EFFICACY OF CARIPRAZINE FOR ANHEDONIA SYMPTOMS: A POOLED ANALYSIS OF PATIENTS WITH MAJOR DEPRESSIVE DISORDER AND BIPOLAR I DEPRESSION

Introduction

Anhedonia is a core feature of major depressive disorder (MDD) and bipolar I (BP-I) depression and is associated with suicidality and comorbidities. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, is approved for the treatment of manic/mixed and depressive episodes of BP-I and for the treatment of MDD as an adjunctive therapy to antidepressants. This pooled analysis evaluates the anti-anhedonic effects of CAR in MDD and BP-I depression.

Methods

Data were collected from pivotal clinical trials evaluating CAR for the adjunctive treatment of MDD (NCT03738215 and NCT01469377) and the treatment of BP-I depression (NCT02670551, NCT01396447, and NCT02670538). The trials were 6-8 weeks in duration, with CAR doses of 1-4.5 mg/d in MDD and 1.5-3 mg/d in BP-I. The pooled analysis compared the change from baseline to week 6 or week 8 (NCT01469377 only) between CAR and placebo in Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia factor score (items: 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]). Extracted data included least-squares (LS) mean changes, standard errors, and the least-squares mean differences (LSMDs) with 95% CIs derived from mixed models for repeated measures. A multilevel random-effects model accounted for multiple treatment arms sharing the same placebo group and within-study clustering. Dose and study duration were examined as exploratory moderators and heterogeneity was assessed using Cochran’s Q test and variance component estimates.

Results

CAR significantly reduced MADRS anhedonia factor scores compared to placebo in all 5 included studies. In MDD, the change from baseline to week 6/8 was significantly greater for CAR vs placebo for both doses evaluated in NCT03738215 (1.5 mg/d, LSMD [95% CI]: -1.54 [-2.56, -0.52]; 3 mg/d, -1.09 [-2.11, -0.07]) and the 2-4.5 mg/d dose group in NCT01469377 (1-2 mg/d, -0.81 [-1.79, 0.17]; 2-4.5 mg/d, -1.28 [-2.27, -0.29]). In BP-I depression, the change from baseline to week 6 was significantly greater for CAR vs placebo for both doses in NCT02670551 (1.5 mg/d, -2.05 [-3.15, -0.95]; 3 mg/d, -2.46 [-3.56, -1.36]) and NCT01396447 (1.5 mg/d, -2.22 [-3.40, -1.04]; 3 mg/d, -1.27 [-2.47, -0.07]) and for CAR 1.5 mg/d in NCT02670538 (1.5 mg/d, - 1.14 [-2.21, -0.07]; 3 mg/d, -0.92 [-2.01, 0.17]). The multilevel random-effects model yielded a pooled LSMD in MADRS anhedonia factor score for CAR vs placebo of -1.46 (95% CI: -1.91, -1.00, P < .001). Exploratory moderator analyses showed no effect of dose or study duration on the magnitude of the treatment effect (P=.63). There was no significant heterogeneity in the primary model (Q[9]=9.52, P=.39) and between-study variance was modest (σ²=0.12), while the within-study (arm-level) variance was negligible, indicating most variability reflected differences between studies rather than dose arms.

Conclusions

Cariprazine demonstrated a transdiagnostic effect on symptoms of anhedonia both as adjunctive treatment in MDD and monotherapy in BP-I depression, suggesting cariprazine may be an effective treatment for symptoms of anhedonia regardless of indication.