Safety and Tolerability of Cariprazine for the Adjunctive Treatment of Major Depressive Disorder: A Pooled Analysis of Phase 2B and 3 Clinical Trials

Abstract Background Cariprazine has been shown to be efficacious in placebo-controlled clinical trials. In this pooled analysis, the safety of cariprazine in patients with major depressive disorder (MDD) with inadequate response to antidepressants was evaluated using data from placebo-controlled studies of up to 8 weeks’ duration and a long-term open-label safety study. Methods The safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients with MDD with inadequate response to antidepressant alone was assessed in five placebo-controlled studies (two 6-week fixed-dose studies [NCT03738215; NCT03739203] and three 8-week flexible-dose studies [NCT00854100; NCT01715805; NCT01469377]) and one 26-week open-label flexible-dose study (NCT01838876). Fixed doses of cariprazine 1.5 and 3 mg/d and flexible doses of 0.1-4.5 mg/d were evaluated. Safety assessments included adverse event (AE) reporting, clinical laboratory tests, weight and other vital signs, and suicide evaluation with Columbia-Suicide Severity Rating Scale (C-SSRS). Pooled analyses of the incidence of safety endpoints overall and within each treatment arm were performed using the most frequent (modal) daily dose taken by patients during the study. Results A total of 2,222 MDD patients with an ongoing antidepressant received treatment with cariprazine, representing 370 patient-years of exposure in placebo-controlled and open-label studies. In the placebo-controlled studies, 1,969 patients were randomized to cariprazine (dose range, 0.1–4.5 mg/d) and 1,108 patients were randomized to placebo. Overall, treatment-emergent AEs occurred in 61% of cariprazine- and 48% of placebo-treated patients; discontinuation due to an AE occurred with 6% of cariprazine- and 2% of placebo-treated patients. The 2 AEs that occurred in at least 5% of cariprazine-treated patients and at a rate at least twice the rate in placebo-treated patients were akathisia (cariprazine=11%; placebo=2%) and restlessness (cariprazine=6%; placebo=2%). Changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar in cariprazine- and placebo-treated patients. In the long-term safety study, mean weight change was 1.6 kg over 6 months. In the placebo-controlled and long-term studies, other safety endpoints including laboratory and C-SSRS assessments of suicidality were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder and schizophrenia. Conclusion Cariprazine is generally safe and well-tolerated in MDD patients with inadequate response to antidepressant monotherapy. Safety analysis of 2,222 cariprazine-treated patients with MDD revealed no new safety signals, and the data is consistent with the currently approved prescribing information. Funding AbbVie