Treatment-resistant Bipolar Disorder

Results of a MEDLINE Search by Ivan Goldberg, M.D.

1: J Clin Psychiatry 2002 Apr;63(4):275-83

Third generation anticonvulsants in bipolar disorder: a review of efficacy and
summary of clinical recommendations.

Yatham LN, Kusumakar V, Calabrese JR, Rao R, Scarrow G, Kroeker G.

Department of Psychiatry, University of British Columbia, Vancouver, Canada.

BACKGROUND: To review the literature on efficacy of third generation
anticonvulsants for treatment of bipolar disorder and provide clinical
recommendations. METHOD: Open and controlled studies, case reports, and case
series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and
zonisamide were located through electronic searches of several databases, by
manual search of proceedings of international meetings, and through contacting
authors of recent reports. RESULTS: Lamotrigine is the best studied
anticonvulsant and has efficacy in acute bipolar depression and in longer term
treatment of bipolar depression as well as rapid-cycling bipolar II disorder but
not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct
in bipolar disorder, but double-blind trials failed to confirm efficacy in acute
mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is
reported to be effective in acute mania and rapid-cycling bipolar disorder in
several open studies, but methodological problems in a double-blind study led to
a failed study in acute mania. However, topiramate may lead to weight loss in
some patients. Zonisamide deserves further investigation, but tiagabine does not
appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an
unmet need in treating bipolar depression and rapid-cycling bipolar disorder.
Other third generation anticonvulsants with the exception of tiagabine offer
promise but require confirmation of their efficacy from double-blind studies.

PMID: 12000201 [PubMed – in process]


2: Neuropsychobiology 2002;45 Suppl 1:33-6

Bupropion as add-on strategy in difficult-to-treat bipolar depressive patients.

Erfurth A, Michael N, Stadtland C, Arolt V.

Department of Psychiatry, Munster University Hospital, Germany.

Bupropion, a selective norepinephrine and dopamine reuptake inhibitor, has been
suggested for the treatment of bipolar depression, not only because of its
efficacy, but also because of a probably lower risk of inducing switches to
hypomania or mania. Most studies on bupropion treatment in bipolar patients have
been performed in moderately ill out-patients. In contrast, we report on a
sample of difficult-to-treat, predominantly severely ill, co-morbid, psychotic
or therapy-refractory bipolar depressive in-patients. In this open and
prospective study, 13 patients were treated with bupropion as an add-on strategy
mainly to other antidepressants and to various mood stabilizers. Our data
support the idea that bupropion is a first-line antidepressant in the treatment
of severe bipolar depression. Eight of 13 patients showed a >50% reduction of
Montgomery-Asberg Depression Scale ratings within 4 weeks. Co-medication with
drugs commonly used in treatment-resistant bipolar disorder including
venlafaxine, clozapine, lithium, topiramate and sodium valproate was safe in our
small sample. While adhering to the suggestion of Goren and Levin not to exceed
a daily dose of 450 mg of bupropion when treating bipolar depressed patients, we
did not observe any switch from depression to hypomania or mania. Copyright 2002
S. Karger AG, Basel

Publication Types:
Review, Tutorial

PMID: 11893875 [PubMed – indexed for MEDLINE]


3: Neuropsychopharmacology 2001 Nov;25(5):713-28

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side
effects, and predictors of outcome.

Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, Johnson CR,
Seidman S, Giller C, Haines S, Simpson RK Jr, Goodman RR.

Department of Biological Psychiatry, New York State Psychiatric Institute, 1051
Riverside Drive, New York, NY 10032, USA.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with
treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the
response rate; 2) determine the profile of side effects; and, most importantly;
3) establish predictors of clinical outcome. Participants were outpatients with
nonatypical, nonpsychotic, major depressive or bipolar disorder who had not
responded to at least two medication trials from different antidepressant
classes in the current MDE. While on stable medication regimens, the patients
completed a baseline period followed by device implantation. A 2-week, single
blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59
completers (one patient improved during the recovery period), the response rate
was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg
Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global
Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was
voice alteration or hoarseness, 55.0% (33/60), which was generally mild and
related to output current intensity. History of treatment resistance was
predictive of VNS outcome. Patients who had never received ECT (lifetime) were
3.9 times more likely to respond. Of the 13 patients who had not responded to
more than seven adequate antidepressant trials in the current MDE, none
responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS
appears to be most effective in patients with low to moderate, but not extreme,
antidepressant resistance. Evidence concerning VNS’ long-term therapeutic
benefits and tolerability will be critical in determining its role in
treatment-resistant depression.

Publication Types:
Clinical Trial

PMID: 11682255 [PubMed – indexed for MEDLINE]


4: J Clin Psychopharmacol 2001 Oct;21(5):469-73

Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar

Vieta E, Reinares M, Corbella B, Benabarre A, Gilaberte I, Colom F,
Martinez-Aran A, Gasto C, Tohen M.

Department of Psychiatry, Hospital Clinic, University of Barcelona, Spain.

The aim of this study was to estimate the long-term effectiveness of olanzapine
as adjunctive therapy in patients with bipolar disorder who exhibited an
inadequate response to mood stabilizers. Twenty-three Research Diagnostic
Criteria (RDC) patients with bipolar I and II were assessed by means of the
Schedule for Affective Disorders and Schizophrenia and entered if they gave
their consent to participate. All of them had experienced frequent relapses,
residual subsyndromal symptoms, and inadequate responses to other drugs, such as
lithium, valproate, or carbamazepine. While maintaining other drugs, they all
received open-label, increasing doses of olanzapine, until achieving clinical
response. Other drugs were maintained. The patients were assessed several
consecutive times from baseline to the endpoint with the Clinical Global
Impressions (CGI) scale for use in bipolar illness. Records of recurrences,
hospitalizations, and side effects were also collected. The
last-observation-carried-forward analysis showed that there was a significant
reduction of CGI scores after the introduction of olanzapine, either in manic
symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p =
0.0003). The most frequent adverse events were somnolence (17%) and weight gain
(13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1
mg/day. Olanzapine may be a useful medication for the long-term adjunctive
treatment of patients with bipolar disorder who exhibit a poor response to mood
stabilizers, such as lithium, valproate, or carbamazepine. These results suggest
mood-stablizing properties of olanzapine.

Publication Types:
Clinical Trial

PMID: 11593070 [PubMed – indexed for MEDLINE]


5: Aust N Z J Psychiatry 2001 Oct;35(5):631-8

Are atypical antipsychotic drugs also atypical antidepressants?

Parker G, Malhi G.

School of Psychiatry, University of New South Wales, Prince of Wales Hospital,
Randwick, New South Wales 2031, Australia.

