A pooled post hoc analysis evaluating the safety and tolerability of cariprazine in bipolar depression

Abstract

Background: The safety and efficacy of cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was evaluated in 4 randomized, double-blind, placebo-controlled trials in patients with bipolar depression.

Methods: Safety and tolerability were evaluated in 2 post hoc analyses. Modal dose analysis: pooled data from all 4 flexible/fixed-dose trials (dose groups: <1.5, 1.5, 3 mg/d). Fixed-dose analysis: pooled data from 2 identically designed fixed-dose trials (1.5 and 3 mg/d dose groups).

Results: The modal dose and fixed-dose analyses evaluated data from 1775 and 970 patients, respectively. Cariprazine was generally safe and well tolerated; study completion rates were 78% and 82% in the modal dose and fixed-dose analyses, respectively. In modal dose analysis, treatment-emergent adverse events (TEAEs) occurred in 60% of overall cariprazine- and 55% of placebo-treated patients; nausea (8% vs 3%) and akathisia (7% vs 2%) occurred in ≥5% of cariprazine patients and twice the rate of placebo. Metabolic changes were small and generally similar for cariprazine and placebo; mean increase in glucose was 3.1 mg/dL for cariprazine and 2.6 mg/dL for placebo. Fixed-dose and modal dose findings were generally consistent; values for most metabolic parameters were slightly higher for fixed-dose 3 mg/d versus 1.5 mg/d.

Limitations: Post hoc analyses, modal dose groups, short treatment duration.

Conclusions: In modal dose (0.25-3 mg/d) and fixed-dose (1.5 and 3 mg/d) analyses, cariprazine was generally safe and well tolerated in the treatment of bipolar depression. Slightly improved tolerability was observed with fixed-dose cariprazine 1.5 mg/d versus 3 mg/d.

Trial registration: clinicaltrials.gov NCT00852202, NCT01396447, NCT02670538, NCT02670551.

Keywords: Bipolar depression; Bipolar disorder; Cariprazine; Safety; Tolerability.

Conflict of interest statement

Declaration of Competing Interest Roger S. McIntyre has received research grant support from Lundbeck, Shire, Otsuka, National Institute of Mental Health, Stanley Medical Research Institute, Canadian Institutes for Health Research, and The Brain and Behavior Research Foundation, and the Chinese National Natural Research Foundation. He has also received speaker/consultant fees from Lundbeck, Pfizer, AstraZeneca, Eli Lilly, Janssen Sunovion, Bausch Health, Takeda, Otsuka, Shire, Allergan, Purdue, Minerva, and Neurocrine. Trisha Suppes in the last 36 months has reported grants from National Institute of Mental Health, Sunovion Pharmaceuticals, Elan Pharma International Limited, VA Cooperative Studies Program, Pathway Genomics, Stanley Medical Research Institute, National Institute of Health, Palo Alto Health Sciences, and National Institute on Drug Abuse; consulting fees from Sunovion and Allergan, Inc.; honoraria from Medscape Education, Global Medical Education, and CMEology; and royalties from Jones and Bartlett, UpToDate, and Hogrefe Publishing. Joseph Calabrese has received federal funding from the Department of Defense, Health Resources Services Administration and National Institute of Mental Health; research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, NARSAD, Repligen, Stanley Medical Research Institute, Takeda, and Wyeth; served on advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo, EPI Q, Inc., Forest Laboratories, Inc., France Foundation, Gedeon Richter Plc., GlaxoSmithKline, Janssen, Johnson and Johnson, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Otsuka, Pfizer, Repligen, Schering-Plough, Servier, Solvay, Supernus, Synosia, Takeda, and Wyeth; and provided CME lectures supported by AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Sanofi Aventis, Schering-Plough, Pfizer, Solvay, and Wyeth. Lakshmi N. Yatham has received research support from or served as a consultant or speaker for Alkermes, AstraZeneca, Bristol-Myers Squibb, the Canadian Psychiatric Foundation, Canadian Institutes of Health Research, Dainippon Sumitomo, Forest, GlaxoSmithKline, Johnson & Johnson, Lilly, Lundbeck, NARSAD, Novartis, Otsuka, Pfizer, Servier, the Stanley Foundation, Sunovion, Teva, Valeant, and Wyeth. Willie R. Earley, Maria Burgess, Ludmyla Rekeda, and Arlene Hankinson are employees of Allergan.

Copyright © 2019. Published by Elsevier B.V.