Drug Treatment of Bipolar Disorder

A MEDLINE search by Ivan Goldberg, MD

1: J Clin Psychiatry. 2003;64 Suppl 8:35-40.

Decision tree for the treatment of bipolar disorder.

Sachs GS.

Partners Bipolar Treatment Center, Massachusetts General Hospital, Boston,
Mass., USA. sachsg@aol.com

Clinicians managing patients with bipolar disorder confront a myriad of complex
treatment decisions. This complexity limits the practicality of treatment
guidelines, which attempt to be comprehensive. A user-friendly guide can,
however, be constructed by considering only the most common early critical
decision points likely to be encountered in the management of bipolar patients:
new onset of an acute manic or mixed episode, interepisode treatment entry, and
initial treatment for acute bipolar depression. Three general treatment
principles, i.e., use proven treatments first, use a mood stabilizer in every
phase of the illness, and use a multiphase treatment strategy to link current
assessment with an appropriate treatment plan, can be applied to guide decision
making at critical decision points that follow entry into clinical care. To
guide the selection of appropriate therapeutic agents, a simple grading system
can be used to evaluate the weight of evidence supporting use of various
options. Multiple high-quality studies with positive results support the use of
lithium, divalproex, carbamazepine, olanzapine, and haloperidol as initial
intervention for acute mania; other agents with positive results in one
double-blind mania trial are reasonable first-line alternatives. In the absence
of high-quality evidence to guide treatment selection for nonacutely ill bipolar
patients, guidelines recommend maintenance mood-stabilizer treatment. Standard
antidepressant medications do not appear to add statistically significant
benefit beyond that of mood stabilizers alone; lithium and lamotrigine have
shown some benefit, and promising preliminary data have been presented on the
antidepressant benefit of divalproex and topiramate as well.
2: J Clin Psychiatry. 2003;64 Suppl 8:30-4.

Newer anticonvulsants: dosing strategies and cognition in treating patients with
mood disorders and epilepsy.

Meador KJ.

Department of Neurology, Medical College of Georgia, Augusta, USA.

BACKGROUND: Anticonvulsants are employed to treat a variety of disorders. The
most common adverse side effects of anticonvulsants are mediated via the central
nervous system. Examples include sedation, dizziness, psychomotor slowing, and
impairment of attention, memory, and other cognitive functions. Since multiple
new anticonvulsants have been introduced in recent years, the question arises as
to the frequency and magnitude of their cognitive side effects. METHODS:
Experimental design flaws in assessing the cognitive effects of anticonvulsants
were reviewed. A MEDLINE search of the medical literature was conducted,
cross-referencing terms related to cognition and anticonvulsants. Research
articles were selected based on their relevance to the topic and adherence to
methodological criteria. RESULTS: Incomplete information is available on the new
anticonvulsants, but the present data suggest that some of the newer
anticonvulsants possess favorable cognitive profiles. Also, the importance of
dosing regimens and titration speed at drug initiation is discussed. CONCLUSION:
All anticonvulsants possess some cognitive side effects, but differential
effects can be seen. The cognitive effects of several newer anticonvulsants have
been examined, but additional studies are needed to fully establish the
cognitive effects of these agents. Dosage, titration rate at initiation,
comedications, individual sensitivity, and underlying disease processes may
influence cognitive side effects. Understanding these factors is important to
maximize the benefits of anticonvulsant therapy. Cognitive side effects are one
of the factors that physicians should consider in drug choice and monitoring of
their patients.
3: J Clin Psychiatry. 2003;64 Suppl 8:9-14.

Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders.

Evins AE.

Schizophrenia Research Program, Department of Psychiatry, Massachusetts General
Hospital, Boston, USA. a_eden_ewin@hms.harvard.edu

