Antidepressant monotherapy for bipolar type II major depression

Transcription

1 Bipolar Disorder 2003: 5: 38S-395 Copyrighi Blackwell Miink.sgiiaril 2003 BIPOLAR DISORDERS Review Article Antidepressant monotherapy for bipolar type II major depression Amsterdam JD, Brunswick DJ. Antidepressant monotherapy for bipolar type II major depression. Bipolar Disord 2003: 5: Blackwell Munksgaard, 2003 Objectives: Bipolar type II (BP II) disorder is thought to be distinct from BP I disorder on genetic and biological grounds, and it is not merely a milder form of the illness. It affects % of the US adult population, and is characterized by highly recurrent depressive episodes with a substantial morbidity from alcoholism and non-affective psychopathology, and a higher suicide rate than either BP I or unipolar depression. Treatment recommendations for BP II depression are based upon concerns over drug-induced manic-switch episodes, and suggest using either a mood stabilizer alone or a combination of an SSRI plus a mood stabilizer. Recent evidence, however, indicates that the rate of manic switch episodes may be modest in BP II patients. Recent studies have provided evidence that antidepressant monotherapy may be an effective initial and long-term treatment for BP II major depression with a low manic-switch rate. Methods: In this article, we review the recent literature on BP II disorder, with a focus on the treatment of BP II major depression. Results: We present a summary of data from recent studies by our group and otiiers indieating that antidepressant monotherapy for BP II depression may be safe and effective with a low manic-switch rate. Conclusion: Antidepressant monotherapy may be beneficial for some patients with BP II major depression. Jay D Amsterdam and David J Brunswick Department of Psychiatry, Depression Research Unit, University of Pennsylvania Schooi of Medicine, Phiiadeiphia, PA, USA Key vifords: antidepressant - bipolar II disorder - mood stabiiizer - treatment Received 7 May 2002, revised and accepted for publication 29 October 2002 Corresponding author: Jay D. Amsterdam, MD, Depression Research Unit, University Science Center - 3rd Floor, 3535 Market Street, Phiiadeiphia, PA 19104, USA, Fax: (215) ; iamsterd@mail.med.upenn.edu Introduction Incidence and epidemiologic factors There has been a growitig awareness of the prevalence and importance of bipolar type II (BP II) disorder. The financial impact of BP II disorder (in terms of medical costs and lost productivity) is considerable and has been estimated to be about $20 billion annually (1). Despite this, most BP II patients receive an incorrect diagnosis of recurrent unipolar depression (2). As a result, Goodwin and Ghaemi (3) have estimated that the apparent incidence of BP II major depression can vary widely depending upon the ascertainment method used. Community-based epidemiologic studies have found a prevalence rate of 1.5-^2.5% for BP II disorder (1, 4, 5). However, estimates vary widely. Two recent clinical surveys have estimated that approximately 40% of patients with a diagnosis of major depression may have BP II disorder (6, 7). This is consistent with a vast underdiagnosis of BP II disorder. In this regard, in two recent office-based surveys, 40-45% of patients diagnosed with BP II major depression had previously been diagnosed as recurrent unipolar MDE (3, 8). Thus, BP II disorder may characterize a high proportion of affectively ill patients seen in physician's offices. It would appear that BP II depression represents the most common expression of BP disorder (2). Clinical characteristics Bipolar II disorder was initially described in 1976 (9). As defined in DSM-IV, it is characterized by a preponderance of depressive episodes with a lifetime history of one or more hypomanic episodes 388

2 Antidepressant monotherapy for bipolar type II major depression lasting for a minimum of 4 days. It is thought to be distinct from BP 1 disorder on both genetic and biological grounds, and is felt to be not merely a milder form of the illness. BP II disorder is diagnostically stable over time (10-13) and rarely evolves into BP I (manic-depressive) disorder (12). The impact of BP II disorder in terms of morbidity, mortality and health care costs has only recently been recognized. It is frequently unrecognized and often misdiagnosed. This is largely the result of a failure to recognize prior hypomanic episodes which can frequently manifest as brief periods of irritability and agitation (rather than an enhanced sense of well-being). Misdiagnosis also results from the lack of subjective and objective symptoms (of mania), which might otherwise result in treatment intervention. Periods of increased productivity and an enhanced sense of well-being that can occur during hypomania are generally not viewed by patients or physicians as illness-related symptoms. Patients with these 'hyperthymic' symptoms are rarely considered to be in need of treatment (14). As a result, BP II disorder is generally diagnosed only by painstaking history-taking, and usually when the patient seeks treatment for a depressive episode. Bipolar II disorder is highly recurrent, with the majority of episodes being depression (rather than hypomania) (2, 15, 16). For example, Coryell et al. (12) reported an affective relapse rate of 70% (mostly depressive) in BP I and BP II patients during lithium maintenance; while O'Connell et al. (17) found a 44% relapse rate (mostly depressive) during a 1-year follow-up of 243 BP I and BP II patients on lithium maintenance. The high recurrence rate of BP II depressive episodes (even during lithium maintenance) can result in substantial morbidity and mortality (16, 18-20). Dunner (21) has indicated that a history of multiple suicide attempts is suggestive of BP II disorder, and that the rate of successful suicides may be higher in BP II patients when compared with BP I and unipolar major depression. Manic switch episodes during treatment of BP major depression The use of antidepressants for treating BP II major depression has been discouraged due to the perceived risk of drug-induced mania. However, the data on drug-induced manic-switch rates in BP II depression are surprisingly few, and most estimates are based upon data obtained using tricyclic antidepressants (TCAs) in patients with BP I disorder. As part of a study examining the relative efiicacy of long-term, relapse-prevention therapy in BP disorder, Prien et al. (22) reported the presence of drug-induced mania in 67% of 44 BP I depressed patients taking imipramine, 12% of patients taking lithium, and 33% of patients taking placebo. A larger study in 117 remitted BP I patients taking either imipramine, lithium or a combination of lithium and imipramine, found manic episodes in 53% of imipramine-treated patients, 26% of lithium-treated patients and 28% of patients receiving the combined therapy (23). Wehr and Goodwin (24) reported accelerated 'cycling' during TCA treatment in five rapidly cycling, female BP I patients. In a subsequent study, Sachs et al. (25) compared add-on therapy with bupropion versus desipramine to a mood stabilizer in 19 BP 1 depressed patients. They observed a 55% manic switch rate with desipramine and 11% with bupropion. Based upon these limited, controlled data, many clinicians prescribe bupropion for the treatment of BP I and BP II depression. More recently, Bottlender et al. (26) suggested that the concurrent use of a mood stabilizer may reduce the likelihood of a manic switch in BP I patients. However, controlled studies on this issue are limited in number. In a naturalistic study, Boerlin et al. (27) found a similar (~20%) rate of hypomanic switch episodes in 13 BP patients on a combination of a mood stabilizer plus an antidepressant and 14 BP patients on a mood stabilizer alone. In contrast, in a controlled lithium discontinuation study on BP I and BP II patients, established on maintenance lithium therapy, Faedda et al. (28) found that 20 of 38 (53%) BP I patients, and none of 26 BP II patients developed a manic episode following lithium discontinuation. While TCAs appear to result in manic-switch episodes in a substantial percentage of BP 1 depressed patients (24, 29), manic-switch rates resulting from selective serotonin reuptake inhibitors (SSRIs) may be substantially lower. In this regard, Cohn et al. (30) compared fiuoxetine mg/day, imipramine mg/day and placebo in a 6-week trial in BP I depressed patients generally not taking a mood stabilizer. After this initial treatment period, the patients were followed in open-label continuation therapy (where they were free to select either antidepressant treatment). In the initial 6-week period, only two of 30 patients (6.6%) on imipramine had a manic episode, while none of 30 fiuoxetine and none of 29 placebo patients had a manic episode. Similarly, during the open-label continuation phase of the study, none of 18 fiuoxetine patients had a manic episode, while 389

