title: Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial.
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.
authors.affiliation: Department of Psychiatry and Psychotherapy (TW, BG), Georg-August-Universtat Goettingen, Goettingen; Centre of Mental Health (TW), County Hospitals Darmstadt-Dieburg, Groß-Umstadt. Electronic address: t.wobrock@kreiskliniken-dadi.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wobrock
authors.affiliation: Department of Psychiatry and Psychotherapy (TW, BG), Georg-August-Universtat Goettingen, Goettingen.
authors.forename: Birgit
authors.initials: B
authors.lastname: Guse
authors.affiliation: Department of Psychiatry and Psychotherapy, Heinrich-Heine University, Düsseldorf; Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich, Heine University, Düsseldorf.
authors.forename: Joachim
authors.initials: J
authors.lastname: Cordes
authors.affiliation: Department of Psychiatry and Psychotherapy, Heinrich-Heine University, Düsseldorf; Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich, Heine University, Düsseldorf.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wölwer
authors.affiliation: Department of Psychiatry and Psychotherapy, Heinrich-Heine University, Düsseldorf; Charité-Universitätsmedizin Berlin, Berlin.
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
authors.affiliation: Department of Psychiatry and Psychotherapy, Heinrich-Heine University, Düsseldorf; Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich, Heine University, Düsseldorf.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gaebel
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg.
authors.forename: Berthold
authors.initials: B
authors.lastname: Langguth
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg; Department of Psychiatry, Psychosomatics and Psychotherapy, kbo-Lech-Mangfall-Klinik, Agatharied.
authors.forename: Michael
authors.initials: M
authors.lastname: Landgrebe
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg.
authors.forename: Peter
authors.initials: P
authors.lastname: Eichhammer
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg.
authors.forename: Elmar
authors.initials: E
authors.lastname: Frank
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Sozialstiftung Bamberg, Bamberg.
authors.forename: Göran
authors.initials: G
authors.lastname: Hajak
authors.affiliation: Coordination Centre for Clinical Trials, Heinrich-Heine University, Düsseldorf.
authors.forename: Christian
authors.initials: C
authors.lastname: Ohmann
authors.affiliation: Coordination Centre for Clinical Trials, Heinrich-Heine University, Düsseldorf.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Verde
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Institute of Central Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Institut für anwendungsorientierte Forschung und klinische Studien GmbH, Goettingen, Germany.
authors.forename: Raees
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Department of Psychiatry and Institute of Mental Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: William G
authors.initials: WG
authors.lastname: Honer
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universtat, Munich, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Malchow
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universtat, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider-Axmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universtat, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universtat, Munich, Germany.
authors.forename: Alkomiet
authors.initials: A
authors.lastname: Hasan
mesh_terms: D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D007839:Functional Laterality / Q000502:physiology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000502:physiology*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000503:physiopathology* / Q000628:therapy*; D050781:Transcranial Magnetic Stimulation / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
keywords: Brain stimulation; Evidence-based psychiatry; Negative symptoms; Randomized controlled trial; Repetitive transcranial magnetic stimulation; Schizophrenia