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Targeting Serotonin 5-HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches

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Abstract

Schizophrenia is a major mental illness associated with profound disability. Current treatments for schizophrenia (antipsychotics) all have a similar mechanism of action and are primarily dopamine type 2 receptor (D2R) antagonists. Antipsychotics are not fully effective for the majority of schizophrenia patients, suggesting the need for alternative approaches. The primary focus of this review is to assess the evidence for the role of the serotonin type 2A receptor (5-HT2AR) in schizophrenia. Topics include an overview of 5-HT2AR physiology and pathophysiology in schizophrenia, 5-HT2AR interaction with other neurotransmitter systems, including the glutamatergic system, a review of the 5-HT2AR/d-lysergic acid diethylamide (LSD) model of schizophrenia, a contrast of the 5-HT2AR and glutamatergic models of schizophrenia, and finally, a review of Food and Drug Administration (FDA)-approved and investigational 5-HT2AR-modulating compounds. Recent studies with lumeteperone, pimavanserin, and roluperidone are highlighted.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY, USA

    Joshua T. Kantrowitz

  2. Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032, USA

    Joshua T. Kantrowitz

  3. Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY, 10914, USA

    Joshua T. Kantrowitz

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Dr. Kantrowitz reports having received consulting payments within the last 24 months from Krog & Partners Incorporated, Alphasights, Charles River Associates, Putnam Associates, Third Bridge, Piper Jaffray, MEDACorp, Simon Kucher, LifeSci Capital, ECRI Institute, ExpertConnect, Cellohealth, Acsel Health, Strafluence, Guidepoint, L.E.K. and System Analytic. He has served on the Aristada Schizophrenia Advisory Board for Alkermes and the MedinCell Psychiatry Advisory Board. He has conducted clinical research supported by the NIMH, Roche, Sunovion, the Stanley Foundation, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, Teva and Lilly within the last 24 months. Dr. Kantrowitz is a co-investigator on a study that receives lumeteperone and reimbursement for safety testing for investigator-initiated research from Intra-Cellular Therapies Inc. He owns a small number of shares of common stock from GSK.

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Kantrowitz, J.T. Targeting Serotonin 5-HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches. CNS Drugs 34, 947–959 (2020). https://doi.org/10.1007/s40263-020-00752-2

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