3 Amsterdam and Brunswick four of 25 patients (16%) who switched to fluoxetine from imipramine or placebo had a manic episode. In contrast to BP I depression, the evidence for a high manic-switch rate during antidepressant monotherapy in BP IT depression is surprisingly limited. Moreover, BP II patients rarely switch into mania (12) and are much less likely than BP I depressed patients to undergo a drug-induced manic switch (31). In an open and uncontrolled study, Kupfer et al. (32) found BP II depressed patients no more likely to develop hypomania than unipolar depressed patients receiving imipramine monotherapy mg/day. Furthermore, even when mood induction occurred in BP II patients, it was generally mild, time-limited and did not alter the overall treatment regimen (32). The effectiveness of SSRI monotherapy in BP depression was initially noted over 20 years ago (33), and other reports have indicated that shortterm SSRI treatment is highly effective in BP II depression (30, 34-36). Recent evidence suggests that the manic-switch rates in BP II depressed patients treated with SSRIs are substantially lower than that of TCAs in BP I patients. Peet (37) estimated SSRI-induced manic-switch rates at < 5%, a figure that compares with recent observations of 3.8% from our group (38). Despite the growing literature suggesting that SSRIs may be effective in BP II major depression and have a low incidence of manic induction (38), there is still disagreement concerning the use of SSRIs in BP depression (39). Persistent fear of mania during an SSRI treatment continues to plague clinicians (40). Thus, while the most accepted treatment for BP I depression is a mood stabilizer alone or in combination with an SSRI (41), there is little consensus regarding the appropriate management of BP II depression, and most current recommendations are based on those of BP I disorder. Current treatment guidelines for BP II major depression Bipolar II depression is generally considered to be less responsive to antidepressant monotherapy (2) and possibly to lithium monotherapy as well (4). Nevertheless, based upon early studies of lithium prophylaxis in BP II disorder (42, 43), it is now widely believed that a mood stabilizer may be needed in the treatment of BP II depression, and that antidepressants (if they are used at all) should be limited to the lowest possible dose for the shortest possible time. Despite the relative ineffectiveness of mood stabilizer monotherapy for the acute treatment of BP II major depression (4), the 390 use of mood stabilizer monotherapy is recommended, while the use of antidepressant monotherapy is discouraged in BP II depression. A number of treatment algorithms have been proposed for the acute treatment of BP H major depression. These algorithms are not based upon controlled clinical trials, but all express considerable concern about the use of antidepressants in the treatment of BP depression. These concerns have been summarized by Ghaemi et al. (44) who wrote that 'experts in the treatment of BP disorder have recommended avoidance of antidepressant treatment except in the brief, short-term treatment of severe, acute Bipolar depression in conjunction with mood stabilizing agents... There is some evidence that patients with milder variations of BP disorder, such as type II, may be at more risk of misdiagnosis as unipolar major depressive disorder and over-treatment with antidepressants resulting in a worsened rapid-cycling course.' The American Psychiatric Association Practice Guideline for the Treatment of Patients with Bipolar Disorder (41) has recommended that BP MDE patients should begin mood-stabilizer (generally lithium) therapy, and that patients given a concurrent antidepressant should receive the lowest effective dose of SSRI for the shortest time. This algorithm makes no distinction between the treatment of BP I and BP II depression. Similar recommendations have been made by an Expert Consensus Guideline Series based upon the recommendations of 61 American experts on BP disorder (45). However, in contrast to the APA recommendations, they suggested that antidepressant monotherapy may be considered in BP patients who have had a history of minimal hypomania (i.e. BP II