OBJECTIVE: To report a case series and review the psychopharmacology of the
neuroleptic drugs to suggest that the atypical antipsychotic drugs may have an
antidepressant action, at least for those patients with the melancholic subtype.
METHOD: We note the literature suggesting that the older (or typical)
antipsychotic drugs were established as having antidepressant activity, describe
an open study of some two dozen patients with a treatment-resistant melancholic
depression, describe rapid resolution of depression and augmentation benefits
associated with commencing an atypical antipsychotic drug in a percentage of
subjects, and then review relevant psychopharmacological studies to consider
whether there is a rationale for use of antipsychotic drugs to treat depression.
RESULTS: Of some two dozen patients treated with an atypical antipsychotic drug,
almost immediate improvement was noted in four patients, and evidence of
augmentation benefit obtained in another three patients. CONCLUSIONS:
Impressions from this case series are encouraging. However, as open clinical
observational studies are problematic, controlled studies are required to
establish whether the atypical antipsychotic drugs have a role in the management
of certain expressions of depression, and, in particular, treatment-resistant
melancholic depression.

Publication Types:
Review of Reported Cases

PMID: 11551279 [PubMed – indexed for MEDLINE]


6: Pharmacopsychiatry 2001 Jul;34(4):137-41

Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an
open case series.

Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H.

Department of Psychiatry, University of Pisa, Italy.

OBJECTIVE: Previous studies and case observations have suggested that dopamine
agonists (DAAs) such as pramipexole (PPX) and ropinirole (RPN) might be
effective for major depression, but their adjunctive use in treatment-resistant
bipolar II depression has not yet been specifically addressed. METHOD: A chart
review was conducted on 18 patients with a DSM-III-R bipolar NOS (Bipolar II)
major depressive episode who were admitted to the day-hospital of the Department
of Psychiatry at the University of Pisa. DAAs were added to ongoing treatments
with conventional antidepressants and mood stabilizers to which patients had no
responded after a period of at least 8 weeks. Clinical state and adverse effects
were assessed at each visit. Final improvement in CGI scores of 1 or 2 were
considered as responders. RESULTS: Mean DAA trial duration was 17.6 (sd = 7.8,
range 4-34) weeks, with a mean final dose of 1.23+/-0.32 mg/day (range,
0.75-1.50mg/day) for PPX, and 2.97+/-0.99mg/day (range, 1.50-5.00mg/day) for
RPN. DAAs were well tolerated and did not show any negative interaction with
concomitant psychotropic medications. Only one patient became worse (final CGI =
5), and had to interrupt PPX due to nausea, increased agitation and
irritability. Eight patients (44.4%) were considered responders (4 with PPX and
4 with RPN): 5 showed marked improvement (CGI = 1), and 3 showed moderate
improvement (CGI = 2); another 5 (27.8%) manifested a transient response not
sustained up to the end. The initial and final scores of CGI severity scale for
all patients (responders and non-responders combined) were, respectively,
5.33+/-0.7 and 3.94+/-1.3 (mean +/- S.D). The mean change according to the CCI
severity scale was statistically significant (t=4.74. p < 0.0002). CONCLUSION:
From the results, PPX and RPN appear to be well tolerated and potentially useful
in the adjunctive treatment of drug-resistant bipolar II depression.

Publication Types:
Clinical Trial

PMID: 11518474 [PubMed – indexed for MEDLINE]


7: J Clin Psychiatry 2001;62 Suppl 16:10-7

The definition and meaning of treatment-resistant depression.

Sackeim HA.

Department of Biological Psychiatry, New York State Psychiatric Institute, NY
10032, USA.

Most patients treated for an episode of unipolar or bipolar major depression are
treatment resistant in the sense that the majority do not achieve full remission
with the first somatic or psychosocial treatment they receive. Little attention
has been given to formalizing criteria for evaluating the nature and extent of
treatment resistance, even though determining the adequacy and outcome of prior
treatment trials is key in clinical decision making about subsequent treatment.
Furthermore, determining the adequacy of prior treatment is essential since
substantial evidence indicates that large numbers of depressed patients are
undertreated, resulting in prolonged episodes and the appearance of
“pseudoresistance.” Adequacy of antidepressant treatment trials should be
defined in terms of thresholds for the dosage and duration of medication,
adherence, and clinical outcome. The Antidepressant Treatment History Form is
presented as one method to formalize the evaluation of treatment adequacy and
treatment resistance.

Publication Types:
Review, Tutorial

PMID: 11480879 [PubMed – indexed for MEDLINE]


8: Tidsskr Nor Laegeforen 2001 May 10;121(12):1473-7

Comment in:
Tidsskr Nor Laegeforen. 2001 Jun 20;121(16):1954.

[Lamotrigine in the treatment of mental disorders] [Article in Norwegian]

Malt UF, Fladvad T.

Seksjon for Nevropsykiatri, Psykosomatisk avdeling, Rikshospitalet, 0027 Oslo.

BACKGROUND: Bipolar and other mood disorders often do not respond satisfactorily
to lithium, valproate, carbamazepine or antidepressants. MATERIAL AND METHODS:
On the basis of six years of clinical experience with lamotrigine in the
treatment of psychiatric disorders, supplemented by three case reports and a
comprehensive literature review of empirical studies, we discuss the possible
indications for lamotrigine in psychiatric disorders. RESULTS: Lamotrigine seems
to have a stronger antidepressant effect in bipolar 1 disorders than
gabapentine, carbamazepine and valproate, but a weaker effect on manic
symptomatology than the latter two. Lamotrigine may be of value in the treatment
of bipolar 2 disorders in which chronic treatment resistant depression is often
a complication, including rapid cycling and, in the unipolar version of rapid
cycling, brief recurrent depression. We have also used to good effect the
neuroprotective effects of lamotrigine in prophylactic treatment of
neurodegenerative disorders (e.g. Huntington’s chorea). INTERPRETATION:
Lamotrigine is an anticonvulsant with an efficacy profile in psychiatric
disorders different from those of valproate, carbamazepine and gabapentine. The
drug represents an important supplement to the treatment options in chronic
recurrent mood and neuropsychiatric disorders.

PMID: 11449770 [PubMed – indexed for MEDLINE]


9: Actas Esp Psiquiatr 2001 May-Jun;29(3):148-52

[Effectiveness and safety of topiramate in treatment-resistant bipolar disorder] [Article in Spanish]

Vieta E, Gilabert A, Rodriguez A, Garcia-Castrillon A, Luna MJ, Arrufat E,
Garcia-Pares G.

Programa de Trastornos Bipolares. Centro de la Stanley Foundation de Barcelona,
Hospital Clinic, IDIBAPS, Barcelona.

