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Objectives: Biological strategies to improve treatment efficacy in clozapine-treated patients are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) merits consideration as intervention for patients with persistent auditory hallucinations (AH) or negative symptoms (NS) not responding sufficiently to clozapine treatment. Methods: Data from 10 international RCTs of rTMS for patients being treated with clozapine were pooled. Two levels of symptomatic response were defined: improvement of >= 20% and >= 50% on study-specific primary endpoint scales. Changes in the positive and negative syndrome scale (PANSS) from baseline to endpoint assessment were also analysed. Results: Analyses of 131 patients did not reveal a significant difference for >= 20% and >= 50% response thresholds for improvement of AH, negative or total symptoms between active and sham rTMS groups. The number needed to treat (NNT) for an improvement in persistent AH was nine following active rTMS. PANSS scores did not improve significantly from baseline to endpoint between active and sham groups in studies investigating NS and AH. Conclusions: rTMS as a treatment for persistent symptoms in clozapine-treated patients did not show a beneficial effect of active compared to sham treatment. For AH, the size of the NNTs indicates a possible beneficial effect of rTMS.

This exploratory study reports on the effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on (prefrontal) brain activity changes during ambiguous emotional evaluation in patients with schizophrenia. Before and after randomly assigned treatment with active and sham rTMS, patients performed the Wall of Faces task during fMRI scanning. fMRI analysis showed that rTMS treatment resulted in reduced activation of striato-fronto-parietal brain areas, while activation increased compared to baseline after sham. Thus, prefrontal rIMS may normalize an increased brain response to ambiguous emotional stimuli, but future studies should confirm these findings. (C) 2018 Elsevier B.V. All rights reserved.

Background Prefrontal cortical dysfunction is frequently reported in schizophrenia and is thought to underlie negative symptoms of schizophrenia. Repetitive Transcranial Magnetic Stimulation (rTMS) can modulate neuronal activity and has been shown to improve negative symptoms in patients with schizophrenia, but the underlying neural mechanism is unknown. Objective To examine whether 3 weeks of 10 Hz rTMS treatment of the bilateral dorsolateral prefrontal cortex (DLPFC) would improve frontal brain activation in patients with negative symptoms of schizophrenia, as measured by functional magnetic resonance imaging (fMRI) during the Tower of London (ToL) task. Methods 24 patients with the diagnosis of schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale ≥ 15) participated. Patients were randomized to a 3-week (15 day) course of active or sham rTMS. All patients performed the ToL task during fMRI scanning both pre-treatment and post-treatment. Differences in brain activation between the two groups were compared non-parametrically. Results After rTMS treatment, brain activity in the active group increased in the right DLPFC and the right medial frontal gyrus as compared to the sham group. In addition, the groups significantly differed with regard to activation change in the left posterior cingulate, with decreased activation in the active and increased activation in the sham group. Conclusions Treatment with rTMS over the DLPFC may have the potential for increasing task-related activation in frontal areas in patients with schizophrenia. Effects of different rTMS parameters and fMRI tasks targeting relevant brain circuitry deserve further investigation. Trial registration Nederlands Trial Register, registration number: NTR1261