Cariprazine as Adjunctive Treatment for Major Depressive Disorder: Benefit and Risk Assessment Using Number Needed to Treat and Number Needed to Harm

Purpose This post hoc analysis investigated efficacy and tolerability of adjunctive cariprazine (CAR) in patients with major depressive disorder (MDD) using evidence-based medicine metrics of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods Data sources were five completed Phase II/III, 6-8 week, randomized, double-blind, placebo-controlled studies. Efficacy outcomes included acute response (≥50% decrease from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS] total score). Tolerability outcomes included commonly occurring adverse events (AEs) and rates of discontinuation because of an AE, with data pooled across all studies for the CAR 1-2 mg/day plus 1.5 mg/day dose groups, 2-4.5 mg/day plus 3 mg/day dose groups, and for all groups where CAR dose was ≥1 mg/day. NNT and NNH were calculated for adjunctive CAR vs. adjunctive placebo. Results MADRS response rates at Week 8 for CAR 2-4.5 mg/day vs. placebo were 134/271 (49.4%) vs. 101/264 (38.3%), resulting in a NNT of 9 (95% CI 6-36). In study NCT03738215, MADRS response rates at Week 6 for CAR 1.5 mg/day vs. placebo were 110/250 (44.0%) vs. 87/249 (34.9%), resulting in a NNT of 11 (95% CI 6-193). For the pooled CAR ≥1 mg/day group, MADRS response rates at Week 6 were 765/1887 (40.5%) for CAR vs. 354/1101 (32.2%) for placebo, resulting in a NNT of 12 (95% CI 9-21). For the pooled CAR ≥1 mg/day group, rates of akathisia vs. placebo were 209/1893 (11.0%) vs. 25/1108 (2.3%) for placebo, resulting in a NNH of 12 (95% CI 10-14). This appears dose related as the NNH for akathisia vs. placebo was 24 (95% CI 17-43) for the 1-2 mg/day plus 1.5 mg/day dose groups, and 9 (95% CI 7-11) for the 2-4.5 mg/day plus 3 mg/day dose groups. For the pooled CAR ≥1 mg/day group, rates of discontinuation because of an AE vs. placebo were 122/1893 (6.4%) vs. 26/1108 (2.3%) for placebo, resulting in a NNH of 25 (95% CI 19-38). This appears dose related as the NNH for discontinuation because of an AE vs. placebo was 94 (ns) for the 1-2 mg/day plus 1.5 mg/day dose groups, and 17 (95% CI 13-28) for the 2-4.5 mg/day plus 3 mg/day dose groups. For the pooled CAR ≥1 mg/d group, rates of weight gain ≥7% from baseline vs. placebo were 35/1893 (1.8%) vs. 12/1108 (1.1%) for placebo, resulting in a NNH of 131 (ns). LHH comparing MADRS response vs. discontinuation because of an AE is >1, and >>1 for the lower dose range. Indirect comparisons of the above results with that of the effect sizes seen in positive studies of other adjunctive antipsychotic treatments vs. adjunctive placebo in MDD demonstrate similar values for NNT for response, and when the lower dose range of CAR is used, a more favorable NNH regarding discontinuation because of an AE. Importance The benefit-risk profile of CAR is favorable for adjunctive treatment of MDD. Funding AbbVie