Over half of patients with treatment refractory schizophrenia will not respond to clozapine.1 A potential non-pharmacological strategy for clozapine augmentation is repetitive transcranial magnetic stimulation (rTMS). There is meta-analytic evidence that rTMS can reduce auditory hallucinations and negative symptoms in patients with schizophrenia on any antipsychotic.2
A recent study found rTMS was associated with reductions in total and positive psychotic symptoms in clozapine-treated patients with schizophrenia and predominant negative symptoms.3 Heterogeneity was assessed using the I2 statistic. The authors also performed sensitivity analysis based on location of electrode placement and study duration.
Siskind and colleagues4 conducted a systematic review and pairwise meta-analysis of rTMS studies in clozapine refractory schizophrenia. They searched multiple databases to identify all randomized-controlled trials of rTMS versus sham treatment in patients with clozapine-refractory schizophrenia. They performed pairwise meta-analysis on endpoint data: the primary outcome was total psychotic symptoms, and secondary outcomes were positive and negative symptoms.
The authors identified 88 unique articles and performed full-text review of 24 studies, of which 3 studies were included in the meta-analysis. Studies were conducted in Brazil and Germany, and treatment duration ranged from 10 to 28 days. Fifty-four participants (26 rTMS and 28 sham treatment) were included in the meta-analysis. Two studies placed electrodes over the left temporoparietal cortex, and the other stimulated the left dorsolateral prefrontal cortex. The sham stimulus was coil tilted at 45 degrees in two studies and a sham coil in the other study.
There was no significant difference between rTMS and sham for total, positive, and negative symptoms, with low between-study heterogeneity. Four patients in the rTMS group and none in the sham group reported headaches, and there was no significant difference in dropout rates between studies.
The authors found no benefit of rTMS for psychotic symptoms in clozapine refractory patients, which is in contrast to a previous meta-analysis of rTMS in with schizophrenia.2 They posit that the ultra-refractory nature of clozapine nonresponse may confer additional resistance to rTMS. Important limitations are the small number of studies and cumulative sample size, as well as variable electrode placement and sham stimulus. The authors note that need for effective pharmacological and non-pharmacological approaches for this patient population.
The bottom line
At present, there is not evidence to support the use of rTMS in patients with schizophrenia and inadequate response to clozapine.
Dr Miller is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is the Schizophrenia Section Editor for Psychiatric Times.
The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
1. Siskind D, Siskind V, Kisely S. Clozapine Response Rates Among People With Treatment-Resistant Schizophrenia: Data From a Systematic Review and Metaanalysis. Can J Psychiatry. 2017;62:772-777
2. Kennedy NI, Lee WH, et al. Efficacy of non-invasive brain stimulation on the symptom dimensions of schizophrenia: a meta-analysis of randomized controlled trials. Eur Psychiatry. 2018;48:69–77.
3. Wagner E, Wobrock T, Kunze B, et al. Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine. Schizophr Res. 2019;208:370-376.
4. Siskind D, Honarparvar F, Hasan A, et al. rTMS for clozapine refractory schizophrenia – A systematic review and pairwise meta-analysis. Schizophr Res. 2019;211:113-114