxetine (chi 2 = 14.36, p = .006), and
bupropion compared with TCAs (chi 2 = 6.45, p = .04). There was a trend for
bupropion to be prescribed more over time compared with fluoxetine (chi 2 =
5.09, p = .08). There were no significant changes in the prescribing of other
antidepressants or in the use of ECT. CONCLUSION: At our center, prescribing of
bupropion and MAOIs in bipolar depression has increased significantly. This may
be related to the reports in the literature of the low switch rates to mania
with the use of these drugs.

———-

Can J Psychiatry 1995 Jun;40(5):270-4

A comparison of comorbid patterns in treatment-resistant unipolar and bipolar
depression.

Sharma V, Mazmanian D, Persad E, Kueneman K

Mood Disorders Unit, London Psychiatric Hospital, Ontario.

OBJECTIVE: To examine the occurrence of concomitant psychiatric disorders in
patients with treatment-resistant unipolar and bipolar depression. METHOD:
Forty-nine patients participated as subjects. Twenty-four (49%) had unipolar
depression and 25 (51%) had bipolar depression using DSM-III-R criteria.
Structured clinical interviews were conducted with all patients. Chart reviews
and interviews with family members were also carried out. Information relating
to both current and lifetime diagnoses was obtained. RESULTS: Of the entire
sample, 75.5% were found to have at least one other Axis I diagnosis and 46.9%
had at least two additional Axis I diagnoses. The unipolar group had
significantly more current comorbid diagnoses. When type of diagnoses was
examined, unipolar patients had significantly more anxiety diagnoses at the
time of the index episode, and over their entire lifetime. Bipolar patients had
significantly more lifetime substance abuse diagnoses. CONCLUSIONS: Axis I
comorbidity appears to be differentially associated with treatment resistance
in unipolar and bipolar depression.

———-

J Clin Psychiatry 1994 Dec;55(12):533-5

Is there a role for neuroleptics in bipolar depression?

Hendrick V, Altshuler LL, Szuba MP

Department of Psychiatry and Biobehavioral Sciences, University of California,
Los Angeles School of Medicine.

BACKGROUND: Lithium, carbamazepine, and valproic acid reduce relapse rates in
most bipolar patients. However, some patients with bipolar illness fail to
obtain antidepressant benefits from these medications, despite appropriate
dosages of and duration on therapy with these drugs. METHOD: Three bipolar
patients were followed in an open fashion on thymoleptic and neuroleptic
medications. With discontinuation of neuroleptics, each patient relapsed into
depression and was then restarted on neuroleptic treatment. RESULTS: These
three patients responded rapidly to readministration of neuroleptics to their
pharmacologic regimen. CONCLUSION: Some bipolar patients experience depressive
relapse following neuroleptic discontinuation. With reinstitution of the
neuroleptic, they show rapid improvement in mood.

———-

J Clin Psychiatry 1994 Sep;55(9):391-3

A double-blind trial of bupropion versus desipramine for bipolar depression.

Sachs GS, Lafer B, Stoll AL, Banov M, Thibault AB, Tohen M, Rosenbaum JF

Department of Psychiatry, Harvard Medical School, Boston, Mass.

BACKGROUND: Although treatment of bipolar depression is a frequent clinical
problem, double-blind studies of the treatment of bipolar depression are
scarce. Some case series and uncontrolled data suggest antidepressants may
differ in their propensity to induce mania or their efficacy for bipolar
depression. METHOD: The authors conducted a prospective double-blind trial to
assess efficacy and rate of treatment-emergent mood elevation in depressed
bipolar patients when bupropion or desipramine was added to an ongoing
therapeutic regimen of lithium or an anticonvulsant. Results were assessed
after 8 weeks of acute treatment and during maintenance treatment up to 1 year.
RESULTS: No difference was found for acute efficacy between the two drugs.
Mania/hypomania was observed in 5 of 10 desipramine-treated patients, but only
1 of 9 bupropion-treated patients. The occurrence of hypomania or mania was
correlated with treatment group (Kendall’s tau correlation = 0.42; Z = -2.5, p
< .012). CONCLUSION: These pilot findings suggest that bupropion is less likely
to induce mood elevation than desipramine. For treatment of bipolar depression,
bupropion and desipramine appear to have similar antidepressant efficacy.

PMID: 7929019, UI: 95014093

———-

Biol Psychiatry 1994 Apr 15;35(8):539-44

Elevated cerebrospinal fluid protein in men with unipolar or bipolar
depression.

