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Advances in the pharmacologic treatment of bipolar depression
Advances in the Pharmacologic Treatment of Bipolar Depression Paul E. Keck, Jr., Erik B. Nelson, and Susan L. McElroy The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment. Biol Psychiatry 2003;53:671– 679 © 2003 Society of Biological Psychiatry Key Words: Bipolar disorder, depression, antidepressants, mood stabilizers, antipsychotic
Introduction
T
he treatment of bipolar depression is remarkably understudied, both in absolute terms and in comparison with the treatment of acute bipolar mania (Ghaemi et al 2001; Grunze et al 2000; Sachs et al 2000a). The paucity of research in this phase of the illness is all the more remarkable considering that depressive symptoms and episodes often dominate the course of bipolar disorder and are associated not only with suffering but also with functional impairment, suicide and other causes of excess From the Division of Psychopharmacology Research, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio. Address reprint requests to Paul E. Keck, Jr., M.D., Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670559, Cincinnati OH 45267-0559. Received May 31, 2002; revised September 9, 2002; accepted September 11, 2002.
© 2003 Society of Biological Psychiatry
mortality (Angst and Sellaro 2000; Gladstone et al 2001; Hiroeh et al 2001; Lopez et al 2001; Nierenberg et al 2001). Previously, in an environment of sparse data, treatment guidelines for bipolar disorder tended to rely on expert consensus (Frances et al 1998; Sachs et al 2000a) and left many important practical clinical questions unanswered. For example, debate continues regarding whether bipolar depression has reliable phenomenologic differences from unipolar depression and what the relationship is between psychotic and bipolar depression (Mitchell et al 2001; Parker et al 2000; Roth 2001). The relative risk of antidepressant-associated switch into mania or rapid cycling compared with mania occurring as part of the natural course of illness, and whether or how well mood stabilizers reduce these risks is also a matter of controversy (Bottlender et al 2001; Henry et al 2001; Preda et al 2001; Post et al 2001). Some guidelines recommend avoiding antidepressants altogether, or restricting their use to brief intervals, despite limited data regarding the efficacy of lithium and other mood stabilizers in the treatment of acute bipolar depression (Grunze et al 2000; Sachs et al 2000b). In contrast, Thase and Sachs (2000) have observed that there are no compelling data to suggest that antidepressants cannot be used alone (without a mood stabilizer) in the treatment of bipolar II depression. Finally, a number of new candidate mood-stabilizing agents have emerged, but most have been studied thus far only in the treatment of acute bipolar mania. In this article we review the most recent data from clinical trials regarding the acute treatment and prevention of bipolar depression conducted during the past 5 years. These trials signal the emergence of a new era of research in bipolar depression.
Acute Bipolar Depression Six randomized controlled trials of pharmacologic agents in the treatment of acute bipolar depression have been recently reported (Calabrese et al 1999; Frye et al 2000; Nemeroff et al 2001; Silverstone 2001; Tohen and Baker, unpublished data; Young et al 2000). The results of these studies are summarized in Table 1. Two trials examined the efficacy of lamotrigine monotherapy (Calabrese et al 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)01741-9
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Table 1. New Randomized Controlled Trials of Pharmacologic Therapy for Acute Bipolar Depression Study Calabrese et al 1999 Frye et al 2000 Young et al 2000
Nemeroff et al 2001
Silverstone 2001 Tohen et al 2002
Agents
Results
Lamotrigine 50 mg/day, lamotrigine 200 mg/day, placebo Lamotrigine mean 274 mg/day, gabapentin mean 3987 mg/day, placebo Paroxetine mean 36 mg/day versus lithium mean .8 mmol/L or valproate mean 510 mmol/L, adjunct to lithium or valproate Paroxetine mean 33 mg/day, imipramine mean 167 mg/day, placebo adjunct to lithium
Moclobemide, imipramine alone or adjunct to mood stabilizer Olanzapine mean 9 mg/day, olanzapine-fluoxetine combination (olanzapine mean 7 mg/day, fluoxetine mean 38 mg/day), placebo
Lamotrigine 50 mg and 200 mg/day greater than placebo on MADRS, CGI Lamotrigine greater than placebo on CGI-BP, gabapentin same as placebo on CGI-BP Paroxetine plus lithium or valproate same as lithium plus valproate on HDRS Lithium (⬎ .8 mmol/L): paroxetine same as imipramine and placebo on HDRS; lithium (ⱕ .8 mmol/L): paroxetine greater than placebo; imipramine greater than placebo and on HDRS Moclobemide same as imipramine Olanzapine-fluoxetine combination ⬎ olanzapine ⬎ placebo on MADRS, weeks 4 – 8; olanzapinefluoxetine combination same as olanzapine ⬎ placebo on MADRS weeks 1–3
CGI, Clinical Global Impression Scale; CGI-BP, Clinical Global Improvement Scale for Bipolar Disorder; MADRS, Montgomery-Asberg Depression Rating Scale; HDRS, Hamilton Depression Rating Scale.
1999; Frye et al 2000). In the first study, Calabrese et al (1999) randomly assigned 195 patients with bipolar I depression to receive lamotrigine at 50 mg/day, lamotrigine at 200 mg/day, or placebo for 7 weeks. Both lamotrigine treatment groups displayed significantly greater reductions in depressive symptoms on Montgomery–Asberg Depression Rating Scale (MADRS) total scores from baseline to end point than did the placebo group. There were no significant differences in efficacy between the two lamotrigine groups, although a trend toward greater improvement was suggested for the 200mg/day group. Because of the slow titration required for lamotrigine, the 200-mg/day group did not reach that dose until the fourth week of the study. Thus greater differences between the two dosage groups might have been evident if the study duration had been longer. Importantly, there were no significant differences in switch rates among the three treatment groups: Placebo 5%, lamotrigine 50 mg/ day 3%, and lamotrigine 200 mg/day 8% (Table 2). Adverse events and other safety assessments were similar among the three groups, except for a higher incidence of headache in the lamotrigine groups. In the second lamotrigine acute treatment trial, Frye et al (2000) randomly assigned patients with treatmentrefractory bipolar disorder (presenting in various mood states, including mania, hypomania, depression, and rapid cycling) to receive lamotrigine (mean dose 274 mg/day), gabapentin (mean dose 3987 mg/day), or placebo for 6 weeks in a series of crossover trials. Patients receiving lamotrigine displayed significant reductions in depressive symptoms as measured by the Clinical Global Impression Scale-Bipolar Disorder (CGI-BP) relative to patients receiving placebo. The design of this trial did not allow
examination of possible differences in switch rates. Taken together, the results of these two trials indicate that monotherapy with lamotrigine at 50 to 300 mg/day was efficacious and generally well tolerated in the treatment of acute bipolar depression. Two randomized controlled trials examined paroxetine added to mood stabilizers for acute bipolar depression (Nemeroff et al 2001; Young et al 2000). Young et al (2000) compared the efficacy of paroxetine (mean dose 36
Table 2. Switch Rates into Mania or Hypomania in Acute Treatment Trials of Bipolar Depression Study
Trial Duration
Calabrese et al 1999
7 wks
Frye et al 2000
6 wks
Young et al 2000
6 wks
Nemeroff et al 2001
Silverstone et al 2001 Tohen et al 2002
10 wks
8 wks 8 wks
Agents LTG 50 mg/d LTG 200 mg/d Placebo LTG GBP Placebo PAR Li or VPA Adjunct to Li or VPA Low Li: PAR High Li: PAR Low Li: IMI High Li: IMI MCL IMI OLZ OFC Placebo
Switch Rates 3% 8% 5% (NS) ND
0% 7% (NS) 0% 0% 11% 6% (NS) 4% 11% (NS) 6% 6% 7% (NS)
LTG, lamotrigine; NS, differences not statistically significant; GBP, gabapentin; PAR, paroxetine; Li, lithium; VPA, valproate; IMI, imipramine; MCL, moclobemide; OLZ, olanzapine; OFC, olanzapine-fluoxetine combination.
