Effect of Cariprazine on Anhedonia in Patients with Bipolar I Depression: Post Hoc Analysis of Three Randomized Placebo-Controlled Clinical Trials

Introduction: Anhedonic symptoms in bipolar I (BP-I) depression are associated with decreased quality of life and impaired functioning. We evaluated the effects of cariprazine in patients with BP-I depression with lower or higher levels of anhedonia at baseline. Methods: Data were pooled from three clinical trials (NCT01396447, NCT02670538, NCT02670551) analyzing the effects of cariprazine 1.5 and 3 mg/day in adults with BP-I depression. During post hoc analysis, patients were stratified by baseline median Montgomery-& Aring;sberg Depression Rating Scale (MADRS) anhedonia factor score into a lower (score < median) or higher (score >= median) anhedonia subgroup. Outcomes included change from baseline to week 6 in MADRS total and anhedonia factor score, with the latter also evaluated after adjusting for other depressive symptoms. Between-group differences in change from baseline to week 6 were compared using least-squares mean differences (LSMD) analyzed via a mixed-effect model for repeated measures. Results: Median baseline anhedonia factor score was 19, defining the lower (placebo = 211; cariprazine 1.5 mg/day = 200, 3 mg/day = 212) and higher (placebo = 249; cariprazine 1.5 mg/day = 261, 3 mg/day = 250) anhedonia subgroups. In the lower subgroup, cariprazine 1.5 mg/day but not 3 mg/day was superior to placebo in reducing MADRS total (LSMD [95% CI] 1.5 mg/day = - 2.61 [- 4.28, - 0.93], P = .0024) and anhedonia factor scores (- 1.70 [- 2.77, - 0.62], P = .0021) at week 6. In the higher subgroup, both cariprazine doses were associated with significantly greater reductions than placebo in MADRS total (1.5 mg/day = - 3.01 [- 4.84, - 1.19], P = .0012; 3 mg/day = - 3.26 [- 5.12, - 1.40], P = .0006) and anhedonia factor scores (1.5 mg/day = - 1.97 [- 3.13, - 0.81], P = .0009; 3 mg/day = - 2.07 [- 3.26, - 0.89], P = .0006). Anti-anhedonic effects were preserved after adjusting for other depressive symptoms, suggesting the effect was not pseudospecific. Patients in the higher subgroup had higher baseline depression and therefore the lower subgroup may have had a floor effect. Conclusion: Cariprazine demonstrated antidepressant and specific anti-anhedonic effects regardless of baseline anhedonia symptoms in patients with BP-I depression.