New and Emerging Treatments for Schizophrenia: Beyond Postsynaptic Dopamine Receptor Blockage

Abstract

Despite the discovery of chlorpromazine over 70 years ago and substantial pharmacologic advances, postsynaptic dopamine blockade has remained the sole mechanism of action of approved drugs for schizophrenia. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation.

This presentation describes and evaluates recently FDA approved agents or those in development that target efficacy and/or tolerability gaps in the management of schizophrenia via one or more mechanisms of action that go beyond postsynaptic dopamine blockade. Newly/recently approved agents include vesicular monoamine transporter-2 inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and, possibly, residual positive symptoms; olanzapine/samidorphan combination, lumateperone, new formulations, including subcutaneous injections, of long-acting injectable antipsychotics. Emerging agents in development that have at least one positive phase 1B, 2 or 3 trial include the trace amine-associated receptor-1 (TAAR1) ulotaront, M1/M4 muscarinic agonist xanomeline plus peripherally restricted anticholinergic trospium, the M4 muscarinic positive allosteric modulator emraclidine, as well as multiple other muscarinic receptor modulators for total psychopathology, the glycine transporter-1 inhibitor Iclepertin, D-amino acid oxidase (DAAO) inhibitor luvadaxistat and other molecules in development targeting cognitive impairment, and evenamide, a voltage-gated sodium channel modulator targeting glutamate signaling for treatment-resistant schizophrenia. Mechanisms of action other than postsynaptic dopamine blockade are urgently needed improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, as well as for cognitive symptoms, negative symptoms, and treatment resistance, each of which remain areas of great need in schizophrenia.

Learning Objectives

1.Recognize efficacy and tolerability characteristics and gaps of current postsynaptic antidopaminergic antipsychotic agents;

2.Identify mechanisms of action and efficacy signals of new and emerging molecules beyond postsynaptic dopamine blockade targeting different symptom domains in schizophrenia; and

3.Differentiate adverse effect profiles of new and emerging treatments for schizophrenia from agents with postsynaptic dopamine modulation and from each other.

Literature References

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2. Correll CU, Citrome L. Pharmacologic Treatment of Schizophrenia BeyondDopamine Receptor Blockade-Has Its Time Come Yet? JAMA Psychiatry. 2024 Feb1;81(2):118-120.