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

Abstract

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.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

“…The reported effects were either AEs typical of tDCS or of the medication, e.g., vertigo, tiredness, vomiting, (dopaminergics, NMDA receptor antagonists or benzodiazepines). No SAEs have been reported with combinations, e.g., tDCS and clozapine (Arumugham et al, 2016). Thus, currently there is no evidence that the combination of pharmacotherapy with TES results in enhanced risks exceeding AEs, which can attributed to the respective single interventions.…”

Adverse events of tDCS and tACS: A review

“…Indeed, in a rat seizure model, Liebetanz et al (2006) reported that seizure threshold was not reduced by anodal tDCS (Liebetanz et al, 2006). tDCS within the standard protocols is considered safe for both adults and children and for both healthy subjects and patients (Nitsche and Paulus, 2001, Nitsche and Paulus, 2015, Nitsche et al, 2003a, Nitsche et al, 2003b, Arul-Anandam et al, 2009, Borckardt et al, 2011, Borckardt et al, 2012, Peruzzotti-Jametti et al, 2013, Bennabi et al, 2015, Gillick et al, 2015, Ho et al, 2015, Krishnan et al, 2015, Matsumoto and Ugawa, 2015, Meron et al, 2015, Moliadze et al, 2015, Oberman and Enticott, 2015, San-Juan et al, 2015, Smit et al, 2015, Xu et al, 2015, Aparício et al, 2016, Arumugham et al, 2016, Bikson et al, 2016, Cha et al, 2016, Gbadeyan et al, 2016, Hu et al, 2016, Muszkat et al, 2016, Palm et al, 2016, Rubio et al, 2016, Shivakumar et al, 2016, Woods et al, 2016). Yet it remains important to be aware of the potential adverse effects of tDCS.…”

Clozapine-resistant schizophrenia – non pharmacological augmentation methods

“…CSP elongation was also observed after successful treatment of schizophrenia by ECT and rTMS [22,23]. In connection with the evidence suggesting GABABneurotransmissiondeficiency in schizophrenia [24], it seems reasonable to combine these stimulation methods with clozapine in patients resistant to antipsychotic therapy [11].…”

“…It should be noted that treatment with clozapine only is sometimes associated with the risk of serious side effects (hematologic, cardiac or metabolic), which should be taken into account in choosing the appropriate method of augmentation [11]. This problem, among other things, prompts the search for non-pharmacological methods of augmentation with clozapine.…”

“…In comparison to studies on pharmacotherapy, much less space is devoted to combining clozapine with electroconvulsive therapy (C+ECT), transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) [11].…”