Targeting Serotonin 5-HT 2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches
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REVIEW ARTICLE
Targeting Serotonin 5‑HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches Joshua T. Kantrowitz1,2,3
© Springer Nature Switzerland AG 2020
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. Key Points There are no Food and Drug Administration (FDA)approved non-dopaminergic antipsychotics for schizophrenia. While the LSD model of schizophrenia is imperfect, evidence supports a role for serotonin type 2A receptor (5-HT2AR) pathophysiology in schizophrenia. Many antipsychotics have binding affinity at both the dopamine type 2 receptor and 5-HT2AR, but the clinical relevance of 5-HT2AR antagonism for FDA-approved antipsychotics remains unclear. Promising recently approved and investigational 5-HT2AR-modulating treatments include lumeteperone, pimavanserin, and roluperidone.
* Joshua T. Kantrowitz [email protected] 1
Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY, USA
2
Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA
3
Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY 10914, USA
1 Introduction Schizophrenia is a major mental illness associated with psychotic (positive) symptoms, such as hallucinations and delusions, and negative symptoms, such as avolition (e.g., decreased motivation) and asociality (e.g., decreased interest/opportunity in social interactions) [1]. In addition, schizophrenia patients have cognitive deficits [2–4]. The treatment of positive symptoms is clearly important, but the persistent disability of schizophrenia often comes from negative symptoms and cognitive deficits that represent a core feature of the disorder [5, 6] and are highly predictive of functional outcomes [7–10]. Antipsychotics are the mainstay of treatment for schizophrenia. While various subdivisions exist for antipsychotics, including those based on date of release (e.g., first vs. second generation), efficacy or predominant side effects, all marketed antipsych
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