Pharmacologic Treatment of Bipolar Depression
mg/day) with a second mood stabilizer (lithium or divalproex) in a 6-week trial in 27 outpatients with bipolar disorder (type I n ⫽ 11, type II n ⫽ 16) who had a depressive episode despite treatment with divalproex (mean dose 1200 mg/day; mean serum concentration 570 mmol/L) or lithium (mean dose 1200 mg/day; mean serum concentration .8 mmol/L) for at least 3 months. In the combination mood stabilizer group, patients already receiving lithium received divalproex (mean dose 1200 mg/day; mean serum concentration 510 mmol/L), whereas patients already receiving divalproex received lithium (mean dose 1300 mg/day; mean serum concentration .9 mmol/L). Both groups displayed significant reductions in depressive symptoms on Hamilton Depression Rating Scale (HDRS) total scores from baseline to end point, but there were no significant differences in efficacy between groups. More patients randomly assigned to the combination mood stabilizer group (n ⫽ 5) than to the paroxetine group (n ⫽ 1) failed to complete the trial. One patient in the combination mood stabilizer group switched into a mixed episode; there were no switches in the paroxetine group (Table 2). Because of the small sample size and the limited duration of the trial, no definitive statements can be made about the relative efficacies of the different strategies or differences in switch rates. In addition, the divalproex serum concentrations were relatively low. The second randomized, placebo-controlled study compared paroxetine with imipramine in a 10-week trial involving 117 outpatients with bipolar I depression despite treatment with therapeutic dosages of lithium or combinations of lithium with divalproex or carbamazepine (Nemeroff et al 2001). Paroxetine (mean dose 33 mg/day), imipramine (mean dose 167 mg/day), or placebo was added to lithium or lithium and other mood stabilizer combinations. Patients were stratified according to trough serum lithium concentrations obtained at the initial screening visit into two groups: high therapeutic (⬎.8 mEq/L) and low therapeutic (ⱕ.8 mEq/L). In the high therapeutic lithium group, there were no significant differences in efficacy among patients receiving paroxetine, imipramine, or placebo, as measured by changes in the HDRS total scores from baseline to end point; however, in the low therapeutic lithium group, both antidepressants were superior to placebo. Paroxetine was better tolerated than imipramine, and no patients in the paroxetine group switched during the study. In contrast, the incidences of mania among the imipramine-treated patients were 11% in the low therapeutic lithium group and 6% in the high therapeutic lithium group (Table 2). The results of this study suggest that paroxetine and imipramine conferred significant antidepressant efficacy in patients with low therapeutic lithium concentrations, but the antidepressant effects of lithium itself were more pronounced in the high
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therapeutic range. Of note, in an open-label trial Fagiolini et al (2001) reported relatively common adverse events consistent with symptoms of serotonin syndrome in four of 17 patients (29%) receiving paroxetine in addition to lithium in an open-label trial for bipolar depression. Silverstone (2001) compared the reversible monoamine oxidase A inhibitor moclobemide with imipramine, either as monotherapy or added to ongoing mood stabilizers, in an 8-week trial of 156 patients (75% outpatients) with bipolar I depression. In the moclobemide group 46% of patients were receiving lithium (two in combination with carbamazepine). In the imipramine group 49% were receiving lithium (five in combination with carbamazepine and one in combination with valproate). Both treatment groups displayed significant reductions in depressive symptoms, as measured by HDRS and MADRS total scores, but there were no significant differences between the groups. More patients switched into mania in the imipramine group (11%) than in the moclobemide group (4%), and they switched earlier in treatment, although these differences were not significant (Table 2). The authors did not report whether switches occurred more commonly among patients not receiving mood stabilizers. Similarly, mean doses of moclobemide and imipramine were not reported. The most recent randomized, controlled pharmacotherapy trial in bipolar depression compared olanzapine (mean dose 9 mg/day), the combination of olanzapine (mean dose 7 mg/day) and fluoxetine (mean dose 38 mg/day), and placebo in an 8-week trial among 833 patients with bipolar depression (Tohen and Baker, unpublished data). Both active treatment groups displayed significantly greater reductions in depressive symptoms, as assessed by baseline to end point changes in MADRS total scores, than did the placebo group, beginning at week 1. In addition, the olanzapine and fluoxetine group displayed significantly greater reductions in MADRS total scores than seen in the olanzapine group at weeks 4, 6, and 8. There were no significant differences in switch rates among the groups: olanzapine 6%, olanzapine and fluoxetine 6%, and placebo 7% (Table 2). Significantly more patients in the active treatment groups than in the placebo group had weight gain, appetite increase, dry mouth, and asthenia. Notably, this was the first randomized, controlled trial to demonstrate the efficacy of an atypical antipsychotic agent for monotherapy in acute bipolar depression. In addition, the olanzapine and fluoxetine results are consistent with the marked antidepressant response reported by Shelton et al (2001) for patients with treatment-refractory nonpsychotic unipolar depression. Interpretation of the results of this study should be made with the caveat that although these results were presented at a scientific meeting, they have not yet been subjected to peer review.
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Table 3. New Randomized Controlled Trials of Depression Relapse Prevention in Bipolar Disorder Study Calabrese et al 2000 Bowden et al, in press Bowden et al, unpublished data Tohen et al, unpublished data Tohen et al, unpublished data
Agents
Duration
Results
Lamotrigine mean 288 mg/day, placebo, rapid cycling patients Lamotrigine, lithium, placebo, recently manic patients Lamotrigine, lithium, placebo, recently depressed patients Olanzapine, divalproex
6 months
Lamotrigine same as placebo in time to need for additional pharmacotherapy Lamotrigine greater than placebo in time to intervention for depression Lamotrigine greater than placebo in time to intervention for depression Olanzapine same as divalproex in relapse rates
Olanzapine plus lithium or divalproex, lithium or divalproex
A number of impressions emerge from the studies reviewed here. First, lamotrigine was efficacious and generally well tolerated as monotherapy in acute bipolar depression, with rash and headache the most troublesome side effects. Second, lithium monotherapy at the higher end of its therapeutic range exerted significant antidepressant activity. Paroxetine in combination with mood stabilizers exerted significant antidepressant activity in bipolar depression, with generally good tolerability and a very low switch rate in short-term trials. In contrast, relatively high switch rates were reported with tricyclic antidepressants, a finding consistent with earlier studies (Thase and Sachs 2000). Finally, olanzapine and the combination of olanzapine and fluoxetine both demonstrated significant antidepressant activity, with slighter greater efficacy for the combination.
