Adjunctive Cariprazine Safe for Treating Major Depressive Disorder

Michael E. Thase, MD

Credit: Perelman School of Medicine at University of Pennsylvania

A pooled analysis of phase 3 trials found patients on cariprazine for major depressive disorder (MDD) had high rates of study completion with only mild to moderate treatment-emergent adverse events.¹

“In an analysis based on 2 fixed-dose studies using the recommended adjunctive doses of cariprazine in MDD (1.5 and 3 mg/d), outcomes were consistent with the known safety profile in schizophrenia, bipolar mania, and bipolar depression; no new safety signals were identified,” said investigators led by Michael E. Thase, MD, from the Perelman School of Medicine at University of Pennsylvania.

The investigators sought to examine the safety and tolerability of adjunctive cariprazine in patients with MDD and inadequate response to monotherapy antidepressant treatment. The FDA approved cariprazine as an adjunctive treatment with antidepressant therapy for MDD back on December 16, 2026.²

Several trials tested cariprazine in patients with MDD.1 A flexible-dose study demonstrated positive outcomes of cariprazine 2 – 4.5mg/d plus monotherapy antidepressant treatment (ADT) after assessing change from baseline in the Montgomery-Åsberg Depression Rating Scale total score. A fixed-dose study showed positive outcomes of cariprazine 1.5 mg/d plus ADT.

Thase and colleagues conducted several analyses of trials evaluating cariprazine in patients with MDD using different pooling strategies. Altogether, data was leveraged from 5 randomized, double-blind, placebo-controlled, parallel-group trials of cariprazine plus ongoing ADT.

The main analysis pooled data from fixed-dose trials to assess the safety and tolerability of cariprazine 1.5 mg/d and the recommended dose of 3 mg/d. Trials included 1508 patients (cariprazine plus ADT: overall = 1005; 1.5 mg/d = 502; 3 mg/d = 503; placebo plus ADT = 503).

Moreover, a supported analysis pooled data from all 5 fixed and flexible dose trials with cariprazine 1.5 – 4.5 mg/d and included 3077 patients (overall cariprazine = 1969; placebo = 1108).

In the pooled analysis, patients had a 90% complete rate, and only 4.3% discontinued the treatment due to mild or moderate treatment-emergent adverse events. The team observed akathisia, nausea, and insomnia in ≥ 5% of cariprazine patients and at twice the rate of placebo. They saw potential dose-dependent responses for akathisia and insomnia.

Akathisia caused > 1 of patients in any group to discontinue, which is greater than any other adverse event. Less than 1% of participants across groups reported serious adverse events, with 5 patients on cariprazine experiencing serious adverse events such as injury, atrial fibrillation, kidney infection, and social stay hospitalization, and 3 patients in the placebo group experiencing intestinal obstruction, multiple sclerosis, and depression. None of the serious events were drug-related.

The team found a greater percentage of cariprazine patients over placebo needed rescue medications for insomnia (7.2% and 7.6% vs. 4%) and rescue medications for agitation, restlessness, and hospitality (1.3% and 2% vs. 0.4%).

Cariprazine patients had more extrapyramidal event treatment-emergent adverse events (TEAEs) with most mild/moderate (placebo = 100%; overall cariprazine = 96.6%) and none meeting the criteria for a serious adverse event (SAE). More patients with cariprazine than placebo had BARS-defined akathisia.

The investigators also observed a slight decrease in total cholesterol and low-density lipoprotein from baseline to end of treatment for cariprazine and placebo. Changes in high-density lipoprotein were small and variable, and there was a greater increase in triglycerides in cariprazine compared to placebo.

Additionally, the team observed mean changes from baseline in aspartate aminotransferase and alanine aminotransferase were greater for cariprazine than placebo patients. They found mean changes from baseline to end of treatment in blood pressure parameters were small and similar for cariprazine and placebo groups. The number of patients with a Columbia-Suicide Severity Rating Scale-related suicidal ideation during treatment was similar for cariprazine and placebo patients.

Ultimately, cariprazine had a neutral metabolic profile, with a mean weight increase of < 1 kg. Overall, the study found cariprazine had a safe profile and was well-tolerated in patients.

“The high study completion rate, along with low rates of rescue medication use, suggest that TEAEs were generally tolerable and well managed, and in most cases, did not cause treatment discontinuation,” investigators wrote. “Importantly, no increased risk for hypomania/mania was observed in cariprazine-treated patients.”

Investigators pointed out multiple limitations, including the exclusion of participants with potential comorbid conditions, the short study duration, the strict inclusion criteria limiting generalizability, and participants taking both cariprazine and ADT which makes it impossible to evaluate how each treatment contributed to treatment-emergent events or if there were combined effects.

“Although some dose-related effects were observed for cariprazine 1.5 mg/d and 3 mg/d plus ADT in the fixed-dose analysis, high rates of completion, mild or moderate TEAEs, and a neutral metabolic profile suggest that the recommended adjunctive doses were generally appropriate and acceptable for the treatment of patients with MDD,” investigators concluded.

^References

1. ^{Thase ME, Yeung PP, Rekeda L, Liu M, Varughese S. Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials. Int Clin Psychopharmacol. Published online January 25, 2024. doi:10.1097/YIC.0000000000000528}
2. ^{Kunzmann, K. FDA Approves Cariprazine as Adjunctive Major Depressive Disorder Therapy. HCPLive. December 16, 2022. https://www.hcplive.com/view/fda-approves-cariprazine-adjunctive-major-depressive-disorder-therapy. Accessed February 5, 2023.}