BACKGROUND: More treatment options for all phases of bipolar disorder are
needed. While lithium, valproate, and carbamazepine remain the standard of care
for treatment of bipolar disorder, many patients do not respond adequately to
these treatments. Some new antiepileptic medications such as lamotrigine,
gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide are beginning
to be used to treat bipolar disorder. DATA SOURCES: Evidence for effectiveness
of these novel antiepileptic drugs in treating acute mania and depression as
well as in preventing the recurrence of mania and depression is reviewed. A
MEDLINE search (1966-2001) was performed for clinical trials that were published
in English using the keywords lamotrigine, gabapentin, topiramate,
oxcarbazepine, tiagabine, and zonisamide, plus the terms bipolar disorder and
mania. Evidence for effectiveness of monotherapy is presented first when it is
available. Data from augmentation treatment studies and open case series in
which standard ratings of symptoms were employed are presented when these are
the only available data. DATA SYNTHESIS: Twenty-eight reports of the efficacy of
novel antiepileptic medications in bipolar disorder are reviewed. Evidence is
strongest for lamotrigine monotherapy in patients with bipolar depression, in
some patients with rapid-cycling bipolar disorder, and as prophylaxis. Evidence
for the efficacy of topiramate in acute and refractory mania is promising but
comes predominantly from open trials. Although some very small studies have
found that oxcarbazepine and zonisamide may have some effectiveness for treating
mania, these data are very preliminary. Results are mixed from the 2 small open
trials of tiagabine. Although gabapentin is widely used in bipolar disorder,
controlled data do not support the use of gabapentin as an antimanic medication
or mood stabilizer. CONCLUSION: More controlled trials are needed to assess the
effectiveness of novel antiepileptic medications in bipolar disorder.
4: Biol Psychiatry. 2003 Jul 1;54(1):9-16.

An open trial of bupropion for the treatment of adults with
attention-deficit/hyperactivity disorder and bipolar disorder.

Wilens TE, Prince JB, Spencer T, Van Patten SL, Doyle R, Girard K, Hammerness P,
Goldman S, Brown S, Biederman J.

Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts, USA.

BACKGROUND: Despite the increasing recognition of comorbid
attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in
adults, there are no prospective trials of pharmacological agents to treat ADHD
in these patients. Given the efficacy of bupropion for ADHD in adults, as well
as its use in the management of bipolar depression, we studied the tolerability
and efficacy of sustained-release (SR) bupropion in adults with ADHD plus BPD.
METHODS: This was an open, prospective, 6-week trial of bupropion SR (up to 200
mg b.i.d.) in adults with DSM-IV ADHD plus historical bipolar I disorder (BPD I)
(10%) or bipolar II disorder (BPD II) (90%). Adults receiving adjunct antimanic
agents (mood stabilizers and antipsychotics) at baseline were included in the
study. We used standardized psychiatric instruments for diagnosis and outcome.
Efficacy was based primarily on the Clinical Global Impression Scale (CGI) for
ADHD and the ADHD symptom checklist. RESULTS: Of 36 patients entered (75% male,
mean age 34 years), 30 patients (83%) completed the protocol. At end point (last
observation carried forward [LOCF]) compared to baseline, treatment with
bupropion SR resulted in significant reductions in the ADHD symptom checklist
(-55%, z = 5.63, p <.001) and CGI severity of ADHD (-40%, z = 6.285, p <.001).
Bupropion was associated with reductions in ratings of mania and depression.
CONCLUSIONS: The results from this open study of adults with ADHD plus BPD
suggest that sustained-release bupropion may be effective in treating ADHD in
the context of a lifetime diagnosis of BPD, without significant activation of
mania. Further controlled trials are warranted.
5: Psychol Rep. 2003 Jun;92(3 Pt 1):1031-9.

Depression in inpatients: bipolar vs unipolar.

Dorz S, Borgherini G, Conforti D, Scarso C, Magni G.

Affective Disorders Unit, Casa di Cura Parco dei Tigli-Padova, Italy.

162 depressed inpatients were divided into three diagnostic groups to compare
patterns of sociodemographic characteristics, psychopathology, and psychosocial:
35 had a single episode of major depression, 96 had recurrent major depression,
and 31 had a bipolar disorder. Psychopathology and psychosocial functioning were
measured by clinician-rated scales, Montgomery-Asberg Depression Rating Scale,
Hamilton Rating Scale for Depression, Clinical Global Impression, and
self-rating scales, Symptom Checklist-90, Social Support Questionnaire, Social
Adjustment Scale. The three groups were comparable on sociodemographic
variables, with the exception of education. Univariate analyses showed a similar
social impairment as measured by Social Support Questionnaire, Social Adjustment
Scale, and no significant differences were recorded for the psychopathology when
the total test scores (Montgomery-Asberg Depression Rating Scale, Hamilton
Rating Scale for Depression, Clinical Global Index, Symptom Checklist-90) were
evaluated. Some differences emerged for single items in the Montgomery-Asberg
Depression Rating Scale and Symptom Checklist-90. These findings suggest a
substantial similarity among the three groups. Results are discussed in terms of
the clinical similarities between unipolar and bipolar patients during a
depressive episode as well as the limitations of cross-sectional study implies.
6: 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.
7: Biochem Pharmacol. 2003 Jul 15;66(2):179-89.

