New therapeutic approaches for treatment-resistant schizophrenia: A look to the future

• Clozapine remains the drug of choice for treatment-resistant schizophrenia.
• Augmentation strategies to clozapine have yet to be substantiated by convincing evidence.
• Studies with rTMS and tDCS demonstrated short-term improvements in VAH and/or negative symptoms in schizophrenia.

Schizophrenia for many patients is a lifelong mental disorder with significant consequences on most functional domains. One fifth to one third of patients with schizophrenia experience persistent psychotic symptoms despite adequate trials of antipsychotic treatment, and are considered to have treatment-resistant schizophrenia (TRS). Clozapine is the only medication to demonstrate efficacy for psychotic symptoms in such patients. However, clozapine is not effective in 40%–70% of patients with TRS and it has significant limitations in terms of potentially life-threatening side effects and the associated monitoring. Accordingly, a number of pharmacological and non-pharmacological biological approaches for clozapine-resistant TRS have emerged. This article provides a brief updated critical review of recent therapeutic strategies for TRS, particularly for clozapine-resistant TRS, which include pharmacotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation.