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Atypical Antipsychotics in Bipolar Disorder



Although bipolar disorder is one of the most devastating of all psychiatric disorders in terms of risk for suicide, need for hospitalization, and suffering, the available pharmacologic agents for its treatment, until relatively recently, have been quite limited. Although some estimates suggest that the lifetime prevalence of bipolar disorder in the United States is between 1% and 1.6%,[1,2] this rate would be higher if patients with bipolar spectrum disorders beyond bipolar I and II disorder were included. The public health importance of this disease is heightened by the high rate of suicidality and the high economic toll it can take, including lost work days and cost of care, as well as poor financial decision-making characteristics of the manic phase of the illness.[3,4]

Lithium, the first mood stabilizer approved by the US Food and Drug Administration (FDA) for the treatment of mania, is often effective; however, it is likely underutilized to some extent because of its poor tolerability in some patients. In addition to lithium, which has been available in the United States since 1970 and in Europe for a decade longer, the only other FDA-approved medication for the treatment of mania that was available until relatively recently is valproate, which was FDA approved in 1995. Carbamazepine, available for many years as a treatment for epilepsy, has also recently received FDA approval for the management of acute mania in its extended-release form. These 3 mood stabilizers exhibit efficacy in controlling manic symptoms, although their role in treating bipolar depression is less clear (Table).

Table. FDA-Approved Bipolar Treatment Regimens

Generic Name Trade Name Manic Mixed Maintenance Depression
Valproate Depakote X      
Carbamazepine extended release Equestro X X    
Lamotrigine Lamictal     X  
Lithium   X   X  
Aripiprazole Abilify X X X  
Ziprasidone Geodon X X    
Risperidone Risperdal X X    
Quetiapine Seroquel X     X
Chlorpromazine Thorazine X      
Olanzapine Zyprexa X X X  
Olanzapine/fluoxetine Combination Symbyax       X

Although the first-generation antipsychotics such as haloperidol have clear efficacy in the treatment of acute mania, their long-term use in bipolar disorder is limited, largely due to concerns about tardive dyskinesia.[5] Over the past several years, atypical antipsychotics have been used increasingly in the management of bipolar disorder, particularly for acute mania. These agents have been thought to be generally better tolerated and to have lower rates of extrapyramidal symptoms (EPS) than the older so-called "typical" antipsychotics. However, this view is now actively being questioned. Although there are individual differences in pharmacologic potency at various receptor sites, virtually all of the atypical antipsychotic drugs are potent D2 and 5-HT2 receptor antagonists, the former believed to be essential for antipsychotic drug efficacy.

With this in mind, and with the significant cost difference between the gold standard of lithium and the conventional antipsychotics vs the newer atypical antipsychotics, a review of published studies on the efficacy of atypical antipsychotics in the treatment of bipolar mania, bipolar depression, and as maintenance therapy is warranted. This review will highlight the major findings for each member of this new class of agents.


The first of the atypical antipsychotics to receive FDA approval for the treatment of acute manic episodes was olanzapine. The results from a 4-week, double-blind, placebo-controlled study demonstrated that olanzapine (5-20 mg/day) was more effective than placebo in the treatment of manic symptoms as assessed by the Young Mania Rating Scale (YMRS) total score.[6] Olanzapine-treated patients demonstrated a nearly 6-point statistically significant greater decrease in their total YMRS score than placebo-treated patients. Further, the olanzapine effect was observable as early as 1 week after initiation of treatment. The overall rates of EPS were comparable between the 2 groups, but, not surprisingly, in this 1- month study, there was significantly greater weight gain in the olanzapine group than in the placebo group (approximately 2.1 kg vs 0.45 kg).

In a double-blind, randomized, controlled trial comparing valproate (500-2500 mg/day adjusted to a plasma range of 50-125 mcg/mL) with olanzapine (5-20 mg/day) in the treatment of acute mania,[7] response rates (≥ 50% decrease in YMRS score) for olanzapine and valproate were 54% and 42%, respectively. Furthermore, remission rates, problematically defined as YMRS ≤ 12 in this study, were 47% for olanzapine-treated patients and 34% for valproate-treated patients. A second double-blind, randomized, controlled trial comparing valproate (500-2500 mg/day) with olanzapine (5-20 mg/day) showed comparable results during the 21-day treatment period for the 2 agents, though the valproate-treated patients did demonstrate significantly less weight gain and a more favorable side effect profile.[8]

