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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.

Background Negative symptoms in schizophrenia concern a clinically relevant reduction of goal-directed behavior that strongly and negatively impacts daily functioning. Existing treatments are of marginal effect and novel approaches are needed. Noninvasive neurostimulation by means of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are novel approaches that may hold promise. Objectives To provide a quantitative integration of the published evidence regarding effects of rTMS and tDCS over the frontal cortex on negative symptoms, including an analysis of effects of sham stimulation. Methods Meta-analysis was applied, using a random effects model, to calculate mean weighted effect sizes (Cohen's d). Heterogeneity was assessed by using Cochrans Q and I2 tests. Results For rTMS treatment, the mean weighted effect size compared to sham stimulation was 0.64 (0.32–0.96; k = 22, total N = 827). Studies with younger participants showed stronger effects as compared to studies with older participants. For tDCS studies a mean weighted effect size of 0.50 (−0.07 to 1.07; k = 5, total N = 134) was found. For all frontal noninvasive neurostimulation studies together (i.e., TMS and tDCS studies combined) active stimulation was superior to sham, the mean weighted effect size was 0.61 (24 studies, 27 comparisons, 95% confidence interval 0.33–0.89; total N = 961). Sham rTMS (baseline - posttreatment comparison) showed a significant improvement of negative symptoms, d = 0.31 (0.09–0.52; k = 16, total N = 333). Whereas previous meta-analyses were underpowered, our meta-analysis had a power of 0.87 to detect a small effect. Conclusions The available evidence indicates that noninvasive prefrontal neurostimulation can improve negative symptoms. This finding suggests a causal role for the lateral frontal cortex in self-initiated goal-directed behavior. The evidence is stronger for rTMS than for tDCS, although this may be due to the small number of studies as yet with tDCS. More research is needed to establish moderator variables that may affect response to neurostimulation and to optimize treatment parameters in order to achieve stable and durable (and thus clinically relevant) effects.

Background: Prefrontal repetitive Transcranial Magnetic Stimulation (rTMS) may improve negative symptoms in patients with schizophrenia, but few studies have investigated the underlying neural mechanism.Objective: This study aims to investigate changes in the levels of glutamate and glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate (NAA) in the left dorsolateral prefrontal cortex of patients with schizophrenia treated with active bilateral prefrontal rTMS as compared to sham-rTMS, as measured with H-1-Magnetic Resonance Spectroscopy (H-1-MRS).Methods: Patients were randomized to a 3-week course of active or sham high-frequency rTMS. Pretreatment and post-treatment 1H-MRS data were available for 24 patients with schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale >= 15). Absolute metabolite concentrations were calculated using LCModel with the water peak as reference. To explore the association between treatment condition and changes in concentration of Glx and NAA, we applied a linear regression model.Results: We observed an increase of Glx concentration in the active treatment group and a decrease of Glx concentration in the group receiving sham treatment. The association between changes in Glx concentration and treatment condition was significant. No significant associations between changes in NAA and treatment condition were found.Conclusions: Noninvasive neurostimulation with high-frequency bilateral prefrontal rTMS may influence Glx concentration in the prefrontal cortex of patients with schizophrenia. Larger studies are needed to confirm these findings and further elucidate the underlying neural working mechanism of rTMS. (C) 2016 Elsevier Inc. All rights reserved.

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.

Objective: Negative symptoms can be grouped into two factors, expressive deficits and social-emotional withdrawal. We aimed to examine the neural correlates of the two negative symptom factors during a social cognition task, which measures emotional ambiguity in a social context by presenting an array of faces with varying degrees of consistency in emotional expressions. Methods: Patients with schizophrenia (N=38) and healthy controls (N=20) performed a social cognition task during fMRI that probed both affect and ambiguity. Differences in brain activation between the healthy controls and patients were non-parametrically tested. Subsequently, the expressive deficits and social-emotional withdrawal factors were regressed against task-related brain activation. Results: Severity of expressive deficits was negatively correlated with activation of the ventromedial prefrontal cortex when comparing ambiguous emotional decisions to ambiguous gender decisions. During emotional ambiguity, severity of expressive deficits was negatively correlated with activation in thalamic, prefrontal, precentral, parietal and temporal brain areas. No associations between social-emotional withdrawal and brain activation were observed. Conclusion: Hypoactivation of the fronto-thalamic circuitry during ambiguous social appraisal may imply a reduced action readiness in social situations, underlying expressive deficits but not social-emotional withdrawal. The findings provide further evidence for different neurobiological bases of the two factors of negative symptoms.

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

Background: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for the negative symptoms of schizophrenia. During the past decade, several trials have reported on the efficacy of rTMS treatment; however, the results were inconsistent. Objective: To assess the efficacy of prefrontal rTMS for treating negative symptoms of schizophrenia. Data Sources: A literature search was performed in PubMed, ISI Web of Science, and EMBASE for the years 1985 through July 2008. The search terms used (language not specified) were "transcranial magnetic stimulation," "negative symptoms," and "schizophrenia?' A cross-reference search of eligible articles was performed to identify studies not found in the computerized search. Study Selection: Studies selected were randomized controlled trials assessing the therapeutic efficacy of prefrontal rTMS for negative symptoms in schizophrenia. Data Extraction: Effect sizes (Cohen d) of each study were calculated. The overall standardized mean difference was calculated under a random effects model with 95% confidence intervals. Data Synthesis: Nine trials, involving 213 patients, were included in the meta-analysis. The overall mean weighted effect size for rTMS versus sham was in the small-to-medium range and statistically significant (d = 0.43; 95% CI, 0.05-0.80). When including only the studies using a frequency of stimulation of 10 Hz, the mean effect size increased to 0.63 (95% CI, 0.11-1.15). When including only the studies requiring participants to be on a stable drug regimen before and during the study, the mean weighted effect size decreased to 0.34 (95% CI, 0.01-0.67). Studies with a longer duration of treatment (>= 3 weeks) had a larger mean effect size when compared to studies with a shorter treatment duration: d=0.58 (95% CI, 0.19-0.97) and d=0.32 (95% CI, -0.3 to 0.95), respectively. Conclusions: The results of this meta-analysis warrant further study of rTMS as a potential treatment of negative symptoms of schizophrenia. J Clin Psychiatry 2010;71(4):411-418 (C) Copyright 2010 Physicians Postgraduate Press, Inc.