Relapse Prevention of Bipolar Depression Five recent randomized, controlled trials have addressed the prevention of bipolar depressive episodes with lamotrigine (Bowden et al, in press; Calabrese et al 2000) or olanzapine (Tohen et al, unpublished data). The results of these studies are summarized in Table 3. Among the lamotrigine studies, Calabrese et al (2000) conducted a placebo-controlled, 6-month relapse prevention trial of lamotrigine (mean dose 288 mg/day) in 182 patients with rapid cycling bipolar (I and II) disorder. Patients were first stabilized with lamotrigine at 100 to 300 mg/day, and other psychotropic agents were tapered and discontinued during a 4- to 8-week preliminary screening phase. Of 324 patients treated with lamotrigine during the screening period, 182 met randomization criteria of a minimum dose of lamotrigine of 100 mg/day with HDRS total score no greater than 14 and Mania Rating Scale derived from the Schedule for Affective Disorders and Schizophrenia– Change total score of 12 or less during a 2-week period. There was no significant difference on the primary outcome measure, time until need for additional pharmaco-
18 months 18 months 47 weeks 18 months
Olanzapine plus lithium or divalproex same as lithium or divalproex for depressive relapse
therapy (for recurrent mania or depressive symptoms), between the placebo and lamotrigine treatment groups. Retention in the study was significantly greater for the lamotrigine-treated group. Survival analysis was also performed for patients with bipolar I and bipolar II disorder. In this post-hoc analysis, no significant treatment differences were observed for bipolar I patients; however, in the bipolar II group there was a strong trend (p ⫽ .07) favoring lamotrigine in time until need for additional pharmacotherapy and a significant difference for survival in the study. Moreover, significantly more patients receiving lamotrigine (41%) than patients receiving placebo (26%) remained stable during the 6-month trial. Overall, most patients (80%) required additional pharmacotherapy for the emergence of depressive symptoms. Lamotrigine was well tolerated in the randomized phase of the trial, with no significant differences in adverse events considered reasonably related to the study drug between lamotrigine and placebo. Treatment-related rash occurred in 25 patients (8%) during the open-label phase. Mean body weight was unchanged from screening to the end of the study for patients receiving lamotrigine monotherapy. The results of two 18-month, placebo-controlled maintenance treatment trials comparing lamotrigine with lithium were recently reported (Bowden et al, in press). In the first of these two studies, patients with bipolar I disorder were required to have met DSM-IV criteria (American Psychiatric Association 1994) for a manic or hypomanic episode at time of screening or within 60 days of screening and to have had at least one additional manic or hypomanic and one depressive episode within 3 years of enrollment (Bowden et al, in press). After a screening phase, 349 patients entered an 8- to 16-week open-label phase during which lamotrigine (100 –200 mg/day) was initiated as adjunctive therapy or monotherapy and other psychotropic agents were gradually discontinued. Beginning at week 8 of the open-label phase of the study, patients who tolerated a stable dose of lamotrigine and met the criterion for illness stability, defined as a Clinical
Pharmacologic Treatment of Bipolar Depression
Global Impression-Severity Scale (CGI-S) score of 3 or less maintained for 4 weeks or longer, were eligible for the randomized portion of the trial. Of 349 patients in the open-label phase, 175 met the stabilization criterion and were randomly assigned to receive lamotrigine (100 – 400 mg/day), lithium (titrated to serum concentrations of .8 –1.1 mEq/L), or placebo for as long as 18 months. Approximately halfway through the trial, the lithium arm was closed to enhance enrollment in the primary treatment comparison of interest, lamotrigine versus placebo. Despite lower enrollment of lithium-treated patients, both lamotrigine and lithium were significantly superior to placebo with respect to the primary outcome measure, time to intervention for any mood episode. Similarly, lamotrigine was superior to placebo with respect to overall survival in the study. In the placebo group 16% completed the 18-month trial; figures were 31% in the lamotrigine group and 23% in the lithium group. Interesting differences between drugs emerged when the data were analyzed for type of mood episode necessitating intervention. Lamotrigine but not lithium was superior to placebo in prolonging time before a depressive episode; lithium but not lamotrigine was superior to placebo in prolonging time before a manic, hypomanic, or mixed episode. A trend favored lithium over lamotrigine with respect to this latter outcome as well. As in the acute treatment trial (Calabrese et al 1999), headache occurred significantly more commonly among lamotrigine-treated patients. One patient had a moderately severe rash during open-label treatment; there were no serious rashes during the randomized phase of the study. There was no significant difference among the three treatment groups in the proportion of patients discontinuing the study because of manic episodes. The second 18-month placebo-controlled maintenance trial comparing lamotrigine and lithium was similar in design except that patients were required to have recently experienced an episode of bipolar depression (within 60 days) rather than mania and at least one prior mood episode within the past three years (Bowden et al, unpublished data). Patients (n ⫽ 966) again entered an 8 –16 week open-label phase during which lamotrigine was titrated to 100 to 200 mg/day and concomitant psychotropic agents were tapered and discontinued. At the end of the preliminary open-label treatment phase, 463 patients met stabilization criteria of CGI-S score of 3 or less for at least 4 consecutive weeks, at least 1 week of lamotrigine monotherapy, and appropriate washout of previous treatment. These patients were then randomly assigned to receive lamotrigine at 50 mg/day, 200 mg/day, or 400 mg/day; lithium titrated to .8 to 1.1 mEq/L; or placebo for as long as 18 months (an a priori decision was made to combine the lamotrigine 200- and 400-mg/day groups for
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primary analysis of efficacy). Both lamotrigine and lithium were again significantly superior to placebo in time to intervention for a mood episode, the primary outcome measure. Similarly, lamotrigine but not lithium was superior to placebo with respect to time until intervention for a depressive episode, whereas lithium but not lamotrigine was superior to placebo with respect to time to intervention for a manic episode. Headache was again the most common side effect significantly associated with lamotrigine. Significantly more patients receiving lamotrigine (7%) than patients receiving lithium (4%) or placebo (2%) during the randomized phase of the study had rashes. There was no significant weight gain among the patients receiving lamotrigine. Interpretation of the results of the latter 18-month trials should be made with the caveat that although it has been presented at scientific meetings, it has not yet been subjected to peer review. The results of these three maintenance trials indicate that lamotrigine had significantly greater efficacy in preventing depressive (but not manic) relapse than placebo in patients with bipolar disorder. Lamotrigine was generally well tolerated, with headache the most common side effect. Of nearly 1200 patients who received lamotrigine in these controlled trials, 9% had benign rash (morbilliform or exanthematic eruptions) compared with 8% of the 1056 patients who received placebo. No serious rashes were observed during the randomized, controlled trial phases of these studies. Among nearly 2000 patients receiving lamotrigine in the open-label phases of the trials, the incidence of rash was 13% (Calabrese 2002). Two cases of serious lamotrigine-associated rash (requiring hospitalization) and one case of Stevens–Johnson syndrome not requiring hospitalization were reported. None of these cases were fatal, and all patients recovered. Data from the German Registry for Serious Cutaneous Reactions cited by Calabrese (2002) revealed that the incidence of serious rash with lamotrigine used at recommended titration rates was .12%, and that of Stevens–Johnson syndrome was .05%. Two studies assessed the efficacy of olanzapine in prevention of relapse in patients with bipolar disorder (Tohen et al, unpublished data). In the first study 109 patients responding to olanzapine (mean modal dose 16 mg/day) or divalproex (mean modal dose 1585 mg/day) in a 3-week randomized, controlled trial (Tohen et al 2002a) who elected to continue the blinded study medication were followed for 44 weeks (Tohen et al, unpublished data). The median times to manic relapse were 270 days for the olanzapine group and 74 days for the divalproex group (p ⫽ .33). There were no significant differences in relapse rates between the olanzapine (45%) and divalproex (52%) groups. In a mixed model repeated measures analysis, mean improvement on the HDRS favored olanzapine over
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divalproex (p ⫽ .06). Mean baseline to end point weight gain was significantly greater with olanzapine (3.4 kg) than with divalproex (1.7 kg). The second study consisted of 94 patients who were in syndromic remission after an acute 6-week treatment trial comparing adjunctive olanzapine with placebo in patients partially responding to lithium or divalproex (Tohen et al 2002b). Patients who elected to be randomly assigned again to receive olanzapine in combination with lithium or divalproex or to placebo in combination with lithium or divalproex were then followed up for 18 months (Tohen et al, unpublished data). Patients receiving olanzapine in combination with lithium or divalproex had a significantly longer time to recurrence of mania than did patients receiving placebo in combination with lithium or divalproex. Rates of manic recurrence were also significantly lower in the olanzapine combination therapy group (15%) than in the monotherapy group (35%). Time to recurrence of depressive episodes was not significantly different between the two treatment groups, but there was a trend favoring the olanzapine combination group (155 days) over the monotherapy group (27 days, p ⫽ .07). Significantly more patients in the combination therapy group (31%) than in the monotherapy group (10%) completed the 18-month trial. Weight gain occurred significantly more commonly in the combination group and insomnia occurred more commonly in the monotherapy group. Interpretation of the results of these two olanzapine maintenance studies should be made with the caveat that although they were presented at scientific meetings, they have not yet been subjected to peer review. The results of these relapse prevention studies indicate that lamotrigine had significant efficacy in preventing bipolar depressive episodes, that olanzapine was at least comparable to divalproex in relapse prevention, and that the combination of olanzapine and lithium or divalproex was superior to monotherapy with lithium or divalproex. Perhaps the most striking observation across trials was the high proportion of patients with breakthrough symptoms during monotherapy with any single agent and the relative advantage of combination therapy in this regard.