Search for a common mechanism of mood stabilizers.

Harwood AJ, Agam G.

MRC Laboratory for Molecular Cell Biology, University College London, Gower St.,
London, WC1E 6BT, UK. a.harwood@ucl.ac.uk

Manic-depression, or bipolar affective disorder, is a prevalent mental disorder
with a global impact. Mood stabilizers have acute and long-term effects and at a
minimum are prophylactic for manic or depressive poles without detriment to the
other. Lithium has significant effects on mania and depression, but may be
augmented or substituted by some antiepileptic drugs. The biochemical basis for
mood stabilizer therapies or the molecular origins of bipolar disorder is
unknown. One approach to this problem is to seek a common target of all mood
stabilizers. Lithium directly inhibits two evolutionarily conserved signal
transduction pathways. It both suppresses inositol signaling through depletion
of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a
multifunctional protein kinase. A number of GSK-3 substrates are involved in
neuronal function and organization, and therefore present plausible targets for
therapy. Valproic acid (VPA) is an antiepileptic drug with mood-stabilizing
properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene
expression through inhibition of histone deacetylase. These effects, however,
are not conserved between different cell types. VPA also inhibits inositol
signaling through an inositol-depletion mechanism. There is no evidence for
GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In
contrast, this drug alters neuronal morphology through an inositol-depletion
mechanism as seen with lithium and VPA. Studies on the enzyme prolyl
oligopeptidase and the sodium myo-inositol transporter support an
inositol-depletion mechanism for mood stabilizer action. Despite these
intriguing observations, it remains unclear how changes in inositol signaling
underlie the origins of bipolar disorder.
8: J Clin Psychiatry. 2003 Jun;64(6):680-90; quiz 738-9.

Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective
ratings on the NIMH life chart method.

Post RM, Denicoff KD, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Rush AJ,
Keck PE Jr, McElroy SL, Luckenbaugh DA, Pollio C, Kupka R, Nolen WA.

Stanley Foundation Bipolar Network and Biological Psychiatry Branch, National
Institute of Mental Health, National Institutes of Health, Bethesda, MD
20892-12723, USA. robert.post@nih.gov

BACKGROUND: A number of recent longitudinal outcome studies have found
substantial long-term morbidity in patients with bipolar disorder. The detailed
course and pattern of illness emerging despite comprehensive treatment with mood
stabilizers and adjunctive agents have previously not been well delineated.
METHOD: 258 consecutive outpatients admitted from 1996 to 1999 to the Stanley
Foundation Bipolar Network who had a full year of prospective daily clinician
ratings on the National Institute of Mental Health-Life Chart Method were
included in the analysis. Patients were diagnosed by the Structured Clinical
Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They
completed a questionnaire on demographics and prior illness course, and
variables associated with outcome were examined in a hierarchical multinomial
logistic regression analysis. Patients were treated naturalistically with a mean
of 4.1 psychotropic medications during the year. RESULTS: Despite comprehensive
pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold
higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes
per year. Two thirds of the patients were substantially impacted by their
illness; 26.4% were ill for more than three fourths of the year, and 40.7% were
intermittently ill with major affective episodes. After logistic regression
analysis, those who were ill most of the year, compared with the largely well
group, had a significantly greater family history of substance abuse, 10 or more
depressive episodes, and limited occupational functioning prior to Network
entry. CONCLUSION: A majority of outpatients with bipolar illness, even with
intense monitoring and treatment in specialty clinics, have a considerable
degree of residual illness-related morbidity, including a 3-fold greater amount
of time spent depressed versus time spent manic. A personal or family history of
substance abuse, 10 or more prior depressions, and limited occupational
functioning predicted the poorest outcomes. Additional interventions,
particularly those targeted at treating depressive phases of bipolar illness,
are greatly needed.
9: J Consult Clin Psychol. 2003 Jun;71(3):482-92.

Family-focused treatment versus individual treatment for bipolar disorder:
results of a randomized clinical trial.

Rea MM, Tompson MC, Miklowitz DJ, Goldstein MJ, Hwang S, Mintz J.

Department of Psychiatry, University of California, Los Angeles, USA.