Samuelson SD, Winokur G, Pitts AF

Department of Psychiatry, Kansas City Veterans Administration Medical Center
64128.

We studied a large sample of rigorously diagnosed, generally unmedicated
patients with major depressive disorder (n = 179), bipolar affective disorder
(n = 102), or schizophrenia (n = 125) to determine if increased cerebrospinal
fluid (CSF) protein is associated with a particular diagnosis or gender. Men
had a higher mean CSF protein level than women across all diagnoses (p <
0.001). There were no differences across diagnosis among the female patients.
Men with unipolar depression had a higher mean CSF protein content than other
male patients (n = 0.029), but depressed bipolar males had an equivalently
elevated mean level. Considered apart from unipolar or bipolar diagnosis, the
depressive syndrome was strongly associated with increased CSF protein in men
(p = 0.004); again, there was no difference across type of illness (depression
versus mania) among women. Elevated CSF protein content seems to be associated
with illness syndrome rather than diagnosis, and may represent an important
finding among men with depression.

———-

Ann Clin Psychiatry 1994 Mar;6(1):45-9

Severe imipramine-induced myoclonus in a patient with psychotic bipolar
depression, catatonia, and schizencephaly.

Black KJ, Kilzieh N

Department of Psychiatry, Washington University School of Medicine, St. Louis,
Missouri 63110.

Mild myoclonus is reasonably common with various cyclic antidepressants.
However, antidepressants rarely cause severe myoclonus, and no risk or
predisposing factors have been reported in the literature. We report a case of
exceptionally severe myoclonus developing at therapeutic doses and modest serum
levels of imipramine. The patient went on to experience dystonia and catatonia.
Both of these were in typical settings (after haloperidol and with psychotic
bipolar depression, respectively) and responded to typical treatment. On
further investigation, the patient was found to have left-sided schizencephaly
and a corresponding history of very mild developmental delay. We suggest that
the onset of one movement disorder after drug therapy (eg, myoclonus) may
predict the development of other movement disorders (e.g., catatonia). We
further propose that severe tricyclic-induced myoclonus should prompt the
physician to rule out a coexisting structural lesion of the central nervous
system.

———-

J Psychosom Res 1994;38 Suppl 1:55-60

Sleep disorders in bipolar depression: hypnotics vs sedative antidepressants.

Saiz-Ruiz J, Cebollada A, Ibanez A

Department of Psychiatry, Hospital Ramon y Cajal, Madrid, Spain.

Ninety-six patients with bipolar disorder who attended a lithium clinic were
reviewed in a retrospective study. Sleep disorders were studied in 85
depressive episodes. Eighty-one percent of the subjects presented with
insomnia; the mixed type being the most frequent (49%) followed by early
awakening (25%). The evolution of depression in the patients was compared
according to the treatment received for insomnia: sedative antidepressants vs
other anxiolytic or hypnotic drugs. Fifteen percent of patients shifted to
mania, this group more frequently receiving sedative antidepressants (p <
0.05). Moreover, the patients who had received sedative antidepressants as
therapy for insomnia (N = 61) showed a tendency to have a shorter asymptomatic
interval before the following relapse (13 months vs 19 months; p = 0.06). In
view of these results, we consider that the use of sedative antidepressants as
a treatment for insomnia during depressive episodes in bipolar patients could
be a factor contributing to worse prognoses; in these cases it appears that the
use of other hypnotic drugs would be more advisable.

———-

J Clin Psychopharmacol 1993 Feb;13(1):52-6

Antidepressant-induced rapid cycling: six case reports.

Hurowitz GI, Liebowitz MR

Department of Psychiatry, Columbia University College of Physicians and
Surgeons, New York, New York.

We report six cases of rapid mood cycling induced by antidepressant treatment.
The key to effective treatment involved the recognition of the pattern of
apparent remission, relapse, antidepressant and/or stimulant adjustment,
remission, relapse, etc. Hypomanic episodes were frequently mild and could be
mistaken for remission. The destabilizing effects of antidepressant drugs were
not corrected by the addition of mood stabilizers, necessitating the withdrawal
of the antidepressant agent. All but one case responded to such withdrawal. Two
cases required the addition of high-dose L-thyroxine for stabilization.
Implications for an effective treatment protocol are discussed.

———-

J Clin Psychopharmacol 1993 Dec;13(6):397-408

Treatment of depression in bipolar disorder: new directions for research.

