The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders?

Abstract

Brexpiprazole is a serotonin–dopamine activity modulator in clinical development for schizophrenia, adjunctive treatment of major depressive disorder, agitation in Alzheimer’s disease and post-traumatic stress disorder. It is a partial agonist at 5-HT_1A and D₂ receptors with similar potency, and an antagonist at 5-HT_2A and adrenergic α_1B/2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5-HT_1A receptors and displays less intrinsic activity at D2 receptors. This unique serotonin and dopamine modulatory activity has shown robust antipsychotic, antidepressant-like and anxiolytic activities, and limited extrapyramidal symptom liability with pro-cognitive efficacy in animal models. Phase III clinical trials have been successfully completed in schizophrenia and adjunctive use in major depressive disorder, with the US FDA approval obtained for these uses; Phase III studies in Alzheimer’s disease and post-traumatic stress disorder are ongoing.

Keywords:

• behavioral models
• • brexpiprazole
• pharmacology
• preclinical
• receptor binding

Acknowledgements

In the past 36 months, L Citrome has been engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, Allergan (Actavis, Forest), AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant. K Maeda is a full-time employee of Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan. TB Stensbøl is a full-time employee of H. Lundbeck A/S. Mark Hughes, PhD, (QXV Communications, an Ashfield business, part of UDG Healthcare Plc, Macclesfield, UK) provided medical writing assistance, which was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, USA) and H. Lundbeck A/S (Valby, Denmark).

Financial & competing interests disclosure

L Citrome has served as a consultant for Alexza, Alkermes, Allergan (Actavis, Forest), Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant. L Citrome has served as a speaker for Allergan (Actavis, Forest), AstraZeneca, Janssen, Jazz, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda and Teva. L Citrome also has stocks in Bristol-Myers Squibb, Eli Lilly, J & J, Merck and Pfizer. TB Stensbøl is a full-time employee of H Lundbeck. K Maeda is a full-time employee of Otsuka Pharmaceuticals, Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Brexpiprazole is a serotonin–dopamine activity modulator.

• Brexpiprazole has high binding affinities for 5-HT_1A and D₂ receptors, where it acts as a partial agonist. Compared with aripiprazole, it is more potent at 5-HT_1A receptors and displays less intrinsic activity at D₂ receptors. Brexpiprazole also has antagonistic activity at several 5-HT receptors including 5-HT_2A, as well as at α_1B/2C-adrenergic receptors.

• At clinically relevant doses that showed good D₂ receptor occupancies in vivo, brexpiprazole demonstrated robust effects in animal models predictive of antipsychotic effects in schizophrenia.

• Brexpiprazole demonstrated pro-cognitive effects in rodents, including the reversal of phencyclidine-induced cognitive impairment in executive function.

• Adjunctive brexpiprazole demonstrated effects in animal models of depression- and anxiety-like behavior, including effects in mice on measures of immobility time in the forced swim test and on the reduction in marble-burying behavior.

• Brexpiprazole demonstrated nerve growth factor–induced neurite outgrowth, suggesting a role for neuronal plasticity and neuroprotection.

• Brexpiprazole has been approved by the US Federal Drug Administration based on four completed Phase III trials, two each for schizophrenia and the adjunctive treatment of major depressive disorder. Phase III trials for agitation in Alzheimer’s disease and for adjunctive use in post-traumatic stress disorder are ongoing.

Notes