Exploring Combination Therapy for the Management of Psychotic Disorders: A Comprehensive Review.

Schizophrenia is a severe brain disorder impacting approximately 1% of the overall world population. A large number of FDA-approved antipsychotics are available in the market for the management of schizophrenia and other related disorders. However, 20-30% of patients exhibit treatment resistance, known as pharmacoresistant or refractory schizophrenia, where monotherapy proves to be ineffective. This review describes the various prevalent psychotic disorders, the antipsychotic mechanism of action, and drug resistance in monotherapy. The review highlights the significance of combination drug therapy in addressing treatmentresistant disorders, and various pre-clinical and clinical studies reported for combination therapy, along with modified delivery methods of antipsychotics and their combinations. For this purpose, we obtained evidence from preclinical and clinical studies investigating combinations, including other antipsychotics, mood stabilizers, NMDA receptor modulators, and anti-inflammatory agents. Combination therapy illustrates synergistic effects, enhanced symptom control, and reduced toxicity compared to monotherapy. Adjunctive use of natural compounds may alleviate oxidative stress, neuroinflammation, and neural toxicity. Modified drug-delivery systems further improve therapeutic efficacy. Overall, combination drug therapy represents a potential strategy for treatment-resistant schizophrenia by targeting multiple neurotransmitter pathways and associated pathophysiological mechanisms. Continued clinical validation and optimization of delivery methods are essential to establish their role in complete disease control.