INTRODUCTION: This study was conducted to evaluate the effectiveness and safety
of topiramate as add-on therapy for treatment-resistant bipolar disorder.
METHODS: Twenty-one DSM-IV bipolar patients, considered resistant to treatment
with lithium, carbamazepine or valproate, gave informed consent to receive
increasing doses of the novel anticonvulsant topiramate as adjunctive therapy
for their manic (n= 9), depressive (n= 6), hypomanic (n= 3), mixed (n= 2) or
schizoaffective manic (n= 1) symptoms. The dosage of other mood stabilizer drugs
remained unchanged throughout the 6-week follow-up. Outcome measures included
the YMRS, HDRS-17, and CGI scales. Fifteen out of 21 patients completed the
6-week follow-up. RESULTS: Six patients (40% of completers, 29% by
intention-to-treat) were considered responders to topiramate (> 50% reduction in
YMRS or HDRS-17 and a decrease of 2 points in CGI). The drug was less effective
in intially depressed patients. Topiramate was well tolerated and only one
patient discontinued due to side-effects. The most common adverse effect was
paresthesia (n= 2). Ten patients experienced moderate weight loss during the
follow-up. The mean topiramate dose at endpoint was 158 mg/day. CONCLUSIONS:
These preliminary results suggest that topiramate may be a useful therapy for
bipolar disorders, with promising results even in the most treatment-refractory

Publication Types:
Clinical Trial
Review, Tutorial

PMID: 11412488 [PubMed – indexed for MEDLINE]


10: Bull Menninger Clin 2001 Winter;65(1):26-40

Treatment-resistant bipolar disorder.

Gitlin MJ.

Department of Psychiatry, UCLA School of Medicine, USA.

Over the last few years, the number of potential pharmacotherapies for bipolar
disorder has greatly expanded. Yet the database for virtually all these newer
treatments consists of case reports and case series. Among these newer
treatments, recently released anticonvulsants are most promising. Lamotrigine
has already shown efficacy for treating bipolar depression, while gabapentin’s
efficacy has yet to be documented in a controlled study. Alone among its
medication class, topiramate, another anticonvulsant, is associated with weight
loss. Novel antipsychotics are effective in treating acute mania. With the
exception of clozapine, their efficacy as true mood stabilizers is still
unknown. Utilizing combinations of mood stabilizers is common and appropriate
but demands knowledge of potential pharmacokinetic interactions. Other
approaches for treatment resistant bipolar disorder include high-dose thyroid
hormones, calcium channel blockers, electroconvulsive therapy, and omega-3 fatty
acids. Finally, the efficacy of adjunctive psychosocial strategies is a topic of
active investigation.

Publication Types:
Review, Tutorial

PMID: 11280956 [PubMed – indexed for MEDLINE]


11: Bipolar Disord 2000 Sep;2(3 Pt 1):165-73

The use of nimodipine in the treatment of mood disorders.

Goodnick PJ.

Department of Psychiatry and Behavioral Sciences, University of Miami School of
Medicine, FL 33136, USA.

Nimodipine, a dihydropyridine calcium entry blocker, has been shown to protect
from neuronal damage due to ischemia by providing for increased postischemic
perfusion. Further, it has also been demonstrated to have antiepileptic
properties. These two properties–calcium channel blockade and anticonvulsant
benefits have been applied with success to mood disorder treatment. Although
found helpful nearly a decade ago for uncomplicated mania, nimodipine may have
particular benefits for those diagnostic subclasses of bipolar disorder most
resistant to therapy, e.g., ultra-rapid-cycling bipolars and brief recurrent

Publication Types:

PMID: 11256683 [PubMed – indexed for MEDLINE]


12: Bipolar Disord 1999 Sep;1(1):42-53

Comment in:
Bipolar Disord. 2001 Jun;3(3):161.

Topiramate as add-on treatment for patients with bipolar mania.

Chengappa KN, Rathore D, Levine J, Atzert R, Solai L, Parepally H, Levin H,
Moffa N, Delaney J, Brar JS.

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical
Center, PA 15215-2593, USA.

OBJECTIVE: Anticonvulsant agents such as carbamazepine and valproate are
alternatives to lithium in treating subjects with bipolar disorder. Topiramate
(Topamax), a new antiepileptic agent, is a candidate drug for bipolar disorder.
We evaluated topiramate as adjunctive treatment for bipolar patients. METHODS:
Eighteen patients with DSM-IV bipolar I disorder [mania (n = 12), hypomania (n =
1), mixed episode (n = 5), and rapid cycling (n = 6)], and two subjects with
schizoaffective disorder bipolar type, resistant to current mood-stabilizer
treatment were initiated on topiramate, 25 mg/day, increasing by 25-50 mg every
3 7 days to a target dose between 100 and 300 mg/day, as other medications were
held constant for 5 weeks. The Young Mania Rating Scale (Y-MRS), Hamilton
Depression Rating Scale (Ham-D), and Clinical Global Impression-Bipolar Version
Scale (CGI-BP) were used to rate subjects weekly. RESULTS: By 5 weeks, 12 (60%)
subjects were responders, i.e., 50% reduction in the Y-MRS scores and a CGI of
‘much’ or ‘very much improved’. Three subjects were ‘minimally improved’, four
showed no change, and one was ‘minimally worse’. Six subjects had parasthesia,
three experienced fatigue, and two had ‘word-finding’ difficulties; in all
cases, side effects were transient. All patients lost weight with a mean of 9.4
lb in 5 weeks, and a significant reduction in body mass index (BMI) occurred
too. CONCLUSIONS: Topiramate appears to have efficacy for the manic and mixed
phases of bipolar illness. Other preliminary data suggest antidepressant
efficacy too. Among obese bipolar subjects, the weight loss potential of
topiramate may be beneficial. If controlled trials confirm these initial
results, topiramate may be a significant addition to the available treatments
for bipolar disorder.

Publication Types:
Clinical Trial

PMID: 11256656 [PubMed – indexed for MEDLINE]


13: 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.

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.

Publication Types:
Review, Tutorial

PMID: 11256460 [PubMed – indexed for MEDLINE]


14: J Affect Disord 2001 Mar;63(1-3):1-15

Convulsive therapy: a review of the first 55 years.

Fink M.

Departments of Psychiatry and Neurology, Long Island Jewish-Hillside Medical
Center, Glen Oaks, Long Island, NY 11004, USA.