Zornberg GL, Pope HG Jr

Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA 02178.

The objective of the study was to review the clinical literature on the acute,
somatic treatment of the depressed phase of bipolar disorder. We reviewed all
available published studies of “standard” somatic treatments (lithium,
antidepressant and anticonvulsant agents, and electroconvulsive therapy [ECT])
reporting three or more depressed bipolar patients who were not psychotic,
rapid cycling, or previously treatment refractory. We also reviewed all studies
of “nonstandard” pharmacologic treatments involving even a single case of a
depressed bipolar patient. Data sources included the MEDLINE database and
relevant references from articles obtained in this search and in major reviews.
Five of seven studies comparing ECT with antidepressant agents find ECT more
efficacious. Eight of nine controlled comparisons find lithium superior to
placebo in depressed bipolar patients. Three controlled comparisons of lithium
to tricyclic antidepressants suggest that lithium is equivalent to tricyclic
drugs in such patients. Three double-blind, controlled studies indicate that
carbamazepine is more effective than placebo. Limited data on other
antidepressant classes suggest that monoamine oxidase inhibitors, bupropion,
and serotonergic agents may offer some advantages over tricyclic
antidepressants in this population. Some “nonstandard” treatments also show
some potential in bipolar patients. The possibility of switching into a manic
episode is an important consideration with many of the agents studied, although
little remains known about spontaneous versus treatment-associated mood shifts.
In contrast to the extensive literature on the acute treatment of the manic
phase of bipolar disorder and on the prophylaxis of manic and depressive
episodes, there are few studies of treatment of the depressed phase of bipolar
disorder, and their results generally are limited or inconclusive. Lithium
generated a revolution in psychiatric treatment, but the treatment of the
depressed phase of bipolar disorder remains a relatively neglected corner of
the field. Several study designs may help to augment knowledge in the treatment
of bipolar depression.

———-

Psychol Rep 1992 Dec;71(3 Pt 1):706

Bipolar depression as the prelude to schizoaffective disorder.

Goldwert M

School of Humanities, New York Institute of Technology, NY 10023.

Contending that the mind of a creative person is often characterized by thin
boundaries between the ego and the unconscious, this paper proposes how, on the
manic side of bipolar depression, a creative ego may temporarily make great
strides in intellectuality and creativity. However, as this process proceeds, a
creative ego may lose its boundaries with the unconscious, and a
schizoaffective disorder may emerge.

———-

Biol Psychiatry 1992 Jul 1;32(1):33-47

Abnormal cerebral laterality in bipolar depression: convergence of behavioral
and brain event-related potential findings.

Bruder GE, Stewart JW, Towey JP, Friedman D, Tenke CE, Voglmaier MM, Leite P,
Cohen P, Quitkin FM

Department of Biopsychology, New York State Psychiatric Institute, NY 10032.

Cerebral laterality in bipolar and unipolar major depression was compared using
visual half-field and dichotic listening measures of perceptual asymmetry. The
results replicate our prior finding of abnormal laterality in bipolar depressed
patients on a visuospatial test. Bipolar patients (n = 11) failed to show the
left visual field (right hemisphere) advantage for dot enumeration seen for
both unipolar patients (n = 43) and normal controls (n = 24). Bipolar patients
performed significantly poorer than unipolar patients on normal controls for
left visual field, but not right visual field stimuli. An electrophysiological
correlate of abnormal visual field asymmetry in bipolar depression was found in
brain event-related potentials recorded during audiospatial and temporal
discrimination tasks. Bipolar patients had smaller N100 amplitudes for test
stimuli in the left than right hemifield, whereas unipolar patients and normals
did not. The origins of left hemifield deficits in bipolar depression are
discussed in terms of right-sided dysfunction of an arousal/attentional system
involving temporoparietal and possibly frontal regions.

———-

Am J Psychiatry 1992 Feb;149(2):195-8

Treatment of imipramine-resistant recurrent depression, IV: A double-blind
crossover study of tranylcypromine for anergic bipolar depression.

Thase ME, Mallinger AG, McKnight D, Himmelhoch JM

Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213.