depression). They recommend that antidepressant therapy be limited to SSRIs or bupropion as the first choice. In contrast, a panel of distinguished Canadian psychiatrists recommended against the use of antidepressant monotherapy in the treatment of BP MDE, recommending instead lithium monotherapy as the treatment of choice (46). Where a combination of an antidepressant and mood stabilizer is used in BP MDE, they recommend that the antidepressant dose be reduced and withdrawn completely within 6-12 weeks of remission of depressive symptoms. A recent guideline for the treatment of BP patients recommends that a mood stabilizer alone is the preferred initial strategy for the treatment of a first episode of mild to moderate BP depression (47). In the case of severe BP depression, a combination of a mood stabilizer and antidepressant medication is recommended. The use of an

4 Antidepressant monotherapy for bipolar type II major depression antidepressant alone is not recommended for any BP patient. This report recommended that antidepressants be used at the same target dose as that employed in the treatment of non-bp patients (except in patients with a history of antidepressantinduced mania). No distinction was made in this treatment guideline between therapy for BP I and BP II depression (47). Despite these recommendations, many psychiatrists recognize the limitations of lithium or other mood stabilizer monotherapy for BP II depression. A substantial proportion of BP II depressed patients do not respond to mood-stabilizer monotherapy (48), and many psychiatrists feel that SSRI monotherapy may be favored over mood stabilizer monotherapy for BP MDE (49). In line with this, the Harvard Psychopharmacology Algorithm has recommended that BP II depressed patients, not already taking a mood stabilizer, should be treated with an SSRI or bupropion alone (50). However, as with all the foregoing algorithms, this recommendation is not based upon controlled clinical trials. Treatment studies Acute fluoxetine monotherapy of BP II major depression We examined the efficacy and safety of short-term (12 weeks) fiuoxetine monotherapy in 89 BP II major depressed patients, and compared it with that of 89 unipolar depressed patients (38). Methods. In brief, as part of a five-site, prospective, double-blind, placebo-controlled 839 patient study, we identified 89 patients meeting DSM III-R criteria for BP II major depression. This patient cohort was age- and gender-matched to 89 unipolar depressed patients for outcome comparison. The study was divided into two phases: (i) an initial, 12-week open-label, fixed-dose fiuoxetine 20 mg daily treatment; and (ii) a 50-week doubleblind, placebo-substitution, relapse-prevention phase for patients who remitted during the initial treatment phase. Remission during the initial phase was defined as a reduction in the baseline HAM-D^ score > 50% plus a final HAM-D.y score <7 from weeks 9-12 of treatment. Adverse events were ascertained from patient-recorded and physician-elicited reports with 'manic switch' rates compiled retrospectively from the adverse events database. A 'manic switch' was defined as any treatment emergent event symptom suggestive of a hypomanic mood change (e.g. rapid thoughts, affective lability, agitation, increased activity and enhanced energy). Results. Fluoxetine monotherapy resulted in a similar efficacy for BP II and unipolar depressed patients. During the initial treatment phase 61% of BP II and 51% of the matched unipolar patients (p = ns) met the response criteria. A similar number of BP II and unipolar patients discontinued treatment for adverse events during the initial treatment phase. Symptoms suggestive of a hypomanic switch were observed in only 3.8% of BP II patients and in none of the unipolar patients during the initial study phase. Long-term fluoxetine monotherapy of BP II major depression We examined the efiicacy and safety of long-term (6 month) fiuoxetine monotherapy in 28 BP II patients, and compared with that of 27 unipolar patients who had remitted from their major depression during initial fiuoxetine treatment (38). Methods. We examined long-term efiicacy (survival) and safety in BP II and unipolar patients who responded to fiuoxetine 20 mg daily with a HAM- D 7 score <7. These patients were enrolled into one of four treatment conditions: (i) continuation fiuoxetine 20 mg daily for 50 