A 6-week study evaluated the efficacy of olanzapine or placebo combined with either lithium or valproate in acute mania. Patients who exhibited an inadequate response (YMRS ≥ 16) after 2 weeks of treatment, in spite of therapeutic blood levels of either lithium (0.6-1.2 mmol/L) or valproate (50-125 mcg/mL), were maintained on their mood stabilizer and randomized to either olanzapine (5-20 mg/day) or placebo augmentation.[9] Baseline YMRS and Hamilton Rating Scale for Depression (HAM-D) scores before the addition of olanzapine or placebo were approximately 22.5 and 14, respectively, indicative of moderately severe manic symptoms and moderate depressive symptoms. The olanzapine plus mood stabilizer combination therapy was significantly more effective than placebo plus mood stabilizer treatment as assessed with the YMRS total score. Response rates, defined by ≥ 50% improvement on the YMRS, were also greater with the antipsychotic-mood stabilizer combination (68% vs 45%). Patients treated with the combination of a mood stabilizer plus olanzapine also exhibited a significant reduction in the HAMD-21 total scores to a greater extent than the mood stabilizer plus placebo group (4.98 vs 0.89 points). However, there was a higher incidence of somnolence, dry mouth, increased appetite, tremor, and weight gain in the olanzapine plus mood stabilizer group.[10]

The long-term efficacy of olanzapine in bipolar disorder has also been investigated in a 47-week trial that compared olanzapine (5-20 mg/day) with valproate (500-2500 mg/day) for acute mania and in a maintenance follow-up study. In this randomized, double-blind study, 251 patients with bipolar I disorder (inclusion criteria YMRS ≥ 20) in manic or mixed episodes were treated with either olanzapine or valproate. Median time to remission of mania was 14 days for olanzapine and 62 days for valproate. However, over the 47-week follow-up, rates of symptomatic mania remission, defined as YMRS ≤ 12, and subsequent relapse into mania, defined as YMRS ≥ 15, or depression defined as HAMD-21 ≥ 15, were similar for both groups.[11] This would suggest there is comparable efficacy between the 2 agents in the maintenance of bipolar disorder but a more rapid antimanic effect for olanzapine, at least at the doses employed in this study. However, other studies have shown a much more rapid antimanic effect for valproate than the median of 62 days reported here.[12]

In a subsequent 18-month study, acutely manic patients were first treated with olanzapine plus valproate or lithium and then continued in a maintenance treatment phase on either lithium (plasma levels of 0.6-1.2 mmol/L) or valproate (plasma levels of 50-125 mcg/mL). This was followed by a double-blind trial in which patients received either olanzapine (5-20 mg/day combination therapy, n = 51) or placebo (n = 48, monotherapy).[13] Combination therapy did not significantly reduce syndromic relapse rates into either mania or depression, the primary outcome in the study, but did significantly reduce the rate of symptomatic relapse.


A number of studies have demonstrated that quetiapine is effective in the treatment of acute mania. A double-blind, placebo-controlled trial comparing quetiapine (flexibly dosed up to 800 mg/day), haloperidol (up to 8 mg/day), and placebo in the treatment of acute mania demonstrated significant separation from placebo on YMRS scores for haloperidol as early as day 4, and for quetiapine starting at day 21.[14] A second study, which pooled results from 2 separate monotherapy trials with quetiapine (up to 800 mg/day), demonstrated significant improvement as early as day 4.[15]

In a 12-week study comparing monotherapy with lithium, quetiapine, or placebo in the treatment of acute mania,[16] the efficacy of quetiapine was superior to placebo and comparable to lithium. A double-blind, placebo-controlled study of quetiapine (titrated to 800 mg/day) combined with lithium or valproate for 21 days in patients with acute mania demonstrated a significant and clinically meaningful advantage for the quetiapine plus mood stabilizer combination. The response rate, defined as a ≥ 50% YMRS reduction, was 54% in the patients treated with the combination therapy vs 33% in the placebo plus mood stabilizer treatment group. The rate of clinical remission, defined as YMRS ≤ 12, was 46% for combination therapy vs 26% in the mood stabilizer plus placebo group.[17]