OBJECTIVE: Few trials of monoamine oxidase inhibitors (MAOIs) in
tricyclic-resistant depression have had double-blind conditions. In the
authors’ previous double-blind comparison of tranylcypromine and imipramine in
anergic bipolar depression, tranylcypromine was significantly more effective.
This investigation was a crossover study of nonresponders in the initial study.
METHOD: The subjects were 16 outpatients with anergic bipolar depression.
Fourteen had not responded to 4 weeks of treatment with at least 30 mg/day of
tranylcypromine or 150 mg/day of imipramine, and two patients were crossed over
because of intolerable side effects from the initial drug. The crossover
medication was prescribed as in the initial double-blind study. RESULTS: Twelve
patients were crossed over from imipramine to tranylcypromine; nine of them
responded to tranylcypromine. Highly significant improvements were documented
on the Hamilton, Beck, and Pittsburgh Reversed Vegetative Symptom Scales. Four
patients were switched from tranylcypromine to imipramine, but only one
responded. CONCLUSIONS: The high rates of response to tranylcypromine in both
the initial and crossover double-blind studies document the efficacy of MAOI
treatment for anergic bipolar depression. Moreover, the results further
illustrate the utility of MAOIs in tricyclic-resistant depressions.

———-

Am J Psychiatry 1991 Sep;148(9):1177-81

Hypersomnia in bipolar depression: a comparison with narcolepsy using the
multiple sleep latency test.

Nofzinger EA, Thase ME, Reynolds CF 3d, Himmelhoch JM, Mallinger A, Houck P,
Kupfer DJ

Department of Psychiatry, University of Pittsburgh School of Medicine, PA.

OBJECTIVE: This study characterized objectively the hypersomnia frequently seen
in the depressed phase of bipolar affective disorder. On the basis of previous
work in sleep and affective disorders, it has been hypothesized that the
hypersomnia is related to greater REM sleep. This hypothesis was tested by
using a multiple sleep latency test to compare bipolar affective disorder with
narcolepsy, a well-defined primary sleep disorder associated with known REM
sleep dysfunction. METHOD: Twenty-five bipolar depressed patients were selected
on the basis of complaints of hypersomnia. They underwent 2 nights of
polysomnography followed by a multiple sleep latency test. Data on their
nocturnal sleep and daytime naps were compared with similar data on 23
nondepressed narcoleptic patients referred for sleep evaluation. RESULTS:
Despite their complaints of hypersomnia, no abnormalities were noted for the
bipolar group in the results from the multiple sleep latency test. Contrary to
the working hypothesis, REM sleep was notably absent during daytime naps in the
depressed patients, in marked contrast to the findings for the narcoleptic
group. CONCLUSIONS: The complaint of sleepiness in the hypersomnic bipolar
depressed patient appears to be related to the lack of interest, withdrawal,
decreased energy, or psychomotor retardation inherent in the anergic depressed
condition, rather than an increase in true sleep propensity or REM sleep
propensity.

———-

Am J Psychiatry 1991 Jul;148(7):910-6

Tranylcypromine versus imipramine in anergic bipolar depression.

Himmelhoch JM, Thase ME, Mallinger AG, Houck P

Department of Psychiatry, University of Pittsburgh School of Medicine, PA.

OBJECTIVE: This investigation compared the efficacy of the monoamine oxidase
inhibitor (MAOI) tranylcypromine with that of the tricyclic imipramine in the
treatment of anergic bipolar depressive illness. METHOD: A controlled,
double-blind comparison was used to study 56 outpatients who met
operationalized criteria for anergic bipolar depression. Patients with bipolar
I and II depression were equally distributed between comparison groups. Outcome
was measured by the patient-rated Beck Depression Inventory and the
clinician-rated Hamilton Rating Scale for Depression, Raskin Mania and
Depression Scales, Clinical Global Impression Scale, and the Pittsburgh
Reversed Vegetative Symptom Scale. Twenty-eight patients were treated with
tranylcypromine and 28 with imipramine. Seventy-three percent of bipolar
depressive patients screened for the study met criteria for anergic depression,
consistent with previous findings from studies in bipolar illness that stretch
back over 100 years. RESULTS: Tranylcypromine produced statistically
significant superior outcome in terms of lower attrition, greater symptomatic
improvement, and higher global response without increased risk of
treatment-emergent hypomania or mania. CONCLUSIONS: The authors propose that
the apparently superior efficacy of tranylcypromine in bipolar depression is
specifically linked to anergia and reversed neurovegetative symptoms. Bipolar I
and bipolar II patients had comparable outcomes, but bipolar I patients had a
significantly greater risk of treatment-emergent mood swings. Although the
relatively poor showing of imipramine warrants close scrutiny, these findings
provide further documentation of the utility of MAOIs in patients presenting
with anergia, motor retardation, hyperphagia, and/or hypersomnia.

