English-language literature cited in MEDLINE from January, 1980 to October 30, 2014 was searched by using terms of
antipsychotic, generic and brand names of atypical
antipsychotics, "
bipolar depression/
bipolar disorder", "placebo", and "trial". The parameters of response (≥50% improvement on MADRS, Montgomery-Asberg Depression Rating Scale total score), remission (either ≤12 or 8 on MADRS total score at endpoint), discontinuation due to adverse events (DAEs),
somnolence, ≥7%
weight gain, overall extrapyramidal side-effects (EPSs), and
akathisia, were extracted from originally published primary outcome papers. The number needed to treat to benefit (NNT) for response and remission or harm (NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95% confidence interval.
Olanzapine monotherapy,
olanzapine-fluoxetine combination (OFC),
quetiapine-IR monotherapy,
quetiapine-XR monotherapy,
lurasidone monotherapy, and
lurasidone adjunctive
therapy were superior to placebo with NNTs for responses of 11-12, 4, 7-8, 4, 4-5, and 7, and NNTs for remission of 11-12, 4, 5-11, 7, 6-7, and 6, respectively. There was no significant difference between OFC and
lamotrigine, and between
aripiprazole or
ziprasidone and placebo in response and remission.
Olanzapine monotherapy,
quetiapine-IR,
quetiapine-XR,
aripiprazole, and
ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24, 8-14, 9, 12, and 10, respectively. For
somnolence,
quetiapine-XR had the smallest NNH of 4. For ≥7%
weight gain,
olanzapine monotherapy and OFC had the smallest NNHs with both of 5. For
akathisia,
aripiprazole had the smallest NNH of 5. These findings suggest that among the FDA-approved agents including OFC,
quetiapine-IR and -XR,
lurasidone monotherapy and adjunctive
therapy to a mood stabilizer, the differences in the NNTs for response and remission are small, but the differences in NNHs for DAEs and common side-effects are large. Therefore, the selection of an FDA-approved atypical
antipsychotic for
bipolar depression should be based upon safety and tolerability.