The efficacy of quetiapine in the treatment of depression in bipolar I or II disorder has also been recently demonstrated by Calabrese and colleagues,[17] confirmed in a second study by Thase and associates,[18] and has received recent FDA approval. In the first study, which was 8 weeks in duration, patients were randomly assigned to receive quetiapine (300 or 600 mg/day) or placebo. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Response rates, defined as a ≥ 50% decrease in MADRS score, were significantly greater in patients receiving either dose of quetiapine, 58%, vs 36% in the placebo group. Remission rates, defined as an MADRS score ≤ 12 instead of the conventional MADRS ≤ 10, followed a similar trend, with 53% of patients treated with quetiapine vs 28% with placebo. A second identically designed study produced similar results, also showing comparable efficacy of 300 and 600 mg of quetiapine.[19] Significant improvements in HAM-D scores were observed as early as 1 week and persisted throughout the 8-week study duration.


A 21-day randomized, placebo-controlled, double-blind trial of risperidone (up to 6 mg/day)[20] in the treatment of acute mania (YMRS ≥ 20) demonstrated significantly greater effects of risperidone (average dose 4.1 mg/day, mean change in YMRS -10.6) compared with placebo (mean YMRS change -4.5). A second 21-day randomized, placebo-controlled, double-blind trial in which patients with acute mania (average YMRS score of approximately 37 at study entry) received risperidone 1-6 mg/day also demonstrated the superiority of this atypical antipsychotic relative to placebo.[21]

The combination of risperidone with a mood stabilizer, either lithium or valproate, was shown to be equal in efficacy to haloperidol (plus a mood stabilizer) and superior in efficacy to placebo (plus a mood stabilizer) in the treatment of acute mania.[22] In a large open-label study, risperidone added to lithium or valproate also showed similar benefits.[23]


Two randomized, placebo-controlled, double-blind, 3-week trials have demonstrated the efficacy of ziprasidone in the management of acute mania. As observed in the studies of other atypical antipsychotic drugs, ziprasidone (target dose of 80-160 mg/day) was superior to placebo by day 2 in a study by Keck and associates.[24] This beneficial effect persisted throughout the duration of the study, with response rates of 40% for ziprasidone vs 19% for placebo. A second trial, with a very similar design, produced very similar positive results.[25] An open year-long continuation study revealed continued beneficial effects of ziprasidone. A comprehensive review of the data on ziprasidone treatment of bipolar disorder has been published.[26]


The effectiveness of aripiprazole in the treatment of acute mania or mixed states was demonstrated in 2 large, double-blind, placebo-controlled trials. In the first study, aripiprazole (initiated at 30 mg/day and reduced to 15 mg/day if needed for tolerability) was shown to be more effective than placebo.[27] Aripiprazole separated from placebo as early as day 4, and response rates (≥ 50% decrease in YMRS score) were significantly higher in the aripiprazole group (40%) when compared with placebo (19%). A second similarly designed study also favored aripiprazole, with response rates of 53% at 3 weeks for aripiprazole-treated patients compared with 32% for placebo.[28]

In a long-term study, acutely manic patients were first treated with open-label aripiprazole (15-30 mg/day). Patients meeting remission criteria for 6 consecutive weeks (YMRS ≤ 10 and MADRS score ≤ 13) were randomized in a double blind fashion to either continue on aripiprazole or switch to placebo. Relapse was defined as relapse to a manic, mixed, or depressive episode necessitating hospital admission and/or psychotropic medication changes, other than the study drugs, for manic and/or depressive symptomatology. During the 26-week follow-up, nearly 43% of patients maintained on placebo relapsed compared with 25% of patients treated with aripiprazole.[29]

Clinical Implications of the Atypicals in Treating Bipolar Disease

With the advent and/or FDA approval of several new antipsychotics and mood stabilizers (eg, lamotrigine, carbamazepine) for the treatment of bipolar disorder, our ability to optimize treatments for individual patients continues to improve. The available data suggest that atypical antipsychotics are more effective than placebo for the treatment of acute mania and maintenance of bipolar disorder, and even more effective when combined with lithium or valproate. The fact that some of the studies reported more rapid onset in the control of manic symptoms than others may simply be related to differences in study design, and/or the use of additional psychopharmacologic agents such as benzodiazepines, rather than related to significant differences between the atypical antipsychotics themselves. Direct comparative studies would be required to determine whether such differences between agents truly exist.