weeks; (ii) continuation fiuoxetine for 38 weeks and then placebo for 12 weeks; (iii) continuation fiuoxetine for 14 weeks and then placebo for 36 weeks; or (iv) continuation placebo for 50 weeks. Relapse was defined as a sustained increase in HAM-D;? score >14 for 3 weeks, or DSM III-R criteria for major depression for 2 weeks. The presence of hypomanic symptoms were ascertained as described. Results. Eluoxetine monotherapy was effective in long-term relapse-prevention for BP II patients who remitted from their major depression. Kaplan-Meier survival curves for the BP II (n = 28) and unipolar (n = 27) patients who received at least 26 weeks of fiuoxetine maintenance therapy showed a slightly better outcome in the BP II patients (78%) versus unipolar patients (67%) (p = ns). Symptoms suggestive of a hypomanic switch were observed in only 1 (3.6%) BP II patient. These retrospective data support the contention that SSRI monotherapy may be a safe and effective treatment for BP II depression (Table 1). Venlafaxine monotherapy in BP II major depression We examined the safety and efficacy of acute (6-week) and long-term (3-month) relapse-prevention venlafaxine monotherapy in BP II and unipolar patients with DSM-IV major depression (51, 52). This was a 391

5 Amsterdam and Brunswick Table 1. Venlafaxine monotherapy in BP II and unipolar major depression Weekly HAMD21 scores Weekly MADRS scores BP (n = 16) UP (n = 26) p-value BP (n = 16) UP (n = 26) p-value Week 1 Week 2 Week 3 Week 4 Week 6 22 ± 6 16 ±8 11 ±5 11 ± 5 9±7 20 ± 5 19 ± ± 8 10 ± ± 7 17 ± 8 12 ±7 11 ± 6 9±8 25 ± 6 22 ± 9 19 ± 9 14 ± 9 10 ± Values are represented as mean ± S.D. p-values are bipolar (BP) versus unipolar (UP). single-site, double-blind, placebo-controlled, doseescalation comparison of once versus twice daily venlafaxine treatment. Methods. In brief, patients met DSM-IV criteria for MDE and had a baseline HAM-D21 score >20. Following a 1-week placebo lead-in period, patients were randomized to either once or twice daily venlafaxine dosing starting at 37.5 mg daily and increasing to 225 mg daily during weeks 4-6. Responders with a final reduction in HAM-D21 score > 50% continued in double-blind therapy for an additional 3 months. Results. A total of 48 patients were enrolled into the study over a 6-month period. Of these, 42 (88%) of the patients (16 BP II and 26 unipolar) completed the 6-week trial. Completer analyses demonstrated a significant overall reduction in HAM-D21 and Montgomery Asberg Depression Rating Scale (MADRS) scores (p < 0.001). There was similar overall efficacy among the BP II and unipolar depressed patients. Moreover, the BP II patients appeared to have a more rapid dechne in mean HAM-D2, (ANOVA; p = 0.03) and MADRS (p = 0.02) scores by week 3. There were no episodes of manic induction detected in any patient during the acute (6-week) or relapseprevention (3-month) phase. Venlafaxine monotherapy in BP II depressed women Gender differences in the presentation, course and outcome of BP disorder in women have been reported. For example, women with BP I disorder may be more likely to have recurrent depressive episodes (53), develop rapid cychng (54, 55), have dysphoric mania (56) and drug-induced manicswitch episodes (29, 57). Therefore, we specifically examined the comparative safety and outcomes of venlafaxine monotherapy in women with BP II and unipolar depression (58). Methods. The methods are as described in Ref. (38). In brief, 15 women with BP II depression (mean ± SD age 37 ± 12 years) and 17 women with unipolar depression (41 ± 12 years) were treated with venlafaxine, starting at 37.5 mg/day and increased to a maximum of 225 mg/day for 6 weeks. Responders were continued for an additional 3 months of relapse-prevention therapy. Results. A total of 31 women (15 BP II and 16 unipolar) received venlafaxine for >1 week and 28 (14 BP II and 14 unipolar) women completed the initial 6-week trial. Efficacy was similar among BP and unipolar-depressed women (Table 2). BP II depressed women showed a slightly more rapid improvement on the Clinical Global Impression, Table 2. Venlafaxine monotherapy in BP II and unipolar depressed women Weekly HAMDg, scores Weekly MADRS scores BP (n = 15) UP(n = 16) p-value BP(n = 15) UP(n = 16) p-value Baseline Week 1 Week 2 Week 3 Week 4 Week 6 24 ± 3 20 ± 6 17±8 13 ± 7 12 ± 7 11 ± 9 23 ± 3 21 ± 5 18 ±8 16 ± 7 12 ± 6 11 ± ±4 22 ± 7 18±9 14 ± 8 12 ± 8 11 ± ± 5 25 ± ± ± 8 14 ± 7 11 ± Values are represented as mean ± S.D. p-values are bipolar (BP) versus unipolar (UP). 392

