Impact of Cariprazine on Anhedonia Symptoms in Patients with Bipolar I Depression: Pooled Analysis of 3 Pivotal Clinical Trials

Purpose Anhedonia characterizes major depressive episodes in bipolar depression and is associated with more severe illness/poor prognosis. These post hoc analyses assess effect of cariprazine 1.5 and 3 mg/d on anhedonia symptoms in patients with bipolar I depression. Methods Data were pooled from 3 randomized, double-blind, placebo-controlled bipolar I depression trials in cariprazine. Cariprazine 1.5 and 3 mg/d versus placebo were evaluated in patient subgroups stratified by median baseline MADRS anhedonia score (higher anhedonia=score ≥19; lower anhedonia=score <19). Outcomes included mean change from baseline to week 6 in MADRS total and anhedonia factor score (sum of apparent sadness, reported sadness, concentration, lassitude, and inability to feel items). The proportion of patients with week 6 anhedonia factor response (≥50% improvement from baseline) was also determined. Changes from baseline were analyzed using a mixed-effect model for repeated measures. Results There were 760 patients in the higher anhedonia subgroup (placebo=249, cariprazine: 1.5 mg/d=261; 3 mg/d=250) and 623 patients in the lower anhedonia subgroup (placebo=211, cariprazine: 1.5 mg/d=200; 3 mg/d=212). Mean baseline MADRS total score was higher in the higher anhedonia subgroup (total=33.6) than in the lower anhedonia subgroup (total=27.6). Change from baseline to week 6 in MADRS total score was greater for both cariprazine doses versus placebo in the higher anhedonia subgroup (least squares mean difference [LSMD] and 95% confidence interval [CI]: 1.5 mg/d=-3.01 [-4.84, -1.19], P =.0012; 3 mg/d: -3.26 [-5.12, -1.40], P =.0006); in the lower anhedonia subgroup, cariprazine 1.5 mg/d was statistically significant versus placebo (-2.61 [-4.28, -0.93], P =.0024). In the higher anhedonia subgroup at week 6, change from baseline in anhedonia factor score was significant versus placebo for both cariprazine doses (1.5 mg/d=-1.97 [-3.13, -0.81], P =.0009; 3 mg/d=-2.07 [-3.26, -0.89], P =.0006); in the lower subgroup, the difference was significant versus placebo for cariprazine 1.5 mg/d (-1.70 [-2.77, -0.62], P =.0021). After adjusting for changes in other depressive symptoms, LSMDs versus placebo in the anhedonia factor score remained significant for cariprazine 1.5 mg/d (-1.21 [-2.05, -0.36], P =.0052) and 3 mg/d (-1.00 [-1.86, -0.14], P =.0233) in the higher anhedonia subgroup, and for 1.5 mg/d (-1.06 [-1.92, -0.19], P =.0164) in the lower subgroup. In the higher anhedonia subgroup, rates of anhedonia factor response were greater versus placebo (31.7%) for cariprazine 1.5 mg/d (44.8%, P =.0028) and 3 mg/d (45.6%, P =.0019); in the lower subgroup, response rates were 39.3% for placebo, 48.0% for 1.5 mg/d, and 46.7% for 3 mg/d. Adverse events in ≥5% cariprazine and twice placebo were nausea, akathisia, restlessness, and EPS. Importance Those with bipolar depression and anhedonia cariprazine demonstrated a potent antidepressant and antianhedonic effect in higher/lower anhedonia subgroups. Funding AbbVie This data was previously presented at the European College of Neuropsychopharmacology (ECNP) Congress; Barcelona, Spain; October 7 – 10, 2023.