———-

Psychiatr Pol 1991 May-Aug;25(3-4):76-82

[Transition from the depressive stage to the manic stage during the treatment
with antidepressive drugs].
[Article in Polish]

Koszewska I, Puzynski S

II Kliniki Psychiatrycznej Instytutu Psychiatrii i Neurologii.

The effects of antidepressant drugs on phase switching was studied in 602
individuals treated for endogenous depression. Altogether 869 depressed phases
were evaluated retrospectively–there were 470 depressed phases in the course
of bipolar affective disorder and 399 of unipolar disorder or with the
undefined course. Switching from depression to mania was observed in patients
with bipolar disorder–in 27.9% of cases of bipolar depression and in 21.5% of
bipolar patients. Most frequently the switching was observed during management
of depressed phase with amitriptyline (24.4% of treatments with this drug). The
results point to a role of cholinergic system in pathophysiology of switching
out of depression into mania during treatment with antidepressant drug.

———-

J Psychiatr Res 1991;25(4):185-90

Tyramine conjugation test distinguishes unipolar from bipolar depressed
patients and controls.

Hale AS, Sandler M, Hannah P, Glover V, Bridges PK

Department of Psychiatry, United Medical School, St. Thomas’ Hospital, London.

Tyramine sulphate conjugation following oral tyramine administration (the
tyramine test) has previously been found to distinguish endogenous unipolar
from neurotic depression and appears to be a trait marker. In this study, the
test was used in 24 unipolar depressed patients compared with similar sized
matched groups of bipolar depressed patients and normal controls. Most of the
depressed patients in each group showed endogenous features. The study found
that whereas tyramine sulphate conjugation was significantly impaired in
unipolar patients, values in the bipolars were similar to those of controls.
These results provide further evidence for the biological difference between
unipolar and bipolar depression.

———-

Int Clin Psychopharmacol 1989 Oct;4(4):313-22

A comparison of fluoxetine imipramine and placebo in patients with bipolar
depressive disorder.

Cohn JB, Collins G, Ashbrook E, Wernicke JF

Department of Psychiatry, University of California, Los Angeles.

This was a 6-week, double-blind comparison of fluoxetine, imipramine, and
placebo in 89 patients with bipolar depression. Using the criteria of greater
than or equal to 50% improvement in the HAMD-total score after at least 3 weeks
on study drug, endpoint analysis showed 86% of the fluoxetine-treated patients
improved compared with 57% of the imipramine-treated and 38% of the
placebo-treated patients. Significantly fewer fluoxetine-treated patients
discontinued due to adverse events than did imipramine-treated patients (7% vs.
30%, respectively).

———-

Am J Psychiatry 1989 Mar;146(3):329-33

Sleep EEG and DST findings in anergic bipolar depression.

Thase ME, Himmelhoch JM, Mallinger AG, Jarrett DB, Kupfer DJ

University of Pittsburgh School of Medicine, Western Psychiatric Institute and
Clinic, PA 15213.

The authors report sleep EEG and dexamethasone suppression test (DST) findings
for a homogeneous sample of anergic bipolar depressed outpatients (bipolar I, N
= 7; bipolar II, N = 19) characterized by motor retardation, volitional
inhibition, hypersomnia, or weight gain and sleep EEG findings for 26 age- and
sex-matched normal control subjects. Sleep architecture was abnormal in bipolar
depression, particularly with respect to little stage 1 sleep. The biological
profile of an anergic episode of bipolar depression did not include a shorter
than normal mean REM latency, poor sleep continuity, or abnormally low amounts
of stages 3 and 4 sleep, and only three (13%) of 23 patients manifested
cortisol nonsuppression.

———-

Psychiatry Res 1989 Jan;27(1):23-9

Lithium delays circadian phase of temperature and REM sleep in a bipolar
depressive: a case report.

Campbell SS, Gillin JC, Kripke DF, Janowsky DS, Risch SC

Institute for Circadian Physiology, Boston, MA 02215.

The effects of lithium on the circadian rhythms of body temperature and rapid
eye movement (REM) sleep were examined in a patient with bipolar depression.
The acrophase of body temperature showed a phase delay of 74 min after 1 week
of lithium treatment. REM latency increased significantly with lithium, and the
onset of subsequent REM periods was also delayed. The proportion of the night
spent in REM sleep decreased significantly. There was no effect of lithium on
the patient’s mood. The data are consistent with the hypothesized
phase-delaying properties of lithium but do not support the causal link between
circadian phase and affective state.