Recently hospitalized bipolar, manic patients (N = 53) were randomly assigned to
a 9-month, manual-based, family-focused psychoeducational therapy (n = 28) or to
an individually focused patient treatment (n = 25). All patients received
concurrent treatment with mood-stabilizing medications. Structured follow-up
assessments were conducted at 3-month intervals for a 1-year period ofactive
treatment and a 1-year period of posttreatment follow-up. Compared with patients
in individual therapy, those in family-focused treatment were less likely to be
rehospitalized during the 2-year study period. Patients in family treatment also
experienced fewer mood disorder relapses over the 2 years, although they did not
differ from patients in individual treatment in their likelihood of a first
relapse. Results suggest that family psychoeducational treatment is a useful
adjunct to pharmacotherapy in decreasing the risk of relapse and hospitalization
frequently associated with bipolar disorder.
10: Biol Psychiatry. 2003 Jun 1;53(11):1028-42.

Rationale, design, and methods of the systematic treatment enhancement program
for bipolar disorder (STEP-BD).

Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, Lavori P,
Lebowitz B, Rudorfer M, Frank E, Nierenberg AA, Fava M, Bowden C, Ketter T,
Marangell L, Calabrese J, Kupfer D, Rosenbaum JF.

Partners Bipolar Treatment Center, Department of Psychiatry, Massachusetts
General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was
conceived in response to a National Institute of Mental Health initiative
seeking a public health intervention model that could generate externally valid
answers to treatment effectiveness questions related to bipolar disorder.
STEP-BD, like all effectiveness research, faces many design challenges,
including how to do the following: recruit a representative sample of patients
for studies of readily available treatments; implement a common intervention
strategy across diverse settings; determine outcomes for patients in multiple
phases of illness; make provisions for testing as yet undetermined new
treatments; integrate adjunctive psychosocial interventions; and avoid biases
due to subject drop-out and last-observation-carried-forward data analyses. To
meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data
as patients make transitions between naturalistic studies and randomized
clinical trials. Bipolar patients of every subtype with age >/= 15 years are
accessioned into a study registry. All patients receive a systematic assessment
battery at entry and are treated by a psychiatrist (trained to deliver care and
measure outcomes in patients with bipolar disorder) using a series of model
practice procedures consistent with expert recommendations. At every follow-up
visit, the treating psychiatrist completes a standardized assessment and assigns
an operationalized clinical status based on DSM-IV criteria. Patients have
independent evaluations at regular intervals throughout the study and remain
under the care of the same treating psychiatrist while making transitions
between randomized care studies and the standard care treatment pathways. This
article reviews the methodology used for the selection and certification of the
clinical treatment centers, training study personnel, the general approach to
clinical management, and the sequential treatment strategies offered in the
STEP-BD standard and randomized care pathways for bipolar depression and relapse
11: 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

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.
12: Can J Psychiatry. 2003 May;48(4):258-64.

Switch to mania upon discontinuation of antidepressants in patients with mood
disorders: a review of the literature.

Ali S, Milev R.

Queen’s University, Kingston, Ontario. shereseali@hotmail.com

OBJECTIVE: To review the literature for reported cases of mania related to
discontinuing antidepressant treatment, as well as for possible explanations of
this phenomenon, and to present a case report. METHOD: We undertook a literature
review through the PubMed index, using the key words mania, antidepressant
withdrawal, and antidepressants in bipolar disorder. We reviewed 11 articles
featuring 23 cases. Where available, we noted and tabulated certain parameters
for both bipolar disorder (BD) and unipolar depression. We use a case example to
illustrate the phenomenon of mania induced by antidepressant withdrawal.
RESULTS: For patients with unipolar depression, we found 17 reported cases of
mania induced by antidepressant withdrawal. Antidepressants implicated included
tricyclic antidepressants (TCAs) (12/17), monoamine oxidase inhibitors (MAOIs)
(2/17), trazodone (1/17), mirtazapine (1/17), and paroxetine (1/17). For
patients with BD, we found 19 reported cases of mania induced by antidepressant
withdrawal, including our own case example. Of these, selective serotonin
reuptake inhibitors (SSRIs) (10/19), TCAs (4/19), MAOIs (2/19), and serotonin
norepinephrine reuptake inhibitors (SNRIs) (2/19) were implicated. CONCLUSION:
Our case report supports the observation of antidepressant withdrawal-induced
mania in patients with BD. It is distinguishable from antidepressant-induced
mania, physiological drug withdrawal, and mania as a natural course of the
illness. Many theories have been put forward to explain this occurrence.
Noradrenergic hyperactivity and “withdrawal-induced cholinergic overdrive and
the cholinergic-monoaminergic system” are the 2 most investigated and supported
models. The former is limited by poor clinical correlation and the latter by its
applicability only to anticholinergic drugs.
13: J Clin Psychiatry. 2003 May;64(5):532-9.