Convulsive therapy was introduced to psychiatric practice in 1934. It was widely
hailed as an effective treatment for schizophrenia and quickly recognized as
equally effective for the affective disorders. Like other somatic treatments, it
was replaced by psychotropic drugs introduced in the 1950s and 1960s. But two
decades later, ECT was recalled to treat pharmacotherapy-resistant cases. Avid
searches to optimize seizure induction and treatment courses, to reduce risks
and fears, to broaden the indications for its use, and to understand its
mechanism of action followed. Unlike other medical treatments, however, these
searches were severely impeded by a vigorous antipsychiatry movement among the
public and within the profession. ECT is effective in the treatment of patients
with major depression, delusional depression, bipolar disorder, schizophrenia,
catatonia, neuroleptic malignant syndrome, and parkinsonism, and this breadth of
action is both remarkable and unique. ECT is a safe treatment. No age or
systemic condition bars its use. Its major limitations are the high relapse
rates and the occasional profound effects on memory and recall that mar its
success. Experiments to sustain its benefits with medications and with
continuation ECT are underway. Its mode of action remains a mystery and this
puzzle is an unappreciated challenge. The full impact of this intervention is
yet to be felt.

Publication Types:
Historical Article

PMID: 11246075 [PubMed – indexed for MEDLINE]


15: 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.

Publication Types:
Review, Tutorial

PMID: 11018227 [PubMed – indexed for MEDLINE]


16: Am J Psychiatry 2000 Aug;157(8):1341

Quetiapine for treatment-resistant mania.

Dunayevich E, Strakowski SM.

Publication Types:

PMID: 10910805 [PubMed – indexed for MEDLINE]


17: J ECT 2000 Jun;16(2):204-7

Combined ECT and clozapine in treatment-resistant mania.

Chanpattana W.

Department of Psychiatry, Srinakharinwirot University, Bangkok, Thailand.

A treatment-resistant manic patient failed to respond to conventional treatment,
adjunctive olanzapine (20 mg/day), clozapine (600 mg/day), or ECT alone, but did
respond to ECT combined with low dose clozapine (200 mg/day). Maintenance ECT
combined with clozapine resulted in a remission over the 18-month period.

PMID: 10868331 [PubMed – indexed for MEDLINE]


18: J Psychiatry Neurosci 2000 May;25(3):276-80

Diltiazem as augmentation therapy in patients with treatment-resistant bipolar
disorder: a retrospective study.

Silverstone PH, Birkett L.

Department of Psychiatry, University of Alberta, Edmonton.

OBJECTIVE: To examine the efficacy of a slow-release formulation of diltiazem as
adjunctive therapy in patients with treatment-resistant bipolar disorder.
DESIGN: Retrospective study. PATIENTS: Eight female patients with
treatment-resistant bipolar disorder. INTERVENTIONS: Patients were administered
diltiazem and monitored for a 6-month period before starting diltiazem and a
6-month period after starting the drug. OUTCOME MEASURES: All patients were seen
at least monthly and usually every 2 weeks. The frequency and severity of both
depressive and manic episodes were examined during the 6-month period after
starting diltiazem, and compared with those during the 6-month period before
diltiazem treatment. RESULTS: There was a statistically significant decrease in
the frequency and severity of both manic and depressive episodes in these
patients after they started treatment with diltiazem, compared with the period
before they started treatment with diltiazem (p < 0.001). There was no evidence
of side effects requiring patient withdrawal or of drug interactions.
CONCLUSIONS: The results support previous suggestions that calcium-channel
antagonists may be an effective adjunctive treatment in the management of
bipolar disorder. Further controlled clinical studies are needed to confirm this
small, open-label, retrospective study.

Publication Types:
Clinical Trial

PMID: 10863888 [PubMed – indexed for MEDLINE]


19: J Affect Disord 2000 Jan-Mar;57(1-3):249-53

Mexiletine in treatment-resistant bipolar disorder.

Schaffer A, Levitt AJ, Joffe RT.

Department of Psychiatry, Sunnybrook Health Science Center, 2075 Bayview Avenue,
Room FG46, University of Toronto, Toronto, Canada.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of
mexiletine, a medication with antiarrhythmic, anticonvulsant and analgesic
properties, in treatment-resistant bipolar disorder patients. METHODS: Twenty
subjects with rapid-cycling bipolar disorder who had failed to respond or were
intolerant to lithium, valproic acid and carbamazepine were entered into the
6-week, open label study. Subjects were followed on a weekly basis for dosing of
mexiletine, blood levels, and completion of the Hamilton Depression Rating Scale
(HAM-D) and the Manic State Rating Scale (MSRS). “Burden of Mood Symptoms” (BMS)
was calculated by combining scores for the HAM-D and MSRS. RESULTS: Thirteen
subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of
illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine
was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of
the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note,
5/5 subjects with a mixed or manic state demonstrated a full or partial
response. LIMITATIONS: This study has an open label design, and a small number
of subjects. CONCLUSIONS: Mexiletine may be effective and safe in patients with
highly treatment-resistant, chronic bipolar disorder. Randomized, controlled
trials are required to confirm the current results.

Publication Types:
Clinical Trial

PMID: 10708839 [PubMed – indexed for MEDLINE]


20: Clin Neuropharmacol 2000 Jan-Feb;23(1):14-6

Combined electroconvulsive-clozapine therapy.

Kupchik M, Spivak B, Mester R, Reznik I, Gonen N, Weizman A, Kotler M.

Ness Ziona Mental Health Center, Israel.

We reviewed 36 reported psychiatric patients who were treated with a combination
of electroconvulsive therapy (ECT) and clozapine. The indication of the
ECT-clozapine treatment was resistance to classical antipsychotic agents,
clozapine, or ECT alone. Sixty-seven percent of the patients benefited from the
combined treatment. In most of the patients, the combined treatment was safe and
well tolerated. Adverse reactions occurred in 16.6% of the patients and included
prolonged ECT-induced seizures (one case), supraventricular (one case) and sinus
tachycardia, and blood pressure elevation. It seems that combined ECT-clozapine
treatment is effective and safe. This strategy may be a therapeutic option in
treatment-resistant patients.

Publication Types:

PMID: 10682225 [PubMed – indexed for MEDLINE]


21: Psychiatr Clin North Am 1999 Sep;22(3):585-607

Rapid-cycling bipolar disorder. An overview of research and clinical experience.

Kilzieh N, Akiskal HS.

VA Puget Sound Health Care Services, Tacoma, Washington, USA.

