Br J Psychiatry. 2006 Jan;188:46-50.
Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised
double-blind placebo-controlled study.
Frangou S, Lewis M, McCrone P.
Section of Neurobiology of Psychosis, PO66, Institute of Psychiatry, De
Crespigny Park, London SE5 8AF, UK. s.frangou@iop.kcl.ac.uk
BACKGROUND: Epidemiological and clinical studies suggest that increased intake
of eicosapentaenoic acid (EPA) alleviates unipolar depression. AIMS: To examine
the efficacy of EPA in treating depression in bipolar disorder. METHOD: In
a12-week, double-blind study individuals with bipolar depression were randomly
assigned to adjunctive treatment with placebo (n=26) or with 1 g/day (n=24) or 2
g/day (n=25) of ethyl-EPA. Primary efficacy was assessed by the Hamilton Rating
Scale for Depression (HRSD), with changes in the Young Mania Rating Scale and
Clinical Global Impression Scale (CGI) as secondary outcome measures. RESULTS:
There was no apparent benefit of 2 g over 1 g ethyl-EPA daily. Significant
improvement was noted with ethyl-EPA treatment compared with placebo in the HRSD
(P=0.04) and the CGI (P=0.004) scores. Both doses were well tolerated.
CONCLUSIONS: Adjunctive ethyl-EPA is an effective and well-tolerated
intervention in bipolar depression.
----------
Clin Psychol Rev. 2005 Dec;25(8):1076-100. Epub 2005 Sep 2.
The nature and treatment of depression in bipolar disorder: a review and
implications for future psychological investigation.
Mansell W, Colom F, Scott J.
Psychological Treatments PO96, Department of Psychological Medicine, Institute
of Psychiatry, London SE5 8AF, UK. warren.mansell@manchester.ac.uk
Bipolar depression is poorly understood and researched, yet it is has a huge
impact on functioning in bipolar disorder. This review explores the current
status of research regarding the phenomenology, natural history,
neuropsychology, psychosocial predictors and cognitive style of bipolar
depression. The current status of pharmacotherapy and psychological treatment of
bipolar depression is also described. In particular, the manner in which
cognitive behaviour therapy for bipolar depression has been adapted from CBT for
unipolar depression is critically evaluated. It is concluded that there appears
to be a considerable overlap between the features of unipolar and bipolar
depression, yet there is also emerging evidence for specific elements. The
ability of current psychological theories of bipolar disorder to account for the
findings are compared, and as a consequence, a new preliminary integrative model
is proposed to direct future hypothesis-led research, which will need to
incorporate more suitable populations and utilise more objective methods of
assessment.
----------
J Clin Psychiatry. 2005 Dec;66(12):1535-1540.
Combined Total Sleep Deprivation and Light Therapy in the Treatment of
Drug-Resistant Bipolar Depression: Acute Response and Long-Term Remission Rates.
Benedetti F, Barbini B, Cigala Fulgosi M, Colombo C, Dallaspezia S, Pontiggia A,
Smeraldi E.
From the Department of Neuropsychiatric Sciences, Scientific Institute and
University Vita-Salute San Raffaele (all authors), and CERMAC (Centro di
Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San
Raffaele (Drs. Benedetti, Colombo, and Smeraldi), Milan, Italy.
BACKGROUND: Drug resistance remains a persistent source of morbidity and
mortality for patients with bipolar depression. A growing number of clinical
studies support the usefulness of chronotherapeutic interventions, such as total
sleep deprivation (TSD) and light therapy (LT), in the treatment of nonresistant
bipolar depression. METHOD: To investigate the clinical usefulness of TSD plus
LT in the treatment of drug-resistant bipolar depression, we treated 60
inpatients for 1 week with repeated TSD and LT combined with ongoing
antidepressants and lithium salts. All patients had a DSM-IV diagnosis of
bipolar I disorder. Drug resistance was rated according to Thase and Rush
criteria. The pattern of relapses and recurrences was assessed during a
prospective 9-month follow-up. Data were gathered from September 2002 to July
2004. RESULTS: A 2-way repeated-measures analysis of variance with changes in
self-rated perceived mood scores as dependent variable and with time and group
(history of drug resistance) as independent factors confirmed significant
time-by-group interaction (p = .0339). A logistic regression on rates of
achievement of response (50% reduction in Hamilton Rating Scale for Depression
ratings) confirmed the significance of observed differences: overall, 70%
(23/33) of nonresistant versus 44% (12/27) of drug-resistant patients achieved
response (p = .045). A survival time analysis (Cox proportional hazards model)
showed that history of drug resistance significantly influenced the pattern of
relapses and recurrences, with 57% (13/23) of nonresistant responders and 17%
(2/12) of drug-resistant responders being euthymic after 9 months (p = .0212).
DISCUSSION: The combination of repeated TSD and LT in drug-resistant patients
was useful in triggering an acute response. Further clinical research is needed
to optimize this treatment option for drug-resistant patients in the long term.
---------
Am J Psychiatry. 2005 Nov;162(11):2146-51.
Bipolar depression in a low-income primary care clinic.
Olfson M, Das AK, Gameroff MJ, Pilowsky D, Feder A, Gross R, Lantigua R, Shea S,
Weissman MM.
New York State Psychiatric Institute, Department of Psychiatry, Columbia
University, 1051 Riverside Dr., Unit 24, New York, NY 10032, USA.
mo49@columbia.edu
OBJECTIVE: This study estimated the proportion of patients attending an urban
general medical practice with current major depression and a history of bipolar
disorder and compared the history, presentation, and treatment of patients with
unipolar and bipolar depression. METHOD: A group of 1,143 patients was assessed
with measures of past and current mental health and treatment. Patients were
partitioned into bipolar and unipolar groups based on a predefined cutoff on the
Mood Disorder Questionnaire. The groups were compared on sociodemographic
characteristics, depressive symptoms, comorbid mental disorders, and mental
health treatment. RESULTS: Approximately one-quarter of the patients with major
depression had lifetime bipolar depression. Patients with unipolar and bipolar
depression did not significantly differ on background or health characteristics.
Patients with bipolar depression were significantly more likely to report
hallucinations, current suicidal ideation, and low self-esteem than patients
with unipolar depression but less likely to report disturbed appetite. Patients
with bipolar depression were significantly more likely to have an alcohol use
disorder and to report inpatient psychiatric care and antipsychotic treatment
during the past month than patients with unipolar depression. Nearly one-half of
the patients with bipolar depression had taken an antidepressant in the last
month, but most were not also being treated with an antipsychotic or mood
stabilizer. CONCLUSIONS: Bipolar depression is common in urban general medicine
practice. When patients took antidepressants, they seldom received concurrent
antimanic medications. Because of the risks of treating bipolar disorder with
antidepressant monotherapy, physicians should assess their depressed patients
for mania before prescribing antidepressants.
----------
J Clin Psychiatry. 2005 Nov;66(11):1376-85.
Typical and atypical antipsychotics in bipolar depression.
Gao K, Gajwani P, Elhaj O, Calabrese JR.
Mood Disorders Program, Department of Psychiatry, University Hospitals of
Cleveland, Case Western Reserve University School of Medicine, 11400 Euclid
Avenue, Cleveland, OH 44106, USA. keming.gao@uhhs.com
BACKGROUND: Symptomatic bipolar patients experience more depressive than manic
symptoms, but fewer studies have been designed for bipolar depression than for
bipolar mania. Since the antipsychotic agents have been shown to diminish
depressive symptoms during the treatment of mania, atypical agents are now being
studied for use in bipolar depression. DATA SOURCES: English-language articles
published from 1980 through July 2004 and cited in MEDLINE were searched using
the keywords antipsychotics, typical antipsychotics, atypical antipsychotics,
bipolar depression, bipolar disorder, manic-depressive illness, placebo, and
clinical trial. The generic and brand names of individual antipsychotics were
also entered as keywords. Peer-reviewed abstracts of placebo-controlled studies
assessing acute or long-term efficacy in bipolar depression presented at major
scientific meetings were also reviewed. STUDY SELECTION: Use of a depression
rating scale was required for inclusion of studies of the atypical antipsychotic
agents in our analysis. DATA SYNTHESIS: Twenty-one randomized trials and 13
nonrandomized prospective trials were identified. In the only 2 acute,
double-blind, placebo-controlled studies of antipsychotics in bipolar
depression, the effect size of olanzapine was small (0.32) compared with the
effect sizes of quetiapine (0.91-1.09, depending on dose). The effect size in
acute mania of olanzapine at week 4 and quetiapine at week 3 was 0.50 and 0.39,
respectively. Both olanzapine and quetiapine have been shown to be superior to
placebo in the acute treatment of bipolar I depression. In addition, olanzapine
has been shown to be more effective than placebo in delaying relapse into
bipolar depression. With the exception of a 6-month perphenazine study, there
are no other randomized studies of typical antipsychotics that support the
conclusion that this class of medication worsens bipolar depression. CONCLUSION:
Emerging data suggest that the atypical antipsychotic agents have a role in the
acute and long-term treatment of bipolar depression. No convincing data support
the impression that the typical antipsychotic agents worsen bipolar depression.
---------
Harv Rev Psychiatry. 2005 Sep-Oct;13(5):257-71.
Bipolar depression: issues in diagnosis and treatment.
Thase ME.
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh,
PA 15213, USA. thaseme@upmc.edu
Although bipolar affective disorder is defined by the history of manic or
hypomanic episodes, depression is arguably a more important facet of the
illness. Depressive episodes, on average, are more numerous and last longer than
manic or hypomanic episodes, and most suicides occur during these periods.
Misdiagnosis of major depressive disorder delays initiation of appropriate
therapy, further worsening prognosis. Distinguishing features of bipolar
depression include earlier age of onset, a family history of bipolar disorder,
presence of psychotic or reverse neurovegetative features, and
antidepressant-induced switching. Bipolar I depressions should initially be
treated with a mood stabilizer (carbamazapine, divalproex, lamotrigine, lithium,
or an atypical antipsychotic); antidepressant monotherapy is contraindicated.
More severe or "breakthrough" episodes often require a concomitant
antidepressant, such as bupropion or a selective serotonin reuptake inhibitor
(SSRI). The first treatment specifically approved for bipolar depression is a
combination of the SSRI fluoxetine and the atypical antipsychotic olanzapine.
For refractory depressive episodes, venlafaxine, the monoamine oxidase inhibitor
tranylcypromine, and ECT are most widely recommended. The optimal duration of
maintenance antidepressant therapy has not been established empirically and,
until better evidence-based guidelines are established, should be determined on
a case-by-case basis.
----------
Eur Arch Psychiatry Clin Neurosci. 2005 Aug 4; [Epub ahead of print]
Do recent efficacy data on the drug treatment of acute bipolar depression
support the position that drugs other than antidepressants are the treatment of
choice? A conceptual review.
Moller HJ, Grunze H, Broich K.
Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7,
80336, Munich, Germany, hans-juergen.moeller@med.uni-muenchen.de.
This conceptual review summarises the results of relevant studies on
antidepressants, mood stabilisers such as lithium and anticonvulsants, and
second generation antipsychotics in the indication of bipolar depression. Based
on methodological and clinical considerations, the position of antidepressants
and the possible alternatives in this indication are reviewed very carefully. In
addition the regulatory requirements for licensing a drug for the indication
'short-term treatment of bipolar depression' are described.
PMID: 16078087 [PubMed - as supplied by publisher]
9: Acta Psychiatr Scand. 2005 Aug;112(2):105-9.
One-year outcome with antidepressant--treatment of bipolar depression.
Joffe RT, MacQueen GM, Marriott M, Young LT.
Department of Psychiatry, UMDNJ-New Jersey Medical School, Newark, NJ 07101,
USA. Joffe@umdnj.edu
OBJECTIVE: To examine the risk of relapse into mania or depression with varying
duration of antidepressant treatment in a cohort of 59 patients with bipolar
disorder. METHOD: An open naturalistic evaluation using life charting methods of
patients with 1 year follow-up, who responded to antidepressant treatment and
who then less or more than 6 months of antidepressant treatment. RESULTS:
Patients who received more than 6 months of antidepressant treatment were less
likely to relapse into depression at follow-up of 1 year. There was no
difference in relapse rates for mania in the different antidepressant treatment
duration groups. Gender and bipolar subtype did not significantly affect relapse
rates for depression or mania. CONCLUSION: Our data, taken with other studies,
suggest that the duration of optimal antidepressant treatment in bipolar
disorder must be further evaluated. Copyright 2005 Blackwell Munksgaard.
----------
Neuro Endocrinol Lett. 2005 Aug;26 Suppl 1:27-47.
Treatment of bipolar depression.
Svestka J.
Antidepressants have insufficient effect in 20-40% of patients treated for
depressive disorders. This is particularly true for psychotic and agitated
depression. When administered on a long-term basis, antidepressants cause a
switch into mania in 25-40% of patients and induce rapid cycling (Wehr et al.,
1979, 1987; Goldberg et al., 2001). Classical antipsychotics have exhibited good
therapeutic efficacy in the treatment of various forms of depression, especially
psychotic and agitated forms, albeit burdened with many, above all
extrapyramidal, side effects (for review see Thase, 2002). When administered
over long periods of time, classical antipsychotics may have a depressogenic
effect. Second-generation antipsychotics have started to be increasingly used in
this indication for a variety of reasons including: their antidepressant effect
attributable to raised concentrations of catecholamines in the prefrontal
cortex, their impact on serotonin transmission, their antipsychotic effect due
to their mode of action including the mesolimbic blockade of dopamine D2
receptors, and the low incidence of extrapyramidal and other side effects. The
following text encompasses the results of controlled trials using
second-generation antipsychotics in the treatment of acute depressive disorders.
----------
Am J Psychiatry. 2005 Jul;162(7):1351-60.
A randomized, double-blind, placebo-controlled trial of quetiapine in the
treatment of bipolar I or II depression.
Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler
AJ, McCoy R, Wilson E, Mullen J.
University Hospitals of Cleveland and Case University School of Medicine, 11400
Euclid Ave., Suite 200, Cleveland, OH 44106, USA. joseph.calabrese@uhhs.com
OBJECTIVE: There is a major unmet need for effective options in the treatment of
bipolar depression. METHOD: Five hundred forty-two outpatients with bipolar I
(N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV)
were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo.
The primary efficacy measure was mean change from baseline to week 8 in the
Montgomery-Asberg Depression Rating Scale total score. Additional efficacy
assessments included the Hamilton Depression Rating Scale, Clinical Global
Impression of severity and improvement, Hamilton Anxiety Rating Scale,
Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction
Questionnaire. RESULTS: Quetiapine at either dose demonstrated statistically
significant improvement in Montgomery-Asberg Depression Rating Scale total
scores compared with placebo from week 1 onward. The proportions of patients
meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale
score improvement) at the final assessment in the groups taking 600 and 300
mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for
placebo. The proportions of patients meeting remission criteria
(Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups
taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at
600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg
Depression Rating Scale items, respectively, compared to placebo, including the
core symptoms of depression. Treatment-emergent mania rates were low and similar
for the quetiapine and placebo groups (3.2% and 3.9%, respectively).
CONCLUSIONS: Quetiapine monotherapy is efficacious and well tolerated for the
treatment of bipolar depression.
----------
J Am Board Fam Pract. 2005 Jul-Aug;18(4):271-81.
Is your depressed patient bipolar?
Kaye NS.
Department of Psychiatry and Family Medicine, Jefferson Medical College,
Wilmington, Delaware 19808, USA. nskaye@aol.com
Accurate diagnosis of mood disorders is critical for treatment to be effective.
Distinguishing between major depression and bipolar disorders, especially the
depressed phase of a bipolar disorder, is essential, because they differ
substantially in their genetics, clinical course, outcomes, prognosis, and
treatment. In current practice, bipolar disorders, especially bipolar II
disorder, are underdiagnosed. Misdiagnosing bipolar disorders deprives patients
of timely and potentially lifesaving treatment, particularly considering the
development of newer and possibly more effective medications for both depressive
features and the maintenance treatment (prevention of recurrence/relapse). This
article focuses specifically on how to recognize the identifying features
suggestive of a bipolar disorder in patients who present with depressive
symptoms or who have previously been diagnosed with major depression or
dysthymia. This task is not especially time-consuming, and the interested
primary care or family physician can easily perform this assessment. Tools to
assist the physician in daily practice with the evaluation and recognition of
bipolar disorders and bipolar depression are presented and discussed.
----------
J Clin Psychiatry. 2005 Jun;66(6):726-9.
Omega-3 eicosapentaenoic acid in bipolar depression: report of a small
open-label study.
Osher Y, Bersudsky Y, Belmaker RH.
Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion
University of the Negev, Beer Sheva, Israel. yamy@bgumail.bgu.ac.il
INTRODUCTION: Epidemiologic studies have suggested that consumption of cold
water fish oils may have some protective function against depression. This
proposition is supported by a series of biochemical and pharmacologic studies
that have suggested that fatty acids may modulate neurotransmitter metabolism
and cell signal trans-duction in humans and that abnormalities in fatty acid and
eicosanoid metabolism may play a causal role in depression. Aware of the
critical need for antidepression treatments that might not carry the risk of
precipitating a manic episode in bipolar patients, we decided to conduct an
open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression.
METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by
DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to
6 months. The study was conducted between September 2001 and January 2003.
RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up
achieved a 50% or greater reduction in Hamilton Rating Scale for Depression
scores within 1 month. No patients developed hypomania or manic symptoms. No
significant side effects were reported. LIMITATIONS: This study is limited both
by the open-label design and by the small sample size. As in all previous
reported studies, patients in this study were treated in an outpatient setting,
so that the most severely depressed bipolar patients (requiring hospitalization)
are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty
acids in bipolar depression is still an open question, we believe that these
initial results are encouraging, especially for mild to moderate bipolar
depression, and justify the continuing exploration of its use.
----------
Psychiatr Clin North Am. 2005 Jun;28(2):349-70, vii.
Treatment of bipolar depression.
Dubovsky SL.
Department of Psychiatry, State University of New York at Buffalo, 462 Grider
Street, Buffalo, NY 14215, USA. Dubovsky@buffalo.edu
This article discusses current practices in the treatment of bipolar depression.
In the absence of more definitive research, the treatment of bipolar depression
is guided by clinical experience and expert opinion, and sometimes by marketing
and popular trends, as much as it is by hard data. Considering the limitations
of current knowledge is an essential component of the scientific practice of
psychiatry.
----------
J Clin Psychiatry. 2005 May;66(5):611-6.
Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in
the treatment of bipolar depression.
Keck PE Jr, Corya SA, Altshuler LL, Ketter TA, McElroy SL, Case M, Briggs SD,
Tohen M.
Psychopharmacology Research Program, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, OH 45267, USA. paul.keck@ic.edu
BACKGROUND: Treatment-emergent mania is a potential risk when patients with
bipolar disorder are treated with antidepressant agents. These subanalyses
compare treatment-emergent mania rates in bipolar I depressed patients treated
with olanzapine, placebo, or olanzapine/fluoxetine combination. METHOD: In this
8-week, double-blind investigation, patients with bipolar I depression (DSM-IV
criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total
score > or = 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370),
placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50
mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania
Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP)
Severity of Mania scale, and adverse events records. RESULTS: Overall rates of
study discontinuation due to mania were low and not significantly different
among the therapy groups (p = .358). Incidence of treatment-emergent mania
(defined as a YMRS score < 15 at baseline and > or = 15 at any subsequent visit)
did not differ significantly among therapy groups (olanzapine 5.7%, placebo
6.7%, olanzapine/fluoxetine combination 6.4%; p = .861). Subjects receiving
olanzapine or olanzapine/fluoxetine combination had greater mean decreases in
YMRS scores than those receiving placebo (p < .001 for both). Subjects receiving
olanzapine or olanzapine/fluoxetine combination also had greater mean decreases
in CGI-BP scores than those receiving placebo (p = .040 and p = .003,
respectively). CONCLUSION: These results suggest that olanzapine/fluoxetine
combination does not present a greater risk of treatment-emergent mania compared
to olanzapine or placebo over 8 weeks of acute treatment for bipolar I
depression. Due to the cyclical nature of bipolar disorder, patients taking
olanzapine/fluoxetine combination for bipolar depression should still be
monitored for signs or symptoms of emerging mania.
----------
J Affect Disord. 2005 Apr;85(3):259-66.
Divalproex in the treatment of bipolar depression: a placebo-controlled study.
Davis LL, Bartolucci A, Petty F.
Veteran's Affairs Medical Center (151), 3701 Loop Road East, Tuscaloosa, AL
35404, USA. lori.davis@med.va.gov
BACKGROUND: The treatment of bipolar disorder in the depressed phase is
complicated by a tendency for conventional antidepressant drugs to worsen the
course of the illness by precipitating a manic episode or increasing cycle
frequency. Thus, the potential antidepressant efficacy of mood stabilizers, such
as divalproex, which is an effective treatment for the manic phase of bipolar
disorder, is of considerable interest. METHODS: The clinical efficacy of
divalproex (valproate, Depakote) was tested in an 8-week, double-blind,
placebo-controlled, randomized clinical trial in 25 outpatients with bipolar I
depression. The primary outcome measure was the 17-item Hamilton Rating Scale
for Depression, and secondary measures included the Hamilton Rating Scale for
Anxiety, the Clinician Administered Rating Scale for Mania, and the Clinical
Global Impression scale. RESULTS: Using repeated measures ANOVA with last
observation carried forward, divalproex was more effective than placebo in
improving symptoms of depression (p = 0.0002) and symptoms of anxiety (p =
0.0001) than placebo. LIMITATIONS: The sample size was small, and most patients
were male. CONCLUSIONS: These pilot results indicate that divalproex is
effective in reducing the symptoms of depression and anxiety in bipolar I,
depressed phase. These positive results support the need to perform a larger,
multisite study of divalproex treatment for bipolar depression.
---------
J ECT. 2005 Mar;21(1):31-4.
Efficacy of electroconvulsive therapy in treatment-resistant bipolar disorder: a
case series.
Macedo-Soares MB, Moreno RA, Rigonatti SP, Lafer B.
Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo,
Brazil. marciabms@uol.com.br
The response to electroconvulsive therapy for six bipolar patients after
pharmacotherapy failure is discussed. METHODS: Inclusion criteria were as
follows: (1) bipolar mood disorder, manic, depressive or mixed episode (DSM-IV);
(2) failure of pharmacotherapy, that is, for mania, manic episode unresponsive
to at least 2 adequate antimanic trials for 6 weeks; and for bipolar depression,
bipolar depressive episode unresponsive to at least 2 adequate antidepressant
trials for 8 weeks. The patients underwent 12 bilateral sessions of ECT 3 times
per week. Clinical response was considered a reduction of 50% or greater in the
Young Mania Rating Scale (YMRS) and in the Hamilton Rating Scale for
Depression-21 items (HAMD-21). Final YMRS <6 and HAMD-21 <8 defined remission.
RESULTS: Six of the 9 referred patients consented to be submitted to ECT. Four
were male, with ages ranging from 29 to 61 years, and their age at onset ranged
from 19 to 49 years. Four showed psychotic features. All responded to ECT.
----------
J Affect Disord. 2005 Feb;84(2-3):117-25.
A different depression: clinical distinctions between bipolar and unipolar
depression.
Bowden CL.
Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd
Curl Drive, 7th Floor (Mail Code 7792), San Antonio, TX 78229-3900, USA.
bowdenc@uthscsa.edu
Delayed diagnosis or misdiagnosis can prolong the suffering of patients with
bipolar disorder. Accurate early diagnosis is sometimes difficult, however,
particularly because patients often present in the depressive phase, which can
easily be mistaken for unipolar depression. Unfortunately, therapy appropriate
for unipolar depression can increase the risk of manic switch or cycle
acceleration in bipolar disorder, especially in those with a family history of
bipolarity and suicide, although some antidepressants may be useful in some
bipolar patients. In addition, most currently available mood stabilizers, though
effective in managing mania, do not effectively resolve depression. In contrast,
lamotrigine has shown activity in bipolar depression and has a very low risk of
manic switch. Bipolar depression, compared with unipolar depression, is more
likely to be associated with hypersomnia, motor retardation, mood lability,
early onset, and a family history of bipolar disorder. Awareness of these
distinctions can greatly improve diagnosis of bipolar disorder and provide an
opportunity for effective therapeutic intervention.
---------
J Clin Psychiatry. 2005 Feb;66(2):195-8.
A preliminary open-label study of zonisamide treatment for bipolar depression in
10 patients.
Anand A, Bukhari L, Jennings SA, Lee C, Kamat M, Shekhar A, Nurnberger JI Jr,
Lightfoot J.
Department of Psychiatry, Indiana University School of Medicine, IN 46202, USA.
aanand@iupui.edu
OBJECTIVE: The purpose of this study was to investigate the effectiveness of
zonisamide in the treatment of bipolar depression. METHOD: Ten patients with
DSM-IV bipolar disorder, depressed phase, who had either not tolerated or not
responded to previous treatments were given zonisamide in this add-on open-label
study. Zonisamide treatment was started at 100 mg/day and increased by 100 mg
every 2 weeks to a maximum of 300 mg/day in divided doses (b.i.d. or t.i.d.).
Subjects underwent weekly visits at which they were administered the 17-item
Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS),
and Clinical Global Impressions scale (CGI). Every 2 weeks, subjects also
underwent laboratory tests, a urine examination, and a verbal memory test.
Outcome measures were analyzed with repeated-measures analysis of variance.
RESULTS: Eight subjects completed all 8 weeks of the study. Two subjects
completed more than 4 weeks of the study, and their data were analyzed using the
last observation carried forward. Bipolar depression subjects had a significant
reduction in HAM-D scores (p < .001) and in CGI-Improvement (CGI-I) scores (p <
.001). Five of 8 subjects who completed all 8 weeks of the study had more than a
50% decrease in HAM-D scores and were rated much improved on the CGI-I at the
end of 8 weeks of treatment. There was no significant drug effect on YMRS
scores, weight, or verbal memory. CONCLUSION: Zonisamide may be a useful drug in
the treatment of bipolar depression. Further controlled clinical trials are
needed.
----------
Bipolar Disord. 2005;7 Suppl 5:13-23.
Newer treatment studies for bipolar depression.
Gao K, Calabrese JR.
NIMH Bipolar Research Center, Mood Disorders Program, University Hospitals of
Cleveland/Case Western Reserve University School of Medicine, Cleveland, OH,
USA. keming.gao@uhhs.com
OBJECTIVE: Depressive symptoms of bipolar disorder have more negative impact on
a patient's life than manic symptoms. This review focused on the emerging
efficacy data for treatments in bipolar depression. METHODS: English-language
literature cited in Medline was searched with terms bipolar depression, clinical
trial, and trial. Randomized, placebo-controlled trials of newer studies with
older agents and all studies with newer or novel agents were prioritized.
Open-label studies of novel agents presented at major scientific meetings were
also included. RESULTS: Olanzapine, olanzapine-fluoxetine combination (OFC), and
quetiapine were superior to placebo in the acute treatment of bipolar
depression. Lamotrigine only significantly reduced core symptoms of depression
compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and
omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood
stabilizer (MS) had superiority to placebo in reducing depressive symptoms.
Topiramate augmentation of an MS was equally as effective as Bupropion-SR.
Patients treated with an MS responded well to the addition of agomelatine, a
melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol
and repetitive transcranial magnetic stimulation did not separate from placebo.
Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to
placebo in preventing depressive relapses. All agents were relatively well
tolerated. CONCLUSIONS: Olanzapine, OFC, and quetiapine are effective in the
acute treatment of bipolar depression. Compared with lithium and divalproex,
lamotrigine is more effective in preventing bipolar depression. Larger
controlled studies of the other agents in the acute and maintenance treatment of
bipolar depression are warranted.
----------
Bipolar Disord. 2005;7 Suppl 5:3-12.
Benefits and limitations of antidepressants and traditional mood stabilizers for
treatment of bipolar depression.
Goldberg JF, Nassir Ghaemi S.
Affective Disorders Program, Silver Hill Hospital, New Canaan, CT 06840, USA.
jgoldberg@silverhillhospital.org
OBJECTIVE: The aim of this paper was to review the rationales, risks, and
benefits for using standard antidepressants versus mood stabilizing agents
and/or atypical antipsychotics to treat bipolar depression. METHOD: A selective
literature review was conducted using key terms and by reference known to the
authors. Bibliographies of articles and book chapters were further scrutinized
for relevant literature. RESULTS: The strengths and limitations of current
studies are described and critically reviewed in order to present optimal
strategies for effective pharmacotherapy. Clinical factors that can mitigate or
confound simple bivariate relationships between antidepressant use and outcome
have seldom been examined using multivariate statistical techniques. For many of
the key questions there is a paucity of informative literature and randomized
clinical trials are of limited value in addressing some of the issues.
CONCLUSIONS: Clinicians and investigators should be aware of the methodological
shortcomings of existing studies. Decisions about the relative merits versus
contraindications for antidepressant use should be made via more individualized,
case-by-case profiling rather than by rigid prescribing practices.
----------
Bipolar Disord. 2005;7 Suppl 4:34-40.
Bipolar depression: a new role for atypical antipsychotics?
Keck PE Jr.
Psychopharmacology Research Program, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA. paul.keck@uc.edu
Bipolar depression, the most common phase of bipolar disorder, causes
significant morbidity and mortality. Traditional drugs such as lithium,
lamotrigine or antidepressants each offer some clinical efficacy; however,
efficacy can be limited and side effects are sometimes problematic. Thus there
is a major unmet need for effective, well-tolerated agents for the treatment of
bipolar depression. The atypical antipsychotics, with their proven efficacy
against manic symptoms, are emerging as candidates for use against the
depressive phase of bipolar disorder. Several studies have shown that some
atypicals improve depressive symptoms in mixed episodes in patients with bipolar
disorder; however, few studies have been performed in patients specifically with
bipolar depressive episodes. In a randomized, placebo-controlled trial in
patients with acute bipolar I depression, olanzapine monotherapy and an
olanzapine-fluoxetine combination significantly improved Montgomery-Asberg
Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001)
with corresponding effect sizes (improvement of active treatment over placebo
divided by pooled standard deviation) of 0.32 and 0.68, respectively.
Importantly, there were no significant differences in rates of switch into mania
among the three groups. Recent results from an 8-week, randomized
placebo-controlled trial in patients with bipolar I and II disorder who were
experiencing a bipolar depressive episode showed that quetiapine (300 and 600
mg/day) had significantly greater efficacy compared with placebo in improving
the core symptoms of depression, including suicidal thoughts. Quetiapine
significantly improved MADRS total scores compared with placebo (p < 0.001);
effect sizes (improvement of quetiapine over placebo divided by pooled standard
deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively,
were observed. Both doses of quetiapine significantly improved symptoms of
anxiety, sleep quality and global quality of life (all, p < 0.001 versus
placebo). These initial findings suggest that atypical antipsychotics may prove
to be important future treatments for patients with bipolar depression.
----------
Drugs. 2005;65(17):2533-51.
Quetiapine: a review of its use in acute mania and depression associated with
bipolar disorder.
Dando TM, Keating GM.
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in
the treatment of schizophrenia, shows efficacy in the treatment of acute mania
and depression associated with bipolar disorder.Quetiapine, either as
monotherapy or in combination with lithium or divalproex sodium (valproate
semisodium), is generally well tolerated and effective in reducing manic
symptoms in adult and adolescent patients with acute bipolar mania, and is
approved for use in adults for this indication. As monotherapy, the drug is also
effective in reducing depressive symptoms in patients with bipolar depression.
It is associated with a low incidence of extrapyramidal symptom (EPS)-related
adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows
potential in the treatment of bipolar depression, and represents a useful agent
for the treatment of acute bipolar mania.
----------
Expert Rev Neurother. 2005 Jan;5(1):69-78.
Treatment of bipolar depression: focus on pharmacologic therapies.
Mitchell PB, Malhi GS.
University of New South Wales, School of Psychiatry, Prince of Wales Hospital,
Randwick, New South Wales 2031, Australia. phil.mitchell@unsw.edu.au
Recent studies have highlighted significant limitations in our capacity to
effectively treat bipolar depression. This article reviews the present status of
treatments for this condition, highlighting emerging new pharmacotherapies such
as lamotrigine, olanzapine and quetiapine, while also addressing modern
psychologic interventions such as cognitive behavioral therapy and
psychoeducation. The role of older treatments such as lithium and the
antidepressants is also discussed, particularly as a recent meta-analysis has
thrown into question current heightened concern over antidepressant-induced
mania. The advent of new pharmacologic and psychologic treatments provides
optimism for improved outcomes for this highly disabling condition.
----------
J Clin Psychiatry. 2005;66 Suppl 5:40-8.
Atypical antipsychotics in bipolar depression: potential mechanisms of action.
Yatham LN, Goldstein JM, Vieta E, Bowden CL, Grunze H, Post RM, Suppes T,
Calabrese JR.
Department of Psychiatry, The University of British Columbia, UBC Hospital,
Vancouver, Canada. Yatham@interchange.ubc.ca
"Conventional" antidepressants, such as the selective serotonin reuptake
inhibitors (SSRIs), bupropion, or serotonin-norepinephrine reuptake inhibitors,
are not recommended as monotherapy for bipolar depression. Although they are
likely to provide effective symptom relief in combination with mood stabilizers,
the risk of precipitating a switch to mania often complicates their use even as
combination therapy. Recently, 2 psychotropic medications approved for treating
acute mania, olanzapine and quetiapine, have also been shown to possess
antidepressant activity without destabilizing mood and, as such, are potential
mood stabilizers. This article aims to review the mechanism of action of
conventional antidepressants and newer agents that are effective in the
treatment of bipolar depression. A number of mechanisms have been postulated to
play a role in the effective treatment of bipolar depression, including targets
as diverse as serotonin (5-HT), norepinephrine, dopamine, gamma-aminobutyric
acid (GABA), glutamate, and various second messenger signaling pathways. A
review of the data reveals an important point of commonality among the
antidepressant treatments, olanzapine, and quetiapine. Antidepressant
treatments, such as norepinephrine reuptake inhibitors, SSRIs, and
electroconvulsive therapy, induce a reduction of 5-HT(2A) receptors. Both
olanzapine and quetiapine not only are antagonists at this receptor but also
induce downregulation of 5-HT(2A) receptors. It is possible that the
antidepressant efficacy of these agents is mediated by this receptor, while the
additional benefit of olanzapine and quetiapine over unimodal antidepressant
treatments, in terms of stabilizing mood, may be provided by their concomitant
dopamine D(2) antagonism. Further studies should be conducted to examine these
hypotheses.
---------
J Clin Psychiatry. 2005;66 Suppl 5:26-33.
Clinical highlights in bipolar depression: focus on atypical antipsychotics.
Calabrese JR, Elhaj O, Gajwani P, Gao K.
University Hospitals of Cleveland/Case Western Reserve University School of
Medicine, Cleveland, Ohio, USA. joseph.calabrese@uhhs.com
Despite the considerable burden of bipolar depression, the treatment of this
debilitating phase of bipolar disorder is suboptimally addressed by currently
available pharmacologic options. Consequently, there is a need for the
development of new treatment options with enhanced efficacy and tolerability.
Evidence of antidepressant efficacy for some of the atypical antipsychotics in
the treatment of bipolar depression has recently emerged. The findings of a
large-scale, placebo-controlled, double-blind, randomized clinical study of
olanzapine alone and in combination with fluoxetine, and a similar study of
quetiapine monotherapy, suggest that some of the atypical antipsychotics may be
efficacious in treating depressive symptoms in patients with bipolar I disorder.
Subpopulation analyses suggest that quetiapine monotherapy and the olanzapine
plus fluoxetine combination appear to be effective in treating depression in
patients with a rapid-cycling course. The magnitude of improvement in depressive
symptoms in the bipolar I population appears to be larger for quetiapine
monotherapy compared with either olanzapine or olanzapine plus fluoxetine;
however, the limitations of such a cross-study comparison are acknowledged. Both
olanzapine monotherapy and combination therapy, as well as quetiapine
monotherapy, were well tolerated. The overall incidence of treatment-emergent
mania was low and comparable with placebo in both studies. Somnolence, weight
gain, increased appetite and nonfasting glucose and cholesterol levels were more
commonly reported in patients treated with olanzapine monotherapy or combination
therapy compared with placebo. Dry mouth, sedation/somnolence, dizziness, and
constipation were more commonly associated with quetiapine treatment. Large,
controlled studies are needed to determine whether other psychotropic agents
have antidepressant properties that would make them suitable for use in patients
with bipolar depression. In addition, direct comparison of the regimens used in
the current study should determine whether the differences evident between them
can be confirmed.
----------
J Clin Psychiatry. 2005;66 Suppl 5:11-6.
Challenges in the management of bipolar depression.
Suppes T, Kelly DI, Perla JM.
Department of Psychiatry, University of Texas Southwestern Medical Center,
Dallas 75390-9121, USA. trisha.suppes@utsouthwestern.edu
Bipolar depression has started to receive more attention in clinical trials only
relatively recently, despite the fact that patients spend more time in the
depressed phase than in the manic phase of bipolar disorder. The diagnosis and
management of bipolar depression are challenging, and many patients are
undiagnosed or misdiagnosed due to symptom similarities with unipolar depression
or other illnesses and/or comorbidities. Untreated or inappropriately treated
bipolar depression adds to the burden of illness and is associated with a
greater risk of suicide. Treatment options include lithium, lamotrigine,
atypical antipsychotics, and traditional antidepressants, such as the selective
serotonin reuptake inhibitors. However, traditional antidepressants are
recommended with caution due to their potential risk of switching patients into
mania. Some atypical antipsychotics have shown efficacy in bipolar depression,
although longer-term studies are warranted. The choice of treatment for
different subgroups of patients with bipolar depression, including those with
comorbid anxiety, may vary and also needs further study. Other important issues
that require further investigation include the recognition of the core features
of bipolar depression and the threshold symptoms for treatment, as well as the
optimal treatment choices for monotherapy or combination therapy, and acute
versus long-term management of bipolar depression.
----------
J Clin Psychiatry. 2005;66 Suppl 5:5-10.
The impact of bipolar depression.
Post RM.
Bipolar Collaborative Network, Chevy Chase, MD, USA. robert.post@nih.gov
Bipolar disorder is a chronic, intermittent illness that is associated with high
morbidity and mortality. In addition, patients with bipolar disorder often have
comorbid psychiatric conditions (such as anxiety disorders, alcohol or substance
abuse, and eating disorders) or medical disorders (such as obesity), which
result in increased burden of illness for the patients, family members, and
treating clinicians. Although bipolar disorder consists of recurring episodes of
mania and depression, patients spend more time depressed than manic. Bipolar
depression is associated with a greater risk of suicide and of impairment in
work, social, or family life than mania. This health burden also results in
direct and indirect economic costs to the individual and society at large.
Bipolar depression is often undiagnosed or misdiagnosed as unipolar depression,
resulting in incorrect or inadequate treatment. Available treatments for bipolar
depression include medications such as lithium, selected anticonvulsants, and
the atypical antipsychotics. Traditional antidepressants are not recommended as
monotherapy for bipolar depression as they can induce switching to mania. Early
and accurate diagnosis, aggressive management, and earlier prophylactic
treatment regimens are needed to overcome the impact of depressive episodes in
patients with bipolar disorder.
----------
J Clin Psychiatry. 2005;66 Suppl 1:3-6.
Treatment options for bipolar depression.
Bowden CL.
Department of Psychiatry, University of Texas Health Science Center, San
Antonio, TX 78229-3900, USA. bowdenc@uthscsa.edu
Bipolar disorder is often misdiagnosed as major depressive disorder because of
the high frequency of depressive symptomatology in many patients with bipolar
disorder. Depressive episodes that are resistant to treatment may also be
associated with a worse course of illness in bipolar disorder, but we do not yet
understand all the factors in the connection between bipolar disorder and
depression. The data on the effectiveness of antidepressants in the treatment of
depression in bipolar disorder vary greatly, and there have been few
prospective, randomized studies on the subject. From the data so far, the rates
of induction of mania for selective serotonin reuptake inhibitors and
lamotrigine seem similar to those seen with placebo. The optimal length of time
to continue antidepressant treatment in patients with bipolar disorder has not
yet been determined; however, research tends to indicate that a longer term of
treatment (6 months or more) may aid in the prevention of relapse. Newer U.S.
Food and Drug Administration-approved treatments for depression in bipolar
disorder include a combination of olanzapine and fluoxetine, which is used for
depressive episodes in bipolar disorder, and lamotrigine, which is used for
maintenance treatment of bipolar I disorder. Psychoeducation has also been
examined as a possible treatment for depression in bipolar disorder, and a study
has shown that patients receiving psychoeducation plus medication may have a
lower rate of relapse than patients who receive medication alone.
----------
World J Biol Psychiatry. 2005;6(4):231-41.
Bipolar disorder, antidepressants and induction of hypomania or mania. A
systematic review.
Visser HM, Van Der Mast RC.
De Geestgronden, Institute for Mental Health Care, Hoofddorp, The Netherlands.
OBJECTIVE: The literature cautions against the induction of (hypo)mania owing to
the use of antidepressants in bipolar disorder. Objectives of this review are to
examine: (1) the evidence for this assumption; (2) underlying risk factors; and
(3) the extent to which a mood stabilizer may be protective. METHOD: A
systematic literature review was conducted. RESULTS: Thirteen relevant studies
were included. All of them had methodological shortcomings. Overall, there is no
strong evidence that use of antidepressants in bipolar disorder increases the
risk of (hypo)mania. Possible, although unreplicated, risk factors are: a short
allele of the promoter region of the serotonin transporter gene SCL6A4,
substance abuse or dependence, multiple antidepressant trials, lower number of
previous manias, less delusions during illness, depressive polarity at illness
onset, and rapid cycling that has, however, been contradicted by another study.
Subtype of bipolar disorder (I or II) has been considered in four studies, with
conflicting results. Mood stabilizers are possibly protective. CONCLUSION: There
is an urgent need for adequate studies of sufficient size. For the time being,
treatment of bipolar depression may best be based on the results of the life
chart of the individual patient keeping in mind the risk factors found until
now.
----------
Biol Psychiatry. 2004 Dec 15;56(12):957-63.
Mood state at study entry as predictor of the polarity of relapse in bipolar
disorder.
Calabrese JR, Vieta E, El-Mallakh R, Findling RL, Youngstrom EA, Elhaj O,
Gajwani P, Pies R.
Case University School of Medicine, University Hospitals of Cleveland, 11400
Euclid Avenue, Suite #200, Cleveland, OH 44106, USA. joseph.calabrese@uhhs.com
Of the placebo-controlled maintenance studies conducted in bipolar disorder, few
have enrolled patients who present depressed. In fact, only lithium and
lamotrigine have been studied over the long term with placebo-controlled designs
in recently manic and recently depressed bipolar patients. Given the magnitude
of the unmet medical need and the data suggesting that symptomatic patients with
bipolar disorder spend the majority of their time depressed, this is
unfortunate. Our review of the pre-lithium literature and more recent
publications suggests that mood state at study entry predicts the polarity of
relapse and the response to treatment. Accordingly, a need exists to enroll
recently depressed patients in maintenance studies to elucidate the complete
spectrum of efficacy of putative mood stabilizers and improve the long-term
treatment of bipolar depression. Patients presenting depressed for a maintenance
study tend to relapse into depression; those presenting manic, into
hypomania/mania/mixed states. This is particularly true during the first several
months of the randomized treatment. The polarity of the index episode tends to
predict the polarity of relapse into a subsequent episode in a ratio of about
2:1 to 3:1. We conclude that putative mood stabilizers must be tested in
recently manic and recently depressed patients to determine their spectrum of
prophylactic efficacy.
----------
Bipolar Disord. 2004 Dec;6(6):530-9.
Bipolar depression: phenomenological overview and clinical characteristics.
Mitchell PB, Malhi GS.
School of Psychiatry, University of New South Wales and Mood Disorders Unit,
Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
phil.mitchell@unsw.edu.au
OBJECTIVES: There has been increasing interest in the depressed phase of bipolar
disorder (bipolar depression). This paper aims to review the clinical
characteristics of bipolar depression, focusing upon its prevalence and
phenomenology, related neuropsychological dysfunction, suicidal behaviour,
disability and treatment responsiveness. METHODS: Studies on the prevalence of
depression in bipolar disorder, the comparative phenomenology of bipolar and
unipolar depression, as well as neuropsychology and brain imaging studies, are
reviewed. To identify relevant papers, a literature search using MEDLINE and
PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance
in bipolar disorder, and most frequently presents as subsyndromal, minor or
dysthymic depression. Compared with major depressive disorder (unipolar
depression), bipolar depression is more likely to manifest with psychosis,
melancholic symptoms, psychomotor retardation (in bipolar I disorder) and
'atypical' symptoms. The few neuropsychological studies undertaken indicate
greater impairment in bipolar depression. Suicide rates are high in bipolar
disorder, with suicidal ideation, suicide attempts and completed suicides all
occurring predominantly in the depressed phase of this condition. Furthermore,
the depressed phase (even subsyndromal) appears to be the major contributant to
the disability related to this condition. CONCLUSIONS: The significance of the
depressed phase of bipolar disorder has been markedly underestimated. Bipolar
depression accounts for most of the morbidity and mortality due to this illness.
Current treatments have significant limitations. Blackwell Munksgaard, 2004
----------
Curr Psychiatry Rep. 2004 Dec;6(6):459-65.
Separate and concomitant use of lamotrigine, lithium, and divalproex in bipolar
disorders.
Lieberman DZ, Goodwin FK.
Department of Psychiatry and Behavioral Sciences, George Washington University,
2150 Pennsylvania Ave, NW, Washington, DC 20037, USA.
Expert consensus emphasizes the need for better recognition and accurate
diagnosis of bipolar disorder. Current research on lithium, divalproex, and
lamotrigine provides new insight into the effective management of this illness.
Advances in identifying the mechanism of action of mood stabilization has
focused on signaling pathways within the cell that are associated with
neurotrophic effects. Clinical research has led to confirmatory evidence of the
efficacy of lithium in all phases of bipolar disorder, with the greatest effects
seen in the treatment and prevention of mania. Compared to divalproex, lithium
also has been found to have greater efficacy in the prevention of suicide.
Lamotrigine has emerged as a first line treatment for bipolar depression, which
is an area of weakness for other mood stabilizers. Oral loading of divalproex
leads to rapid stabilization of mania without imposing a greater adverse effect
burden than conventional dosing. Because no agent is universally effective in
all phases of the illness, combination therapy with two or more agents often is
the best option.
----------
Expert Rev Neurother. 2004 Nov;4(6 Suppl 2):S27-33.
Bipolar depression: the role of atypical antipsychotics.
Post RM, Calabrese JR.
robert.post@nih.gov
Acute manic episodes in bipolar disorder require rapid and effective relief.
Bipolar depression is a major component of the bipolar disorder spectrum.
Existing treatment options for bipolar depression include lithium, lamotrigine
and conventional antidepressants. However, lithium is more effective in treating
mania or hypomania than depression, both acutely and prophylactically,
lamotrigine has only been demonstrated to be effective in one adequately powered
study in acute bipolar I depression, and conventional antidepressants have been
associated with emergent mania and cycle acceleration. Symptomatic outpatients
can expect to spend, on average, 33% of their time in the depressive phase
compared with 11% in the manic phase. Consequently, there is a need for
additional agents to effectively treat bipolar depression. The atypical agents
olanzapine, risperidone and quetiapine have demonstrated efficacy against the
manic phase of bipolar disorder and appear also to have potential in the
depressive phase. Olanzapine monotherapy significantly improved depressive
symptoms compared with placebo in patients with bipolar disorder in an 8-week
randomized, controlled clinical study, but the magnitude of the clinical effect
was small. The observed improvement in depressive symptoms became moderately
large when olanzapine was combined with the antidepressant fluoxetine.
Quetiapine monotherapy also resulted in significant improvements compared with
placebo in patients with either bipolar I or bipolar II disorder in another
8-week randomized, controlled clinical study, but the effect size was large. A
6-month open-label study of risperidone added to ongoing therapy demonstrated
improvements in depressive symptoms in patients with bipolar and schizoaffective
disorders experiencing a manic, hypomanic, mixed or depressive episode. The
receptor-binding profile of these agents supports a role in the treatment of
depressive symptoms and clinical data are beginning to emerge of their efficacy
in both the acute and maintenance setting.
---------
Bipolar Disord. 2004 Oct;6(5):432-4.
Acute treatment of bipolar depression with adjunctive zonisamide: a
retrospective chart review.
Baldassano CF, Ghaemi SN, Chang A, Lyman A, Lipari M.
Bipolar Outpatient Program, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104-3309, USA. cfb@mail.med.upenn.edu
BACKGROUND: This retrospective chart review evaluated the use of zonisamide as
adjunctive treatment in patients with bipolar depression. METHOD: The charts of
outpatients with bipolar I or II disorder treated with adjunctive zonisamide
were reviewed. The efficacy of zonisamide was assessed via comparison of
physician-rated Global Assessment of Functioning (GAF) and Clinical Global
Impression of Severity (CGI-S) Scale scores at baseline and after 6 weeks of
therapy using paired t-tests. Patients who scored < or = 2 on the CGI-S after 6
weeks of zonisamide therapy were considered good responders to zonisamide.
RESULTS: Charts for 12 patients (four men and eight women) with a mean (+/- SD)
age of 39.6 (+/- 7.6) years were evaluated. Patients received a mean (+/- SD)
zonisamide dosage of 236 (+/- 68) mg/day. Mean GAF scores significantly improved
from 44.0 at baseline to 59.3 at week 6 (P = 0.05). Mean CGI-S scores improved
from 4.54 at baseline to 3.42 at week 6, but the change was not statistically
significant. Six patients (50.0%) were considered responders to zonisamide. Four
patients discontinued zonisamide therapy, two for an adverse event (sedation)
and two for lack of efficacy. CONCLUSIONS: Zonisamide may be a useful adjunctive
treatment for some patients with bipolar depression. Conclusions from this study
are limited due to its retrospective design. Further investigation of zonisamide
in the treatment of bipolar depression is warranted.
----------
Bipolar Disord. 2004 Oct;6(5):416-20.
Adjunctive stimulant use in patients with bipolar disorder: treatment of
residual depression and sedation.
Carlson PJ, Merlock MC, Suppes T.
Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9121,
USA.
BACKGROUND: Residual depression and medication-induced sedation remain
significant problems for many patients with bipolar disorder (BD). Some evidence
indicates that bipolar depression may be more responsive to dopaminergic agents,
suggesting that adjunctive stimulant medication may be an effective treatment
for bipolar depression as well as for medication-induced sedation. However,
there are few data regarding the use of these medications in BD, likely due in
part to concerns regarding potential stimulant-induced switching and stimulant
abuse. METHODS: In order to evaluate the effectiveness and safety of
psychostimulants in BD, we retrospectively reviewed the cases of eight
consecutive individuals from our clinic (five with bipolar I and three with
bipolar II) who received adjunctive stimulants (either methylphenidate or
amphetamine) within the last 2 years. Primary target symptoms of stimulant
therapy included residual depression and medication-induced sedation. The degree
of clinical change in target symptoms was estimated, and the Clinical Global
Impression-BP Version scale (CGI-BP) was used to evaluate the overall severity
of illness at baseline, 6 months after stimulant initiation, and at last visit.
RESULTS: The eight patients generally showed moderate clinical improvement in
their target symptoms and substantial improvement of overall bipolar illness
(mean change in CGI-BP overall score 2.9). There was no evidence of
stimulant-induced switching or abuse. The stimulants were well tolerated.
CONCLUSION: The present case series suggests that adjunctive stimulants may be a
reasonable therapeutic option for treating residual depression and
medication-induced sedation in some patients. Controlled trials are needed to
assess the safety and effectiveness of stimulant augmentation in BD.
----------
Am J Psychiatry. 2004 Sep;161(9):1537-47.
Comment in:
Am J Psychiatry. 2005 Aug;162(8):1545-6; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1546-7; author reply 1547-8.
Am J Psychiatry. 2005 Aug;162(8):1546; author reply 1547-8.
Evid Based Ment Health. 2005 May;8(2):35.
Antidepressants for bipolar depression: a systematic review of randomized,
controlled trials.
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM.
Department of Psychiatry, Warneford Hospital, Oxford, UK.
harm.gijsman@doctors.net.uk
OBJECTIVE: This study reviewed the evidence from randomized, controlled trials
on the efficacy and safety of antidepressants in the short-term treatment of
bipolar depression. METHOD: The authors performed a systematic review and
meta-analysis of randomized, controlled trials. They searched the Cochrane
Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register,
incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX,
and LILACS. The main outcome measures were the proportion of patients who
clinically responded to treatment and the rate of switching to mania. RESULTS:
Twelve randomized trials were included, with a total of 1,088 randomly assigned
patients. Five trials compared one or more antidepressants with placebo: 75% of
these patients were receiving a concurrent mood stabilizer or an atypical
antipsychotic. Antidepressants were more effective than placebo. Antidepressants
did not induce more switching to mania (the event rate for antidepressants was
3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two
antidepressants. The rate of switching for tricyclic antidepressants was 10%,
and for all other antidepressants combined, it was 3.2%. CONCLUSIONS:
Antidepressants are effective in the short-term treatment of bipolar depression.
The trial data do not suggest that switching is a common early complication of
treatment with antidepressants. It may be prudent to use a selective serotonin
reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic
antidepressant as first-line treatment. Given the limited evidence, there is a
compelling need for further studies with longer follow-up periods and careful
definition and follow-up of emerging mania and partial remission.
----------
CNS Spectr. 2004 Sep;9(9 Suppl 9):11-8.
Rethinking the treatment paradigm for bipolar depression: the importance of
long-term management.
Baldassano CF, Ballas CA, O'Reardon JP.
Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, PA 19104, USA. cfb@mail.med.upenn.edu
The need for long-term management of bipolar disorder is evident. Bipolar
patients spend more time depressed than manic; however, few agents used for
maintenance therapy of bipolar disorder have demonstrated good efficacy in
delaying relapse into depression. This article provides a comprehensive review
of open-label and randomized, controlled studies examining prophylactic efficacy
in bipolar disorder, especially bipolar depression. Lithium, considered the gold
standard for bipolar disorder maintenance therapy may be more effective in
delaying manic relapse than in delaying depressive relapse. Evidence for the
efficacy of divalproex and carbamazepine in delaying depressive relapse is yet
to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time
to depressive relapse. Unpublished studies show olanzapine's efficacy in
preventing manic recurrence, while its efficacy in preventing depressive
recurrence is yet to be proven. As patients with bipolar disorder are prone to
experiencing depressive episodes, more attention needs to be focused on
preventing depressive relapse. To date, three agents--lithium, lamotrigine, and
olanzapine--have been shown to have prophylactic benefits in treating this
highly recurrent disorder.
----------
IDrugs. 2004 Sep;7(9):846-50.
Bipolar depression: an overview.
Oral ET, Vahip S.
Mood Disorders Outpatient Program, Bakirkoy State Hospital for Research and
Training in Neurology & Psychiatry, Istanbul 34747, Turkey.
etoral@superonline.com
Depressive episodes are significant in bipolar illness since patients can spend
up to one-third of their lives in depression. Although the treatment of bipolar
depression remains an understudied area, new data from randomized, controlled
trials and naturalistic studies have expanded the range of treatments available.
The main aim in the treatment of bipolar depression is the prevention of the
patient switching to mania and cycle acceleration, and antidepressant therapy
may be contraindicated because of the risk for switching. Guidelines for the
acute treatment of bipolar depression emphasize treatment with a mood
stabilizer, of which lithium has been the most thoroughly studied in randomized,
controlled trials in acute bipolar depression. Lamotrigine has also demonstrated
significant efficacy in recent studies and has been approved by the FDA.
----------
J Am Osteopath Assoc. 2004 Jun;104(6 Suppl 6):S9-14.
Comment in:
J Am Osteopath Assoc. 2004 Dec;104(12):516; discussion 517; author reply
517.
Bipolar depression in primary care: a hidden threat.
Lewis FT.
CNS Clinical Research Group, 8100 Royal Palm Blvd, Coral Springs, FL 33065-5733,
USA. flewisdo@bellsouth.net
With the recent awareness of the bipolar spectrum, the interest and concern of
physicians regarding the depressive side of bipolar disorder has emerged.
Depression is the modal phase of bipolar disorder, as well as the phase that
imparts the greatest risk for suicide. Despite these realities, little is known
about the management of bipolar depression and much of what is known is
complicated by conflicting reports regarding the use of antidepressants as
either short- or long-term treatment modalities. This fear among physicians of
complicating a patient's course secondary to antidepressant use combined with
the fact that presently available mood stabilizers are less than reliable
antidepressants has resulted in far more questions about management than
answers. This article explores the clinical issues involving the depressive
states, reviews some of the emerging data, and, it is hoped, lends some guidance
regarding treatment options.
----------
Eur Neuropsychopharmacol. 2004 May;14 Suppl 2:S89-93.
Lamotrigine: a depression mood stabiliser.
Herman E.
Psychiatric Clinic, Psychiatric Office, Charles University, Na Markvartce 8, 160
00 Praha, Prague 6, Czech Republic. aapsych@mbox.vol.cz
Depression mood stabilisers, which stabilise mood from below the mood baseline
(euthymia) without inducing switch into mania or episode acceleration, are
urgently needed for the effective treatment of bipolar depression. The
anticonvulsant lamotrigine, recently approved as maintenance therapy for bipolar
depression, has undergone evaluation as acute and maintenance therapy for
bipolar disorder in several controlled clinical trials. Data from these trials
suggest that lamotrigine is effective in the treatment and prevention of bipolar
depression without destabilising mood. Although the majority of evidence comes
from studies in patients with bipolar I disorder, a recent naturalistic study
suggests that these observations may also extend to patients with bipolar II
disorder. Lamotrigine may therefore fulfil the unmet need for an effective
depression mood stabiliser.
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Expert Opin Pharmacother. 2004 May;5(5):1101-7.
Pharmacotherapy for bipolar depression: an economic assessment.
Bowden CL, Krishnan AA.
Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 78229-3900, USA. bowden@uthscsa.edu
Bipolar disorder (BPD) is a common, severe and recurrent mood disorder
associated with high rates of comorbidities, suicide, dysfunction and a high
socioeconomic burden. Although the management of BPD has traditionally focused
on the acute treatment of mania, the chronic nature of BPD necessitates
long-term maintenance treatment. Bipolar depression is the predominant abnormal
affective pole and causes greater disability and economic burden than mania.
Maintenance pharmacotherapy can reduce rates of future episodes, and
subsequently, the associated risks, functional disability and economic burden of
bipolar illness.
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J Clin Psychiatry. 2004 May;65(5):627-33.
Comment in:
J Clin Psychiatry. 2004 Nov;65(11):1578-9; author reply 1579.
Anger attacks in bipolar depression: predictors and response to citalopram added
to mood stabilizers.
Mammen OK, Pilkonis PA, Chengappa KN, Kupfer DJ.
Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. msmmenok@msx.upmc.edu
BACKGROUND: Of the 2 reports in the literature on anger attacks in bipolar
depression, one found them to be uncommon (12%) compared with the rate in
bipolar mixed states and unipolar depression (40%-60%), whereas the other found
them to be common (62%). We examined anger attacks among participants in an
8-week trial of open-label citalopram added to mood stabilizer for the treatment
of bipolar depression. We also examined trait anger, hypomanic symptoms, and
depressive symptoms as predictors of anger attacks. We hypothesized that if
anger attacks were related to hypomanic symptoms they would respond unfavorably
to citalopram, whereas if they were related to trait anger or depressive
symptoms they would respond favorably. METHOD: In 45 participants with a DSM-IV
diagnosis of bipolar I or II depression, anger attacks, hypomanic symptoms, and
depressive symptoms were assessed using a modified Anger Attacks Questionnaire,
Young Mania Rating Scale, and Hamilton Rating Scale for Depression,
respectively. Trait anger was measured using the State-Trait Anger Inventory.
Posttreatment data were collected at the end of 8 weeks of treatment with
citalopram or at dropout from the trial. The first participant study visit was
in November 1998, and the final participant study visit was in December 2000.
RESULTS: Before treatment with citalopram, 17 (38.6%) of 44 participants
reported anger attacks (data on anger attacks were missing for 1 participant
before treatment and 4 after treatment). Significantly fewer participants
reported anger attacks after treatment (6 of 41, 14.6%; McNemar test, p <.05,
2-tailed). At pretreatment and post-treatment, trait anger was the only
significant predictor of anger attacks (p <.05). CONCLUSIONS: These findings
suggest that in bipolar depression anger attacks are common, may respond
favorably to acute treatment with citalopram added to mood stabilizer, and are
better predicted by trait anger than hypomanic or depressive symptoms. Further
studies are needed to clarify the diagnostic and treatment implications of anger
attacks in bipolar depression.
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Am J Psychiatry. 2004 Mar;161(3):564-6.
Preliminary randomized, double-blind, placebo-controlled trial of pramipexole
added to mood stabilizers for treatment-resistant bipolar depression.
Goldberg JF, Burdick KE, Endick CJ.
Department of Psychiatry, Weill Medical College of Cornell University, New York,
NY, USA. jgoldber1@lij.edu
OBJECTIVE: Previous studies suggest that the dopamine agonist pramipexole may
possess antidepressant properties. The authors conducted a preliminary
randomized, placebo-controlled trial to determine the safety and antidepressant
efficacy of pramipexole in treatment-resistant bipolar depression. METHOD:
Twenty-two depressed outpatients with DSM-IV nonpsychotic bipolar disorder were
randomly assigned to receive placebo or flexibly dosed pramipexole (mean maximum
dose=1.7 mg/day, SD=1.3) added to existing mood stabilizers for 6 weeks. The
primary outcome measure was response, defined as improvement in Hamilton
Depression Rating Scale score of 50% or more over the baseline score; secondary
analyses involved changes in Clinical Global Impression (CGI) severity scores.
RESULTS: More patients given pramipexole (10 [83%] of 12) than patients given
placebo (six [60%] of 10) completed the study. Eight (67%) of 12 patients taking
pramipexole and two (20%) of 10 taking placebo had an improvement of at least
50% in their Hamilton depression scale scores. The mean percentage of
improvement from baseline Hamilton depression scale scores was greater for
patients taking pramipexole (48%) than for those taking placebo (21%). Mean
improvements in CGI severity were also greater with pramipexole than placebo. No
patients discontinued the study because of adverse events except for one patient
who became hypomanic while taking pramipexole. CONCLUSIONS: Pramipexole was a
safe and effective antidepressant among patients with bipolar depression. Larger
randomized, controlled trials are needed to affirm these initial observations.
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J Clin Psychiatry. 2004 Feb;65(2):204-10.
A 52-week, open-label continuation study of lamotrigine in the treatment of
bipolar depression.
McElroy SL, Zarate CA, Cookson J, Suppes T, Huffman RF, Greene P, Ascher J.
Psychopharmacology Research Program, University of Cincinnati College of
Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0559, USA.
susan.mcelroy@uc.edu
BACKGROUND: Lamotrigine has demonstrated efficacy for the acute treatment of
depression in bipolar I patients in a placebo-controlled, monotherapy study. We
describe the results of a 52-week, open-label continuation of that trial.
METHOD: Patients meeting DSM-IV criteria for bipolar I disorder with a current
major depressive episode who completed a 7-week, double-blind study of bipolar
depression were offered 1 year of open-label lamotrigine therapy (flexible doses
of 100-500 mg/day) in a continuation study. To maintain the acute study blind,
the first 3 weeks of the continuation study remained blinded while patients
previously randomly assigned to placebo were titrated to a lamotrigine dose of
50 mg/day. Patients who had been randomly assigned to lamotrigine continued at
their fixed doses. Beginning at week 4, all patients received open-label
lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications
were permitted during the open-label phase. Effectiveness (Montgomery-Asberg
Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale)
and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The
study was conducted from June 1996 to December 1998. RESULTS: Of 135 patients
completing the acute study, 124 (92%) entered the continuation study: 77 had
received lamotrigine and 47 had received placebo in the acute study. The mean
duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187
mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and
sustained improvement from baseline was seen in mean observed MADRS scores (p
<.05). The proportion of patients achieving remission (MADRS score < or = 11) by
week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less
frequently than in the preceding year. Headache was the most common drug-related
adverse event. CONCLUSION: During 1 year of open-label therapy with lamotrigine
as adjunctive therapy or monotherapy, bipolar I patients experienced sustained
improvement in depressive symptoms without evidence of mood destabilization.
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Am J Psychiatry. 2004 Jan;161(1):163-5.
Antidepressant treatment in bipolar versus unipolar depression.
Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ.
Department of Psychiatry, Cambridge Hospital, MA 02139, USA.
ghaemi@hms.harvard.edu
OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar
depression. METHOD: The authors analyzed clinical records for outcomes of
antidepressant trials for 41 patients with bipolar depression and 37 with
unipolar depression, similar in age and sex distribution. RESULTS: Short-term
nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%)
depression. Manic switching occurred only in bipolar depression but happened
less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle
acceleration occurred only in bipolar depression (25.6%), with new rapid cycling
in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and
withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in
unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid
cycling, or response loss. Modern antidepressants, in general, did not have
lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS:
The findings suggest an unfavorable cost/benefit ratio for antidepressant
treatment of bipolar depression.
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Am J Psychiatry. 2004 Jan;161(1):93-8.
Low-field magnetic stimulation in bipolar depression using an MRI-based
stimulator.
Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen
BM, Renshaw PF.
Brain Imaging Center, McLean Hospital, Belmont, MA 02478, USA.
mrohan@mclean.harvard.edu
OBJECTIVE: Anecdotal reports have suggested mood improvement in patients with
bipolar disorder immediately after they underwent an echo-planar magnetic
resonance spectroscopic imaging (EP-MRSI) procedure that can be performed within
clinical MR system limits. This study evaluated possible mood improvement
associated with this procedure. METHOD: The mood states of subjects in an
ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief
Affect Scale, a structured mood rating scale, immediately before and after an
EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects
with bipolar disorder, and actual EP-MRSI was administered to a comparison group
of healthy subjects. The characteristics of the electric fields generated by the
EP-MRSI scan were analyzed. RESULTS: Mood improvement was reported by 23 of 30
bipolar disorder subjects who received the actual EP-MRSI examination, by three
of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14
healthy comparison subjects who received actual EP-MRSI. Significant differences
in mood improvement were found between the bipolar disorder subjects who
received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects
who received actual EP-MRSI, between the healthy subjects and the bipolar
disorder subjects and to a lesser extent between the unmedicated bipolar
disorder subjects and the bipolar disorder subjects who were taking medication.
The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than
fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of
depression (1-500 V/m) and also extended uniformly throughout the head, unlike
the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train
of monophasic trapezoidal gradient pulses, differed from that used in rTMS.
CONCLUSIONS: These preliminary data suggest that the EP-MRSI scan induces
electric fields that are associated with reported mood improvement in subjects
with bipolar disorder. The findings are similar to those for rTMS depression
treatments, although the waveform used in EP-MRSI differs from that used in
rTMS. Further investigation of the mechanism of EP-MRSI is warranted.
----------
CNS Drugs. 2004;18(1):63-7.
Spotlight on lamotrigine in bipolar disorder.
Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established
anticonvulsant agent that has shown efficacy in the prevention of mood episodes
in adult patients with bipolar I disorder. The mechanism of action of the drug
in patients with bipolar disorder may be related to the inhibition of sodium and
calcium channels in presynaptic neurons and subsequent stabilisation of the
neuronal membrane. Lamotrigine monotherapy significantly delayed time to
intervention with additional pharmacotherapy or electroconvulsive therapy for
any new mood episode (mania, hypomania, depression and mixed episodes), compared
with placebo, in two large, randomised, double-blind trials of 18 months'
duration. Additionally, lamotrigine was significantly superior to placebo at
prolonging time to intervention for depression. These effects of lamotrigine
were demonstrated in both recently manic/hypomanic and recently depressed
patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in
pooled data only, although lithium was superior to lamotrigine on this measure.
Two of four double-blind, short-term studies have shown lamotrigine to be more
effective than placebo in the treatment of patients with treatment-refractory
bipolar disorder or those with bipolar depression. Lamotrigine has not
demonstrated efficacy in the treatment of acute mania. Lamotrigine was generally
well tolerated in maintenance studies with the most common adverse events being
headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor
were significantly lower in lamotrigine- than in lithium-treated patients. The
incidence of serious rash with lamotrigine treatment was 0.1% in all studies of
bipolar disorder and included one case of mild Stevens-Johnson syndrome.
Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine
is titrated over a 6-week period to 200 mg/day to minimise the incidence of
serious rash. Adjustments to the initial and target dosages are required if
coadministered with valproate semisodium or carbamazepine. CONCLUSION:
Lamotrigine has been shown to be an effective maintenance therapy for patients
with bipolar I disorder, significantly delaying time to intervention for any
mood episode. Additionally, lamotrigine significantly delayed time to
intervention for a depressive episode and showed limited efficacy in delaying
time to intervention for a manic/hypomanic episode, compared with placebo.
Although not approved for the short-term treatment of mood episodes, lamotrigine
has shown efficacy in the acute treatment of patients with bipolar depression
but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine
is generally well tolerated, does not appear to cause bodyweight gain and,
unlike lithium, generally does not require monitoring of serum levels.
----------
Depress Anxiety. 2004;20(3):131-8.
Pramipexole in treatment-resistant depression: an extended follow-up.
Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano
GB.
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology,
University of Pisa, Pisa, Italy. pcassano@partners.org
We evaluated the long-term antidepressant safety and response of adjunctive
pramipexole, a D2-D3 dopamine agonist, in the course of drug-resistant
depression. Twenty-three patients with treatment-resistant major depressive
episode (MDE) were followed up after a 16-week pramipexole add-on trial.
Pramipexole was added to current treatment with TCA or SSRI, at increasing doses
from 0.375-1.500 mg/day. The LIFE scale was administered at baseline of the
acute trial, at Weeks 16, 32, and 48. Patients were analyzed for sustained
remission (score= <2 at LIFE for at least 8 weeks) and recurrence (after
remission score > =3 at LIFE for at least 2 weeks) of depression. Of 23
patients, 12 had major depression and 11 had bipolar depression (16 women; mean
age=52.8 years). Mean age of onset and median duration of current MDE were 35.1
years and 6 months, respectively; all subjects had at least two prior MDEs. Mean
pramipexole dose was 0.990 mg/day. Median duration of follow-up was 28 weeks.
Mean baseline MADRS and CGI-S scores were 33.7+/-8.4 (sd) and 4.6+/-0.8,
respectively. Median time to sustained remission from baseline was 10 weeks and
overall 60.9% (14/23) of subjects recovered within Week 22. Recurrence of
depression occurred in 35.7% (5/14) of remitters after Week 24 and within Week
28 from remission. Although there were no sleep attacks, two cases of hypomania
and one case of psychotic mania occurred at Weeks 22, 24, and 30, respectively.
Pramipexole augmentation of antidepressant treatment was relatively safe and
presumably effective in the long-term course of treatment resistant depression.
(c) 2004 Wiley-Liss, Inc.
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Depress Anxiety. 2004;19(4):199-208.
Unmet needs in bipolar depression.
Frye MA, Gitlin MJ, Altshuler LL.
UCLA Bipolar Disorder Research Program, David Geffen School of Medicine,
University of California, Los Angeles, CA 90095, USA. MFrye@mednet.ucla.edu
Bipolar disorders, particularly bipolar spectrum disorders, frequently go
unrecognized and undiagnosed by clinicians and thus remain untreated or
inappropriately treated. Although the symptoms of bipolar I disorder are widely
acknowledged and recognized among clinicians, epidemiology sampling studies over
the past several years have found that bipolar II disorder and bipolar spectrum
disorders are likely to be more prevalent and more challenging to diagnose,
particularly as depressive presentations are far more common in these groups.
Bipolar disorder is associated with increased morbidity and mortality, as well
as higher healthcare costs, but it is unclear how much of the consequences of
bipolar disorder are unrecognized in the face of poor recognition of bipolar II
and bipolar spectrum disorders. This article addresses challenges in diagnosing
and treating bipolar disorder in the face of a depressive episode, and offers
guidelines for recognizing and appropriately managing these patients. Studies
with the newer anticonvulsant mood stabilizer lamotrigine have shown
antidepressant effects in bipolar disorder, and may fill an unmet need for
treatment options in patients who present with depression in the context of
bipolar disorder.
----------
Drug Saf. 2004;27(3):173-84.
Safety and tolerability of lamotrigine for bipolar disorder.
Bowden CL, Asnis GM, Ginsberg LD, Bentley B, Leadbetter R, White R.
Department of Psychiatry, University of Texas Health Science Center at San
Antonio, San Antonio, Texas 78229-3900, USA. bowdenc@uthscsa.edu
Tolerability and safety are important considerations in optimising
pharmacotherapy for bipolar disorder. This paper reviews the tolerability and
safety of lamotrigine, an anticonvulsant recommended in the 2002 American
Psychiatric Association guidelines as a first-line treatment for acute
depression in bipolar disorder and one of several options for maintenance
therapy. This paper reviews the tolerability and safety of lamotrigine using
data available from a large programme of eight placebo-controlled clinical
trials of lamotrigine enrolling a total of nearly 1800 patients with bipolar
disorder. This review is the first to collate all the safety information from
these clinical trials, including data from four unpublished studies. The results
these trials in which 827 patients with bipolar disorder were given lamotrigine
as monotherapy or adjunctive therapy for up to 18 months for a total of 280
patient-years of exposure demonstrated that lamotrigine is well-tolerated with
an adverse-event profile generally comparable with that of placebo. The most
common adverse event with lamotrigine was headache. Lamotrigine did not appear
to destabilise mood and was not associated with sexual adverse effects, weight
gain, or withdrawal symptoms. Few patients experienced serious adverse events
with lamotrigine, and the incidence of withdrawals because of adverse events was
low. Serious rash occurred rarely (0.1% incidence) in the clinical development
programme including both controlled and uncontrolled clinical trials. These
findings - considered in the context of data showing lamotrigine to be effective
for bipolar depression - establish lamotrigine as a well-tolerated addition to
the psychotropic armamentarium.
----------
Ann Pharmacother. 2003 Dec;37(12):1807-9.
Modafinil for remitted bipolar depression with hypersomnia.
Fernandes PP, Petty F.
Omaha Veterans Affairs Medical Center and Creighton University School of
Medicine, Omaha, NE. Praveen.Fernandes@med.va.gov
OBJECTIVE: To report 2 cases of bipolar disorder with recent depression in
remission with prominent residual hypersomnia, responding well to the addition
of the psychostimulant modafinil.CASE SUMMARIES: Two patients with bipolar
disorder with recent depressive episodes in remission are presented. Despite the
absence of prominent depressive symptoms, both patients had significant
hypersomnia, with scores ranging from 15 to 20 (maximum 24) on the Epworth
Sleepiness Scale. The addition of modafinil to their medication regimen resulted
in a decrease in hypersomnia and improvement in their level of
functioning.DISCUSSION: This is the first report (MEDLINE search, October 7,
2003) demonstrating the use of modafinil in the treatment of hypersomnia in
bipolar disorder while mood symptoms were in remission. Hypersomnia frequently
occurs in depressive episodes and can be disabling when severe. The patients had
optimal mood stabilization with mood stabilizers and antidepressants, but
continued to experience excessive daytime sleepiness. Conventional stimulants
were not considered because of the risk of triggering mania. The addition of the
selective psychostimulant modafinil resulted in significant improvement in the
hypersomnia, with improvement in functioning. No adverse effects or mood changes
were noted.CONCLUSIONS: Modafinil may be a well-tolerated and effective
alternative to conventional stimulants in the treatment of hypersomnia,
especially in bipolar disorder, where there is considerable risk of switch to
mania with stimulant medications. Modafinil may be useful even when depressive
symptoms are not prominent.
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Bipolar Disord. 2003 Dec;5(6):456-63.
Clinical consequences of under-recognized bipolar spectrum disorder.
Dunner DL.
Department of Psychiatry and Behavioral Sciences, Center for Anxiety and
Depression, University of Washington School of Medicine, Seattle, WA 98105, USA.
ddunner@uwashington.edu
The prevalence of bipolar disorder is higher than previously believed,
especially when bipolar spectrum disorders (BSD) are taken into account, and may
approach rates as high as 5%. Difficulties in diagnosing bipolar II and BSD
arise from complexities associated with defining and diagnosing hypomania.
Additionally, bipolar disorder and BSD are often misdiagnosed because of
symptoms that overlap with other psychiatric disorders, particularly unipolar
depression. Recognition of the broader spectrum of bipolar disorders and their
adequate treatment is paramount because bipolar disorder exacts such a high
personal and societal toll, with high rates of suicide and interpersonal
problems and a substantial economic burden. Recognition can be improved with
active screening, and screening tools such as the Mood Disorders Questionnaire
can be easily included in the initial assessment of patients who present with
depressive symptoms. Depressive episodes are common in patients who experience
BSDs, and increasingly treatment approaches designed specifically for bipolar
depression are being studied.
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Bipolar Disord. 2003 Dec;5(6):421-33.
Comment in:
Bipolar Disord. 2003 Dec;5(6):434-5.
Antidepressants in bipolar disorder: the case for caution.
Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK.
Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA and Harvard
Medical School, Boston, MA 02139, USA. ghaemi@hms.harvard.edu
The 2002 American Psychiatric Association (APA) guidelines for the treatment of
bipolar disorder recommended more conservative use of antidepressants. This
change in comparison with previous APA guidelines has been criticized,
especially from some groups in Europe. The Munich group in particular has
published a critique of assumptions underlying the conservative recommendations
of the recent APA treatment guidelines. In this paper, we re-examine the
argument put forward by the Munich group, and we demonstrate that indeed,
conceptually and empirically, there is a strong rationale for a cautious
approach to antidepressant use in bipolar disorder, consistent with, and perhaps
even more strongly than, the APA guidelines. This rationale is based on support
for the following four propositions: (i) The risk of antidepressant induced
mood-cycling is high, (ii) Antidepressants have not been shown to definitively
prevent completed suicides and reduce mortality, whereas lithium has, (iii)
Antidepressants have not been shown to be more effective than mood stabilizers
in acute bipolar depression and have been shown to be less effective than mood
stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood
stabilizers, especially lithium and lamotrigine, have been shown to be effective
in acute and prophylactic treatment of bipolar depressive episodes. We therefore
draw three conclusions from this interpretation of the evidence: (i) There are
significant risks of mania and long-term worsening of bipolar illness with
antidepressants, (ii) Antidepressants should generally be reserved for severe
cases of acute bipolar depression and not routinely used in mild to moderate
cases and (iii) Antidepressants should be discontinued after recovery from the
depressive episode, and maintained only in those who repeatedly relapse after
antidepressant discontinuation (a minority we judge to represent only about
15-20% of bipolar depressed patients).
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Bipolar Disord. 2003 Dec;5(6):396-406.
A re-evaluation of the role of antidepressants in the treatment of bipolar
depression: data from the Stanley Foundation Bipolar Network.
Post RM, Leverich GS, Nolen WA, Kupka RW, Altshuler LL, Frye MA, Suppes T,
McElroy S, Keck P, Grunze H, Walden J; Stanley Foundation Bipolar Network.
Department of Health and Human Services, National Institutes of Health, National
Institute of Mental Health, Biological Psychiatry Branch, Bethesda, MD
20892-1272, USA. postr@intra.nimh.nih.gov
OBJECTIVES: The risk-to-benefit ratio of the use of unimodal antidepressants
(ADs) as adjuncts to mood stabilizers continues to be an area of controversy and
disagreement among experts in the field. This paper reviews new data on: (1)
depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD
discontinuation that are pertinent to the ongoing discussion and
recommendations. METHODS: In the first study reviewed, 258 outpatients with
bipolar illness were assessed prospectively on a daily basis using the National
Institute of Mental Health-Life Chart Method (NIMH-LCM) for 1 year. In the
second study, 127 bipolar depressed patients were randomized to 10 weeks of
sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers;
non-responders were re-randomized and responders were offered a year of
continuation treatment. In the final study, Altshuler et al. retrospectively and
prospectively assessed the risk of depressive relapses in patients who remained
on ADs after 2 months of euthymia compared with those who discontinued ADs.
RESULTS: Despite intensive naturalistic treatment, the 258 outpatients with
bipolar illness followed prospectively for 1 year showed three times as many
days depressed as days manic, re-emphasizing the considerable depressive
morbidity that remains in bipolar disorder despite the number of treatment
options available. In the study of bipolar depressed patients randomized to one
of three ADs, a range of severities and durations of hypomanic to manic switches
were discerned following 175 trials of AD augmentation of treatment with a mood
stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into
hypomania or mania and another 9.1% with a week or more of hypomania alone (with
no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2%
were similarly associated with hypomanic to manic and hypomanic switches,
respectively. In the Altshuler et al. studies, those who remained well on any AD
for more than 2 months (only 15-20% of those initially treated) and who
continued on ADs showed a lesser rate of relapse into depression over 1 year (35
and 36% in the first and second study, respectively) compared with those who
discontinued their ADs (68 and 70% relapsing into depression). Surprisingly,
this continuation of ADs was associated with no increase in the rate of
switching into mania compared with those stopping ADs. CONCLUSIONS: These data
reveal that depression and depressive cycling remain a substantial problem in
some two-thirds of intensively treated bipolar outpatients. Acute AD
augmentation was associated with a modest response rate and 18.2% switched into
a hypomanic to manic episode, and 35.6% of the continuation trials showed these
two types of switches. Two separate studies suggest that in the very small
subgroup who remain well on ADs for at least 2 months, one should consider
continuation of this AD augmentation treatment, because AD discontinuation
appears associated with a substantially increased risk of depression relapse
over the subsequent year with no reduced risk of switching into mania.
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CNS Spectr. 2003 Dec;8(12):1-10; quiz 11.
Treatment of bipolar depression.
Post RM, Baldassano CF, Perlis RH, Ginsberg DL.
Bipolar Collaborative Network, Chevy Chase, Maryland, USA.
Bipolar disorder is underdiagnosed and often mistaken for unipolar depression.
Bipolar patients spend 33% of their time in a state of depression compared to
11% of time spent in a manic state. Duration of time depressed and severity of
depression are associated with increased risk for suicide, which occurs in 10%
to 20% of bipolar patients. Antidepressants are increasingly being used as
adjuncts in the depressed phase of bipolar disorder, although they provide a
moderate risk for switch into mania. Lithium and some antiepileptics and
atypical antipsychotics have shown antidepressant effects in the treatment of
bipolar disorder. Other adjuncts for treatment-refractory patients include
monoamine oxidase inhibitors and electroconvulsive therapy.
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Ann Clin Psychiatry. 2003 Sep-Dec;15(3-4):225-32.
What drugs are best for bipolar depression?
Baldassano CF, Datto SM, Littman L, Lipari MA.
Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104, USA. cfb@mail.med.upenn.edu
Bipolar depression is a severe, potentially lethal disorder for which there are
no specific, FDA-indicated pharmacotherapies. Research in this area has been
limited, and most treatments are based on unsupported extrapolation from the
treatment of unipolar depression, or follow guidelines derived largely from the
clinical practice experience of experts in this field. There is clearly a
medical need for new and more effective treatments for bipolar depression.
Recently, the newer antiepileptic drugs, and atypical antipsychotics, have been
studied to evaluate their role in bridging this gap in the psychopharmacologic
armamentarium. Drugs in these classes will be reviewed, in addition to serotonin
reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive
therapy. In this paper, current trends in the acute and long-term medication
treatment of bipolar depression will be described, with particular focus on
evidence from the existing literature. Additional factors, such as side effects,
risk/benefit issues, and drug-drug interactions, will be considered in an
attempt to make overall recommendations for medication selection.
----------
Int J Neuropsychopharmacol. 2003 Sep;6(3):285-91.
Comment in:
Int J Neuropsychopharmacol. 2004 Mar;7(1):105-6; author reply 107.
Recent placebo-controlled acute trials in bipolar depression: focus on
methodology.
Muzina DJ, Calabrese JR.
Cleveland Clinic Foundation, Cleveland, Ohio, USA. muzinad@ccf.org
The completion of three recent large-scale, double-blind controlled acute trials
in bipolar I depression has improved our understanding of the management of
major depressive episodes associated with bipolar disorder. In contrast to the
cross-over designs used in the early studies of lithium in bipolar depression,
the designs utilized in these recent studies have employed random assignment to
parallel arms including the use of placebo as a monotherapy in one study. The
analyses of recent studies have all been conducted on intent-to-treat data, and
included two types, change from baseline analyses and responder analyses.
Lamotrigine monotherapy was shown to be superior to placebo with both types of
analyses on the Montgomery-Asberg Depression Rating Scale (MADRS) and the
Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton
Depression Rating Scale (HAMD) (n=195). The percentage of patients responding to
placebo as a monotherapy were 29, 26 and 37%, respectively; there were no
differences in switch rates (5% vs. 5%). Paroxetine augmentation was no better
than placebo augmentation overall with both types analyses on the CGI and HAMD
(n=117); the MADRS was not used. In patients with lithium levels < or =0.8
mequiv./l, the change from baseline analysis showed paroxetine to be superior to
placebo, but responder analyses were negative; switch rates with paroxetine,
imipramine, and placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in
efficacy to imipramine (n=156), but had a lower rate of switching (4% vs. 11%).
----------
J Clin Psychiatry. 2003 Jul;64(7):825-33.
A computer algorithm for calculating the adequacy of antidepressant treatment in
unipolar and bipolar depression.
Oquendo MA, Baca-Garcia E, Kartachov A, Khait V, Campbell CE, Richards M,
Sackeim HA, Prudic J, Mann JJ.
Silvio O. Conte Centers for the Neuroscience of Mental Disorders for the Study
of the Neurobiology of Suicidal Behavior, New York, USA.
moquendo@neuron.cpmc.columbia.edu
BACKGROUND: Major depression is often treated with medications in doses that are
too low or too short in duration. We published an early version of the
Antidepressant Treatment History Form (ATHF) that rates the adequacy of
antidepressant treatment. The updated ATHF presented here includes newer
medications and a computer algorithm to automate the evaluation of the adequacy
of pharmacotherapy or electroconvulsive therapy for depression. METHOD: The
computer algorithm was written in MS-DOS Q-BASIC and in Visual Basic 5.0.
Treatment data from 47 depressed (Structured Clinical Interview for DSM-III-R)
patients were scored by the computer algorithm and assigned a number from 0 to 5
for the adequacy of antidepressant treatment. A psychiatrist blinded to the
computer ratings manually rated the treatment using the ATHF. RESULTS: The
computer algorithm, based on an updated version of the ATHF, estimates the
adequacy of treatment of unipolar and bipolar depression. Computer algorithm
results agreed with those generated by a clinician completing the form manually
(kappa = 0.88 to 1.00). CONCLUSION: The computer algorithm can be used to
analyze large databases and may help reduce the morbidity and mortality
associated with major depression by improving the assessment of adequacy of
pharmacologic treatments for research and quality assurance purposes. The
availability of the updated ATHF on the Internet for downloading allows for
modifications according to the user's purposes.
----------
Psychopharmacol Bull. 2003 Summer;37(3):118-26.
Effects of tranylcypromine on the sleep of patients with anergic bipolar
depression.
Jindal RD, Fasiczka AL, Himmelhoch JM, Mallinger AG, Thase ME.
Department of Psychiatry, University of Pittsburgh School of Medicine, Western
Psychiatric Institute and Clinic, Pittsburgh, PA 15313, USA.
jindalr@msx.upmc.edu
A significant proportion of patients with bipolar disorder are hypersomnolent.
It is not clear if this affects response to treatment because few studies have
systematically examined treatment effects on sleep in patients with bipolar
depression. Reported herein are the results of what we believe to be the first
study of the effects of the monoamine oxidase inhibitor tranylcypromine (average
dose=37 mg/day) on the sleep of patients with bipolar depression.Twenty-three
patients with anergic bipolar depression completed sleep studies before and
after pharmacotherapy. Changes in polysomnographic variables were examined using
paired t tests. The patients experienced a 40% reduction in rapid eye movement
(REM) sleep time, as well as significant decreases in REM percentage,REM
activity, number of REM periods, and REM intensity.REM latency was prolonged by
nearly 3-fold.The decrease in REM sleep was accompanied by a modest (8%)
reduction in total sleep time and increased "light" sleep. There was no change
in sleep continuity indices or slow wave sleep. Correlational analyses suggested
that antidepressant response was only weakly associated with changes in REM
sleep. These findings indicate that tranylcypromine's effects on REM sleep
greatly surpass effects on sleep architecture or sleep maintenance. Moreover,
effective treatment of bipolar depression did not "normalize" the
hypersomnolence associated with bipolar depression.
----------
J Psychiatr Pract. 2003 May;9(3):181-94.
When do antidepressants worsen the course of bipolar disorder?
Goldberg JF.
Zucker Hillside Hospital/North Shore Long Island Jewish Health System, Glen
Oaks, NY 11002, USA.
Bipolar disorder may be more prevalent than previously believed. Because a
substantial number of patients with bipolar disorder present with an index
depressive episode, it is likely that many are misdiagnosed with unipolar major
depression. Even if a correct diagnosis is made, depressive symptoms in bipolar
disorder are notoriously difficult to treat. Patients are often treated with
antidepressants, which, if used improperly, are known to induce mania and
provoke rapid cycling. This article explores diagnostic conundrums in bipolar
depression and their possible solutions, based on current research evidence. It
also elucidates current evidence regarding the risks and benefits associated
with antidepressant use and evaluates alternative treatment regimens for the
depressed bipolar population, including the use of traditional mood stabilizers
such as lithium, novel anticonvulsants such as lamotrigine, and atypical
antipsychotics.
----------
Drugs. 2003;63(19):2029-50.
Lamotrigine: a review of its use in bipolar disorder.
Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.
Adis International Limited, Mairangi Bay, Auckland, New Zealand.
demail@adis.co.nz
Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established
anticonvulsant agent that has shown efficacy in the prevention of mood episodes
in adult patients with bipolar I disorder. The mechanism of action of the drug
in patients with bipolar disorder may be related to the inhibition of sodium and
calcium channels in presynaptic neurons and subsequent stabilisation of the
neuronal membrane. Lamotrigine monotherapy significantly delayed time to
intervention with additional pharmacotherapy or electroconvulsive therapy for
any new mood episode (mania, hypomania, depression and mixed episodes), compared
with placebo, in two large, randomised, double-blind trials of 18 months'
duration. Additionally, lamotrigine was significantly superior to placebo at
prolonging time to intervention for depression. These effects of lamotrigine
were demonstrated in both recently manic/hypomanic and recently depressed
patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in
pooled data only, although lithium was superior to lamotrigine on this measure.
Two of four double-blind, short-term studies have shown lamotrigine to be more
effective than placebo in the treatment of patients with treatment-refractory
bipolar disorder or those with bipolar depression. Lamotrigine has not
demonstrated efficacy in the treatment of acute mania.Lamotrigine was generally
well tolerated in maintenance studies with the most common adverse events being
headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor
were significantly lower in lamotrigine- than in lithium-treated patients. The
incidence of serious rash with lamotrigine treatment was 0.1% in all studies of
bipolar disorder and included one case of mild Stevens-Johnson syndrome.
Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine
is titrated over a 6-week period to 200 mg/day to minimise the incidence of
serious rash. Adjustments to the initial and target dosages are required if
coadministered with valproate semisodium or carbamazepine. CONCLUSION:
Lamotrigine has been shown to be an effective maintenance therapy for patients
with bipolar I disorder, significantly delaying time to intervention for any
mood episode. Additionally, lamotrigine significantly delayed time to
intervention for a depressive episode and showed limited efficacy in delaying
time to intervention for a manic/hypomanic episode, compared with placebo.
Although not approved for the short-term treatment of mood episodes, lamotrigine
has shown efficacy in the acute treatment of patients with bipolar depression
but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine
is generally well tolerated, does not appear to cause bodyweight gain and,
unlike lithium, generally does not require monitoring of serum levels.
----------
Am J Psychiatry. 2003 Jul;160(7):1252-62.
Impact of antidepressant discontinuation after acute bipolar depression
remission on rates of depressive relapse at 1-year follow-up.
Altshuler L, Suppes T, Black D, Nolen WA, Keck PE Jr, Frye MA, McElroy S, Kupka
R, Grunze H, Walden J, Leverich G, Denicoff K, Luckenbaugh D, Post R.
Stanley Bipolar Treatment Network, USA. laltshuler@mednet.ucla.edu
OBJECTIVE: While guidelines for treating patients with bipolar depression
recommend discontinuing antidepressants within 6 months after remission, few
studies have assessed the implications of this strategy on the risk for
depressive relapse. This study examined the effect of antidepressant
discontinuation or continuation on depressive relapse risk among bipolar
subjects successfully treated for an acute depressive episode. METHOD:
Eighty-four subjects with bipolar disorder who achieved remission from a
depressive episode with the addition of an antidepressant to an ongoing mood
stabilizer regimen were followed prospectively for 1 year. The risk of
depressive relapse among 43 subjects who stopped antidepressant treatment within
6 months after remission ("discontinuation group") was compared with the risk
among 41 subjects who continued taking antidepressants beyond 6 months
("continuation group"). RESULTS: A Cox proportional hazards regression analysis
indicated that shorter antidepressant exposure time following successful
treatment was associated with a significantly shorter time to depressive
relapse. Furthermore, patients who discontinued antidepressant treatment within
the first 6 months after remission experienced a significantly shorter period of
euthymia before depressive relapse over the length of 1-year follow-up. One year
after successful antidepressant response, 70% of the antidepressant
discontinuation group experienced a depressive relapse compared with 36% of the
continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84
subjects had experienced a manic relapse; only six of these subjects were taking
an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of
depressive relapse in patients with bipolar illness was significantly associated
with discontinuing antidepressants soon after remission. The risk of manic
relapse was not significantly associated with continuing use of antidepressant
medication and, overall, was substantially less than the risk of depressive
relapse. Maintenance of antidepressant treatment in combination with a mood
stabilizer may be warranted in some patients with bipolar disorder.
----------
Neuropsychopharmacology. 2003 Jul;28(7):1374-82. Epub 2003 May 28.
Maintenance efficacy of divalproex in the prevention of bipolar depression.
Gyulai L, Bowden CL, McElroy SL, Calabrese JR, Petty F, Swann AC, Chou JC,
Wassef A, Risch CS, Hirschfeld RM, Nemeroff CB, Keck PE Jr, Evans DL, Wozniak
PJ.
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104,
USA. gyulai@mail.med.upenn.edu
Breakthrough depression is a common problem in the treatment of bipolar
disorder. Only one, recently published, double-blind, placebo-controlled trial
has examined the efficacy of divalproex in the prevention of depressive episodes
in bipolar patients. This report describes, in further detail, the findings from
that trial of the effect of divalproex on multiple dimensions of depressive
morbidity in bipolar disorder. A randomized, double-blind, parallel-group,
multicenter study was conducted over a 52-week maintenance period. Bipolar I
patients, who may have been treated with open-label lithium or divalproex and
who met recovery criteria within 3 months of onset of an index manic episode,
were randomized to maintenance treatment with divalproex, lithium, or placebo in
a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough
depression was allowed in maintenance phase. Outcome measures were the rate of
early discontinuation for depression, time to depressive relapse, proportion of
patients with depressive relapse, mean change in Depressive Syndrome Scale
score, proportion of patients receiving antidepressants, and time in the study.
Among patients taking an antidepressant, a higher percentage of patients on
placebo than divalproex discontinued early for depression. Patients who were
previously hospitalized for affective episodes or took divalproex in the open
period relapsed later on divalproex than on lithium during the maintenance
period. Divalproex-treated patients had less worsening of depressive symptoms
than lithium-treated patients during maintenance. Indices of severity of
prestudy illness course predicted worse outcome in all treatment groups.
Divalproex improved several dimensions of depressive morbidity and reduced the
probability of depressive relapse in bipolar disorder, particularly in patients
who had responded to divalproex when manic, and among patients with a more
severe course of illness.
----------
Psychiatr Clin North Am. 2003 Jun;26(2):495-518.
Treatment of bipolar depression: current status, continued challenges, and the
STEP-BD approach.
Thase ME, Bhargava M, Sachs GS.
Department of Psychiatry, University of Pittsburgh Medical Center, Western
Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213-2593,
USA. thaseme@msx.upmc.edu
Even though at least 10% (if not 20%) of those who experience a first lifetime
episode of depression will subsequently develop bipolar disorder, the alliance
of academic and industry research agendas that leads to developing and testing
new antidepressants has failed to produce a sufficient knowledge base. It is
therefore impossible to apply a truly empirical approach to guide the treatment
of people with bipolar depression. Consequently, there are holes in contemporary
evidenced-based practice guidelines large enough to drive a truck through;
furthermore, there are some recommendations that have no factual basis other
than expert opinion. However, with new research emerging on lamotrigine and
olanzapine, in addition to the pending results of larger studies supported by
the National Institute of Mental Health and the Stanley Foundation, there is
evidence that some progress is being made.
----------
J Clin Psychiatry. 2003;64 Suppl 5:32-7.
Lithium combinations in acute and maintenance treatment of unipolar and bipolar
depression.
Fawcett JA.
Department of Psychiatry, University of New Mexico School of Medicine,
Albuquerque 87131, USA. jfawcett@salud.unm.edu
Bipolar illness and unipolar depression are both affective disorders associated
with high lifetime morbidity and premature mortality due to suicide. Numerous
double-blind, placebo-controlled trials have shown that lithium augmentation
therapy is effective in treating acute episodes of bipolar depression,
refractory major depression, and delusional depression as well as in reducing
recurrences of these illnesses. Lithium is the only agent approved by the U.S.
Food and Drug Administration for maintenance treatment of bipolar disorder.
Further research is needed to specifically address whether the antidepressant
effect of adding lithium is greater in bipolar disorder or in unipolar
depressions. This article will summarize available evidence and clinical
considerations regarding the use of lithium augmentation in acute and
maintenance treatment of unipolar and bipolar depressions.
----------
Biol Psychiatry. 2003 Apr 15;53(8):691-700.
Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.
Acceleration and augmentation strategies for treating bipolar depression.
Altshuler LL, Frye MA, Gitlin MJ.
Department of Psychiatry and Biobehavioral Sciences, University of California,
Los Angeles, Los Angeles, California 90095, USA.
Despite the prevalence and morbidity of bipolar depression, few randomized
treatment trials have been conducted to assess clinical efficacy. Even fewer
studies have assessed approaches that optimize treatment response for bipolar
depression. This review will define three types of common combination
strategies--adjunctive, acceleration and augmentation--and discuss the limited
literature of controlled studies reported on acceleration and augmentation
approaches. Copyright 2003 Society of Biological Psychiatry
----------
Biol Psychiatry. 2003 Apr 15;53(8):671-9.
Comment in:
Biol Psychiatry. 2003 Apr 15;53(8):633-4.
Advances in the pharmacologic treatment of bipolar depression.
Keck PE Jr, Nelson EB, McElroy SL.
Division of Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.
The pharmacologic treatment of bipolar depression has not been well studied in
randomized, controlled trials. Thus important clinical questions regarding the
efficacy in bipolar depression of mood stabilizers, antidepressants, and new
antiepileptic and atypical antipsychotic agents have been relatively
unaddressed. Until recently there were few data regarding the degree to which
mood stabilizers reduce the risk of switching associated with antidepressant
treatment. Likewise, although treatment guidelines have often recommended
limiting antidepressant exposure in the maintenance treatment of bipolar
depression, the potential risks of depressive relapse after antidepressant
discontinuation were largely unknown. We review here data from new randomized,
controlled trials published or presented during the past 5 years regarding the
efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in
the acute and maintenance treatment of bipolar depression. We also review new
studies clarifying the protective effect of coadministration of mood stabilizers
from antidepressant-associated switching and the risk of depressive relapse when
antidepressants are discontinued during maintenance treatment. Copyright 2003
Society of Biological Psychiatry
----------
Arch Gen Psychiatry. 2003 Apr;60(4):392-400.
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance
treatment in recently manic or hypomanic patients with bipolar I disorder.
Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery
P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group.
Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 78229, USA. bowdenc@uthscsa.edu
BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar
depression and rapid cycling in placebo-controlled clinical trials. This
double-blind, placebo-controlled study was conducted to assess the efficacy and
tolerability of lamotrigine and lithium compared with placebo for the prevention
of relapse or recurrence of mood episodes in recently manic or hypomanic
patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label
phase during which treatment with lamotrigine was initiated and other
psychotropic drug regimens were discontinued, patients were randomized to
lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as
double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349
patients who met screening criteria and entered the open-label phase, 175 met
stabilization criteria and were randomized to double-blind maintenance treatment
(lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both
lamotrigine and lithium were superior to placebo at prolonging the time to
intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs
placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to
a depressive episode (P =.02). Lithium was superior to placebo at prolonging the
time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse
event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and
lithium were superior to placebo for the prevention of relapse or recurrence of
mood episodes in patients with bipolar I disorder who had recently experienced a
manic or hypomanic episode. The results indicate that lamotrigine is an
effective, well-tolerated maintenance treatment for bipolar disorder,
particularly for prophylaxis of depression.
----------
Bipolar Disord. 2003 Apr;5(2):85-97.
Bipolar depression: criteria for treatment selection, definition of
refractoriness, and treatment options.
Yatham LN, Calabrese JR, Kusumakar V.
Department of Psychiatry, The University of British Columbia, Vancouver, British
Columbia, Canada. yatham@interchange.ubc.ca
OBJECTIVE: This paper reviews controlled studies of bipolar depression, outlines
criteria for choosing treatment, defines refractoriness in bipolar depression,
and provides options for treatment of refractory bipolar depression. METHODS:
Controlled studies that examined the efficacy of treatments for acute and
long-term treatment of bipolar depression were located through electronic
searches of several databases and by manual crosssearch of references and
proceedings of international meetings. RESULTS: Lithium comes close to
fulfilling the proposed criteria for first-line treatment for bipolar
depression, and those not responding to lithium should be considered to have
refractory bipolar depression. Options for such patients include addition of
lamotrigine or a second mood stabilizer, or a newer-generation antidepressant
such as a serotonin re-uptake inhibitor or bupropion, or the atypical
antipsychotic olanzapine. CONCLUSIONS: Although there is a paucity of research
in the treatment of refractory bipolar depression, available data could be used
for providing rational treatment options for such patients. However, further
studies are urgently needed to determine which options are most appropriate for
which type of patients.
----------
Drug Saf. 2003;26(5):337-51.
Avoiding drug-induced switching in patients with bipolar depression.
Henry C, Demotes-Mainard J.
Service Universitaire de Psychiatrie, CH Charles Perrens, Bordeaux, France.
chantal.henry@bordeaux.inserm.fr
Antidepressant-induced switching is a major risk during the treatment of bipolar
depression. Despite several clinical studies, questions remain regarding both
the definition of these mood switches and the most appropriate therapeutic
strategy to avoid this adverse effect.This review will first briefly consider
the current guidelines for the acute treatment of bipolar depression. We will
then review the mechanisms of action of antidepressant and mood stabilisers, and
the switches induced by various types of antidepressant treatments, or triggered
by antidepressant withdrawal, as well as by atypical antipsychotics. We then
will address the risk of mood switch according to the type of mood stabiliser
used. The propensity to mood switches in bipolar patients is subject to
individual differences. Therefore we will describe both the clinical and
biological characteristics of patients prone to mood switches under
antidepressant treatment. However, the clinical characteristics of the
depressive syndrome may also be a key determinant for mood switches. Various
data help identify the most appropriate drug management strategies for avoiding
mood switches during the treatment of bipolar depression. Selective serotonin
reuptake inhibitors appear to be the drugs of first-choice because of the low
associated risk of mood switching. Antidepressants must be associated with a
mood stabiliser and the most effective in the prevention of switches seems to be
lithium. Whatever the mood stabiliser used, effective plasma levels must be
ensured. The optimal duration of antidepressant treatment for bipolar depression
is still an open issue - prolonged treatments after recovery may be unnecessary
and may facilitate mood elation. Moreover, some mood episodes with mixed
symptoms can be worsened by antidepressants pointing to the need for a better
delineation of the categories of symptoms requiring antidepressant treatment.
Finally, as a result of this review, we suggest some propositions to define
drug-induced switches in bipolar patients, and to try to delineate which
strategies should be recommended in clinical practice to reduce as far as
possible the risk of mood switch during the treatment of bipolar depression.
----------
Ann Clin Psychiatry. 2002 Dec;14(4):223-32.
Combining lithium and anticonvulsants in bipolar disorder: a review.
Pies R.
Tufts University School of Medicine, Boston, Massachusetts, USA.
ronpies@massmed.org
While the benefits of lithium in bipolar disorder are evident, its limitations
as monotherapy are well recognized, particularly in bipolar depression. This has
propelled trials of combined lithium-anticonvulsant therapy in many bipolar
patients. The present review of the English-language literature examines both
controlled and open studies of such combination therapy, including the risk of
drug-drug interactions. Trials of lithium plus either carbamazepine or
divalproex have generally produced favorable results, although increased rates
of adverse effects may reduce treatment adherence. More recent reports suggest
that lithium may be safely and effectively combined with lamotrigine, and
perhaps with topiramate, although controlled studies are required. The combined
use of lithium with newer, putative mood stabilizers, such as zonisamide or
levetiracetam, cannot yet be recommended, but is an important area for future
research. Provisional recommendations for combined treatment are provided.
----------
J Clin Psychiatry. 2003;64 Suppl 1:13-8.
New approaches in managing bipolar depression.
Keck PE Jr, McElroy SL.
Program Psychopharmacology Research, Department of Psychiatry, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.
paul.keck@uc.edu
Historically, the pharmacologic treatment of bipolar depression has not been
well studied. New data are beginning to emerge regarding the efficacy of new
medications and the use of combinations of mood stabilizers and antidepressants
in acute and long-term treatment of bipolar depression. We reviewed data from
recent randomized, controlled trials of mood stabilizers and antidepressants in
the treatment of bipolar depression and naturalistic studies examining the risk
of switching and depressive relapse with ongoing antidepressant treatment.
---------
World J Biol Psychiatry. 2000 Jul;1(3):129-36.
New perspectives in the acute treatment of bipolar depression.
Grunze H, Schlosser S, Walden J.
Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstrasse 7,
80336 Munich, Germany.
In contrast to mania, bipolar depression is usually characterised by
longer-lasting episodes and a higher incidence of treatment refractoriness.
Additionally, the risks of antidepressive standard treatment regimens are
increasingly recognised, especially the risk of a switch into mania or induction
of a rapid cycling course. Mood stabilisers, e.g. lithium, and some
anticonvulsants, appear to have at least some antidepressant efficacy, which,
however, may not be sufficient for treating severe depression. Currently, their
use as a monotherapy of mild depression and at the start as a co-medication to
antidepressants in severe depression is under consideration. The potential
usefulness and risks of currently applied antidepressive treatment strategies as
wel
