Beyond Dopamine: Exploring Novel Pharmacological Targets for Improved Antipsychotic Outcomes

Schizophrenia is a disorder characterized by a multifaceted pathogenic mechanism impacted by numerous genes. The investigation of its pathophysiology is mostly dominated by the dopamine hypothesis. Multi-target therapies represent a viable strategy for addressing polygenic disorders characterized by intricate pathomechanisms, such as schizophrenia. Second-generation or atypical antipsychotics do, target many aminergic G protein-coupled receptors (GPCRs) at the same time. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. Dopaminergic receptor antagonism, which inhibits dopamine D2 receptors in the brain to produce antipsychotic effects, served as the foundation for the development of the first generation of antipsychotics. Antipsychotics of the second generation work by blocking both dopamine and 5-hydroxytryptamine receptors. From the third generation of antipsychotics onward, therapeutic targets for antipsychotic schizophrenia shifted away from D2 receptor blockage and toward D2 receptor partial agonism and the antipsychotic effects of novel targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3. Various receptors, such as 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors, NMDARs, and norepinephrine, contribute to schizophrenia development. As a result, the goal of developing new antipsychotic medications has shifted toward agonism or inhibition of these receptors. This study intends to present a narrative review of the research on therapeutic targets and drugs for schizophrenia, thereby providing significant insights for both therapy and future research in this area.