New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists

Abstract

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis—The Case of the Xanomeline–Trospium Combination: A Systematic Review

“…However, in the last decade, other pathophysiological mechanisms have been investigated in SSDs, and new drugs are in the pipeline that explore different neurotransmitter pathways [29,30]. For example, dysfunctions of serotonin, glutamate, gamma-aminobutyric acid (GABA), acetylcholine (Ach), norepinephrine, or cannabinoid systems, but also other non-neurotransmitter-related mechanisms, like dysregulation of gene expression, alteration of immune reactions, or neurodevelopmental abnormalities, have all been suggested as potential contributors to the onset of SSDs [29][30][31][32]. Also, the modulation of the trace amineassociated receptor 1 (TAAR-1) is being investigated as a possible way to reduce aberrant dopamine signaling and improve cerebral metabolism [33,34].…”

The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis—The Case of the Xanomeline-Trospium Combination: A Systematic Review

“…However, in the last decade, other pathophysiological mechanisms have been investigated in SSD, and new drugs are in the pipeline that explore different neurotransmitter pathways [29,30]. For example, dysfunctions of serotonin, glutamate, gamma-aminobutyric acid (GABA), acetylcholine (Ach), norepinephrine, or cannabinoid systems, but also other non-neurotransmitter-related mechanisms, like dysregulation of gene expression, alteration of immune reactions, or neurodevelopmental abnormalities, all have been suggested as potential contributors to the onset of SSD [29][30][31][32]. Also, modulation of the trace amine-associated receptor 1 (TAAR-1) is being investigated as a possible way to reduce aberrant dopamine signaling and improve cerebral metabolism [33,34].…”