Targeting Serotonin 5-HT_2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches

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-HT_2AR) in schizophrenia. Topics include an overview of 5-HT_2AR physiology and pathophysiology in schizophrenia, 5-HT_2AR interaction with other neurotransmitter systems, including the glutamatergic system, a review of the 5-HT_2AR/d-lysergic acid diethylamide (LSD) model of schizophrenia, a contrast of the 5-HT_2AR and glutamatergic models of schizophrenia, and finally, a review of Food and Drug Administration (FDA)-approved and investigational 5-HT_2AR-modulating compounds. Recent studies with lumeteperone, pimavanserin, and roluperidone are highlighted.