The Problem of Switching Moller and Grunze (2000) summarized the recommendations of a number of treatment guidelines for bipolar disorder in both the United States and Europe as suggesting that antidepressants be avoided in mild to moderate bipolar depression (relying on mood stabilizers alone) and that when antidepressants were added to mood stabilizers for severe bipolar depression they be withdrawn as soon as possible. These conservative recommendations were based on limited data available during the 1990s regarding the
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relative risks and benefits of withholding antidepressant treatment compared with intervention with antidepressant agents (in combination with mood stabilizers in bipolar I depression) and the possible risk of switching and induction of cycling. A number of recent naturalistic studies, as well as the acute and maintenance randomized, controlled trials summarized here, provide much needed data to inform this clinical dilemma. Reported switch rates among patients with bipolar depression treated with antidepressants have ranged widely, from 10% to 70% (Moller and Grunze 2000; Sachs et al 2000b). These disparate estimates reflect widely diverse circumstances, including data derived from naturalistic compared with randomized, controlled trials and data from patients receiving various mood stabilizers and combinations or antidepressants alone. Justification of antidepressant use with mood stabilizers for bipolar depression would be enhanced with additional knowledge about the degree to which mood stabilizers decrease or protect against the risk of switch and about the risk of depressive relapse associated with antidepressant discontinuation in patients with acute response to such an intervention. A number of recent studies have attempted to clarify the switch rates and the degree to which mood stabilizers reduce this risk in patients with bipolar depression. Bottlender et al (2001) reviewed the medical records of 158 inpatients with bipolar I depression to examine the incidence of mania and hypomania in relation to pharmacotherapy. The overall switch rate was 25%. Among patients switching, 80% received tricyclic antidepressants, a significantly higher proportion than those not switching who received tricyclic antidepressants (51%). Overall switch rates were 34% for patients receiving tricyclic antidepressants, 12% for those receiving serotonin reuptake inhibitors, 8% for those receiving monoamine oxidase inhibitors, and 14% for those receiving other agents. The protective effects of mood stabilizers were most apparent for patients receiving tricyclic antidepressants, because significantly more patients receiving tricyclic antidepressants but not receiving mood stabilizers (57%) switched compared with those taking tricyclic antidepressants and mood stabilizers (26%). In the overall group, the percentage of patients switching while receiving mood stabilizers was significantly lower (59%) than the percentage of patients switching without mood stabilizers (82%). These findings are consistent with earlier studies suggesting that coadministration of lithium reduces the risk of antidepressant-associated switching by approximately 50% (Boerlin et al 1998; Prien et al 1984; Rouillon et al 1992). Post et al (2001) reviewed switch data from an ongoing double-blind randomized, comparison trial in the Stanley
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Foundation Bipolar Network of bupropion, sertraline, and venlafaxine added to therapeutic doses of mood stabilizers for bipolar depression. Nonresponders to the initial antidepressant could be randomly reassigned to an alternative agent. Data were analyzed for switch rates for the 10-week acute treatment trial and for the 1-year maintenance phase (for responders in the 10-week trial). Thirteen of the 95 patients in the acute treatment trial (14%) switched into mania (n ⫽ 6, 6%) or hypomania (n ⫽ 7, 8%). Among the 48 maintenance trials in acute responders, 16 patients (33%) switched, six of them (13%) into mania and 10 of them (20%) into hypomania. There were no significant differences in switch rates among the three antidepressants, as ascertained by data safety monitoring because the study is still blinded and ongoing. Because of the lack of a placebo control, it is difficult to compare these rates with those associated with spontaneous rates from the illness, but the switch rates into mania were lower than anticipated. Henry et al (2001) compared patients who switched with those who did not in a naturalistic study of 44 patients treated with antidepressants for acute bipolar depression in a 6-week trial. Overall, 12 patients (27%) switched, seven of them (16%) into mania and of them (11%) into hypomania. Mood switches were significantly less frequent among patients receiving lithium (15%) than among those not receiving lithium (44%). The number of previous manic episodes was not associated with a risk of switching, although a high score on the hyperthymic component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching. The results of these studies suggest that mood stabilizers significantly reduce but do not eliminate the risk of switching for patients with bipolar depression treated concurrently with antidepressants.
Antidepressant Discontinuation and Relapse Although limiting antidepressant exposure may reduce the risk of switching, discontinuing antidepressants during maintenance treatment may also increase the risk of depressive relapse. Altshuler et al (in press) examined the risk of depressive relapse in two studies. The first study retrospectively compared the relapse rate of 25 patients who discontinued antidepressants (in conjunction with mood stabilizers) with that of 19 patients who continued to receive antidepressants (with mood stabilizers) after initial improvement (Altshuler et al 2001). Termination of antidepressants was significantly associated with an increased rate of depressive relapse (odds ratio 3.13, p ⫽ .007), but antidepressant continuation was not significantly associated with an increased risk of mania (odds ratio 1.92, p ⫽ .35).
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In a follow-up prospective study (Altshuler et al, in press) from the Stanley Foundation Bipolar Network, 84 patients successfully treated with sertraline, venlafaxine, or bupropion in addition to a mood stabilizer for acute bipolar depression were followed up for 1 year. Patients who discontinued antidepressants within the first 6 months after successful treatment had a significantly shorter period of euthymia before depressive relapse than did those who continued treatment with an antidepressant. At 1 year after an initial antidepressant response, 71% of the antidepressant discontinuation group had experienced relapse, compared with 41% of the continuation group. Fifteen (18%) of the 84 patients experienced a manic relapse during the 1-year follow-up, but only six were receiving antidepressants at the time of manic relapse. Thus the risk of depressive relapse was significantly associated with antidepressant discontinuation soon after remission, but the risk of manic relapse was not significantly associated with continued use of antidepressants in conjunction with mood stabilizers. The results of these two studies suggest that the use of antidepressants in combination with mood stabilizers to prevent recurrence of bipolar depression may be indicated and necessary for many patients.
Conclusions A wealth of new data has emerged during the last 5 years regarding important aspects of the treatment of bipolar depression (American Psychiatric Association 2002). Coadministration of mood stabilizers appears to markedly reduce the risk of antidepressant-associated switching. This is good news, because many patients responding acutely to antidepressants for bipolar depression appear to require longer-term maintenance treatment with these agents to reduce the risk of depressive relapse. Two new agents with novel mechanisms of action, lamotrigine and olanzapine, have demonstrated efficacy in the acute and maintenance treatment of bipolar depression. The efficacy of olanzapine appears to be greatest when it is administered in combination with fluoxetine in acute treatment and in maintenance treatment with lithium or divalproex compared with olanzapine monotherapy. The findings reviewed from these studies suggest many more important avenues for further study. For example, the efficacy of other atypical antipsychotic agents in the acute and maintenance treatment of bipolar depression, alone or in combination with antidepressants, lithium, or divalproex, requires further study. The efficacy of lithium and lamotrigine in combination in preventing manic and depressive relapse needs to be studied. The relative protective effects (and possible dose or serum concentration relationships) against switching of lithium, divalproex, carbamazepine, and atypical antipsychotic agents coadministered
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with antidepressants remain to be clarified. The optimal duration of antidepressant maintenance treatment and possible predictors of switch versus depressive relapse also await further study.
Aspects of this work were presented at the conference, “Difficult-toTreat Depression,” held April 21–22, 2002 in San Francisco, California. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.
References Altshuler L, Kiriakos L, Calcagno J, Goodman R, Gitlin M, Frye M, et al (2001): The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: A retrospective chart review. J Clin Psychiatry 62:612–616. Altshuler L, Suppes T, Black D, Nolen WA, Keck PE, Frye MA, et al (in press): Impact of antidepressant discontinuation after acute remission from bipolar depression on rates of depressive relapse at one-year follow-up. Am J Psychiatry American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press. American Psychiatric Association (2002): Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 159(suppl):1–50. Angst J, Sellaro R (2000): Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 48:445–457. Boerlin J, Gitlin MJ, Zoellner LA, Hammen CL (1998): Bipolar depression and antidepressant-induced mania: A naturalistic study. J Clin Psychiatry 59:374 –379. Bottlender R, Rudolf D, Strauss A, Moller HJ (2001): Moodstabilizers reduce the risk of developing antidepressantinduced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord 63:79 – 83. Bowden CL, Calabrese JR, Sachs GS, Yatham LN, Asghar SA, Hompland M, et al (in press): A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. Calabrese JR (2002): Clinical relevance and management of bipolar disorders: Weighing benefits versus risks. Presentations in Focus, Medical Education Network. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd (1999): A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 60:79 –88. Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, et al (2000): A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 61:841–850. Fagiolini A, Buysse DJ, Frank E, Houck PR, Luther JF, Kupfer DJ (2001): Tolerability of combined treatment with lithium
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and paroxetine in patients with bipolar disorder and depression. J Clin Psychopharmacol 21:474 –478. Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL (1998): The Expert Consensus Guidelines for treating depression in bipolar disorder. J Clin Psychiatry 59(suppl 4):73–79. Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, et al (2000): A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 20:607–614. Ghaemi SN, Lenox MS, Baldessarini RJ (2001): Effectiveness and safety of long-term antidepressant treatment of bipolar disorder. J Clin Psychiatry 62:565–569. Gladstone GL, Mitchell PB, Parker G, Wilhelm K, Eyers K (2001): Indicators of suicide over 10 years in a specialist mood disorders unit sample. J Clin Psychiatry 62:945–951. Grunze H, Schlosser S, Walden J (2000): New perspectives in the acute treatment of bipolar depression. World J Biol Psychiatry 1:129 –136. Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M (2001): Antidepressant-induced mania in bipolar patients: Identification of risk factors. J Clin Psychiatry 62:249 –255. Hiroeh U, Appleby L, Mortensen PB, Dunn G (2001): Death by homicide, suicide, and other unnatural causes in people with mental illness: A population-based study. Lancet 358:2110 – 2112. Lopez P, Mosquera F, de Leon J, Gutierrez J, Ramirez F, Ganzalez-Pinto A (2001): Suicide attempts in bipolar patients. J Clin Psychiatry 62:963–966. Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS (2001): The clinical features of bipolar depression: A comparison with matched major depressive disorder patients. J Clin Psychiatry 62:212–216. Moller HJ, Grunze H (2000): Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants? Eur Arch Psychiatry Clin Neurosci 250:57–68. Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, et al (2001): Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 158:906 –912. Nierenberg AA, Gray SM, Grandin LD (2001): Mood disorders and suicide. J Clin Psychiatry 62(suppl 25):3–11. Parker F, Roy K, Wilhelm K, Mitchell P, Hadzi-Pavlovic D (2000): The nature of bipolar depression: Implications for the definition of melancholia. J Affect Disord 59:217–224. Post RM, Altshuler LL, Frye MA, Suppes T, Rush AJ, Keck PE, et al (2001): Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 3:259 –265. Preda A, MacLean RW, Mazure CM, Bowers MB (2001): Antidepressant-associated mania and psychosis in psychiatric admissions. J Clin Psychiatry 62:30 –33. Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, et al (1984): Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry 41:1096 –1104.
