Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial

Biol Psychiatry. 2015 Jun 1;77(11):979-88. doi: 10.1016/j.biopsych.2014.10.009. Epub 2014 Oct 23.


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.

Trial registration: ClinicalTrials.gov NCT00783120.

Keywords: Brain stimulation; Evidence-based psychiatry; Negative symptoms; Randomized controlled trial; Repetitive transcranial magnetic stimulation; Schizophrenia.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Double-Blind Method
  • Electroencephalography
  • Female
  • Functional Laterality / physiology*
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Prefrontal Cortex / physiology*
  • Psychiatric Status Rating Scales
  • Schizophrenia / physiopathology*
  • Schizophrenia / therapy*
  • Transcranial Magnetic Stimulation / methods*
  • Treatment Outcome
  • Young Adult

Associated data

  • ClinicalTrials.gov/NCT00783120