Combination vs Single Medication Treatment of Bipolar Disorder

Paul E. Keck, Jr., MD


October 11, 2005

In This Article

Acute Mania

The goals of treatment of acute bipolar manic or mixed episodes are rapid amelioration of mood symptoms, agitation, and suicidal ideation, along with restoration of functioning.[1] The long-term goal of treatment of bipolar disorder is prevention of recurrent mood symptoms and episodes, that is, complete recovery.

Although these treatment goals are relatively straightforward, meeting them can nevertheless be challenging. The number and variety of medications for the treatment and prevention of hypomanic, manic, mixed, and depressive symptoms and episodes have expanded substantially over the past 10 years, but most randomized, controlled trials of these agents have focused on their efficacy as monotherapy. In parallel with these pivotal and often landmark randomized, controlled trials, several other studies of the naturalistic treatment of patients with bipolar disorder indicate that the vast majority receive treatment with more than 1 agent.[2,3] In other words, combination therapy of bipolar disorder has become the rule rather than the exception in clinical practice. This is probably due in part to renewed efforts to treat symptoms to achieve and maintain remission, the inherent instability of bipolar disorder, the complicating factors of high rates of psychiatric and medical comorbidity, and limitations in the overall mood-stabilizing efficacy and tolerability of available agents. In the past several years, studies of combination therapy have begun to emerge to address the relative efficacy and tolerability of this strategy compared with monotherapy. This column reviews randomized, controlled trials of combination therapy involving acute bipolar mania, depression, and long-term prevention of relapse of these disorders.

Most recent practice guidelines suggest combination treatment with an atypical antipsychotic agent and an antimanic mood stabilizer (eg, lithium, divalproex, or carbamazepine) in hospitalized patients with severe manic or mixed episodes, especially if such episodes are accompanied by psychotic symptoms.[1,4,5] This practice has been commonplace in the United States for many years but has ironically only recently been examined in comparison trials of therapy with an antipsychotic agent or antimanic mood stabilizer alone. To date, 8 such trials have been conducted. Muller-Oerlinghausen and colleagues[6] conducted the first trial, in which 136 inpatients with acute mania were randomly assigned to receive valproate or placebo in addition to an antipsychotic medication. By week 3, significantly more patients in the valproate group had responded and also had a significant decrease in the need for and dose of concomitant antipsychotic medication.

This is the only trial comparing the combination of a mood stabilizer and an antipsychotic agent with an antipsychotic agent as monotherapy (with placebo). All other combination therapy studies in patients with acute manic or mixed episodes compared the combination of an atypical antipsychotic agent and an antimanic mood stabilizer with antimanic mood-stabilizer monotherapy (with placebo). Among the atypical or second- generation antipsychotic agents, risperidone has been studied most extensively, in 3 comparison trials of combination therapy.[7,8,9] Sachs and coworkers[7] conducted a 3-week double-blind trial in hospitalized, acutely manic patients and found that response rates were significantly greater in those receiving risperidone plus lithium or divalproex and haloperidol plus lithium or divalproex than in those receiving placebo plus lithium or divalproex. Similarly, Vieta and colleagues[8] reported superior response rates in patients receiving combination risperidone and antimanic mood stabilizers compared with those receiving mood-stabilizer monotherapy in an open-label comparison trial. In contrast, Yatham and coworkers[9] found no significantly greater efficacy in patients receiving risperidone in combination with lithium, divalproex, or carbamazepine compared with those receiving the latter 3 agents as monotherapy (plus placebo) in a 3-week double-blind trial. However, a substantial proportion of patients in this study were receiving carbamazepine and may have had clinically significant reductions in plasma risperidone concentrations, undercutting risperidone's efficacy.

Two randomized, double-blind, placebo-controlled trials[10,11] in adult patients with acute mania (no patients with mixed mania were included) assessed the efficacy of quetiapine plus lithium or divalproex compared with lithium or divalproex alone. The combination quetiapine group had a higher mean reduction in manic symptoms compared with the single-agent lithium and divalproex groups. In addition, the combination of quetiapine and divalproex was superior to divalproex alone in the only randomized, controlled trial involving treatment of adolescents with manic or mixed episodes.[12]

In another trial,[13] olanzapine was used in combination with lithium or divalproex purely as an adjunctive agent compared with placebo in patients with manic symptoms who had only a partial response to 2 weeks of monotherapy with lithium or divalproex. Patients receiving adjunctive olanzapine had significantly greater mean reductions in manic symptoms and greater response rates compared with the adjunctive placebo group after 6 weeks.

Ziprasidone alone was compared with combination ziprasidone/lithium in a placebo-controlled study designed to demonstrate a more rapid rate of antimanic activity by day 14.[14] Although no significant differences in rate of improvement were seen between the 2 groups at day 14, the combination ziprasidone/lithium group displayed a greater reduction in manic symptoms than the placebo/lithium group at day 4, the time of the first rating of improvement. This study was limited by the selection of the trial end point.

To date, no randomized, controlled trials have examined aripiprazole in combination with an antimanic mood stabilizer.

Overall, the results of these trials indicate that hospitalized patients with acute mania of moderate or greater severity with or without psychotic symptoms show greater mean reduction in manic symptoms and greater initial response rates with combination treatment than with monotherapeutic strategies within time frames of 3 to 6 weeks.


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