Although many studies of RCBD have been reported over the last 2 decades,
knowledge remains limited. Higher incidence in women is the sole clearly
replicated finding in most studies. This finding might be mediated by
cyclothymia, a temperament that is of higher prevalence in women and that might
be considered as a normal variant of RC. Many questions remain unanswered.
Review of putative risk factors, such as hypothyroidism and treatment with
antidepressants, provides no conclusive answers. There is clinical evidence to
implicate both factors. In principle, the thyroid connection can be approached
rationally, yet there seems to be no relationship between thyroid status and
response to thyroid augmentation. For this reason and given the potential risks
of long-term thyroid use, this strategy should not be the first one to be tried
in RC. Cumulatively, naturalistic studies over the past 30 years have strongly
implicated antidepressants in switching and cycle acceleration, yet the
double-blind, controlled, prospective studies that are needed to provide
definitive answers are unlikely to be conducted for ethical reasons discussed in
this article. Bipolar family history of RC probands appears indistinguishable
from non-RC probands, indicating that most likely RCBD does not breed true.
Although RC seems to be more lithium resistant with less likelihood of being
symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless
have resolution of the RC course. There is no marked difference in suicide
rates. An association of RC with bipolar type II, D-M-I pattern and those who
switch into mania or hypomania on antidepressants is a provocative possibility:
Antidepressants might introduce RC by first inducing a switch during a
depressive episode, creating a D-M-I pattern, a pattern that is poorly
responsive to lithium, which eventually degenerates into RC. Again, this
sequence might be mediated by the high prevalence of cyclothymia in bipolar II
patients. Thus, data from phenomenology, family history, and long-term outcome
do not support RC as a separate entity. RC appears to be a temporary complicated
phase in the illness, not a stable feature. This was noted by Kraepelin: I think
I am convinced that that kind of classification must of necessity wreck on the
irregularity of the disease. The kind and duration of the attacks and the
intervals by no means remain the same in the individual case but may frequently
change, so that the case must be reckoned always to new forms. Data by
Gottschalk et al testify to the chaotic mood swings of contemporary bipolar
disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in
which patients have phases of increase in frequency of episodes (seizures) that
become refractory to treatment. Further longitudinal prospective studies are
required to understand the complexity of this intriguing phenomenon and to
provide better treatments. Algorithms deriving from tertiary research or
university-based clinical experience may not generalize to RC or otherwise
treatment-resistant bipolar patients seen in more routine practice. Illness
severity in RCBD generally precludes double-blind controlled investigations.
Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining
patients on combined mood stabilizers–of which valproate is probably the most
useful–and making judicious use of atypical neuroleptics. Benzodiazepines and
alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright
light, and sleep deprivation during excited phases should be avoided. Thyroid
and nimodipine augmentation can be considered in those with the most malignant
course. These are patients who need the maximal support that their psychiatrist
can provide them. Office visits must be arranged as the last appointment of the

Publication Types:
Review, Tutorial

PMID: 10550857 [PubMed – indexed for MEDLINE]


22: Acta Med Austriaca 1999;26(4):129-31

[Administration of thyroid hormones in therapy of psychiatric illnesses] [Article in German]

Weissel M.

Universitatsklinik fur Innere Medizin III, Wien.

This review tries to give the state of the art of the therapeutic use of thyroid
hormones in psychiatric disorders, mainly in depression. Four hypotheses suggest
an effect in these ailments: 1) a local relative T4 excess present (or better
postulated to be present) in the brain of depressed patients is lowered by
triiodothyronine (T3), by lowering serum levels of thyroxine (T4), 2) the effect
of a depression-mediated cerebral lack of catecholamines is compensated by the
T3/T4 induced activation of beta-receptors, 3) a postulated depression-induced
local cerebral hypothyroidism can be counteracted by T3 and T4. 4) thyroid
hormones increase the cerebral content of serotonin. This may be beneficial in
depression, where shortage of serotonin in the brain is accused to be
etiologically important. Thyroid hormones have been used so far in the following
ways: 1) as T3 monotherapy in depression; 2) initial additive T3 for
acceleration of the response to treatment with tricyclic antidepressants (TCA);
3) additive T3 for augmentation of the response to TCA in therapy-resistant
patients with depression, 4) as high-dose (250-500 micrograms/die) T4-treatment
of “rapid cycling bipolar disorder”. Low dose (5-50 mg/die) T3 “augmentation
therapy” is the best documented form of treatment with thyroid hormones in
depression. The results suggest a convincing benefit for a varying percentage of
non responders to therapy with TCA. For the other forms of treatment
placebo-controlled double blind studies are not yet available or give
conflicting results.

Publication Types:
Review Literature

PMID: 10526631 [PubMed – indexed for MEDLINE]


23: Pharmacopsychiatry 1999 Jul;32(4):136-41

Clinical experience using adjunctive gabapentin in treatment-resistant bipolar
mixed states.

Perugi G, Toni C, Ruffolo G, Sartini S, Simonini E, Akiskal H.

Institute of Psychiatry, University of Pisa, Italy.

OBJECTIVE: Open studies and case observations have suggested that gabapentin may
be effective in the treatment of bipolar disorder. However, the adjunctive use
of the drug in bipolar mixed states has not been specifically addressed before.
METHODS: Twenty-one patients with bipolar I mixed episodes as defined by
Diagnostic and Statistical Manual of Mental Disorders (Revised) (DSM-III-R), who
were admitted to the outpatient department at the Psychiatry Clinic of the
University of Pisa, were treated adjunctively with gabapentin for a period of
eight weeks. All patients had been resistant to therapeutic levels of standard
mood stabilizers, and had a mean clinical global impression (CGI) of 5.2+/-0.8
when entering the study. Gabapentin treatment was started at 300 mg/day and
increased up to 2000 mg/day. Patients were evaluated using the Hamilton Rating
Scale for Depression (HRSD), the Young Mania Rating Scale (YMRS), and CGI.
Patients with final CGI scores of 1 or 2 were regarded as responders. RESULTS:
Only one patient had to interrupt the drug treatment, due to irritability and
ataxia. Negative interactions between gabapentin and concomitant psychotropic
medications were not observed. The condition deteriorated in only one patient
(final CGI = 5). Ten patients were regarded as responders: four showed marked
improvement (CGI = 1), and six had moderate improvement (CGI = 2). The mean dose
of gabapentin at week 8 was 1130 mg (range 600-2000 mg). The mean final CGI
score for all patients (responders and nonresponders combined) was 3.7+/-1.1
(the mean change in CGI was significant, t=6.1, P<0001). The reduction in the
mania score was minimal and statistically insignificant. However, the mean HRSD
score showed a statistically significant reduction from 18.2 to 10.6 (t=5.73,
P<0.0001), irrespective of the baseline severity of the mania. All but one of
the responders maintained these therapeutic improvements over 4-12 months, in
most cases requiring less concomitant antidepressant and neuroleptic
medications. CONCLUSIONS: These results show that gabapentin appears to be
potentially useful in the adjunctive treatment of drug-resistant bipolar mixed
states, and that it was particularly effective in relation to depressive

Publication Types:
Clinical Trial
Review Literature

PMID: 10505483 [PubMed – indexed for MEDLINE]


24: Ann Clin Psychiatry 1999 Sep;11(3):137-40

Erratum in:
Ann Clin Psychiatry 2000 Mar;12(1):63

The use of quetiapine for treatment-resistant bipolar disorder: a case series.

Ghaemi SN, Katzow JJ.

Massachusetts General Hospital, Consolidated Department of Psychiatry, Harvard
Medical School, Boston 02114, USA.