6 Antidepressant monotherapy for bipolar type II major depression Improvement (CGI/I) scale by day 21 of treatment (p = 0.076), while the pereentage of patients with a >50% reduction in baseline HAM-D21 seore was similar in BP and unipolar women. Two BP II (13%) and three unipolar (18%) women discontinued treatment beeause of adverse events or lack of efficacy (p = ns). No episodes of drug-induced hypomania or rapid cycling were observed in the BP women during the initial or long-term study phase. Discussion Expert panels have recommended the following treatment approaches for BP II depression: (i) avoid the use of antidepressant monotherapy; (ii) initiate antidepressant therapy with a mood stabilizer alone (mild depression), or with a combination of a mood stabilizer and SSRI (severe depression); (iii) limit antidepressant agents to either an SSRI or bupropion, and avoid the use of a TCA; and (iv) initiate an SSRI or bupropion therapy at the lowest effective dose for the shortest possible duration (severe depression) (41, 59). Most of these recommendations are based upon data derived from the BP I depression literature, and none are the result of adequately powered and controlled, prospective clinical trials. In clinical practice, however, most of these guidelines are not followed. Patients and physicians shun the diagnosis of BP disorder, or patients refuse to take long-term mood stabilizer therapy or demonstrate reduced compliance in taking multiple psychotropic medications. Moreover, non-adherenee to therapy substantially increases with treatment duration. Finally, the diagnosis of BP II disorder is often overlooked, and antidepressant monotherapy is repeatedly prescribed for acute BP II depression. In contrast to the expert recommendation that antidepressants other than an SSRI or bupropion be avoided in BP II depression (especially the use of TCAs), there is substantial evidence from controlled trials that TCAs, as well as MAO inhibitors, may be highly effective in BP major depression. For example, Himmelhoch et al. (60) found the antidepressant efficacy of tranylcypromine to be superior to imipramine in BP I and II depressed patients on mood stabilizers. In this study, the side effect burden with tranylcypromine was similar to that of imipramine. We have also reported MAO inhibitor monotherapy to be effective, and without manic induction, in upto 50% of patients with treatment-resistant BP II depression (61). Similarly, Kupfer (16) reported only a 4% hypomanie switch rate in BP II depressed patients treated with imipramine monotherapy > 225 mg daily - suggesting that the previously reported high rates of TCA-induced manic-switch episodes may be limited to patients with BP I disorder. These observations comport well with more recent data from our group in BP II patients treated with fluoxetine (38) and venlafaxine (51, 58). Finally, what is the optimal time duration for the use of antidepressant treatment of BP II depression? Current recommendations indicate that patients with severe BP II depression might be treated with an SSRI (in combination with a mood stabilizer) at the lowest effeetive dose for the shortest possible time before discontinuing the SSRI. In this regard, there are few data in the literature to indicate that Mow dose' antidepressant therapy (alone or in eombination with a mood stabilizer) are effective for BP major depression, or that rapid discontinuation of antidepressant therapy for an illness with highly recurrent depressive episodes is more effective than continuation therapy. In contrast, available data suggests that continuation SSRI therapy may be more beneficial in long-term prevention of BP II depression relapse, suggesting that continuation SSRI therapy may be equally beneficial in BP II and unipolar depressives (38). Conclusion Bipolar II major depression appears to be a diagnostically distinct disorder, and not merely a more mild form of manic-depressive illness. It appears to represent a valid, distinct, highly recurrent and often psyehosocial malignant subtype of BP disorder (62). To date, there is no consensus on treatment approaches for BP II depression, and most recommended treatment algorithms are not based on empirical evidence and may lead to poor outcomes. Based on our