Safety of available agents used to treat bipolar disorder: focus on weight gain.

Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA. cnemero@emory.edu

BACKGROUND: Pharmacotherapeutic management of bipolar disorder has advanced
considerably since the introduction of lithium therapy nearly 50 years ago. The
sizable percentage of patients who do not respond adequately to lithium and/or
are intolerant to its side effects has served as an impetus for identifying
alternative pharmacotherapeutic agents. Recent advances in the understanding of
the neurotransmitter systems and their receptors as it applies to treatment of
bipolar disorder has, in part, led to progress in delineating applications of
anticonvulsant/antiepileptic drugs (AEDs) in this area. Although the efficacy of
many drugs has been evaluated in patients with this disorder, medication
tolerability and adherence issues related to unfavorable side effect profiles
are substantial impediments to the development of novel pharmacotherapies. The
potential for excessive weight gain as a side effect of certain
psychopharmacologic agents remains a concern to both clinicians and patients.
METHOD: English-language literature from 1985-2001 in MEDLINE was searched for
the terms bipolar disorder, anticonvulsant, antiepileptic, lithium,
antipsychotic, weight, and compliance. This article reviewed current therapeutic
options for bipolar disorder, including newer AEDs and atypical antipsychotic
drugs, with emphasis on the issue of weight gain and possible approaches to
minimizing this risk. RESULTS: Certain newer AEDs are characterized by more
favorable safety and tolerability profiles that include weight loss as a
desirable side effect. Because bipolar disorder is associated with unacceptably
high rates of relapse, recurrence, and morbidity, the concept of
pharmacotherapeutic efficacy logically not only includes symptom relief but also
necessarily encompasses issues related to regimen tolerability and adherence.
CONCLUSION: There is a need for guidelines to help physicians carefully
formulate and individualize management plans to reach safe, effective, and
cost-efficient patient outcomes. Monitoring the weight of patients with bipolar
disorder and educating them regarding this issue should be standard components
of any treatment plan.
14: CNS Drugs. 2003;17(7):491-511.

Suicidal behaviour in bipolar disorder: risk and prevention.

Tondo L, Isacsson G, Baldessarini R.

Department of Psychology, University of Cagliari, Centro Lucio Bini-Stanley
Medical Research Institute Research Center, Cagliari, Sardinia, Italy.

Bipolar (manic-depressive) disorder is a common and severe illness. It is also
potentially fatal as a result of accidents and increased mortality associated
with comorbid substance use and medical illnesses, but its highest lethality
results from suicide. Suicide rates, averaging 0.4% per year in men and women
diagnosed with bipolar disorder, are >20-fold higher than in the general
population. Suicidal acts often occur early in the illness course and in
association with severe depressive and dysphoric-agitated mixed phases of
illness, especially following repeated, severe depressions.Systematic
consideration of risk and protective factors enhances assessment of potentially
suicidal patients. Short-term interventions employed empirically to manage acute
suicidality include close clinical supervision, rapid hospitalisation and use of
electroconvulsive treatment. Several plausible therapeutic interventions have
limited evidence of long-term effectiveness against mortality risks associated
with any psychiatric disorder, including antidepressant, antimanic,
antipsychotic and electroconvulsive, as well as psychosocial, treatments.
However, in bipolar disorder and other major affective disorders, lithium
maintenance treatment is a notable exception, with strong and consistent
evidence that it reduces suicidal risk.The growing range of drugs being
introduced to treat acute and long-term phases of bipolar disorder, including
antiepileptic drugs, atypical antipsychotics and relatively safe, modern
antidepressants, require research assessment for their ability to limit
premature mortality from suicide and other causes. For now, however, more can be
done to improve treatment in major affective illnesses by application of current
knowledge in a systematic fashion, with close and sustained clinical follow-up
of patients at risk, hopefully with a resulting reduction of mortality rates.
15: Biol Psychiatry. 2003 May 15;53(10):899-905.

Thyroid hypofunction in patients with rapid-cycling bipolar disorder after
lithium challenge.

Gyulai L, Bauer M, Bauer MS, Garcia-Espana F, Cnaan A, Whybrow PC.

Bipolar Disorders Program, Department of Psychiatry, University of Pennsylvania,
Philadelphia 19104, USA.