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Roth M (2001): Unitary or binary nature of classification of depressive illness and its implications for the scope of manic depressive disorder. J Affect Disord 64:1–18. Rouillon F, Lejoyeaux M, Filteau MJ (1992): Unwanted effects of long-term treatment. In: Montgomery SA, Rouillon F, eds. Long-term Treatment of Depression. New York, NY: Wiley, 81–111. Sachs GS, Koslow CL, Ghaemi SN (2000b): The treatment of bipolar depression. Bipolar Disord 2:256 –260. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP (2000a): The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad Med Spec No.:1–104. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, et al (2001): A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158:131–134. Silverstone T (2001): Moclobemide vs. imipramine in bipolar
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depression: A multicentre double-blind clinical trial. Acta Psychiatr Scand 104:104 –109. Thase ME, Sachs GS (2000): Bipolar depression: Pharmacotherapy and related therapeutic strategies. Biol Psychiatry 48:558 –572. Tohen M, Milton DR, Davis AR (2002a): Olanzapine versus divalproex for the treatment of acute mania. Am J Psychiatry. 154:1011–1017. Tohen M, Chengappa KN, Suppes T, Zarate CA, Calabrese JR, Bowden CL, et al (2002b): Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59:62–69. Young LT, Joffe RT, Robb JC, MacQueen GM, Marrior M, Patelis-Siotis I (2000): Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry 157:124 –127.
Introduction
T
he treatment of bipolar depression is remarkably understudied, both in absolute terms and in comparison with the treatment of acute bipolar mania (Ghaemi et al 2001; Grunze et al 2000; Sachs et al 2000a). The paucity of research in this phase of the illness is all the more remarkable considering that depressive symptoms and episodes often dominate the course of bipolar disorder and are associated not only with suffering but also with functional impairment, suicide and other causes of excess From the Division of Psychopharmacology Research, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio. Address reprint requests to Paul E. Keck, Jr., M.D., Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670559, Cincinnati OH 45267-0559. Received May 31, 2002; revised September 9, 2002; accepted September 11, 2002.
© 2003 Society of Biological Psychiatry
mortality (Angst and Sellaro 2000; Gladstone et al 2001; Hiroeh et al 2001; Lopez et al 2001; Nierenberg et al 2001). Previously, in an environment of sparse data, treatment guidelines for bipolar disorder tended to rely on expert consensus (Frances et al 1998; Sachs et al 2000a) and left many important practical clinical questions unanswered. For example, debate continues regarding whether bipolar depression has reliable phenomenologic differences from unipolar depression and what the relationship is between psychotic and bipolar depression (Mitchell et al 2001; Parker et al 2000; Roth 2001). The relative risk of antidepressant-associated switch into mania or rapid cycling compared with mania occurring as part of the natural course of illness, and whether or how well mood stabilizers reduce these risks is also a matter of controversy (Bottlender et al 2001; Henry et al 2001; Preda et al 2001; Post et al 2001). Some guidelines recommend avoiding antidepressants altogether, or restricting their use to brief intervals, despite limited data regarding the efficacy of lithium and other mood stabilizers in the treatment of acute bipolar depression (Grunze et al 2000; Sachs et al 2000b). In contrast, Thase and Sachs (2000) have observed that there are no compelling data to suggest that antidepressants cannot be used alone (without a mood stabilizer) in the treatment of bipolar II depression. Finally, a number of new candidate mood-stabilizing agents have emerged, but most have been studied thus far only in the treatment of acute bipolar mania. In this article we review the most recent data from clinical trials regarding the acute treatment and prevention of bipolar depression conducted during the past 5 years. These trials signal the emergence of a new era of research in bipolar depression.
Acute Bipolar Depression Six randomized controlled trials of pharmacologic agents in the treatment of acute bipolar depression have been recently reported (Calabrese et al 1999; Frye et al 2000; Nemeroff et al 2001; Silverstone 2001; Tohen and Baker, unpublished data; Young et al 2000). The results of these studies are summarized in Table 1. Two trials examined the efficacy of lamotrigine monotherapy (Calabrese et al 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)01741-9
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Table 1. New Randomized Controlled Trials of Pharmacologic Therapy for Acute Bipolar Depression Study Calabrese et al 1999 Frye et al 2000 Young et al 2000
Nemeroff et al 2001
Silverstone 2001 Tohen et al 2002
Agents
Results
Lamotrigine 50 mg/day, lamotrigine 200 mg/day, placebo Lamotrigine mean 274 mg/day, gabapentin mean 3987 mg/day, placebo Paroxetine mean 36 mg/day versus lithium mean .8 mmol/L or valproate mean 510 mmol/L, adjunct to lithium or valproate Paroxetine mean 33 mg/day, imipramine mean 167 mg/day, placebo adjunct to lithium
Moclobemide, imipramine alone or adjunct to mood stabilizer Olanzapine mean 9 mg/day, olanzapine-fluoxetine combination (olanzapine mean 7 mg/day, fluoxetine mean 38 mg/day), placebo
Lamotrigine 50 mg and 200 mg/day greater than placebo on MADRS, CGI Lamotrigine greater than placebo on CGI-BP, gabapentin same as placebo on CGI-BP Paroxetine plus lithium or valproate same as lithium plus valproate on HDRS Lithium (⬎ .8 mmol/L): paroxetine same as imipramine and placebo on HDRS; lithium (ⱕ .8 mmol/L): paroxetine greater than placebo; imipramine greater than placebo and on HDRS Moclobemide same as imipramine Olanzapine-fluoxetine combination ⬎ olanzapine ⬎ placebo on MADRS, weeks 4 – 8; olanzapinefluoxetine combination same as olanzapine ⬎ placebo on MADRS weeks 1–3
CGI, Clinical Global Impression Scale; CGI-BP, Clinical Global Improvement Scale for Bipolar Disorder; MADRS, Montgomery-Asberg Depression Rating Scale; HDRS, Hamilton Depression Rating Scale.
