Assessing the Benefit-Risk Ratio of Approved Treatments for Bipolar Depression Using Likelihood to be Helped or Harmed (LHH) Analyses

Background: Four medications are FDA approved for acute bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). We examined here the benefit-risk ratios of these treatments.

Methods: Monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg/d), and pooled OFC (considered as monotherapy; fixed doses of 6/25, 6/50, 12/50 mg/d) data. Number needed to treat (NNT) estimates were calculated using the proportions of MADRS responders (defined as  ≥ 50% improvement at study endpoint). Number needed to harm (NNH) data were calculated for the proportions of patients who discontinued due to an adverse event. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio.

Results: The NNT estimates for response vs placebo were: 5 for both LUR 20-60 mg/d and 80-120 mg/d; 10 for both CAR 1.5 mg/d and 3.0 mg/d; 6 for QUE; and 4 for OFC. The LHHs for response vs discontinuation were: 128.4 for LUR 20-60 mg/d and 2.4 for LUR 80-120 mg/d; 29.8 for CAR 1.5 mg/d and 3.1 for CAR 3.0 mg/d; and 1.7 for QUE.

Conclusions: Overall, lurasidone low and high doses were more likely to benefit patients in terms of depression response than to harm them due to poor tolerability. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a marginal benefit-risk ratio. The 1.5 mg/d dose of cariprazine evidenced a better benefit-risk profile than the 3.0 mg/d dose.