BACKGROUND: There is debate whether patients with rapid-cycling bipolar disorder
(BD) are predisposed to thyroid axis abnormalities and whether this may
contribute to development of rapid mood shifts. Using lithium carbonate as a
challenge to the hypothalamic-pituitary-thyroid (HPT) system, we determined
whether patients with rapid-cycling BD are sensitive to the “antithyroid”
properties of lithium. METHODS: We studied the response to thyrotropin-releasing
hormone (TRH) of HPT system hormones in 20 medication-free patients with
rapid-cycling BD and compared these measurements with those of 20 healthy age-
and gender-matched control subjects. The same measurements were repeated after
both groups had received lithium carbonate for 4 weeks in sufficient doses to
maintain blood levels between.7-1.2 mEq/L. RESULTS: At baseline, the results of
thyroid function tests, including the TRH challenge test, did not differ between
patients and control subjects. After treatment with lithium, serum
concentrations of thyroxine significantly decreased, whereas basal thyrotropin
(TSH) and DeltaTSH(max) significantly increased in both patients and control
subjects; however, patients had significantly higher DeltaTSH(max) after TRH
stimulation. More patients than control subjects developed laboratory evidence
consistent with grade III hypothyroidism after lithium treatment. CONCLUSIONS:
Rapid-cycling BD is associated with a latent hypofunction of the HPT system.
This dysfunction becomes manifest with short-term lithium challenge.
16: Curr Womens Health Rep. 2003 Jun;3(3):236-41.

Psychopharmacologic treatment of depression during pregnancy.

Gold LH.


Increasing numbers of patients are being treated for mood disorders. Most of
these patients, particularly those with the diagnosis of major depression, are
women of childbearing years. Depression can also occur in the context of bipolar
disorder. Concerns regarding fetal exposure to medication, either planned or
unplanned, are becoming more pressing in the clinical practices of psychiatrists
and primary care physicians. There are relatively few study data available to
guide clinicians in the use of psychotropic medications during pregnancy, owing
to obvious problems in designing studies of the effects of medications on
pregnant women, fetuses, and infants. In this article clinically relevant study
and practice information is provided, and suggestions regarding the approach to
the treatment of mood disorders during pregnancy based on a risk assessment mode
are given.
17: J Clin Psychiatry. 2003;64 Suppl 5:53-61.

Selecting effective long-term treatment for bipolar patients: monotherapy and

Grof P.

Department of Psychiatry, University of Ottawa Royal Ottawa Hospital, Ottawa,
Ontario, Canada.

This article explores the roles of monotherapy and drug combinations in finding
effective long-term treatment for individual patients with bipolar disorder.
While current practice relies heavily on combinations, many bipolar patients can
be successfully stabilized if the initial monotherapy is carefully selected
according to the patient’s clinical characteristics. The data show that (1)
unequivocal responders to long-term monotherapies such as lithium, lamotrigine,
or atypical neuroleptics each have a very different clinical profile, including
clinical presentation and course, comorbidity, and, in particular, family
history and (2) bipolar patients who respond very well to a long-term
monotherapy have often completely failed on other monotherapies. Combinations
appear indicated particularly in bipolar patients who are treatment-resistant to
monotherapy, do not tolerate it well, or have not yet exhibited the clinical
characteristics needed to choose an effective monotherapy.
18: J Clin Psychiatry. 2003;64 Suppl 5:44-52.

Lithium treatment and suicide risk in major affective disorders: update and new

Baldessarini RJ, Tondo L, Hennen J.

Department of Psychiatry and Neuroscience Program, Harvard Medical School,
Boston, MA, USA. rjb@mclean.org