1999; Frye et al 2000). In the first study, Calabrese et al (1999) randomly assigned 195 patients with bipolar I depression to receive lamotrigine at 50 mg/day, lamotrigine at 200 mg/day, or placebo for 7 weeks. Both lamotrigine treatment groups displayed significantly greater reductions in depressive symptoms on Montgomery–Asberg Depression Rating Scale (MADRS) total scores from baseline to end point than did the placebo group. There were no significant differences in efficacy between the two lamotrigine groups, although a trend toward greater improvement was suggested for the 200mg/day group. Because of the slow titration required for lamotrigine, the 200-mg/day group did not reach that dose until the fourth week of the study. Thus greater differences between the two dosage groups might have been evident if the study duration had been longer. Importantly, there were no significant differences in switch rates among the three treatment groups: Placebo 5%, lamotrigine 50 mg/ day 3%, and lamotrigine 200 mg/day 8% (Table 2). Adverse events and other safety assessments were similar among the three groups, except for a higher incidence of headache in the lamotrigine groups. In the second lamotrigine acute treatment trial, Frye et al (2000) randomly assigned patients with treatmentrefractory bipolar disorder (presenting in various mood states, including mania, hypomania, depression, and rapid cycling) to receive lamotrigine (mean dose 274 mg/day), gabapentin (mean dose 3987 mg/day), or placebo for 6 weeks in a series of crossover trials. Patients receiving lamotrigine displayed significant reductions in depressive symptoms as measured by the Clinical Global Impression Scale-Bipolar Disorder (CGI-BP) relative to patients receiving placebo. The design of this trial did not allow
examination of possible differences in switch rates. Taken together, the results of these two trials indicate that monotherapy with lamotrigine at 50 to 300 mg/day was efficacious and generally well tolerated in the treatment of acute bipolar depression. Two randomized controlled trials examined paroxetine added to mood stabilizers for acute bipolar depression (Nemeroff et al 2001; Young et al 2000). Young et al (2000) compared the efficacy of paroxetine (mean dose 36
Table 2. Switch Rates into Mania or Hypomania in Acute Treatment Trials of Bipolar Depression Study
Trial Duration
Calabrese et al 1999
7 wks
Frye et al 2000
6 wks
Young et al 2000
6 wks
Nemeroff et al 2001
Silverstone et al 2001 Tohen et al 2002
10 wks
8 wks 8 wks
Agents LTG 50 mg/d LTG 200 mg/d Placebo LTG GBP Placebo PAR Li or VPA Adjunct to Li or VPA Low Li: PAR High Li: PAR Low Li: IMI High Li: IMI MCL IMI OLZ OFC Placebo
Switch Rates 3% 8% 5% (NS) ND
0% 7% (NS) 0% 0% 11% 6% (NS) 4% 11% (NS) 6% 6% 7% (NS)
LTG, lamotrigine; NS, differences not statistically significant; GBP, gabapentin; PAR, paroxetine; Li, lithium; VPA, valproate; IMI, imipramine; MCL, moclobemide; OLZ, olanzapine; OFC, olanzapine-fluoxetine combination.
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mg/day) with a second mood stabilizer (lithium or divalproex) in a 6-week trial in 27 outpatients with bipolar disorder (type I n ⫽ 11, type II n ⫽ 16) who had a depressive episode despite treatment with divalproex (mean dose 1200 mg/day; mean serum concentration 570 mmol/L) or lithium (mean dose 1200 mg/day; mean serum concentration .8 mmol/L) for at least 3 months. In the combination mood stabilizer group, patients already receiving lithium received divalproex (mean dose 1200 mg/day; mean serum concentration 510 mmol/L), whereas patients already receiving divalproex received lithium (mean dose 1300 mg/day; mean serum concentration .9 mmol/L). Both groups displayed significant reductions in depressive symptoms on Hamilton Depression Rating Scale (HDRS) total scores from baseline to end point, but there were no significant differences in efficacy between groups. More patients randomly assigned to the combination mood stabilizer group (n ⫽ 5) than to the paroxetine group (n ⫽ 1) failed to complete the trial. One patient in the combination mood stabilizer group switched into a mixed episode; there were no switches in the paroxetine group (Table 2). Because of the small sample size and the limited duration of the trial, no definitive statements can be made about the relative efficacies of the different strategies or differences in switch rates. In addition, the divalproex serum concentrations were relatively low. The second randomized, placebo-controlled study compared paroxetine with imipramine in a 10-week trial involving 117 outpatients with bipolar I depression despite treatment with therapeutic dosages of lithium or combinations of lithium with divalproex or carbamazepine (Nemeroff et al 2001). Paroxetine (mean dose 33 mg/day), imipramine (mean dose 167 mg/day), or placebo was added to lithium or lithium and other mood stabilizer combinations. Patients were stratified according to trough serum lithium concentrations obtained at the initial screening visit into two groups: high therapeutic (⬎.8 mEq/L) and low therapeutic (ⱕ.8 mEq/L). In the high therapeutic lithium group, there were no significant differences in efficacy among patients receiving paroxetine, imipramine, or placebo, as measured by changes in the HDRS total scores from baseline to end point; however, in the low therapeutic lithium group, both antidepressants were superior to placebo. Paroxetine was better tolerated than imipramine, and no patients in the paroxetine group switched during the study. In contrast, the incidences of mania among the imipramine-treated patients were 11% in the low therapeutic lithium group and 6% in the high therapeutic lithium group (Table 2). The results of this study suggest that paroxetine and imipramine conferred significant antidepressant efficacy in patients with low therapeutic lithium concentrations, but the antidepressant effects of lithium itself were more pronounced in the high
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therapeutic range. Of note, in an open-label trial Fagiolini et al (2001) reported relatively common adverse events consistent with symptoms of serotonin syndrome in four of 17 patients (29%) receiving paroxetine in addition to lithium in an open-label trial for bipolar depression. Silverstone (2001) compared the reversible monoamine oxidase A inhibitor moclobemide with imipramine, either as monotherapy or added to ongoing mood stabilizers, in an 8-week trial of 156 patients (75% outpatients) with bipolar I depression. In the moclobemide group 46% of patients were receiving lithium (two in combination with carbamazepine). In the imipramine group 49% were receiving lithium (five in combination with carbamazepine and one in combination with valproate). Both treatment groups displayed significant reductions in depressive symptoms, as measured by HDRS and MADRS total scores, but there were no significant differences between the groups. More patients switched into mania in the imipramine group (11%) than in the moclobemide group (4%), and they switched earlier in treatment, although these differences were not significant (Table 2). The authors did not report whether switches occurred more commonly among patients not receiving mood stabilizers. Similarly, mean doses of moclobemide and imipramine were not reported. The most recent randomized, controlled pharmacotherapy trial in bipolar depression compared olanzapine (mean dose 9 mg/day), the combination of olanzapine (mean dose 7 mg/day) and fluoxetine (mean dose 38 mg/day), and placebo in an 8-week trial among 833 patients with bipolar depression (Tohen and Baker, unpublished data). Both active treatment groups displayed significantly greater reductions in depressive symptoms, as assessed by baseline to end point changes in MADRS total scores, than did the placebo group, beginning at week 1. In addition, the olanzapine and fluoxetine group displayed significantly greater reductions in MADRS total scores than seen in the olanzapine group at weeks 4, 6, and 8. There were no significant differences in switch rates among the groups: olanzapine 6%, olanzapine and fluoxetine 6%, and placebo 7% (Table 2). Significantly more patients in the active treatment groups than in the placebo group had weight gain, appetite increase, dry mouth, and asthenia. Notably, this was the first randomized, controlled trial to demonstrate the efficacy of an atypical antipsychotic agent for monotherapy in acute bipolar depression. In addition, the olanzapine and fluoxetine results are consistent with the marked antidepressant response reported by Shelton et al (2001) for patients with treatment-refractory nonpsychotic unipolar depression. Interpretation of the results of this study should be made with the caveat that although these results were presented at a scientific meeting, they have not yet been subjected to peer review.
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Table 3. New Randomized Controlled Trials of Depression Relapse Prevention in Bipolar Disorder Study Calabrese et al 2000 Bowden et al, in press Bowden et al, unpublished data Tohen et al, unpublished data Tohen et al, unpublished data
Agents
Duration
Results
Lamotrigine mean 288 mg/day, placebo, rapid cycling patients Lamotrigine, lithium, placebo, recently manic patients Lamotrigine, lithium, placebo, recently depressed patients Olanzapine, divalproex
6 months
Lamotrigine same as placebo in time to need for additional pharmacotherapy Lamotrigine greater than placebo in time to intervention for depression Lamotrigine greater than placebo in time to intervention for depression Olanzapine same as divalproex in relapse rates
Olanzapine plus lithium or divalproex, lithium or divalproex
A number of impressions emerge from the studies reviewed here. First, lamotrigine was efficacious and generally well tolerated as monotherapy in acute bipolar depression, with rash and headache the most troublesome side effects. Second, lithium monotherapy at the higher end of its therapeutic range exerted significant antidepressant activity. Paroxetine in combination with mood stabilizers exerted significant antidepressant activity in bipolar depression, with generally good tolerability and a very low switch rate in short-term trials. In contrast, relatively high switch rates were reported with tricyclic antidepressants, a finding consistent with earlier studies (Thase and Sachs 2000). Finally, olanzapine and the combination of olanzapine and fluoxetine both demonstrated significant antidepressant activity, with slighter greater efficacy for the combination.