———-

Neurophysiol Clin 1988 Apr;18(2):141-51

[Neuroendocrine rhythms in uni- and bipolar depressions].
[Article in French] Linkowski P, Van Cauter E, Kerkhofs M, Hubain P, Brasseur M, Leclercq R,
Golstein J, Copinschi G, Mendlewicz J

Service de psychiatrie, Hopital Erasme, Universite libre de Bruxelles,
Belgique.

Eighteen patients with major depressive disorder of the endogenous subtype (8
unipolars and 10 bipolars) were submitted to blood sampling at 15 min interval
for 24 h with polygraphic sleep recording during an acute episode of
depression. Plasma growth hormone (GH), adrenocorticotrophin (ACTH) and
cortisol were measured in each sample. The depressed patients hypersecreted GH
during the daytime and had hypercortisolism which was evident throughout the 24
h span. The nadir of ACTH and cortisol rhythms was advanced by an average of 3
h as compared to the timing observed in normal subjects. These abnormalities
were more pronounced and more consistent in patients with unipolar rather than
bipolar depression. These results are consistent with the hypothesis that
disorders of circadian time-keeping may characterize major endogenous
depression.

———-

Hillside J Clin Psychiatry 1988;10(2):165-72

Diagnosis and subtyping of depressive disorders by quantitative
electroencephalography: III. Discriminating unipolar from bipolar depression.

Lieber AL, Newbury ND

Department of Psychiatry, St. Francis Hospital, Miami Beach, Florida.

One hundred fifty-two inpatient major depressives fulfilled the Research
Diagnostic Criteria for unipolar (N = 111) or bipolar (N = 41) affective
disorder. After at least seven days drug-free, all patients had a thyrotropin
releasing hormone stimulation test (TRHST), a dexamethasone suppression test
(DST) and quantitative electroencephalography (QEEG). Multivariate analysis of
variance was used to compare post-dexamethasone cortisol, delta TSH, six
regional QEEG measures of interhemispheric symmetry and six focal measures of
QEEG frequency. Age, sex and diagnosis were included in the analysis. Unipolar
depressives were discriminated from bipolar depressives by age, delta TSH and
QEEG fast wave abnormalities in the alpha and beta frequency bands. Unipolar
depressives were significantly older, had lower mean delta TSH, showed
excessive alpha activity and deficient beta activity. Bipolar depressives were
younger, had higher mean delta TSH, showed a deficit of alpha activity and
excessive beta activity. Unipolar might be discriminable from bipolar major
depression by the use of two objective procedures–TRHST and QEEG. The two
disorders appear to be biochemical and electrophysiological opposites.
Treatment implications are discussed.

———-

J Affect Disord 1987 Jul-Aug;13(1):83-92

Verbal memory deficits associated with major affective disorders: a comparison
of unipolar and bipolar patients.

Wolfe J, Granholm E, Butters N, Saunders E, Janowsky D

Psychology Service, Boston VA Medical Center, MA 02130.

The verbal learning and fluency of patients with unipolar and bipolar
depression were compared to those of normal controls and patients with
Huntington’s disease. The data demonstrated that the recall and recognition
performance of both groups of depressed patients were impaired relative to the
performance of normal control subjects. The bipolar patients, however, were
more impaired than the unipolar patients on both tasks (P less than 0.024 and P
less than 0.022, respectively). In addition, the unipolar patients generated
more correct responses on a test of verbal fluency (P less than 0.04). The
performance of the bipolar patients was, in fact, similar to that of patients
with Huntington’s disease, a progressive degenerative disorder that primarily
affects subcortical areas.

———-

Biol Psychiatry 1986 May;21(5-6):465-72

Latency of eye movement and other REM sleep parameters in bipolar depression.

Jernajczyk W

Parameters of rapid eye movement (REM) sleep were measured in 10 endogenous
bipolar depressive drug-free patients and in healthy subjects. A significant
reduction of eye movement latency and larger standard deviations in the values
for activity and density of eye movement were found in the depressed patients.
The method applied in this study, embodying an aspect of cybernetic theory in
pattern recognition, proved very useful for the elaboration of the biological
data.