BACKGROUND: Evidence that therapeutic benefits of psychiatric treatments include
reduction of suicide risk is remarkably limited and poorly studied. An exception
is growing evidence for such suicidal risk reduction with long-term lithium
maintenance. This report updates and extends analyses of lithium treatment and
suicides and attempts. METHOD: We pooled data from studies providing data on
suicidal acts, patients at risk, and average exposure times with or without
lithium maintenance therapy, and considered effects of lithium on selected
subgroups. RESULTS: Data from 34 reported studies involved 42 groups with
lithium maintenance averaging 3.36 years, and 25 groups without lithium followed
for 5.88 years, representing 16,221 patients in a total experience of 64,233
person-years. Risks for all suicidal acts/100 person-years averaged 3.10 without
lithium versus 0.210 during treatment (93% difference) versus approximately
0.315 for the general population. For attempts, corresponding rates were 4.65
versus 0.312 (93% difference), and for completed suicides, 0.942 versus 0.174
(82% difference). Subjects with bipolar versus various recurrent major affective
disorders showed similar benefits (95% vs. 91% sparing of all suicidal acts).
Risk reductions for unipolar depressive, bipolar II, and bipolar I cases ranked
100%, 82%, and 67%. Suicide risk without lithium tended to increase from 1970 to
2002, with no loss of effectiveness of lithium treatment. CONCLUSION: The
findings indicate major reductions of suicidal risks (attempts > suicides) with
lithium maintenance therapy in unipolar >/= bipolar II >/= bipolar I disorder,
to overall levels close to general population rates. These major benefits in
syndromes mainly involving depression encourage evaluation of other treatments
aimed at reducing mortality in the depressive and mixed phases of bipolar
disorder and in unipolar major depression.
19: J Clin Psychiatry. 2003;64 Suppl 5:32-7.

Lithium combinations in acute and maintenance treatment of unipolar and bipolar

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.
20: J Clin Psychiatry. 2003;64 Suppl 5:25-31.

Drug combinations for mania.

Mondimore FM, Fuller GA, DePaulo JR Jr.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, MD 21218, USA.

With the release of new medications into the armamentarium for the treatment of
bipolar disorder, clinicians are required to make prudent treatment decisions in
light of insufficient research data for patients with a difficult-to-control
illness. Increasingly, clinicians are turning toward a combination or adjunctive
treatment out of necessity. Many studies suggest effectiveness of add-on agents
in patients with mania who are unresponsive to one or more drugs, while only a
limited number of controlled trials actually compare one particular combination
regimen to another. Despite this lack of data, there has been no lack of advice
for the clinician from clinical recommendations in the form of expert treatment
guidelines to case reports describing suggestive findings from the off-label use
of newer agents. With a particular emphasis on the treatment of mania, this
article reviews the clinical data on the individual agents of foreseeable use in
combination treatment for bipolar disorder. We suggest beginning with an agent
of established effectiveness when combining medications for the treatment of
bipolar disorder.
21: J Clin Psychiatry. 2003;64 Suppl 5:18-24.

Rationale for using lithium in combination with other mood stabilizers in the
management of bipolar disorder.

Goodwin FK.

Psychopharmacology Research Center, George Washington University Medical Center,
Washington, D.C. 20037, USA. fgoodwin@mfa.gwu.edu

Bipolar disorder is a complex illness, and no single agent has been proven in
randomized, placebo-controlled trials to effectively prevent and/or control all
aspects of the illness-acute mania, rapid cycling, and breakthrough depression.
However, for the most important issue, prophylaxis of episodes, lithium has more
evidence of efficacy than any other agent. Like lithium, typical antipsychotics,
carbamazepine, divalproex, and the atypical antipsychotic olanzapine are
effective in the treatment of mania. Carbamazepine, divalproex, and olanzapine
seem effective in preventing manic episodes but, like lithium, are less
effective in preventing depression. Few trials have been conducted in the more
difficult-to-treat characteristics of bipolar disorder, specifically, rapid
cycling and break-through depression. For patients with rapid cycling,
carbamazepine or divalproex therapy may improve symptoms, but only lamotrigine
has been shown to reduce cycling, mostly in the bipolar II group, in a
randomized, placebo-controlled study. For the treatment of depressive episodes,
lithium and olanzapine have shown modest efficacy in controlled trials, and
among the mood stabilizers, lamotrigine has the most robust effect. Because
manic symptoms may respond best to one agent and depressive symptoms to another,
combination therapy may be the optimal treatment for many patients with bipolar
disorder. For example, lithium augmentation may improve overall response rates
to treatment with carbamazepine or divalproex, and the lithium-lamotrigine
combination should provide effective prevention of both mania and depression.
Also, each mood stabilizer may be given at lower doses when given in
combination, resulting in a reduced side effect burden and improved compliance.
22: J Clin Psychiatry. 2003;64 Suppl 6:18-22; discussion 28.

Response, remission, and recovery in bipolar disorders: what are the realistic
treatment goals?

Sachs GS, Rush AJ.