Relapse Prevention of Bipolar Depression Five recent randomized, controlled trials have addressed the prevention of bipolar depressive episodes with lamotrigine (Bowden et al, in press; Calabrese et al 2000) or olanzapine (Tohen et al, unpublished data). The results of these studies are summarized in Table 3. Among the lamotrigine studies, Calabrese et al (2000) conducted a placebo-controlled, 6-month relapse prevention trial of lamotrigine (mean dose 288 mg/day) in 182 patients with rapid cycling bipolar (I and II) disorder. Patients were first stabilized with lamotrigine at 100 to 300 mg/day, and other psychotropic agents were tapered and discontinued during a 4- to 8-week preliminary screening phase. Of 324 patients treated with lamotrigine during the screening period, 182 met randomization criteria of a minimum dose of lamotrigine of 100 mg/day with HDRS total score no greater than 14 and Mania Rating Scale derived from the Schedule for Affective Disorders and Schizophrenia– Change total score of 12 or less during a 2-week period. There was no significant difference on the primary outcome measure, time until need for additional pharmaco-
18 months 18 months 47 weeks 18 months
Olanzapine plus lithium or divalproex same as lithium or divalproex for depressive relapse
therapy (for recurrent mania or depressive symptoms), between the placebo and lamotrigine treatment groups. Retention in the study was significantly greater for the lamotrigine-treated group. Survival analysis was also performed for patients with bipolar I and bipolar II disorder. In this post-hoc analysis, no significant treatment differences were observed for bipolar I patients; however, in the bipolar II group there was a strong trend (p ⫽ .07) favoring lamotrigine in time until need for additional pharmacotherapy and a significant difference for survival in the study. Moreover, significantly more patients receiving lamotrigine (41%) than patients receiving placebo (26%) remained stable during the 6-month trial. Overall, most patients (80%) required additional pharmacotherapy for the emergence of depressive symptoms. Lamotrigine was well tolerated in the randomized phase of the trial, with no significant differences in adverse events considered reasonably related to the study drug between lamotrigine and placebo. Treatment-related rash occurred in 25 patients (8%) during the open-label phase. Mean body weight was unchanged from screening to the end of the study for patients receiving lamotrigine monotherapy. The results of two 18-month, placebo-controlled maintenance treatment trials comparing lamotrigine with lithium were recently reported (Bowden et al, in press). In the first of these two studies, patients with bipolar I disorder were required to have met DSM-IV criteria (American Psychiatric Association 1994) for a manic or hypomanic episode at time of screening or within 60 days of screening and to have had at least one additional manic or hypomanic and one depressive episode within 3 years of enrollment (Bowden et al, in press). After a screening phase, 349 patients entered an 8- to 16-week open-label phase during which lamotrigine (100 –200 mg/day) was initiated as adjunctive therapy or monotherapy and other psychotropic agents were gradually discontinued. Beginning at week 8 of the open-label phase of the study, patients who tolerated a stable dose of lamotrigine and met the criterion for illness stability, defined as a Clinical
Pharmacologic Treatment of Bipolar Depression
Global Impression-Severity Scale (CGI-S) score of 3 or less maintained for 4 weeks or longer, were eligible for the randomized portion of the trial. Of 349 patients in the open-label phase, 175 met the stabilization criterion and were randomly assigned to receive lamotrigine (100 – 400 mg/day), lithium (titrated to serum concentrations of .8 –1.1 mEq/L), or placebo for as long as 18 months. Approximately halfway through the trial, the lithium arm was closed to enhance enrollment in the primary treatment comparison of interest, lamotrigine versus placebo. Despite lower enrollment of lithium-treated patients, both lamotrigine and lithium were significantly superior to placebo with respect to the primary outcome measure, time to intervention for any mood episode. Similarly, lamotrigine was superior to placebo with respect to overall survival in the study. In the placebo group 16% completed the 18-month trial; figures were 31% in the lamotrigine group and 23% in the lithium group. Interesting differences between drugs emerged when the data were analyzed for type of mood episode necessitating intervention. Lamotrigine but not lithium was superior to placebo in prolonging time before a depressive episode; lithium but not lamotrigine was superior to placebo in prolonging time before a manic, hypomanic, or mixed episode. A trend favored lithium over lamotrigine with respect to this latter outcome as well. As in the acute treatment trial (Calabrese et al 1999), headache occurred significantly more commonly among lamotrigine-treated patients. One patient had a moderately severe rash during open-label treatment; there were no serious rashes during the randomized phase of the study. There was no significant difference among the three treatment groups in the proportion of patients discontinuing the study because of manic episodes. The second 18-month placebo-controlled maintenance trial comparing lamotrigine and lithium was similar in design except that patients were required to have recently experienced an episode of bipolar depression (within 60 days) rather than mania and at least one prior mood episode within the past three years (Bowden et al, unpublished data). Patients (n ⫽ 966) again entered an 8 –16 week open-label phase during which lamotrigine was titrated to 100 to 200 mg/day and concomitant psychotropic agents were tapered and discontinued. At the end of the preliminary open-label treatment phase, 463 patients met stabilization criteria of CGI-S score of 3 or less for at least 4 consecutive weeks, at least 1 week of lamotrigine monotherapy, and appropriate washout of previous treatment. These patients were then randomly assigned to receive lamotrigine at 50 mg/day, 200 mg/day, or 400 mg/day; lithium titrated to .8 to 1.1 mEq/L; or placebo for as long as 18 months (an a priori decision was made to combine the lamotrigine 200- and 400-mg/day groups for
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primary analysis of efficacy). Both lamotrigine and lithium were again significantly superior to placebo in time to intervention for a mood episode, the primary outcome measure. Similarly, lamotrigine but not lithium was superior to placebo with respect to time until intervention for a depressive episode, whereas lithium but not lamotrigine was superior to placebo with respect to time to intervention for a manic episode. Headache was again the most common side effect significantly associated with lamotrigine. Significantly more patients receiving lamotrigine (7%) than patients receiving lithium (4%) or placebo (2%) during the randomized phase of the study had rashes. There was no significant weight gain among the patients receiving lamotrigine. Interpretation of the results of the latter 18-month trials should be made with the caveat that although it has been presented at scientific meetings, it has not yet been subjected to peer review. The results of these three maintenance trials indicate that lamotrigine had significantly greater efficacy in preventing depressive (but not manic) relapse than placebo in patients with bipolar disorder. Lamotrigine was generally well tolerated, with headache the most common side effect. Of nearly 1200 patients who received lamotrigine in these controlled trials, 9% had benign rash (morbilliform or exanthematic eruptions) compared with 8% of the 1056 patients who received placebo. No serious rashes were observed during the randomized, controlled trial phases of these studies. Among nearly 2000 patients receiving lamotrigine in the open-label phases of the trials, the incidence of rash was 13% (Calabrese 2002). Two cases of serious lamotrigine-associated rash (requiring hospitalization) and one case of Stevens–Johnson syndrome not requiring hospitalization were reported. None of these cases were fatal, and all patients recovered. Data from the German Registry for Serious Cutaneous Reactions cited by Calabrese (2002) revealed that the incidence of serious rash with lamotrigine used at recommended titration rates was .12%, and that of Stevens–Johnson syndrome was .05%. Two studies assessed the efficacy of olanzapine in prevention of relapse in patients with bipolar disorder (Tohen et al, unpublished data). In the first study 109 patients responding to olanzapine (mean modal dose 16 mg/day) or divalproex (mean modal dose 1585 mg/day) in a 3-week randomized, controlled trial (Tohen et al 2002a) who elected to continue the blinded study medication were followed for 44 weeks (Tohen et al, unpublished data). The median times to manic relapse were 270 days for the olanzapine group and 74 days for the divalproex group (p ⫽ .33). There were no significant differences in relapse rates between the olanzapine (45%) and divalproex (52%) groups. In a mixed model repeated measures analysis, mean improvement on the HDRS favored olanzapine over
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divalproex (p ⫽ .06). Mean baseline to end point weight gain was significantly greater with olanzapine (3.4 kg) than with divalproex (1.7 kg). The second study consisted of 94 patients who were in syndromic remission after an acute 6-week treatment trial comparing adjunctive olanzapine with placebo in patients partially responding to lithium or divalproex (Tohen et al 2002b). Patients who elected to be randomly assigned again to receive olanzapine in combination with lithium or divalproex or to placebo in combination with lithium or divalproex were then followed up for 18 months (Tohen et al, unpublished data). Patients receiving olanzapine in combination with lithium or divalproex had a significantly longer time to recurrence of mania than did patients receiving placebo in combination with lithium or divalproex. Rates of manic recurrence were also significantly lower in the olanzapine combination therapy group (15%) than in the monotherapy group (35%). Time to recurrence of depressive episodes was not significantly different between the two treatment groups, but there was a trend favoring the olanzapine combination group (155 days) over the monotherapy group (27 days, p ⫽ .07). Significantly more patients in the combination therapy group (31%) than in the monotherapy group (10%) completed the 18-month trial. Weight gain occurred significantly more commonly in the combination group and insomnia occurred more commonly in the monotherapy group. Interpretation of the results of these two olanzapine maintenance studies should be made with the caveat that although they were presented at scientific meetings, they have not yet been subjected to peer review. The results of these relapse prevention studies indicate that lamotrigine had significant efficacy in preventing bipolar depressive episodes, that olanzapine was at least comparable to divalproex in relapse prevention, and that the combination of olanzapine and lithium or divalproex was superior to monotherapy with lithium or divalproex. Perhaps the most striking observation across trials was the high proportion of patients with breakthrough symptoms during monotherapy with any single agent and the relative advantage of combination therapy in this regard.