OBJECTIVE: To determine if quetiapine, an atypical antipsychotic agent approved
for the treatment of schizophrenia, is effective in the treatment of bipolar
disorder. MATERIALS AND METHODS: A retrospective chart review identified six
patients with DSM-IV bipolar disorder, type I, who received open uncontrolled
treatment with quetiapine in the setting of nonresponse or intolerance to
traditional mood-stabilizing treatments. Treatment response was based on
moderate to marked improvement on the Clinical Global Impression-Bipolar
Disorder (CGI-BP) scale. RESULTS: Two of six patients showed evidence of
response. The main side effect noted was sedation. CONCLUSIONS: Quetiapine may
be a useful treatment for some patients with treatment-resistant bipolar
disorder. Further studies are needed to assess quetiapine’s effect more

PMID: 10482123 [PubMed – indexed for MEDLINE]


25: Am J Psychiatry 1999 Aug;156(8):1164-9

Clinical outcome in a randomized 1-year trial of clozapine versus treatment as
usual for patients with treatment-resistant illness and a history of mania.

Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ.

Department of Psychiatry, University of Texas Southwestern Medical Center,
Dallas 75235-9070, USA.

OBJECTIVE: Case series and follow-up studies suggest that clozapine may have
mood-stabilizing properties in addition to antipsychotic action in patients with
schizoaffective disorder, bipolar type, and bipolar I disorder, but the
generalizability of these findings is limited. This article describes a
randomized, open study of clozapine add-on therapy versus treatment as usual for
patients with treatment-resistant illness and a history of mania. METHOD:
Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar
disorder that was deemed treatment-resistant were randomly assigned to clozapine
add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and
followed up for 1 year. Patients received monthly ratings on the Brief
Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania
Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive
Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary
Movement Scale, and a 40-item side effect checklist. Differences between
treatment groups were assessed according to a pattern-mix random-regression
model. An additional analysis compared group differences in rating scale scores
against relative time in the study. RESULTS: Significant between-group
differences were found in scores on all rating scales except the Hamilton
depression scale. Total medication use over 1 year significantly decreased in
the clozapine group. No significant differences between groups in somatic
complaints were noted. The subjects with nonpsychotic bipolar I disorder who
received clozapine showed a degree of improvement similar to that of the entire
clozapine-treated group. Clozapine dose was significantly higher for the
patients with schizoaffective illness than for those with bipolar disorder.
CONCLUSIONS: The results of this study support clozapine’s independent
mood-stabilizing property. They demonstrate that clozapine use was associated
with significant clinical improvement relative to treatment as usual.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 10450255 [PubMed – indexed for MEDLINE]


26: Biol Psychiatry 1999 Apr 15;45(8):959-64

Donepezil in treatment-resistant bipolar disorder.

Burt T, Sachs GS, Demopulos C.

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

BACKGROUND: A considerable percentage of patients with bipolar disorder do not
respond or do not tolerate conventional treatment. Cholinesterase (ChE)
inhibitors have been suggested to possess depressogenic and antimanic
properties. METHODS: We report a case series of treatment-resistant bipolar
patients (n = 11) to whom we administered the ChE inhibitor donepezil. Four
patients met criteria for current manic episode, 5 for mixed episode, 1 for
hypomanic episode, and 1 for major depressive episode. Donepezil was added to
current medication on an openlabel basis. Ratings were based on a retrospective
chart review. RESULTS: Of the 11 patients, 6 (54.5%) demonstrated marked
improvement (improvement in CGI-S > or = 2), 3 (27.2%) demonstrated slight
improvement, 1 did not respond, and 1 did not tolerate the medication. Among
those patients who had marked improvement (i.e., responders, n = 6), improvement
was observed within 2 weeks or less in 5 of them (83%). Patients experienced
only minor side effects. CONCLUSIONS: These pilot data suggest the efficacy and
safety of donepezil in the treatment of bipolar disorder. To our knowledge this
is the first published report on the use of donepezil in the treatment of mood
disorders. Controlled, randomized, double-blind studies are necessary to
validate these preliminary observations.

Publication Types:
Clinical Trial

PMID: 10386177 [PubMed – indexed for MEDLINE]


27: Nervenarzt 1998 Nov;69(11):1019-22

[High dosage thyroxine treatment in therapy and prevention refractory patients
with affective psychoses] [Article in German]

Bauer M, Hellweg R, Baumgartner A.

Psychiatrische Klinik und Poliklinik, Universitatsklinikum Benjamin Franklin,
Freie Universitat Berlin.

The following review summarizes current knowledge on the treatment of
therapy-resistant patients with affective disorders with supraphysiological
doses of thyroxine (T4). Several groups have reported independently of each
other that administration of 200-500 micrograms T4/day has excellent effects in
50-65% of patients a) with bipolar disorder, with or without, “rapid cycling”
course, who were previously resistant to all prophylactic drugs and b) in the
treatment of therapy-resistant depression. T4 is effective only in combination
with an antidepressant or a prophylactic drug. Side effects are minimal, even
when T4 is administered over several years. These results now justify to
recommend high dose T4-augmentation as “last-resort” treatment also beyond
research purposes, i.e. in psychiatric wards and in private practice.
Recommendations for clinical applications are given and hypotheses on possible
mechanisms underlying the efficacy of T4 treatment are discussed.

Publication Types:
Review, Tutorial

PMID: 9859125 [PubMed – indexed for MEDLINE]


28: J Affect Disord 1998 Jun;49(3):229-33

Clinical experience using gabapentin adjunctively in patients with a history of
mania or hypomania.

Knoll J, Stegman K, Suppes T.

University of Texas Southwestern Medical Center at Dallas, USA.

BACKGROUND: Gabapentin is an anticonvulsant proposed to have mood-stabilizing
properties. It has been effective in the add-on treatment of refractory partial
seizures and secondary generalized tonic-clonic seizures. It has the advantage
of a favorable side effect profile and lack of drug interactions. METHODS:
Twelve consecutive outpatients with persistent, treatment-resistant bipolar
spectrum disorders were treated with gabapentin in combination with other
medications. Patients were started at 300 mg/day, which was titrated according
to clinical response. Response was assessed every 3-4 weeks with a Clinical
Global Improvement Scale. Dosage and side effects were noted. The median peak
dose was 2400 mg/day. RESULTS: One patient had a marked response to gabapentin;
seven, a moderate response; two, mild; and two, no response to treatment. Six
patients discontinued treatment due to somatic complaints (i.e., sedation or
fatigue). The most frequently reported adverse effect was sedation. LIMITATIONS:
Gabapentin was added openly, and rating was nonblind in this case series. The
use of concomitant medications could have increased the amount of sedation
experienced with gabapentin. CONCLUSION: Overall, gabapentin was associated with
moderate improvement of mood symptoms. Given the severity and chronicity of
these patients’ illness, a moderate response must be considered a relative
success. Controlled studies of gabapentin are needed to clarify its role in the
treatment of bipolar disorder.

