Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial.

BACKGROUND: We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. RESULTS: In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. CONCLUSIONS: The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial.

BACKGROUND: The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. METHODS: As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. RESULTS: In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85 ± 0.37 (SE), df = 28, p = 0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p = 0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. CONCLUSIONS: In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.

Common and Dissociable Dysfunction of the Reward System in Bipolar and Unipolar Depression.

Unipolar and bipolar depressive episodes have a similar clinical presentation that suggests common dysfunction of the brain's reward system. Here, we evaluated the relationship of both dimensional depression severity and diagnostic category to reward system function in both bipolar and unipolar depression. In total, 89 adults were included, including 27 with bipolar depression, 25 with unipolar depression, and 37 healthy comparison subjects. Subjects completed both a monetary reward task and a resting-state acquisition during 3T BOLD fMRI. Across disorders, depression severity was significantly associated with reduced activation for wins compared with losses in bilateral ventral striatum, anterior cingulate cortex, posterior cingulate cortex, and right anterior insula. Resting-state connectivity within this reward network was also diminished in proportion to depression severity, most notably connectivity strength in the left ventral striatum. In addition, there were categorical differences between patient groups: resting-state connectivity at multiple reward network nodes was higher in bipolar than in unipolar depression. Reduced reward system task activation and resting-state connectivity therefore appear to be a brain phenotype that is dimensionally related to depression severity in both bipolar and unipolar depression. In contrast, categorical differences in reward system resting connectivity between unipolar and bipolar depression may reflect differential risk of mania. Reward system dysfunction thus represents a common brain mechanism with relevance that spans categories of psychiatric diagnosis.

Bipolar depression: an evidence-based approach.

Bipolar disorder is a complex, multidimensional illness that is often difficult to treat. Unfortunately, bipolar patients are much more likely to experience depression, which is all too often severe and a potentially lethal phase of the illness. In addition, pharmacotherapies with strong evidence for bipolar depression are limited. Most treatments are based on unsupported extrapolation from the treatment of unipolar depression or are derived largely from the clinical practice experience. In this article, we focus on the treatment of bipolar depression, with particular focus on evidence from the existing literature, to help guide readers in clinical practice.

Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety.

OBJECTIVE: To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression. METHOD: In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups. RESULTS: The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04). CONCLUSIONS: This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.

Correlates of functioning in bipolar disorder.

OBJECTIVES: Our primary aim was to describe unique correlates of functioning in bipolar disorder (BD). EXPERIMENTAL DESIGN: The study included the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Patients were 41.9 +/- 12.7 years old, and diagnosed with bipolar I, II or NOS, verified by structured interview. Overall functionality was determined by the Range of Impaired Function Tool (LIFE-RIFT). Stepwise multiple regression analysis tested the non-redundant-independent-association of 28 variables on functioning. PRINCIPAL OBSERVATIONS: Severity of depression symptoms was significantly and uniquely correlated with impaired functioning in the context of a wide variety of demographic and clinical variables, contributing 60.9% to the total variance in overall functioning (ss = 0.254, p = 0.0001). Substantial variance in function remains unexplained. CONCLUSIONS: Intensity of depressive symptoms is the major determinant of impaired functioning in bipolar disorder, but longitudinal analyses may further explain the substantial variance in function not explained by this large and comprehensive model. Treatments and outcome assessment for patients with bipolar disorders should consider both functional and symptomatic change.

Self-reported history of manic/hypomanic switch associated with antidepressant use: data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

OBJECTIVE: Antidepressant safety and efficacy remain controversial for the treatment of bipolar depression. The present study utilized data from the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) to examine the prevalence and clinical correlates of self-reported switch into mania/hypomania during antidepressant treatment. METHOD: Antidepressant treatment histories were examined from intake assessments for the first 500 subjects enrolled into the STEP-BD between November 1999 and November 2000. Affective switch was defined as a report of mania, hypomania, or mixed episodes within the first 12 weeks of having started an antidepressant. Demographic and clinical characteristics were compared for subjects with or without a history of acute switch during antidepressant treatment. RESULTS: Among the 338 subjects with prior antidepressant treatment and complete data on switch event outcomes, 44% reported at least 1 such occurrence. Patients with a shorter duration of illness (odds ratio [OR] = 1.02, 95% CI = 1.01 to 1.04) and a history of multiple antidepressant trials (OR = 1.73, 95% CI = 1.38 to 2.16) were more likely to report a history of switch than other patients. A significantly increased risk for affective polarity switch was identified in patients who had ever switched to mania/hypomania while taking tricyclic antidepressants (OR = 7.80, 95% CI = 1.56 to 28.9), serotonin reuptake inhibitors (OR = 3.73, 95% CI = 1.98 to 7.05), or bupropion (OR = 4.28, 95% CI = 1.72 to 10.6). Switch was less common during treatment with electroconvulsive therapy or monoamine oxidase inhibitors than other antidepressants. CONCLUSIONS: Antidepressants are associated with the potential risk for treatment-emergent mania or hypomania, particularly in bipolar patients with short illness duration, multiple past antidepressant trials, and past experience of switch with at least one antidepressant.

Illness course, comorbidity, gender, and suicidality in patients with bipolar disorder.

Among patients with bipolar disorder, comorbid conditions are common. Comorbidity is associated with a more difficult course of illness (such as longer episodes, shorter time euthymic, and earlier age at onset) and an increase in related problems (such as suicidality and violence). Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) reveal that anxiety disorders, attention-deficit/hyperactivity disorder, and substance and alcohol use disorder are conditions that commonly co-occur with bipolar disorder. This article details these findings and discusses the complications associated with these comorbid conditions. STEP-BD data about gender differences are also discussed, and correlates of suicidal ideation among patients entering the program are described.

An open prospective study of zonisamide in acute bipolar depression.

OBJECTIVE: To examine the effectiveness and safety of zonisamide in the treatment of acute bipolar depression. METHODS: An open-label, prospective, nonrandomized, 8-week study conducted in bipolar outpatients (type I, type II, or not otherwise specified) with depressive symptoms. No patient was manic or mixed at study entry. Previous treatments were continued unchanged, but no new treatments were allowed. Montgomery Asberg Depression Rating Scale and the Mania Rating Scale from the Schedule of Affective Disorders and Schizophrenia-Change Version were used. RESULTS: Twenty patients (10 men, 10 women) with bipolar disorder (17 type I, 2 type II, 1 NOS), aged 38.1 +/- 8.81 years, received zonisamide at mean dose of 222.5 +/- 85.1 mg/d. Mean Montgomery Asberg Depression Rating Scale scores improved significantly from baseline to endpoint (mean difference = -8.4, 95% confidence interval [4.1, 12.6], P = 0.001). Ten patients (50%) terminated early due to adverse effects, mostly side effects including nausea/vomiting, cognitive impairment, and sedation. One patient experienced increased suicidal ideation, and one patient experienced hypomania. CONCLUSIONS: This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment.

Menstrual dysfunction prior to onset of psychiatric illness is reported more commonly by women with bipolar disorder than by women with unipolar depression and healthy controls.

BACKGROUND: Preliminary reports suggest that menstrual cycle irregularities occur more commonly in women with bipolar disorder and unipolar depression than in the general population. However, it is not always clear whether such abnormalities, reflecting disruption of the hypothalamic-pituitary-gonadal (HPG) axis, are caused by psychotropic treatments or associated with the disorder per se. METHOD: The prevalence of early-onset (within the first 5 postmenarchal years) menstrual cycle dysfunction (menstrual cycle length unpredictable within 10 days or menstrual cycle length<25 days or >35 days) occurring before onset of psychiatric illness was compared between subjects with DSM-IV bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and subjects with DSM-IV unipolar depression or no psychiatric illness participating in the Harvard Study of Moods and Cycles. Data from the Harvard Study of Moods and Cycles were gathered from September 1995 to September 1997, and data from STEP-BD were gathered from November 1999 to May 2001. RESULTS: Early-onset menstrual cycle dysfunction was reported to have occurred in 101/295 women with bipolar disorder (34.2%), 60/245 women with depression (24.5%), and 134/619 healthy controls (21.7%). Women with bipolar disorder were more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=16.58, p<.0001) and depressed women (chi2=6.08, p=.01), while depressed women were not more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=0.81, p=.37). CONCLUSIONS: Compared with healthy controls and women with unipolar depression, women with bipolar disorder retrospectively report early-onset menstrual dysfunction more commonly prior to onset of bipolar disorder. Future studies should evaluate potential abnormalities in the hypothalamic-pituitary-gonadal axis that are associated with bipolar disorder.

Gender differences in bipolar disorder: retrospective data from the first 500 STEP-BD participants.

OBJECTIVE: To examine gender differences in a large sample of patients with bipolar illness. METHODS: Exploratory analysis of baseline data from the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center NIMH project. Participants are allowed to have medical and psychiatric comorbidities, and to enter in any mood state, thus making the population more generalizable than many research cohorts. Diagnoses and history were assessed using structured clinical instruments administered by certified investigators. Given the exploratory nature of these analyses, there is no correction of for multiple comparisons. However, we emphasize findings that are statistically significant at the more stringent p < 0.01 level. RESULTS: Compared with men, women had higher rates of BPII (15.3% M versus 29.0% F, p < 0.01), comorbid thyroid disease (5.7% M versus 26.9% F, p < 0.01), bulimia (1.5% M versus 11.6% F, p < .0.01) and post-traumatic stress disorder (10.6% M versus 20.9% F, p < 0.01). Women and men had equal rates of history of lifetime rapid cycling and depressive episodes. Men were more likely to have a history of legal problems (36% M versus 17.5% F, p < 0.01). CONCLUSIONS: Potentially important gender differences in certain illness characteristics were found in our study; however, in contrast to other reports, we did not find higher rates of lifetime depressive episodes or rapid cycling in women. Although our study is limited by its retrospective study design, its results are strengthened by our large sample size and use of structured interviews.

Assessment tools for screening and monitoring bipolar disorder.

OBJECTIVE: To review the availability and suitability of tools for screening, diagnosing, and monitoring people with bipolar disorder in both psychiatric and general practice. METHODS: Currently available assessment tools suitable for use with patients with bipolar disorder were identified through a MEDLINE search using the following key terms: bipolar, screening, diagnosis, monitoring. Only peer-reviewed papers published in English were considered for further review. RESULTS: A review of the current literature revealed a small number of published and appropriately validated clinical tools suitable for the assessment of bipolar disorder in terms of screening, diagnosis, and long-term monitoring. CONCLUSIONS: While there are a large number of formal rating scales for the assessment of various clinical aspects of bipolar spectrum disorders, there are currently only a limited number of assessment tools well suited for use in routine clinical practice. Widespread use of brief, clinically validated, and easy to use screening tools could facilitate the early identification of patients with bipolar spectrum disorders. A less structured diagnostic approach should facilitate diagnosis of the more subtle forms of the disease, particularly bipolar II disorder. Long-term monitoring tools should strengthen the therapeutic alliance between the patient and clinician and improve long-term quality of care and assessment of outcomes.

Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study.

This is a report on a 37-patient continuation study of the open ended, Omega-3 Fatty Acid (O-3FA) add-on study. Subjects consisted of the original 19 patients, along with 18 new patients recruited and followed in the same fashion as the first nineteen. Subjects carried a DSM-IV-TR diagnosis of Bipolar Disorder and were visiting a Mood Disorder Clinic regularly through the length of the study. At each visit, patients' clinical status was monitored using the Clinical Monitoring Form. Subjects reported on the frequency and severity of irritability experienced during the preceding ten days; frequency was measured by way of percentage of days in which subjects experienced irritability, while severity of that irritability was rated on a Likert scale of 1-4 (if present). The irritability component of Young Mania Rating Scale (YMRS) was also recorded quarterly on 13 of the 39 patients consistently. Patients had persistent irritability despite their ongoing pharmacologic and psychotherapy. Omega-3 Fatty Acid intake helped with the irritability component of patients suffering from bipolar disorder with a significant presenting sign of irritability. Low dose (1 to 2 grams per day), add-on O-3FA may also help with the irritability component of different clinical conditions, such as schizophrenia, borderline personality disorder and other psychiatric conditions with a common presenting sign of irritability.

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

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.

Bipolar spectrum disorder: a pilot study.

OBJECTIVE: To assess depressive features of a proposed definition of bipolar spectrum disorder (BSD). METHODS: Thirty-six patients with bipolar disorder type I or II were compared to 37 patients with unipolar major depressive disorder through patient interview and chart review. RESULTS: Univariate analysis suggests that 7 of 12 (recurrent major depressive episodes, brief major depressive episodes, atypical depressive symptoms, early age of onset, family history of bipolar disorder, antidepressant tolerance, and antidepressant-induced mania) features of major depressive episodes were more likely to occur in bipolar versus unipolar patients. After adjustment in a multivariable regression model, however, the five most powerful predictors of bipolar disorder were brief major depressive episodes, early age of onset, antidepressant- induced mania, postpartum depression, and atypical depressive symptoms. CONCLUSIONS: This preliminary study supports the idea that bipolar disorder is characterized by some depressive features less likely to be found in unipolar depression. Further prospective study needs to be conducted comparing BSD with unipolar depression.

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

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.

The current understanding of lamotrigine as a mood stabilizer.

OBJECTIVE: To examine whether lamotrigine has a unique role in the treatment of bipolar disorder, we evaluated the results of recent clinical trials and molecular and cell biological studies on lamotrigine. DATA SOURCES: Using keywords such as bipolar disorder, lamotrigine, clinical trial, outcomes studies, and mechanisms, we conducted a search for English-language articles on MEDLINE and Index Medicus and also on abstracts presented in recent research conferences. DATA SYNTHESIS: Several studies have strongly suggested that lamotrigine is effective for the acute treatment of bipolar depression as well as for long-term maintenance treatment of bipolar disorder. Stevens-Johnson syndrome is a concern, but the incidence of this side effect may not be as high as previously believed, if dosing is slowly titrated. The action mechanisms underlying the mood-stabilizing effects of lamotrigine are unknown at present but recent studies have produced interesting leads. Lamotrigine modulates various ion channels, altering neuronal excitability. The use-dependent inhibition of neuronal firing by lamotrigine is potentially important because it could result in attenuating supranormal neuronal activities that are possibly associated with bipolar disorder. Lamotrigine inhibits the release of glutamate, similarly to lithium, and its possible association with mood-stabilizing or antidepressant effects needs to be further examined. Unlike lithium or valproic acid, however, lamotrigine does not down-regulate the expression of protein kinase C or MARCKS, suggesting that lamotrigine employs different intracellular mechanisms for long-term changes in neuro-biology from those of lithium or valproic acid. CONCLUSION: The efficacy of lamotrigine for bipolar depression may provide us with new options in the treatment of bipolar disorder. Examining the effects of lamotrigine on various molecular mechanisms in correlation with its unique efficacy on bipolar depression may enhance our understanding of action mechanisms of the mood stabilizers.

Antidepressant treatment in bipolar versus unipolar depression.

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.

Treatment of bipolar depression.

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.

What drugs are best for bipolar depression?

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.