———-

Br J Hosp Med 1985 Sep;34(3):172-5

Drug treatment of bipolar depression and mania.

Cookson JC

Bipolar manic-depressive disorder may present as mania, depression, or mixed
states, and there is increasing knowledge of its responsiveness to drugs as
therapeutic agents. In addition a number of drugs may act as aggravating
factors for the disorder.

———-

Acta Psychiatr Scand Suppl 1985;320:30-7

Clinical and neuroendocrine features of endogenous unipolar and bipolar
depression.

Gurpegui M, Casanova J, Cervera S

A group of 19 patients suffering from endogenous unipolar depression was
compared with another group of eight patients with bipolar depression.
Comparisons were based on psychopathological features together with results of
the dexamethasone suppression test and the thyrotropin releasing hormone
stimulation test. Unipolar patients showed more frequent loss of weight,
reduced appetite, autonomic disturbances, muscular tension, sadness, and
reduced sexual interest, whereas bipolar patients showed more frequent hostile
feelings. Each neuroendocrine test identified at least 50% of the patients in
each group. The combined use of both tests identified about 75% of the
patients. The bipolar depressives obtained slightly but not significantly
higher rates of positive results in each test and a more frequent association
of abnormality in both tests.

———-

Psychol Med 1982 Feb;12(1):25-36

Behavioral measurement and drug response characteristics of unipolar and
bipolar depression.

Katz MM, Robins E, Croughan J, Secunda S, Swann A

This research is part of the NIMH–CRB Collaborative Study on the psychobiology
of depression. The main objective of the research program is to test
hypotheses concerning the interaction of neurobiological mechanisms and
behavior in the depressive disorders. Part I of the report describes the
rationale and the overall approach to measuring behavioral state and outcome
in the research program. Part II reports on the results of applying the
behavioral methods to a comparison of the clinical phenomenology of unipolar
and bipolar depression. The behavioral patterns expressed during the episode
by the two groups are different. Further, the two types are shown to react
differently to treatment with tricyclic drugs, reinforcing the thesis that they
are qualitatively distinct forms of the depressive disorders.

———-

Scott Med J 1981 Jul;26(3):235-9

Morphological studies in a case of thyrotoxicosis complicated by lithium
therapy for bipolar depression.

McLaren KM, Toft AD

The histological and ultrastructural features of the thyroid in a case of
thyrotoxicosis complicated by lithium therapy (for bipolar depression) are
described. Despite the bizarre and disturbing pathological appearances, it is
proposed that their interpretation should be modified in view of the
biosynthetic block imposed by lithium administration. The cellular appearances
are considered to reflect a hyperplastic state with coincidental impairment of
synthetic activity, and not to represent a neoplastic process. The use of
lithium in the management of psychiatric illness is increasing. It is important
to be aware of the possible effect of the drug not only on thyroid function but
also on the histopathological appearances of the thyroid when interpreting any
associated or incidental lesion of the gland.

———-

Psychiatry Res 1980 Dec;3(3):265-71

Prolactin secretion in women with unipolar and bipolar depression.

Linkowski P, Brauman H, Mendlewicz J

Plasma prolactin levels and prolactin response to thyrotropin releasing hormone
(TRH) were studied in 27 unipolar and 24 bipolar depressive female patients
before and after tricyclic antidepressant treatment, as well as in 38 normal
controls matched for age, sex, and menopausal status. Before antidepressant
treatment, basal prolactin levels were significantly lower in both
premenopausal and postmenopausal bipolar patients but only in postmenopausal
unipolar patients when compared to controls. The prolactin response to TRH was
significantly blunted in both unipolar and bipolar postmenopausal subjects but
remained normal in all premenopausal (unipolar and bipolar) patients. These
data suggest that prolactin pituitary function could be useful in the
neuroendocrine study of depressive illness.

———-

Psychiatry Res 1980 Oct;3(2):225-36

Symptom patterns in unipolar and bipolar depression correlating with monoamine
metabolites in the cerebrospinal fluid: II. Suicide.

Agren H

Suicidality scores from the Schedule for Affective Disorders and Schizophrenia
on 21 unipolar and 12 bipolar depressives were correlated with monoamine
metabolites in the cerebrospinal fluid using multiple regression analyses. The
single item of Suicidal Tendencies Worst Week correlated highly significantly
and negatively with 3-methoxy-4-hydroxyphenylglycol (MHPG) and only to a very
slight degree with 5-hydroxyindoleacetic acid (5HIAA). Seriousness of Intent of
Worst Suicide Attempt earlier in life correlated significantly and negatively
with both MHPG and 5HIAA. Subjective Anger was positively and Overt Anger
negatively associated with thoughts of suicide. The results support earlier
reports that depressives with low 5HIAA are prone to violent suicides, but also
point to the equal, if not even greater involvement of MHPG and noradrenergic
neuronal systems in carrying out a wish for death.