PMID: 9629953 [PubMed – indexed for MEDLINE]


29: Clin Neuropharmacol 1998 Jan-Feb;21(1):65-7

Lamotrigine in the treatment of resistant bipolar disorder.

Kotler M, Matar MA.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion
University of the Negev, Beersheva, Israel.

Antiepileptic drugs, such as carbamazepine and sodium valproate, are integral to
psychopharmacologic therapy over the last decades. Lamotrigine is a new
antiepileptic drug that acts on amino acid neurotransmitters/neuromodulators,
most prominently, glutamine, which has been reported to have potential
mood-stabilizing effects. The reports on this effect are limited and sparse, and
systematic investigations have not been published. Here we present two clinical
cases representing atypical patient groups in which lamotrigine was successfully
used as an add-on therapy for resistant bipolar depression.

PMID: 9579289 [PubMed – indexed for MEDLINE]


30: J Affect Disord 1998 Jan;47(1-3):201-5

Divalproate augmentation in lithium-resistant rapid cycling mania in four
geriatric patients.

Schneider AL, Wilcox CS.

Pharmacology Research Institute, Northridge, CA 91324-4625, USA.

This report describes four geriatric patients, with rapid cycling bipolar
disorder, who were treated successfully with divalproex sodium in combination
with lithium carbonate, noting that both drugs were necessary for clinical
remission of symptoms. Divalproex sodium may actually enhance the sensitivity to
lithium carbonate in this population, potentially leading to treatment with
lower lithium concentrations. This strategy has an advantage in enabling a
greater safety range in the use of lithium carbonate in elderly patients. This
report further raises questions as to the nature of rapid cycling illness in the
“old-old” population.

PMID: 9476762 [PubMed – indexed for MEDLINE]


31: Aust N Z J Psychiatry 1997 Jun;31(3):424-6

Clozapine in the management of bipolar and schizoaffective manic episodes
resistant to standard treatment.

Mahmood T, Devlin M, Silverstone T.

Department of Psychological Medicine, Dunedin School of Medicine, University of
Otago, New Zealand.

OBJECTIVE: To test the efficacy of clozapine in treatment-resistant manic
episodes. CLINICAL PICTURE: Three cases, two with bipolar disorder (manic) and
one of schizoaffective disorder (manic), were treated with clozapine. TREATMENT:
Clozapine was used after the failure of standard antipsychotics and mood
stabilizers. OUTCOME: All three cases were successfully treated. CONCLUSION: A
controlled trial of clozapine in treatment-resistant bipolar and schizoaffective
manic episodes is indicated.

PMID: 9226089 [PubMed – indexed for MEDLINE]


32: J Clin Psychopharmacol 1997 Jun;17(3):185-9

The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness.

Sporn J, Sachs G.

Department of Psychiatry, Massachusetts General Hospital, Boston, USA.

Anticonvulsants are used extensively in the treatment of bipolar disorder.
Treating depression in bipolar disorder can be difficult because of the limited
antidepressant effects of the standard mood stabilizers and the tendency of
antidepressants to induce mania or decrease cycle length. Lamotrigine is a new
anticonvulsant with few side effects that may have mood-stabilizing and
elevating effects. Its mechanism of action probably involves the inhibition of
excessive release of excitatory amino acids such as glutamate. Antiglutamatergic
agents may be antidepressant and mood stabilizing. A case series of 16 patients
treated with lamotrigine (dose range 50 mg to 250 mg, mean dose of responders =
141 mg) is presented along with two case reports. All patients were considered
treatment-resistant bipolar type I or II. Patients were rated on average 5 weeks
after starting lamotrigine using a semistructured follow-up form that included
symptom rating, Clinical Global Impressions (CGI), and Global Assessment of
Functioning (GAF) scores. Eight of 16 patients were rated as “responders” (CGI <
or = 2) and had a mean increase of 16 in their GAF scores. Lamotrigine seems to
have antidepressant and mood-stabilizing effects, but this requires confirmation
in randomized, controlled trials.

Publication Types:
Clinical Trial

PMID: 9169963 [PubMed – indexed for MEDLINE]


33: 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.

Publication Types:
Review, Tutorial

PMID: 8827187 [PubMed – indexed for MEDLINE]


34: Am J Psychiatry 1996 Jun;153(6):759-64

Clozapine for treatment-refractory mania.

Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA,
Meltzer HY.

Mood Disorders Program, Case Western Reserve University School of Medicine,
Cleveland, OH, USA.

OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined
in a prospective trial for patients with bipolar or schizoaffective disorder.
METHOD: The subjects were 25 acutely manic patients with either bipolar disorder
(N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium,
anticonvulsants, and neuroleptics had been ineffective, had produced intolerable
side effects, or both. After a 7-day washout, the patients were treated with
clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania
Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25
patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale,
and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients
as compared to schizo-affective patients, and the nonrapid as compared to rapid
cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS:
These results suggest that clozapine is an effective therapy for
treatment-resistant bipolar and schizoaffective mania.

Publication Types:
Clinical Trial

PMID: 8633686 [PubMed – indexed for MEDLINE]


35: Psychopharmacol Bull 1996;32(1):55-61

Risperidone therapy in treatment refractory acute bipolar and schizoaffective

Sajatovic M, DiGiovanni SK, Bastani B, Hattab H, Ramirez LF.

Cleveland Veterans Administration Medical Center, OH-44141, USA.

This pilot study evaluated the efficacy of risperidone therapy in patients with
bipolar I or schizoaffective mania who were treatment resistant or treatment
intolerant. Patient psychopathology and involuntary movements were evaluated
with a variety of scales, and risperidone was administered on an open-label
basis. Five of six patients (all bipolar) discontinued risperidone therapy
because of adverse drug effects (2 patients), lack of significant drug response
and subjective clinical worsening (1 patient), or worsening of manic symptoms (2
patients). One patient with schizoaffective illness improved. Risperidone used
without the addition of a mood stabilizer was ineffective in treating pure manic
psychosis. In some vulnerable bipolar patients, risperidone monotherapy may have
antidepressant activity that could exacerbate mania. If risperidone proves to
have antidepressant activity, it may become an important agent in the therapy of
patients with depressive symptoms and psychosis.

PMID: 8927675 [PubMed – indexed for MEDLINE]


36: Can J Psychiatry 1995 Jun;40(5):270-4

A comparison of comorbid patterns in treatment-resistant unipolar and bipolar

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.

