Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial

doi:10.1016/j.biopsych.2014.10.009

Biological Psychiatry

Volume 77, Issue 11, 1 June 2015, Pages 979-988

https://doi.org/10.1016/j.biopsych.2014.10.009 Get rights and content

Abstract

Background

Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia.

Methods

A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007–2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly.

Results

There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21.

Conclusions

Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

Section snippets

Methods And Materials

Written informed consent was obtained from all subjects after complete description of the study. The local ethics committees approved the protocol, which was conducted in accordance with the Declaration of Helsinki.

Study Subjects

The investigators screened 197 patients, until the recruitment objective was reached. A total of 175 patients were enrolled and randomly assigned into a treatment group. After a 2-week period of assessment of eligibility, 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment; 127 patients remained in the sample at day 21 (see Supplement 1 for dropout analysis and Consolidated Standards of Reporting Trials diagram). Study patients were selected based on having clinically

Discussion

Compared with sham rTMS, augmentation of antipsychotic medication with active 10-Hz rTMS applied to the left DLPFC in patients with predominant negative symptoms of schizophrenia did not offer a benefit for the target symptoms over the 3-week, rater-blind and patient-blind portion or during the extension phase of this study. The global severity of illness and the severity of negative symptoms in this patient group were high, comparable in these domains to patients with refractory forms of

Acknowledgments And Disclosures

This work was supported by the Deutsche Forschungsgemeinschaft Grant No. FA–210/1. The trial protocol has been published (30) and is available at [email protected].

TW has received paid speakerships from Alpine Biomed, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, I3G, Janssen-Cilag, Novartis, Lundbeck, Roche, Sanofi-Aventis, Otsuka, and Pfizer; has accepted travel or hospitality not related to a speaking engagement from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and

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Archival ReportLeft Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods And Materials

Study Subjects

Discussion

Acknowledgments And Disclosures

Eur Neuropsychopharmacol

Brain Stimul

Neuroimage

Neuroimage

Schizophr Res

Psychiatry Res

Psychiatry Res

J Neurosci Methods

Biol Psychiatry

Electroencephalogr Clin Neurophysiol

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Arch Clin Neuropsychol

Schizophr Res

J ECT

Schizophr Res

Biol Psychiatry

Brain Stimul

Brain Stimul

Biol Psychiatry

Schizophr Res

Schizophr Res

Biol Psychiatry

Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States

Curr Med Res Opin

Course and Outcome

The NIMH-MATRICS consensus statement on negative symptoms

Schizophr Bull

Persistent negative symptoms in schizophrenia: an overview

Schizophr Bull

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance

World J Biol Psychiatry

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial

Arch Gen Psychiatry

Transcranial magnetic stimulation during positron emission tomography: A new method for studying connectivity of the human cerebral cortex

J Neurosci

Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation

J Neurosci

rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex

PLoS One

Archival Report
Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial