Psychiatric Annals

CME Article 

Therapeutic Challenge: Antidepressant Monotherapy of Major Depressive Episodes in Bipolar II Disorder

Jay D. Amsterdam, MD; Nancy Rutherford, MSN, CRNP; Justine Shults, PhD

Abstract

The most common phenotypic expression of bipolar illness is bipolar type II disorder,1–4 first described in 1976 by Dunner et al.5 Bipolar II disorder is diagnostically stable over time6 and rarely evolves into bipolar type I disorder.6–10 There is considerable evidence that bipolar II disorder is a distinct clinical entity that differs from bipolar I disorder on the basis of genetic and biological factors.1,6,11 For example, family studies have shown that bipolar II disorder, but not bipolar I disorder, is more prevalent in the relatives of bipolar II probands.11

Bipolar II disorder can be exceedingly difficult to diagnose and frequently goes unrecognized.2–4,12,13 This usually is the result of a failure to recognize past hypomanic episodes, which may manifest as brief periods of irritability and agitation rather than euphoria or a heightened sense of well-being. The relative lack of manic symptoms in bipolar II disorder stands in stark contrast to the devastating morbidity and mortality that result from this disorder.

In this regard, bipolar II disorder is highly recurrent, with the majority of episodes being major depressive episodes.1,2,5 This high recurrence rate seems to appear despite the use of mood stabilizer therapy and ranges from about 44% to 70%.6,14 The recurrence rate also can result in a substantial morbidity and mortality rate,15 including high rates of suicide15 and comorbid nonaffective psychopathology (eg, alcohol and substance abuse, anxiety disorders).3,15 One study reported a suicide ideation rate of 79% in patients with bipolar II during major depressive episodes,16 while a literature survey by Goodwin & Jamieson17 found a lifetime prevalence rate for completed suicide of 19% in patients with bipolar II. Dunner18 reported that the rate of successful suicide is higher in patients with bipolar II major depressive episodes when compared with patients who have either bipolar I or unipolar major depressive episodes. These observations suggest that a diagnosis of bipolar II disorder should be considered in any patient with unipolar major depressive episodes who has a history of multiple suicide attempts.

Although there is a growing awareness of the prevalence of bipolar II disorder in the United States, the public health implications of this disorder have only recently been recognized. In part, this is the result of underrecognition of bipolar II disorder. Most patients with bipolar II who present with major depressive episodes continue to be diagnosed with unipolar illness.1,12

Benazzi12 used the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)19 to re-diagnose 203 patients treated for unipolar major depressive episodes. He found that 45% of these patients met SCID-diagnosed criteria from the Diagnostic and Statistical Manual for Mental Disorders, fourth edition (DSM-IV),20 for bipolar II disorder; 4% met criteria for bipolar I disorder. Given this degree of diagnostic uncertainty, it appears likely that bipolar II disorder may be more common in clinical practice than previously thought.

In patients with bipolar II disorder, it appears that poor functional outcome is highly correlated with the depressive, rather than the manic, symptoms. Bauer et al.21 found that even modest levels of depression had a negative effect on functional outcome. These observations support the need for developing new strategies to recognize and diagnose bipolar II disorder.

While the public health implications of bipolar II disorder are only now emerging in terms of morbidity, mortality, and healthcare costs, the development of new treatment strategies for bipolar II disorder have been understudied. As a result, there is a paucity of information on the best initial and continuation therapy for bipolar II major depressive episodes. This is partly because the medical literature on this subject generally has placed bipolar I and bipolar II disorder together in treatment…

The most common phenotypic expression of bipolar illness is bipolar type II disorder,1–4 first described in 1976 by Dunner et al.5 Bipolar II disorder is diagnostically stable over time6 and rarely evolves into bipolar type I disorder.6–10 There is considerable evidence that bipolar II disorder is a distinct clinical entity that differs from bipolar I disorder on the basis of genetic and biological factors.1,6,11 For example, family studies have shown that bipolar II disorder, but not bipolar I disorder, is more prevalent in the relatives of bipolar II probands.11

Bipolar II disorder can be exceedingly difficult to diagnose and frequently goes unrecognized.2–4,12,13 This usually is the result of a failure to recognize past hypomanic episodes, which may manifest as brief periods of irritability and agitation rather than euphoria or a heightened sense of well-being. The relative lack of manic symptoms in bipolar II disorder stands in stark contrast to the devastating morbidity and mortality that result from this disorder.

In this regard, bipolar II disorder is highly recurrent, with the majority of episodes being major depressive episodes.1,2,5 This high recurrence rate seems to appear despite the use of mood stabilizer therapy and ranges from about 44% to 70%.6,14 The recurrence rate also can result in a substantial morbidity and mortality rate,15 including high rates of suicide15 and comorbid nonaffective psychopathology (eg, alcohol and substance abuse, anxiety disorders).3,15 One study reported a suicide ideation rate of 79% in patients with bipolar II during major depressive episodes,16 while a literature survey by Goodwin & Jamieson17 found a lifetime prevalence rate for completed suicide of 19% in patients with bipolar II. Dunner18 reported that the rate of successful suicide is higher in patients with bipolar II major depressive episodes when compared with patients who have either bipolar I or unipolar major depressive episodes. These observations suggest that a diagnosis of bipolar II disorder should be considered in any patient with unipolar major depressive episodes who has a history of multiple suicide attempts.

Although there is a growing awareness of the prevalence of bipolar II disorder in the United States, the public health implications of this disorder have only recently been recognized. In part, this is the result of underrecognition of bipolar II disorder. Most patients with bipolar II who present with major depressive episodes continue to be diagnosed with unipolar illness.1,12

Benazzi12 used the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)19 to re-diagnose 203 patients treated for unipolar major depressive episodes. He found that 45% of these patients met SCID-diagnosed criteria from the Diagnostic and Statistical Manual for Mental Disorders, fourth edition (DSM-IV),20 for bipolar II disorder; 4% met criteria for bipolar I disorder. Given this degree of diagnostic uncertainty, it appears likely that bipolar II disorder may be more common in clinical practice than previously thought.

In patients with bipolar II disorder, it appears that poor functional outcome is highly correlated with the depressive, rather than the manic, symptoms. Bauer et al.21 found that even modest levels of depression had a negative effect on functional outcome. These observations support the need for developing new strategies to recognize and diagnose bipolar II disorder.

While the public health implications of bipolar II disorder are only now emerging in terms of morbidity, mortality, and healthcare costs, the development of new treatment strategies for bipolar II disorder have been understudied. As a result, there is a paucity of information on the best initial and continuation therapy for bipolar II major depressive episodes. This is partly because the medical literature on this subject generally has placed bipolar I and bipolar II disorder together in treatment outcome studies, rather than assessing them separately.4,13,17

Practice Guidelines

The treatment of major depressive episodes in bipolar II remains a therapeutic challenge for clinicians.22,23 For most patients with bipolar II disorder, the frequency and duration of major depressive episodes appears to increase with age and eventually may dominate the clinical picture.4,17,23 Current practice guidelines for treating major depressive episodes in bipolar II are empirical, and some consensus guidelines disagree with other guidelines.24 None of the guidelines are based on prospective, controlled clinical trials, and most are based on expert opinion that generally recommends a similar approach to treating bipolar II as that recommended for the treatment of bipolar I disorder. In this regard, most guidelines recommend avoiding the use of antidepressant mono-therapy for major depressive episodes in bipolar II and recommend starting initial therapy with a mood stabilizer. For example, the American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Bipolar Disorder25,26 recommends that initial therapy of major depressive episodes in bipolar II begin with mood stabilizer monotherapy (eg, lithium carbonate), with concomitant antidepressant therapy being limited to the lowest effective dose for the shortest possible time.

Similar recommendations have been made by the Expert Consensus Guideline Series, based on the opinions of leading experts in the US.27 In contrast to the APA recommendations, this expert consensus guideline suggests that antidepressant monotherapy may be considered in bipolar II patients with major depressive episodes who have a history of “minimal” hypomania. They recommend that antidepressant therapy be limited to treatment with a serotonin reuptake inhibitor (SSRI) or with bupropion — even though there are limited controlled clinical data to support this recommendation.24

In contrast, a panel of distinguished Canadian psychiatrists have cautioned against the use of antidepressant mono-therapy for major depressive episodes in bipolar II. Instead, they recommend using mood stabilizer monotherapy as the initial treatment28 and that any previously established antidepressant therapy begun before mood stabilizer therapy be tapered and withdrawn within 6 to 12 weeks after remission of the depressive episode. Most recently, practice guidelines for the initial therapy of major depressive episodes in bipolar II recommend starting mood stabilizer monotherapy for mild to moderate depression and combined mood stabilizer plus antidepressant therapy for severe depressive episodes.27

Finally, a Harvard psychopharmacology algorithm for treating major depressive episodes in bipolar II recommends that patients not taking a mood stabilizer may receive antidepressant therapy with an SSRI or bupropion.29 However, this recommendation is not based on controlled clinical data.

Despite these expert recommendations about the use of antidepressant therapy for major depressive episodes in bipolar II, a recent survey has shown that mood stabilizer monotherapy is prescribed to only about 19% of hospitalized patients with bipolar II depressive episodes30 and that most clinicians still prescribe antidepressant monotherapy.13,22 This may be partly because mood stabilizer therapy lacks approved labeling by the Food and Drug Administration for the treatment of major depressive episodes in bipolar II, and partly from the complexity of prescribing mood stabilizer therapy, with its costly laboratory tests and plasma level monitoring.

There also is a paucity of controlled clinical data indicating that mood stabilizer monotherapy is particularly effective for the initial treatment of major depressive episodes in bipolar II.4,17 In this regard, a survey of Canadian psychiatrists has recently shown that SSRI monotherapy is favored over mood stabilizer monotherapy.31

Mood Stabilizer Monotherapy

The use of initial and continuation mood stabilizer monotherapy for major depressive episodes in bipolar II largely is based on therapy recommended for bipolar I disorder.25,26 There are few controlled clinical trials studying the comparable efficacy of mood stabilizer monotherapy for major depressive episodes in bipolar II. Although some researchers have questioned whether anti-depressant therapy is even effective and whether it should be avoided altogether due to concerns about manic switch episodes,1 this perception is not universally supported by the results of controlled antidepressant trials in patients with bipolar II major depressive episodes.

Evidence for the effectiveness of mood stabilizer monotherapy in bipolar II major depressive episodes is extremely limited. Early studies of the efficacy of lithium versus tricyclic antidepressant (TCA) versus combined lithium plus TCA therapy generally have shown that TCA monotherapy (or combined mood stabilizer plus TCA therapy) is superior to lithium monotherapy.17 However, studies of mood stabilizer monotherapy in patients with bipolar major depressive episodes generally have included patients with both bipolar I and bipolar II disorders. As a result, definitive conclusions about the relative efficacy of mood stabilizer monotherapy in bipolar II major depressive episodes reamain unknown.

A more recent trial by Denicoff et al.32 examined the efficacy of lithium monotherapy or carbamazepine mono-therapy for up to 12 months in patients with both bipolar I and bipolar II major depressive episodes. A response rate of only 33% was observed for both mood stabilizer monotherapies. This low overall response rate occurred despite the fact that patients received exemplary care. Moreover, while lithium appeared to be effective in reducing manic episodes, neither mood stabilizer monotherapy appeared to reduce the amount of time spent in depression.

While several studies have shown efficacy of lamotrigine33 and olanzapine34 in bipolar I major depressive episodes, the utility of these agents in bipolar II major depressive episodes is not yet known. Similarly, few studies have examined the efficacy of divalproex in bipolar II major depressive episodes.4 Winsberg et al.35 examined divalproex as initial monotherapy for bipolar II major depressive episodes in 19 patients, 11 of whom were drug naive and eight who had taken prior antidepressants therapy. Although 63% of the patients responded with at least a 50% reduction in baseline Hamilton Depression Ratings (HAMD)36 scores, patients with bipolar II major depressive episodes who had previous received antidepressants therapy had only a 38% response rate.

Controlled clinical trials of newer mood stabilizer agents in bipolar II major depressive episodes are completely lacking. Ghaemi et al.37 conducted a chart review study of the antidepressant efficacy of oxcarbazepine in 25 patients with bipolar I, four patients with bipolar II, and 13 patients with bipolar – not otherwise specified (NOS), all with major depressive episodes and many having mixed manic and depressive symptoms. The review found a moderate to marked clinical global improvement in 52% of patients. However, 22 patients (52%) discontinued therapy due to side effects. There was no difference in the efficacy rate among the various bipolar diagnostic subgroups.

In another chart review study, Ghaemi et al.38 examined the efficacy of gabapentin in 50 patients with bipolar I, bipolar II, bipolar NOS, or unipolar major depressive episodes. Overall, only 30% of patients had a clinical global improvement rating of moderate or marked.

Antidepressant Monotherapy

The reluctance to prescribe antidepressant monotherapy for patients with bipolar II major depressive episodes stems primarily from concerns about antidepressant-induced manic switch episodes.4,24,33 This concern has largely been extrapolated from findings of TCA-induced mania in patients with bipolar I major depressive episodes.17 Given the finding that up to 40% of patients with unipolar major depressive episodes receiving antidepressant monotherapy may actually suffer from bipolar II,12 it seems likely that most patients with bipolar II major depressive episodes taking antidepressant monotherapy do not experience manic switch episodes. Moreover, the evidence of a high manic switch rate in patients with bipolar II major depressive episodes during antidepressant monotherapy is surprisingly limited.

Estimates of manic switch rates in bipolar II major depressive episodes largely have been based on rates reported with TCAs in bipolar I major depressive episodes and range from 2% to 70%.17,33 However, in contrast to patients with bipolar I major depressive episodes, patients with bipolar II major depressive episodes are much less likely to undergo antidepressants-induced manic switch episodes.7–10,39,40 For example, one prospective study found that patients with a history of bipolar II major depressive episodes were no more likely to develop mania than unipolar major depressive episode patients taking TCA monotherapy.39 Moreover, these investigators reported that even in cases where manic symptoms did occur in patients with bipolar II major depressive episodes, these episodes usually were mild and time-limited and did not necessitate discontinuing antidepressant therapy.39 These early observations are now supported by more recent prospective studies showing a low manic switch rate during antidepressant monotherapy in patients with bipolar II major depressive episodes.8–10

SSRI efficacy in bipolar major depressive episodes initially was reported in 1977,41 and subsequent studies have shown that SSRI monotherapy may be relatively safe and effective in patients with either bipolar I or bipolar II major depressive episodes.42 Unfortunately, most antidepressants efficacy trials have pooled data from from bipolar I and bipolar II. Despite this limitation, antidepressants do appear to be effective therapy for bipolar II major depressive episodes.

For example, a retrospective study of 2,000 patients found that antidepressant monotherapy was equally effective in unipolar and bipolar major depressive episodes.43 In addition, a retrospective analysis of a prospective, multi-site, controlled clinical trial compared the efficacy and safety of fluoxetine monotherapy in 89 patients with bipolar II major depressive episodes and 89 patients with unipolar major depressive episodes and found fluoxetine efficacy to be similar in the unipolar (51%) and bipolar II (61%) groups. Mild manic symptoms occurred in only 3.8% of the patients with bipolar II.

Additional studies demonstrating low manic switch rates during initial and continuation antidepressants monotherapy of bipolar II major depressive episodes have now been reported.44,45 Many of these studies have been open-label or chart review studies, although several have been double-blind, randomized comparison studies. In general, they have shown that initial and continuation antidepressant therapy of patients with bipolar I or bipolar II major depressive episodes is effective, with good tolerability and a low manic switch rate.

SSRI or SNRI Therapy

Venlafaxine Monotherapy

A prospective, double-blind, placebo-controlled, dose-escalation comparison study of once versus twice daily venlafaxine monotherapy examined safety and efficacy measures in 17 patients with bipolar II major depressive episodes and 31 patients unipolar major depressive episodes.46 All patients met DSM-IV criteria for moderate to severe major depressive episodes and had a baseline 21-item HAM-D score of 20 or higher. Patients received either once- or twice-daily venlafaxine monotherapy for 6 weeks, starting at 37.5 mg daily and increasing to 225 mg daily. Responders with a 50% or greater reduction in baseline HAM-D score continued on venlafaxine monotherapy for an additional 3 months.

Of the 48 patients enrolled into the 6-week trial, 42 patients (16 bipolar II and 26 unipolar) completed it. There was a significant reduction in HAM-D scores (P < .001), with similar efficacy among patients with bipolar II and unipolar major depressive episodes (P = ns). Patients with bipolar showed a more rapid reduction in mean HAM-D scores (P = .03) by week 3 of therapy. No manic switch episodes were detected.

A subanalysis of the data was performed on the women with bipolar II major depressive episodes, who were at greater risk of poor response and of developing antidepressant-induced manic symptoms.47 Two women with bipolar (13%) and three women with unipolar (18%) discontinued venlafaxine monotherapy due to adverse events or lack of efficacy (P = ns), but not as a result of antidepressant-induced manic symptoms.40

Fluoxetine Monotherapy

A two-phase, double-blind, placebo-substitution trial studied the efficacy and manic switch rate of fluoxetine monotherapy in 37 patients with bipolar II major depressive episodes with a baseline 17-item HAM-D score of 16 or higher.8,10 In study phase I, all patients received fixed-dose fluoxetine monotherapy at a dose of 20 mg daily for 8 weeks. Responders with a final HAM-D score of 9 or lower were enrolled into study phase II and randomized to continue treatment for an additional 6 months with either fluoxetine monotherapy at a dose of 20 mg daily or placebo.

HAM-D and Young mania rating (YMR)48 scores were obtained at weeks 1, 2, 4, 6, and 8 in study phase I, and at weeks 2, 4, 8, 12, 16, 20, and 26 in study phase II. Of the 43 patients enrolled into the study, 37 patients received fluoxetine monotherapy. Fourteen patients (37.8%) discontinued therapy in study phase I: two (5.4%) for side effects, three (8.1%) for nonresponse, and nine (24.3%) for protocol violations or other reasons. Another 14 patients (38%) responded to fluoxetine monotherapy with a final HAM-D score of 9 or lower. Mean HAM-D scores decreased from 21.7 (standard devision [SD] = 3.9) to 14.8 (SD = 8.3) by week 8 of treatment (P < 0.001).

There was no change in mean YMR score at any study visit, compared with YMR scores observed at the pre-treatment baseline period (P = .93). Only three patients (8.1%) had a YMR score of 8 or higher on two study visits. Moreover, the percentage of patients with a YMR score of 8 or higher at any study visit during fluoxetine monotherapy did not differ from the rate seen during the pre-treatment, baseline lead in period. Only three patients (7.3%) met DSM-IV criteria for hypomania in study phase I, but none of them discontinued fluoxetine monotherapy as a result of those symptoms.

In study phase II, seven patients received double-blind fluoxetine monotherapy and five received placebo; 43% of those taking continuation fluoxetine and 100% of placebo-treated patients relapsed with major depressive episodes and a rise in HAM-D score to 14 or higher (P = 0.08; Kaplan-Meier, a test for equality of median time until relapse between groups). The mean change in YMR scores (versus baseline YMR scores) during double-blind monotherapy was 3.0 (SD = 1.8), and the mean change in YMR scores during placebo was 0.2 (SD = 0.45) (P = 0.01). This small difference was not, however, clinically meaningful, and the low YMR scores do not constitute even mild mania.10

Venlafaxine or Fluoxetine Dose Escalation Monotherapy

More recently, a series of preliminary controlled clinical trials has been initiated designed to test the validity of the current practice guidelines recommending initial mood stabilizer monotherapy of bipolar II major depressive episode. In one study, the safety and efficacy of antidepressant monotherapy with venlafaxine was compared with that of mood-stabilizer monotherapy with lithium carbonate in 58 patients with SCID-diagnosed bipolar II major depressive episodes. Patients were randomly assigned to receive either open-label lithium carbonate monotherapy (n = 27) or venlafaxine monotherapy (n = 28) for 12 weeks.

Efficacy ratings (ie, HAM-D, clinical global severity, YMR) and safety ratings (eg, adverse events, vital signs, lithium levels) were obtained at study weeks 1, 2, 4, 6, 8, 10, and 12. HAM-D ratings were performed using a structured interview technique.49 In the lithium monotherapy group, the maximum dose was determined based on maintaining serum lithium levels between 0.6 mmol/L and 1.2 mmol/L, while the maximum dose of venlafaxine was 375 mg daily.

Generalized estimating equation (GEE) analysis was used to compare the rate of change in HAM-D and YMR scores among treatment groups (P = .195). However, more venlafaxine-treated patients (60%) than lithium-treated patients (22%) had a reduction of 50% or more in baseline HAM-D score (P = .01; Fisher's exact test for equality of proportions). A greater reduction also was seen in clinical global severity scores for venlafaxine versus lithium (P = .009). There was no significant change over time in YMR scores in either monotherapy group. There were no differences in the frequency of YMR scores of 8 or higher at any study visit between the antidepressant and mood stabilizer monotherapy groups (P = .623; Fisher's exact test).

Another study examined the safety and efficacy of open-label, dose-escalation (10 mg to 80 mg daily) fluoxetine monotherapy in 88 patients with moderate to severe bipolar II major depressive episodes. Symptom severity measures including HAM-D, clinical global severity, and YMR were obtained screen, baseline, and weeks 1, 2, 4, 6, 8 and 10. Patients who remitted during initial fluoxetine monotherapy with a final 17-item HAM-D score of 8 or lower by week 10 and who maintained this score for 2 additional weeks were then enrolled into double-blind continuation therapy with either fluoxetine monotherapy, lithium monotherapy, or placebo for up to 1 year.

The study examined 56 women (mean age = 33.9) and 32 men (mean age = 36.4). The mean illness duration was 19.7 years (range: 8 to 52 years), and the mean current duration of major depressive episode was 14.2 months (range: 1 to 96 months). The median number of prior major depressive episodes was four (range: 0 to 30), and the median number of prior hypomanic episodes was four (range: 1 to 60).

In total, 59 patients (67%) responded to fluoxetine monotherapy with a final HAM-D score of 8 or lower. In addition, 49% of the patients had a 50% or greater reduction in baseline HAM-D score by week 10 of fluoxetine monotherapy. An analysis based on a paired t-test showed a significant reduction in HAM-D scores by week 6 (P < .0005), week 8 (P < .0005), week 10 (P < .0005), and week 12 (P < .0005) of fluoxetine monotherapy.

GEE analysis was used to analyze the change in HAM-D scores at each study visit and adjusted for the association among repeated HAM-D measures of each patient. A significant reduction in HAM-D scores was observed over time (P < .0005). Generalized estimating equation also adjusted for the influence of age, gender, race, rapid cycling status (ie, 10 or more prior affective episodes), and prior antidepressant therapy on HAM-D scores. Only age was associated with HAM-D scores, with older patients being significantly more likely to have higher HAM-D scores at any study visit (P = .034). The Figure displays the percentage of patients who remitted by each study visit during open-label fluoxetine monotherapy. We observed a consistent increase in the remission rate over time (P < .0005).

Percentage of patients remitting at each study visit during fluoxetine monotherapy.

Figure.

Percentage of patients remitting at each study visit during fluoxetine monotherapy.

Finally, we examined the presence of fluoxetine-induced manic symptoms and manic switch episodes as measured by increases in YMR scores at each study visit compared to the pre-treatment, baseline period. There was no signifi-cant change in YMR scores over time during fluoxetine monotherapy (P = .74; GEE analysis). There was a single episode of mania observed in a 46-year-old man with bipolar I disorder who was misdiagnosed by SCID interview as having bipolar II major depressive episodes. The average YMR score during fluoxetine monotherapy was 0.40, with 95% CI = (0.28,0.53). This observation is of particular importance because a YMR score of 16 or higher generally is required for entry into a clinical trial of even mild mania.

Summary

The results of these prospective, controlled clinical trials indicate that anti-depressant monotherapy may be a safe and effective initial and continuation treatment of bipolar II major depressive episodes. We have observed a substantial response rate that appears to increase over time during antidepressant monotherapy. In addition, these prospective studies also suggest that there generally is no significant increase in manic symptoms over time during antidepressant monotherapy of bipolar II major depressive episodes. Finally, we believe that the results of recent studies of patients with bipolar II major depressive episodes support findings from earlier studies of a low manic switch rate during antidepressant monotherapy. We feel that our preliminary results showing good efficacy of antidepressant monotherapy compared with mood-stabilizer monotherapy. If these initial observations are replicated, we feel that they may have an important public health effect on the current practice guidelines for treating bipolar II major depressive episodes.

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Educational Objectives

  1. Identify the epidemiology and clinical course of bipolar II disorder.

  2. Discuss treatment of bipolar II depression using antidepressant and mood stabilizer therapies.

  3. Describe the use of antidepressant monotherapy for the treatment of bipolar type II major depressive episode.

Authors

Dr. Amsterdam is professor of psychiatry, University of Pennsylvania School of Medicine, and director, Depression Research Unit, University of Pennsylvania Medical Center, Philadelphia, PA. Ms. Rutherford is research nurse practitioner, Depression Research Unit, University of Pennsylvania School of Medicine. Dr. Shults is assistant professor of biostatistics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine.

Address reprint requests to: Jay D. Amsterdam, MD, Depression Research Unit, University Science Center, 3rd Floor, 3535 Market St., Philadelphia, PA 19104-3309; or e-mail: jamsterd@mail.med.upenn.edu.

Dr. Amsterdam receives grant/research support from Forest Laboratories and Lilly, serves as a consultant to Lilly, Pfizer, and Novartis and a scientific advisor to Lilly and Somerset, and is on the Speakers' Bureau for Lilly, Pfizer, and Wyeth. Ms. Rutherford and Dr. Shults have no industry relationships to disclose.

The research on which this article is based was supported by funds provided by National Institutes of Mental Health grant R01 MH060353, The Stanley Medical Research Institute, Lilly Research Laboratories, Wyeth Pharmaceuticals, and the Jack Warsaw Endowment for Research in Biological Psychiatry (Depression Research Unit, University of Pennsylvania School of Medicine).

10.3928/00485713-20051201-05

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