———-

Psychiatry Res 1980 Oct;3(2):211-23

Symptom patterns in unipolar and bipolar depression correlating with monoamine
metabolites in the cerebrospinal fluid: I. General patterns.

Agren H

The symptom scores on the Schedule for Affective Disorders and Schizophrenia
(SADS) of 21 unipolar and 12 bipolar depressive patients diagnosed with
Research Diagnostic Criteria (RDC) were correlated with the monoamine
metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG),
and 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid (CSF). For
the unipolar group, multiple regression analyses revealed strong multiple
correlations (from r = 0.92 to 0.97) to the effect that high- and low-HVA,
high- and low-MHPG, and high- and low-5HIAA syndromes, respectively, could be
isolated. The bipolars were too few for the same analyses to work well, but
there is evidence for the high- and low-monoamine syndromes to be characterized
by differential symptomatology in bipolar and unipolar patients. Through the
comparison of monoamine metabolite values predicted from a total of 18 SADS
symptom items with the true CSF values, a computer program was able to classify
20 of the 21 unipolar and all the 12 bipolars correctly. The results are
consistent with a hypothesis of the pathoplastic role of individually set
(genetically determined?) brain monoamine homeostasis in shaping the profile of
an affective episode.

———-

Psychiatry Res 1980 May;2(2):199-204

The thyroid-stimulating hormone response to thyrotropin-releasing hormone in
mania and bipolar depression.

Extein I, Pottash AL, Gold MS, Cadet J, Sweeney DR, Davies RK, Martin DM

The release of thyroid-stimulating hormone (TSH) from the pituitary after
infusion of 500 microgram of thyrotropin-releasing hormone (TRH) was decreased
(p < 0.01) in manic patients and increased (p < 0.01) in bipolar depressed
patients compared to a control group of patients with personality disorders.
These results suggest that the TRH test may be useful in the diagnosis of
psychiatric disorders and in the prediction of response to pharmacotherapy. We
discuss the role of central monoaminergic systems in changes in the TSH
response to TRH.

———-

Lancet 1979 Nov 17;2(8151):1079-80

TSH responses to TRH in women with unipolar and bipolar depression.

Mendlewicz J, Linkowski P, Brauman H

———-

Adolescence 1979 Fall;14(55):617-20

Bipolar depression (manic-depressive disease) in early adolescence.

Weizman A, Weizman R, Tyano S, Wijsenbeek H

Bipolar Depression is rare in early adolescence. Since only rare cases were
described in the literature, every case is important. In this article we
described three cases of Bipolar Depression who were hospitalized in our
Adolescent Unit during the past three years. All of them started at age 13–14.
It is important to diagnose this illness in order to administer the required
treatment in the acute phase and preventive treatment afterwards. Our
experience indicates that treatment for early adolescents is identical with
treatment for adults and calls for the same dosage.

———-

Arch Gen Psychiatry 1978 Aug;35(8):1017-21

Thyrotrophin-releasing hormone (TRH) stimulation test in manic-depressive
illness.

Kirkegaard C, Bjorum N, Cohn D, Lauridsen UB

The thyrotrophin (TSH) response to thyrotrophin-releasing hormone (TRH 200
microgram intravenously was studied in 19 patients with unipolar depression, 12
with bipolar depression, 14 with mania, and 5 with mixed manic-depressive
illness. The TSH responses were decreased in all of these affective disorders
compared to those found in 10 patients with reactive depression, 5 with
reactive paranoid psychosis, 14 with neurotic depression, and 60 controls. The
decrease of the TSH response in manics could not be accounted for by the
effects of neuroleptic drugs. The TSH response in the groups with reactive
depression, reactive paranoid psychosis, and neurotic depression, respectively,
did not differ significantly from that found in controls. With the exception of
a decrease in serum T3 level and free T3 index in the manics, no significant
differences in serum T3 level or in free T3 and T4 indexes were found between
the groups. Changes found in serum T4 level were due to changes in the
thyroxine-binding proteins.

no