preliminary findings in studies with fluoxetine and venlafaxine monotherapy of BP II depression (38, 51, 58), and a careful review of the literature on this subject, we suggest that antidepressant monotherapy may be safe and effective therapy for most patients with BP II depression. Acknowledgements This research was partially supported by a grant from NIMH (MH ), Lilly Research Laboratories (Eli Lilly and Company), Wyeth-Ayerst Pharmaceuticals, Inc., and the Jack Warsaw Fund for Research in Biological Psychiatry, Depression Research Unit, University of Pennsylvania Medical Center. Presented at the 154th Annual Meeting, American Psychiatric Association, New Orleans, LA, May 6,

7 Amsterdam and Brunswick References 1. Robins LN, Regier DA. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York: The Free Press, Simpson SG, Folstein SE, Meyers DA, McMahon FJ, Brusco DM, DePauo JR Jr Bipolar II: the most common bipolar phenotype. Am J Psychiatry 1993; 150: Goodwin FK, Ghaemi SN. Understanding manic-depressive illness. Arch Gen Psychiatry 1998; 55: Goodwin FK, Jamison KR. Manic Depressive Illness. New York: Oxford University Press, Weissman MM, Myers JK. Affective disorders in a US urban community: the use of Research Diagnostic Criteria in an epidemiological survey. Arch Gen Psychiatry 1978; 35: Hantouche EG, Akiskal HS, Lancrenon S et al. Systematic clinical methodology for validating bipolar-ii disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 1998; 50: Benazzi F. Bipolar II disorder is common among depressed outpatients. Psychiat Clin Neurosci 1999; 53: Benazzi F. Prevalence ofbipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997; 43: Dunner DL, Fleiss JL, Fieve RR. The course of development of mania in patients with recurrent depression. Am J Psychiatry 1976; 133: Akiskal HS, Maser JD, Zeller PJ et al. Switching from "unipolar" to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995; 52: Ayuso-Gutierrez JL, Ramos-Brieva JA. The course of manic-depressive illness: a comparative study of bipolar 1 and bipolar II patients. J Affect Disord 1982; 4: Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS. Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry 1995; 152: Winokur G, Coryell W, Keller M, Endicott J, Akiskal H. A prospective follow-up of patients with bipolar and primary unipolar affective disorder. Arch Gen Psychiatry 1993; 50: Cassano GB, Dell'Osso L, Frank E et al.. The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assessment methodology. J Affect Disord 1999; 54: Akiskal H. The spectrum of bipolar disorder beyond DSM. J Clin Psychopharmacol 1996; 16 (Suppl. 1): 4S- 14S. 16. Kupfer DJ, Carpenter LL, Frank E. Is bipolar II a unique disorder? Compr Psychiatry 1988; 29: O'Connell RA, Mayo JA, Flatow L, Cuthbertson B, O'Brien BE. Outcome of bipolar disorder on long-term treatment with lithium. Br J Psychiatry 1991; 159: Endicott J, Nee J, Andreasen N, Clayton P, Keller M, Coryell W. Bipolar II: combine or keep separate? J Affect Disord 1985; 8: Dunner DL. Sub-types of bipolar affective disorder with particular regard to bipolar II. Psychiatry Dev 1983; 1: Akiskal HS, Cassano GB, Musetti L, Perugi G, Tundo A, Mignani V. Psychopathology, temperament, and past course in primary major depressions. 1. Review of evidence for a bipolar spectrum. Psychopathology 1989; 22: Dunner DL. Bipolar disorders in DSM-IV: impact of inclusion of rapid cycling as a course modifier. Neuropsychopharmacology 1998; 19: Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine in prevention of affective episodes: a comparison in recurrent affective illness. Arch Gen Psychiatry 1973; 29: Prien RF, Kupfer DJ, Mansky PA et al.. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Arch Gen Psychiatry 1984; 41: Wehr TA, Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry 1979; 36: Sachs GS, Lafer B, Stoll AL et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry 1994; 55: Bottlender R, Rudolf D, Strauss A, Moller HJ. Moodstabilizers reduce the risk of developing antidepressantinduced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord 2001; 63: Boerlin HL, Gitlin M, Zoellner LA, Hammen CL. Bipolar depression and antidepressant-induced mania: a naturalistic study. J Clin Psychiatry 1998; 59: Faedda GL, Tondo L, Baldessarini RJ, Suppes T, Tohen M. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50: Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987; 144: Cohn JB, Collins G, Ashbrook E, Wernicke JF. A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 1989; 4: Howland RH. Induction of mania with serotonin reuptake inhibitors. J Clin Psychopharmacol 1996; 16: Kupfer DJ, Carpenter LL, Frank E. Possible role of antidepressants in precipitating mania and hypomania in recurrent depression. Am J Psychiatry 1988; 145: Saletu B, Schjerve M, Grunberger J, Schanda H, Arnold OH. Fluvoxamine - a new serotonin re-uptake inhibitor: first clinical and psychometric experiences in depressed patients. J Neural Transm 1977; 41: Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986; 32: Simpson SG, DePaulo JR. Fluoxetine treatment ofbipolar II depression. J Clin Psychopharmacol 1991; II: Maj M. Selection of the initial drug(s) in the treatment of bipolar disorder, depressed phase. Mod Probl Pharmacopsychiatry 1997; 25: Peet M. Induction of mania with serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994; 164: Amsterdam JD, Garcia-Espana F, Fawcett J et al. Efficacy and safety of fluoxetine in bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18: Benazzi F. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord 1997; 46: Montgomery SA, Schatzberg AF, Guelfi JD et al. Pharmacotherapy of depression and mixed states in bipolar disorder. J Affect Disord 2000; 59: S39-S

8 Antidepressant monotherapy for bipolar type II major depression 41. American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 1994; 151 (Suppl. 1): Fieve RR, Kumbaraci T, Dunner DL. Lithium prophylaxis of depression in bipolar I, bipolar II, and unipolar patients. Am J Psychiatry 1976; 133: Quitkin FM, Kane JM, Rifkin A et al. Lithium and imipramine in the prophylaxis of unipolar and bipolar II depression: a prospective, placebo-controlled comparison. Psychopharm Bull 1981; 17: Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin FK. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord 1999; 52: Treatment of bipolar disorder. The Expert Consensus Panel for Bipolar Disorder. J Clin Psychiatry 1996; 57 (Suppl. 12A): Yatham LN, Kusumakar V, Parikh SV et al. Bipolar depression: treatment options. Can J Psychiatry 1997; 42 (Suppl. 2): 87S-9IS. 47. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. Medication Treatment of Bipolar Disorder Postgraduate Medicine Special Report, April Keck PE Jr, McElroy SL. Outcome in the pharmacologic treatment of bipolar disorder. J Clin Psychopharmacol 1996; 16 (Suppl. 1): I5S-23S. 49. Sharma V, Mazmanian DS, Persad E, Kueneman KM. Treatment of bipolar depression: a survey of Canadian psychiatrists. Can J Psychiatry 1997; 42: Dantzler A, Osser DN. Algorithms for the pharmacotherapy of acute depression in patients with bipolar disorder. Psychiatry Ann 1999; 29: Amsterdam JD. Efficacy and safety of venlafaxine in bipolar type-ii major depressive episode. J Clin Psychopharmacol 1998; 18: Amsterdam JD, Hooper M, Amchin J. Efficacy and safety of once vs. twice daily venlafaxine in patients with major depression. J Clin Psychiatry 1998; 59: Roy-Byrne P, Post RM, Uhde TW, Porcu T, Davis D. The longitudinal course of affective illness: life chart data from research patients at the NIMH. Acta Psychiatry Scand 1985; 71 (Suppl. 317): Coryell W, Endicott J, Kelly M. Rapid cycling altective disorder: demographics, diagnosis, family history, and course. Arch Gen Psychiatry 1992; 49: Bauer MS, Caiabrese J, Dunner DJ et al. Multisite data reanalysis of the validity of rapid cycling as a course for bipolar disorder in DSM IV. Am J Psychiatry 1994; 151: McElroy SL, Keck PE Jr, Pope HG Jr, Hudson Jl, Faeddam GL, Swann AC. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry 1992; 149: Wehr TA, Sack D, Rosenthal N, Cowdry RmW. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry 1988; 145: Amsterdam JD, Garcia-Espana F. Venlafaxine monotherapy in women with bipolar 11 depression. J Affec Disord 2000; 59: Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152: Himmelhoch JM, Thase ME, Mallinger AG et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991; 148: Amsterdam JD. tlse of high dose tranylcypromine in resistant depression. In: Amsterdam J ed. Refractory Depression. New York: Raven Press Ltd, 1991: Vieta E, Gasto C, Otero A, Nieto E, Vallejo J. Differential features between bipolar I and bipolar II disorder. Compr Psychiatry 1997; 38:

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