PMID: 7553547 [PubMed – indexed for MEDLINE]


37: Biol Psychiatry 1995 Apr 15;37(8):553-9

Chronobiological approach for treatment-resistant rapid cycling affective

Kusumi I, Ohmori T, Kohsaka M, Ito M, Honma H, Koyama T.

Department of Psychiatry, Hokkaido University School of Medicine, Sapporo,

PMID: 7619980 [PubMed – indexed for MEDLINE]


38: J Clin Psychiatry 1994 Jul;55(7):295-300

Clozapine therapy in refractory affective disorders: polarity predicts response
in long-term follow-up.

Banov MD, Zarate CA Jr, Tohen M, Scialabba D, Wines JD Jr, Kolbrener M, Kim JW,
Cole JO.

Bipolar and Psychotic Disorders Program, McLean Hospital, Belmont, Mass.

BACKGROUND: To determine the efficacy and tolerance of long-term clozapine
therapy in refractory affective illness. METHOD: Hospital records were reviewed
for 193 treatment-resistant patients with a discharge diagnosis of bipolar
disorder (N = 52), schizoaffective disorder (N = 81), unipolar depression (N =
14), schizophrenia (N = 40), or other disorders (N = 6) started on clozapine
therapy as inpatients at McLean Hospital. An independent “best-estimate”
diagnosis, based on DSM-III-R criteria, was established for each patient.
Patients were contacted at least 6 months after clozapine initiation for
structured follow-up interviews by raters blind to diagnosis. Patients were
stratified by diagnosis, and a variety of patient characteristics and outcome
measures were compared. RESULTS: Subjects were followed up a mean of 18.7 months
after clozapine initiation. Bipolar manic and schizoaffective bipolar subjects
had significantly better outcomes than unipolar, bipolar, and schizoaffective
depressed patients on a variety of measures. One or more episodes of depression
prior to clozapine predicted clozapine discontinuation (p = .01). Affective and
schizoaffective subjects had baseline measures of social functioning similar to
that of the schizophrenics but had significantly greater improvement in scores
at follow-up. CONCLUSION: Clozapine is an efficacious and well-tolerated therapy
for refractory affective illness. Manic symptomatology predicts a more favorable
response than depression.

PMID: 8071290 [PubMed – indexed for MEDLINE]


39: Neuropsychopharmacology 1994 May;10(3):183-9

Treatment of intractable non-rapid cycling bipolar affective disorder with
high-dose thyroxine: an open clinical trial.

Baumgartner A, Bauer M, Hellweg R.

Psychiatrische Klinik and Poliklinik, Universitatsklinikum Rudolf-Virchow
(Charlottenburg), Free University of Berlin, Germany.

Six patients with very severe forms of non-rapid cycling bipolar affective
illness whose symptoms had previously been refractory to all current
antidepressant and/or prophylactic medications were treated with
supraphysiological doses of thyroxine (250 to 500 micrograms/day) as an adjuvant
to their previous medications. The mean follow-up period was 27.8 +/- 12.8
months (range 12 to 46). The mean number of relapses during the follow-up period
of each patient declined from 5.3 +/- 3.1 to 0.8 +/- 0.8 and the mean duration
of hospitalization from 10.0 +/- 5.6 to 0.8 +/- 1.2 months as compared to the
same length of time for each patient before the start of treatment with
high-dose thyroxine (T4). Three of the patients had no further relapses at all.
Thus, for these patients, who had previously been severely ill and
therapy-resistant, high-dose T4 administration proved to have excellent effects
on the course of the illness. However, in five of these patients the effect of
the T4 was strong enough only when it was administered in combination with a
prophylactic and antidepressant and/or neuroleptic drug, of which in some cases
high doses were also needed. The side effects were negligible. Mechanisms that
may possibly underlie the beneficial effects of high-dose T4 in bipolar
affective disorder are discussed.

Publication Types:
Clinical Trial

PMID: 7916915 [PubMed – indexed for MEDLINE]


40: Acta Psychiatr Scand 1993 Aug;88(2):121-3

Patterns of treatment resistance in bipolar affective disorder.

Cole AJ, Scott J, Ferrier IN, Eccleston D.

Department of Psychiatry, School of Neuroscience, University of Newcastle upon
Tyne, United Kingdom.

The mean index episode length in 19 consecutive admissions with
treatment-resistant bipolar affective disorder was 21.7 months. Four patterns of
resistance were identified: rapid cycling (37%), other forms of cycling (32%),
chronic depression (26%) and mixed states (6%). Female gender was significantly
associated with rapid cycling. Other risk factors for treatment-resistant
bipolar disorder, including a high prevalence of family history of affective
disorder (72%) and electroencephalographic abnormalities (54% of recordings),
were not confined to the rapid cycling group.

PMID: 8213204 [PubMed – indexed for MEDLINE]


41: Can J Psychiatry 1993 Apr;38(3 Suppl 2):S57-61

Rapid cycling bipolar disorder and its treatment with valproate.

Calabrese JR, Rapport DJ, Kimmel SE, Reece B, Woyshville MJ.

Mood Disorders Program, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106.

A large subgroup of lithium-resistant manic patients are rapid cyclers and as
many as 82% of them exhibit poor responses to lithium. Thus, a substantial
percentage of poor responses to lithium is accounted for on the basis of rapid
cycling. Although controlled trials have demonstrated the efficacy of
carbamazepine for the treatment of rapid cycling bipolar disorder, the response
to carbamazepine frequently deteriorates. Furthermore, its ability to
auto-induce and hetero-induce drug metabolism complicates its routine use. These
findings suggest that substantial numbers of rapid cyclers do not respond to
either carbamazepine or lithium and that additional mood stabilizers are needed.
Our recent findings on 101 rapid cycling bipolar patients continue to support
the impression that valproate has marked antimanic efficacy and poor to moderate
antidepressant properties. Most patients with mixed states exhibited good
antimixed state responses but then became depressed. Predictors of a good
antimanic response included decreasing or stable episode frequencies and non
psychotic mania. Predictors of a good antidepressant response were non psychotic
mania worsening over the years of the illness and absence of borderline
personality disorder comorbidity. These open prospective trials, as well as
other positive reports of valproate’s efficacy in bipolar rapid cycling, await
replication with ongoing, controlled maintenance trials.

Publication Types:
Review, Tutorial

PMID: 8500080 [PubMed – indexed for MEDLINE]


42: 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.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 1734739 [PubMed – indexed for MEDLINE]


43: Br J Psychiatry 1990 Apr;156:560-4

Resistant bipolar disorder.

Thomas IG, Oswald AG, Eagles JM.

Royal Cornhill Hospital, Aberdeen.

A 66-year-old farmer’s wife had been admitted 31 times over eight years,
suffering from manic depression. A variety of treatments for depressive episodes
led to hypomania, and a case conference was held to discuss treatment.

PMID: 2386867 [PubMed – indexed for MEDLINE]