Harvard Bipolar Research Program, Massachusetts General Hospital, Boston 02114,
USA. sachsg@aol.com

Bipolar disorder presents particular challenges with regard to assessing
response to therapy. Criteria for determining remission and recovery have been
suggested for mood disorders, but the clinical usefulness of these terms in
bipolar disorder is elusive. Formal psychological rating scales may be
impractical in a routine medical practice setting. As an alternative, clinicians
might probe for information about particular “signal events,” such as sleep
disturbances, that may herald mood fluctuations. The ultimate goal of bipolar
management should be complete and sustained remission, whenever possible,
although most patients will not achieve this status for any significant length
of time. Furthermore, overaggressive management might entail pushing medication
doses to intolerable levels. Individual treatment goals should always take into
account patient acceptance of side effect burden, allowing for trade-offs
between treatment effect and quality of life. Noncompliance with therapy,
notoriously common among patients suffering from bipolar disorder, can stem from
drug side effects, treatment ineffectiveness, or even treatment success if the
patient misses the manic symptoms. Despite effective treatment, relapse is
common. Realistic treatment goals should strive for sustained symptom abatement
while maximizing patient quality of life from visit to visit.
23: J Clin Psychiatry. 2003;64 Suppl 6:9-17; discussion 28.

Treatment of bipolar disorder.

Moller HJ, Nasrallah HA.

Psychiatric Department of University Munich, Munich, Germany.

Management strategies for bipolar disorder often entail relatively long-term,
complex medication regimens that combine primary mood stabilizers, antipsychotic
agents, antidepressants, and other medications, such as benzodiazepines. New
strategies for the management of bipolar disorder have recently been evaluated
in controlled clinical trials, including using newer anticonvulsants, replacing
conventional antipsychotics with atypical antipsychotics, and using novel
combination treatments. This article provides an overview of current management
strategies for patients with bipolar disorder and describes how these approaches
can be incorporated into clinical practice.
24: 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
25: 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.
26: Bipolar Disord. 2003 Apr;5(2):79-84.

Comment in:
Bipolar Disord. 2003 Apr;5(2):77-8.

Comment on:
Bipolar Disord. 2003 Feb;5(1):1-5.

Assessment of treatment response in mania: commentary and new findings.

Baldessarini RJ.

Department of Psychiatry and Neuroscience Program, Harvard Medical School,
Boston, MA, USA. rjb@mclean.org

BACKGROUND: Assessment of therapeutic interventions in bipolar disorder is
complicated by rapid, complex clinical changes, high placebo-response rates, and
varying times to specific levels of clinical recovery that may not be adequately
reflected in averaged rating-scale scores particularly in acute mania, calling
for improved methods to evaluate treatment responses. Chengappa et al. (1).
propose operational criteria for specific outcomes based on rating-scale data
from two placebo-controlled trials of olanzapine in mania. METHODS: These trials
and other recent research were considered in commenting on the design, conduct,
analysis and interpretation of experimental therapeutic trials in mania and to
optimize olanzapine versus placebo contrasts by systematically varying end-point
criteria for mania (YMRS) and depression (HDRS) ratings. RESULTS: Olanzapine
versus placebo responses were optimally separated at scores of 10 for final
paired mania and depression ratings, or 5 for each rating scale considered
separately. CONCLUSIONS: Use of empirically determined end-points derived from
standard rating scales used in experimental therapeutics research in mood
disorders can improve both outcome-assessment and separation of active treatment
from placebo responses in acute mania.
27: 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.
28: Bipolar Disord. 2003 Apr;5(2):129-37.

Social support in bipolar disorder: its relevance to remission and relapse.

Johnson L, Lundstrom O, Aberg-Wistedt A, Mathe AA.

Department of Clinical Neuroscience, St Goran’s Hospital, Karolinska Institute,
Stockholm, Sweden. lars.johnson@spo.sll.se

OBJECTIVES: While an association between low-level social support and depression
has been found in many studies, its relevance in bipolar illness has been rarely
investigated. The aim of this study was to investigate the effects of social
support in the remission and relapse of bipolar disorder. METHODS: We obtained
ratings from 94 stabilized bipolar patients using two different questionnaires
that measure perceived social support: the Interview Schedule for Social
Interaction and the Interpersonal Support Evaluation List. RESULTS:
Significantly lower social support was found in patients in partial recovery
compared with those in full recovery (p = 0.003). Patients who relapsed during a
1-year prospective follow-up period perceived a significantly lower level of
social support than patients with no relapse (p = 0.012). CONCLUSIONS: Bipolar
patients with full interepisode remission perceive more social support than
those who do not achieve full remission. Poor social support may increase the
risk of relapse in bipolar disorder.