Efficacy and safety of combining clozapine with electrical or magnetic brain stimulation in treatment-refractory schizophrenia

Introduction: A substantial proportion (40-70%) of patients with treatment-resistant schizophrenia experience persistent symptoms despite an adequate clozapine trial. Brain stimulation techniques (BST) such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) have shown promise in medication-refractory schizophrenia. However, their co-administration with clozapine raises some safety concerns.Areas covered: We conducted a systematic literature search through Pubmed and cross-references for relevant publications evaluating the safety and efficacy of combining BST with clozapine.Expert commentary: Evidence from a randomized controlled trial and open-label trials suggest that ECT is an effective intervention in clozapine-refractory schizophrenia. There is limited evidence that the combination is safe. However, until sufficient data accumulate, it would be prudent to be vigilant against adverse effects related to lowered seizure threshold, cognitive impairment, and cardiovascular events. Both high frequency rTMS over the dorsolateral prefrontal cortex and low frequency rTMS over the temporoparietal cortex have been safely administered in patients receiving clozapine. However, rTMS efficacy in clozapine-refractory patients remains uncertain. The evidence for tDCS-clozapine combination is in the form of case reports and needs to be evaluated in controlled trials. Newer methods of brain stimulation and refinement of existing BSTs hold promise for the future.