Adjunctive therapy with antipsychotics vs. monotherapy in acute bipolar mania

Evidence Summaries

Level of Evidence = A
Adjunctive antipsychotic treatment is more effective than monotherapy with mood stabilisers for patients with acute bipolar mania.

A systematic review 1 including 8 RCTs with a total of 1073 subjects was abstracted in DARE. Maximum follow-up was 8 weeks. Adjunctive treatment with quetiapine, haloperidol, risperidone and olanzapine was associated with a significant reduction in Young Mania Rating Scale (YMRS) scores compared with monotherapy with a mood stabilizer (lithium, valproate or carbamazepine). In 3 studies adjunctive treatment with all atypical antipsychotics combined was associated with a significant reduction in YMRS scores compared with monotherapy (MD -4.41, 95% CI -6.07 to -2.74). Little difference was found in withdrawals between adjunct and monotherapy for haloperidol, olanzapine and quetiapine. However, adjunctive risperidone was associated with lower withdrawal rates for any reason than monotherapy. In one study adjunctive treatment with olanzapine was associated with an increase in withdrawal due to adverse events compared to monotherapy (RR 6.28, 95% CI 1.51 to 26.04). Weight gain was greater with adjunctive olanzapine, quietiapine and risperidone compared to monotherapy. Adjunctive haloperidol was associated with an increase in extrapyramidal adverse events compared with lithium monotherapy but there was little difference between adjunctive quetiapine and monotherapy.

In another meta-analysis 2 including 24 RCTs with 6187 patients with acute bipolar mania atypical antipsychotics were compared with placebo, mood stabiliser (lithium or valproate) or combined with a mood stabiliser. The efficacy was evaluated by YMRS score. Atypical antipsychotics were more effective than placebo (RR 1.67, 95 % CI 1.48 to 1.89, NNT 5). There was no difference in efficacy between atypical antipsychotics and mood stabilisers (RR 1.15, 95 % CI 0.88 to 1.50), but the combination therapy increased the efficacy of mood stabilisers (RR 1.45, 95 % CI 1.27 to 1.66, NNT 6). Weight increase was more common with ketiapine and olanzapine, somnolence with ketiapine, olanzapine, risperidone, aripiprazole ja ziprasidone. No increase in extrapyramidal symptoms was reported for ketiapine or olanzapine.


1. Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psyc Scand 2007;115(1):12-20
2. Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry 2007;64(4):442-55.  [PMID:17404121]

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