Advances in schizophrenia research and treatment: exploring neurotransmitter imbalances, genetics, and innovative therapies

Schizophrenia is a severe mental disorder arising from genetic vulnerability, impaired neurodevelopment, neurobiological dysregulation, and environmental factors. Its pathophysiology involves disturbances in dopamine, glutamate, and serotonin systems, as well as neuroinflammation, oxidative stress, gut–brain axis dysfunction, and altered energy metabolism. Current dopaminergic pharmacotherapy is often complicated by insufficient efficacy, adverse effects, and patient non-compliance. This review summarizes genetic predispositions, neurotransmitter imbalances, and other contributing factors of schizophrenia, as well as therapeutic advances in novel antipsychotic therapies. Newly developed therapeutic agents preferentially target the serotonergic, muscarinic, glutamatergic, and GABAergic neurotransmitter systems. They include muscarinic agonists, glycine transporter type 1 inhibitors, trace amine-associated receptor 1 agonists, D-amino acid oxidase inhibitors, and agonists or positive allosteric modulators of metabotropic glutamate receptors, and serotonin receptor inverse agonists. Recently, the antipsychotics lumateperone and xanomeline-trospium were approved. Iclepertin, ralmitaront, roluperidone, and brilaroxazine are molecules in Phase 2 or 3 clinical trials. Novel antipsychotic drugs are being developed to effectively treat negative symptoms, cognitive deficits, and total psychopathology in patients with schizophrenia. Adjuvant treatments aimed at mitigating neuroinflammation and oxidative stress; microbiome-targeted interventions, neuroprotective and metabolic agents are being explored. Current research efforts aim to improve treatment outcomes by addressing gaps in antipsychotic therapy and mitigating its adverse effects. • Dopaminergic therapy is limited by low efficacy, side effects, and noncompliance. • New antipsychotics target cholinergic, serotonergic, glutamatergic and GABA systems. • New drugs aim to treat negative and cognitive symptoms, and total psychopathology. • Adjunctive therapies target neuroinflammation, oxidative stress, and the microbiome.