The Problem of Switching Moller and Grunze (2000) summarized the recommendations of a number of treatment guidelines for bipolar disorder in both the United States and Europe as suggesting that antidepressants be avoided in mild to moderate bipolar depression (relying on mood stabilizers alone) and that when antidepressants were added to mood stabilizers for severe bipolar depression they be withdrawn as soon as possible. These conservative recommendations were based on limited data available during the 1990s regarding the
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relative risks and benefits of withholding antidepressant treatment compared with intervention with antidepressant agents (in combination with mood stabilizers in bipolar I depression) and the possible risk of switching and induction of cycling. A number of recent naturalistic studies, as well as the acute and maintenance randomized, controlled trials summarized here, provide much needed data to inform this clinical dilemma. Reported switch rates among patients with bipolar depression treated with antidepressants have ranged widely, from 10% to 70% (Moller and Grunze 2000; Sachs et al 2000b). These disparate estimates reflect widely diverse circumstances, including data derived from naturalistic compared with randomized, controlled trials and data from patients receiving various mood stabilizers and combinations or antidepressants alone. Justification of antidepressant use with mood stabilizers for bipolar depression would be enhanced with additional knowledge about the degree to which mood stabilizers decrease or protect against the risk of switch and about the risk of depressive relapse associated with antidepressant discontinuation in patients with acute response to such an intervention. A number of recent studies have attempted to clarify the switch rates and the degree to which mood stabilizers reduce this risk in patients with bipolar depression. Bottlender et al (2001) reviewed the medical records of 158 inpatients with bipolar I depression to examine the incidence of mania and hypomania in relation to pharmacotherapy. The overall switch rate was 25%. Among patients switching, 80% received tricyclic antidepressants, a significantly higher proportion than those not switching who received tricyclic antidepressants (51%). Overall switch rates were 34% for patients receiving tricyclic antidepressants, 12% for those receiving serotonin reuptake inhibitors, 8% for those receiving monoamine oxidase inhibitors, and 14% for those receiving other agents. The protective effects of mood stabilizers were most apparent for patients receiving tricyclic antidepressants, because significantly more patients receiving tricyclic antidepressants but not receiving mood stabilizers (57%) switched compared with those taking tricyclic antidepressants and mood stabilizers (26%). In the overall group, the percentage of patients switching while receiving mood stabilizers was significantly lower (59%) than the percentage of patients switching without mood stabilizers (82%). These findings are consistent with earlier studies suggesting that coadministration of lithium reduces the risk of antidepressant-associated switching by approximately 50% (Boerlin et al 1998; Prien et al 1984; Rouillon et al 1992). Post et al (2001) reviewed switch data from an ongoing double-blind randomized, comparison trial in the Stanley
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Foundation Bipolar Network of bupropion, sertraline, and venlafaxine added to therapeutic doses of mood stabilizers for bipolar depression. Nonresponders to the initial antidepressant could be randomly reassigned to an alternative agent. Data were analyzed for switch rates for the 10-week acute treatment trial and for the 1-year maintenance phase (for responders in the 10-week trial). Thirteen of the 95 patients in the acute treatment trial (14%) switched into mania (n ⫽ 6, 6%) or hypomania (n ⫽ 7, 8%). Among the 48 maintenance trials in acute responders, 16 patients (33%) switched, six of them (13%) into mania and 10 of them (20%) into hypomania. There were no significant differences in switch rates among the three antidepressants, as ascertained by data safety monitoring because the study is still blinded and ongoing. Because of the lack of a placebo control, it is difficult to compare these rates with those associated with spontaneous rates from the illness, but the switch rates into mania were lower than anticipated. Henry et al (2001) compared patients who switched with those who did not in a naturalistic study of 44 patients treated with antidepressants for acute bipolar depression in a 6-week trial. Overall, 12 patients (27%) switched, seven of them (16%) into mania and of them (11%) into hypomania. Mood switches were significantly less frequent among patients receiving lithium (15%) than among those not receiving lithium (44%). The number of previous manic episodes was not associated with a risk of switching, although a high score on the hyperthymic component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching. The results of these studies suggest that mood stabilizers significantly reduce but do not eliminate the risk of switching for patients with bipolar depression treated concurrently with antidepressants.
Antidepressant Discontinuation and Relapse Although limiting antidepressant exposure may reduce the risk of switching, discontinuing antidepressants during maintenance treatment may also increase the risk of depressive relapse. Altshuler et al (in press) examined the risk of depressive relapse in two studies. The first study retrospectively compared the relapse rate of 25 patients who discontinued antidepressants (in conjunction with mood stabilizers) with that of 19 patients who continued to receive antidepressants (with mood stabilizers) after initial improvement (Altshuler et al 2001). Termination of antidepressants was significantly associated with an increased rate of depressive relapse (odds ratio 3.13, p ⫽ .007), but antidepressant continuation was not significantly associated with an increased risk of mania (odds ratio 1.92, p ⫽ .35).
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In a follow-up prospective study (Altshuler et al, in press) from the Stanley Foundation Bipolar Network, 84 patients successfully treated with sertraline, venlafaxine, or bupropion in addition to a mood stabilizer for acute bipolar depression were followed up for 1 year. Patients who discontinued antidepressants within the first 6 months after successful treatment had a significantly shorter period of euthymia before depressive relapse than did those who continued treatment with an antidepressant. At 1 year after an initial antidepressant response, 71% of the antidepressant discontinuation group had experienced relapse, compared with 41% of the continuation group. Fifteen (18%) of the 84 patients experienced a manic relapse during the 1-year follow-up, but only six were receiving antidepressants at the time of manic relapse. Thus the risk of depressive relapse was significantly associated with antidepressant discontinuation soon after remission, but the risk of manic relapse was not significantly associated with continued use of antidepressants in conjunction with mood stabilizers. The results of these two studies suggest that the use of antidepressants in combination with mood stabilizers to prevent recurrence of bipolar depression may be indicated and necessary for many patients.
Conclusions A wealth of new data has emerged during the last 5 years regarding important aspects of the treatment of bipolar depression (American Psychiatric Association 2002). Coadministration of mood stabilizers appears to markedly reduce the risk of antidepressant-associated switching. This is good news, because many patients responding acutely to antidepressants for bipolar depression appear to require longer-term maintenance treatment with these agents to reduce the risk of depressive relapse. Two new agents with novel mechanisms of action, lamotrigine and olanzapine, have demonstrated efficacy in the acute and maintenance treatment of bipolar depression. The efficacy of olanzapine appears to be greatest when it is administered in combination with fluoxetine in acute treatment and in maintenance treatment with lithium or divalproex compared with olanzapine monotherapy. The findings reviewed from these studies suggest many more important avenues for further study. For example, the efficacy of other atypical antipsychotic agents in the acute and maintenance treatment of bipolar depression, alone or in combination with antidepressants, lithium, or divalproex, requires further study. The efficacy of lithium and lamotrigine in combination in preventing manic and depressive relapse needs to be studied. The relative protective effects (and possible dose or serum concentration relationships) against switching of lithium, divalproex, carbamazepine, and atypical antipsychotic agents coadministered
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with antidepressants remain to be clarified. The optimal duration of antidepressant maintenance treatment and possible predictors of switch versus depressive relapse also await further study.
Aspects of this work were presented at the conference, “Difficult-toTreat Depression,” held April 21–22, 2002 in San Francisco, California. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.
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