BackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

BackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy; adjunctive treatment is often used to address this unmet need. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with manic, mixed, or depressive episodes of bipolar I disorder, is under investigation as adjunctive therapy for patients with MDD.MethodsThis randomized, double-blind, phase 3 placebo (PBO)-controlled study assessed the efficacy, safety, and tolerability of CAR 1.5 and 3 mg/d as an adjunct to ADT in adult patients with MDD (18–65 years) and inadequate response to ADT alone (NCT03738215). The primary endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions (CGI) were also assessed. Treatment response was defined as at least 50% decrease in MADRS total score at week 6.ResultsPatients (n=751) in the modified intent-to-treat population were randomly assigned to CAR 1.5 mg/d+ADT (n=250), CAR 3 mg/d+ADT (n=252), or PBO+ADT (n=249). Mean age was 44.8 years and 73.4% were female; mean baseline total scores were: MADRS=32.5, HAMD-17=25.9, HAM-A= 21.4. Overall, 89.7% of patients completed the study; rates of discontinuation due to adverse events (AEs) and lack of efficacy were 3.6% and 0.5%, respectively. The difference in MADRS total score change from baseline to week 6 was statistically significant after multiplicity adjustment for CAR 1.5 mg/d vs PBO (-14.1 vs -11.5; adjusted P=.0050), but not for CAR 3 mg/d (-13.1; P=.0727). Differences for CAR 1.5 mg/d vs PBO were observed by week 2 (nominal P=.0453) and maintained at weeks 4 (nominal P<.0001) and 6 (nominal P=.0025). At week 6, more CAR 1.5 mg/d patients (44%) than PBO patients (34.9%) responded to treatment (nominal P=.0446). Greater improvement in the CGI-I scores was observed for CAR 1.5 (nominal P=.0026) and 3 mg/d (nominal P=.0076) vs PBO. At week 6, improvement in HAMD-17 total score reached nominal significance for CAR 1.5 mg/d vs PBO (-13.1 vs -11.1; nominal P=.0017), but not for CAR 3 mg/day (-12.2; P=.0783). HAM-A improvement was greater for CAR 1.5 mg/d vs PBO (nominal P=.0370). There were no deaths; 2 serious AEs occurred in each group (CAR: kidney infection, social stay hospitalization; PBO: depression, multiple sclerosis). The most common CAR AEs (≥5% and twice PBO) were akathisia and nausea.ConclusionCariprazine 1.5 mg/d was effective as adjunctive treatment in adults with MDD and inadequate response to ADT. Cariprazine was generally well tolerated, with a safety profile that was consistent with other indications. Together with results from a prior flex-dose study, these results suggest that adjunctive cariprazine may be an effective option for patients with inadequate response to ADT alone.FundingAbbVie