Skip to main content
. 2019 Jul 16;17(3):218–231. doi: 10.1176/appi.focus.20190008

TABLE 5.

Randomized trials of mono- versus dual pharmacotherapies for bipolar maintenance and relapse prevention

Trial result and intervention Duration Outcome Adverse effects
Positive trials
 Aripiprazole (N=168) or placebo (N=169) plus lithium or divalproex (81) 12-week acute stabilization followed by 52-week maintenance Lower 52-week relapse rate (any mood episode) with aripiprazole (mean dose 15.8–16.9 mg/day; 17%) than with placebo (29%); aripiprazole was more effective than placebo for mania but not depressive relapse Comparable weight changes or metabolic parameters with aripiprazole or placebo
 Lithium plus divalproex combination vs. either monotherapy (BALANCE; 82) 24 months Lithium plus divalproex (N=110) was more effective than divalproex monotherapy (N=110) but not lithium monotherapy (N=110); lithium was more effective than divalproex for depressive relapses No significant differences in serious adverse events among the treatment arms
 Lithium or divalproex plus aripiprazole of placebo (83) 12-week acute stabilization followed by 52-week maintenance Adjunctive aripiprazole (mean dose=16.1 mg/day if index episode manic, 16.8 mg/day if mixed) was more effective than placebo for prevention of manic but not mixed episodes More tremor with aripiprazole than with placebo
 Olanzapine (N=51) or placebo (N=48) plus lithium or divalproex (84) 18 months Adjunctive olanzapine (mean dose=8.6 mg/day) was more effective than placebo for symptomatic but not syndromal relapse for mania or depression (but no significant differences for time to mania relapse or time to depressive relapse) More weight gain and less insomnia with adjunctive olanzapine than with placebo
 Risperidone long-acting injectable (N=65) or placebo (N=59) plus treatment as usual (85) 16-week open stabilization, then 52 weeks Adjunctive risperidone long-acting injectable (modal dose 25 mg/day) was more effective than placebo for time to any mood episode Tremor, insomnia, muscle rigidity, and mania more likely with risperidone long-acting injectable than with placebo
 Ziprasidone (N=127) or placebo (N=113) plus lithium or divalproex (86) 8-week open stabilization, then 16 weeks Adjunctive ziprasidone (mean modal doses of 80, 119, and 160 mg/day across three strata) was more effective than placebo in time to any mood episode and, separately, time until a manic or until a depressive relapse Incidence of tremor greater with ziprasidone than placebo
Negative trials
 Lurasidone (N=246) or placebo (N=250) plus lithium or divalproex (87) 28 weeks No advantage for adjunctive lurasidone over placebo in time until recurrence of a depressive, manic, or mixed episode; if index episode polarity was depressed, lurasidone was more effective than placebo for time until recurrence of any mood episode No clinically meaningful differences with lurasidone versus placebo
 Oxcarbazepine (N=26) or placebo (N=29) plus lithium (88) 52 weeks No advantage for adjunctive oxcarbazepine (mean modal dose 1,200 mg/day) over placebo in time until recurrence of any mood episode Drowsiness, diarrhea, and tremor more common with oxcarbazepine than placebo