Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis

This study sought to determine the moderators in the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in schizophrenia. We performed a meta-analysis of prospective studies on the therapeutic application of rTMS in schizophrenia assessing the effects of both low-frequency and high-frequency rTMS on negative symptoms. Results indicate that rTMS is effective in alleviating negative symptoms in schizophrenia. The effect size was moderate (0.63 and 0.53, respectively). The effect size of rTMS on negative symptoms in sham-controlled trials was 0.80 as measured by the SANS and 0.41 as measured by the PANSS. A longer duration of illness was associated with poorer efficacy of rTMS on negative symptoms. A 10 Hz setting, at least 3 consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms. The results of our meta-analysis suggest that rTMS is an effective treatment option for negative symptoms in schizophrenia. The moderators of rTMS on negative symptoms included duration of illness, stimulus frequency, duration of illness, position and intensity of treatment as well as the type of outcome measures used.

[1]  T. Kašpárek,et al.  A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: A double-blind trial , 2013, Schizophrenia Research.

[2]  R. Kahn,et al.  Psychosis and brain volume changes during the first five years of schizophrenia , 2009, European Neuropsychopharmacology.

[3]  N. Andreasen.  The Scale for the Assessment of Negative Symptoms (SANS): Conceptual and Theoretical Foundations , 1989, British Journal of Psychiatry.

[4]  Klaus Funke,et al.  Theta burst and conventional low-frequency rTMS differentially affect GABAergic neurotransmission in the rat cortex , 2009, Experimental Brain Research.

[5]  Yong-Ku Kim,et al.  Adjunctive treatment of bimodal repetitive transcranial magnetic stimulation (rTMS) in pharmacologically non-responsive patients with schizophrenia: A preliminary study , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[6]  M. Marcolin,et al.  A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine , 2011, Psychiatry Research.

[7]  S. Marder,et al.  Treatment of schizophrenia negative symptoms: future prospects. , 2006, Schizophrenia bulletin.

[8]  J. Brinkmeyer,et al.  Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia , 2010, Psychiatry Research.

[9]  P. DeRosse,et al.  Cognitive and symptomatic predictors of functional disability in schizophrenia , 2011, Schizophrenia Research.

[10]  P. Fitzgerald,et al.  A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia , 2012, Brain Stimulation.

[11]  S. Potkin,et al.  Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia. , 2005, Schizophrenia bulletin.

[12]  J. Ballenger,et al.  Are There Progressive Brain Changes in Schizophrenia? A Meta-Analysis of Structural Magnetic Resonance Imaging Studies , 2012 .

[13]  J. Lieberman,et al.  Antipsychotic Drugs for First-Episode Schizophrenia , 2009, CNS drugs.

[14]  I. Nimmo-Smith,et al.  Hypofrontality in schizophrenia: a meta‐analysis of functional imaging studies , 2004, Acta psychiatrica Scandinavica.

[15]  J. Rollnik,et al.  Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia , 2003, Psychiatry Research.

[16]  Julie Kreyenbuhl,et al.  The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. , 2010, Schizophrenia bulletin.

[17]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[18]  V. Peralta,et al.  Psychometric properties of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia , 1994, Psychiatry Research.

[19]  P. Rossini,et al.  Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. , 1994, Electroencephalography and clinical neurophysiology.

[20]  Gaby S. Pell,et al.  Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: Influence of timing and geometrical parameters and underlying mechanisms , 2011, Progress in Neurobiology.

[21]  E. Stip,et al.  Hypofrontalité et symptômes négatifs dans la schizophrénie : synthèse des acquis anatomiques et neuropsychologiques et perspectives écologiques , 2001 .

[22]  P. Fitzgerald,et al.  A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia , 2008, Brain Stimulation.

[23]  B. Crespo-Facorro,et al.  Prognostic value of cognitive functioning for global functional recovery in first-episode schizophrenia , 2009, Psychological Medicine.

[24]  Valerie Treyer,et al.  Time-course of “off-line” prefrontal rTMS effects — a PET study , 2008, NeuroImage.

[25]  Antonio P. Strafella,et al.  rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex , 2009, PloS one.

[26]  E. Vicaut,et al.  Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: a double blind sham controlled study. , 2005, Journal of psychiatric research.

[27]  N C Andreasen,et al.  Negative symptoms in schizophrenia , 1982 .

[28]  D. Wiersma,et al.  Duration of untreated psychosis and negative symptoms — A systematic review and meta-analysis of individual patient data , 2012, Schizophrenia Research.

[29]  R. Findling,et al.  A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. , 2008, The American journal of psychiatry.

[30]  D. Koren,et al.  Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham- controlled pilot study , 1999, Biological Psychiatry.

[31]  T. Kašpárek,et al.  Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study , 2007, Schizophrenia Research.

[32]  Nancy C. Andreasen,et al.  Negative symptoms in schizophrenia , 1982 .

[33]  N. Goyal,et al.  Efficacy of adjuvant high frequency repetitive transcranial magnetic stimulation on negative and positive symptoms of schizophrenia: preliminary results of a double-blind sham-controlled study. , 2007, The Journal of neuropsychiatry and clinical neurosciences.

[34]  P. Sachdev,et al.  Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: A pilot investigation , 2005, Psychiatry and clinical neurosciences.

[35]  H. Hoek,et al.  Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. , 2010, The Journal of clinical psychiatry.

[36]  Alvaro Pascual-Leone,et al.  Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia , 2009, Schizophrenia Research.

[37]  F. Fregni,et al.  Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis , 2009, PloS one.

[38]  Robert W. Buchanan,et al.  The schedule for the deficit syndrome: An instrument for research in schizophrenia , 1989, Psychiatry Research.

[39]  R. Rosenheck,et al.  Comparison of first‐episode and chronic patients diagnosed with schizophrenia: symptoms and childhood trauma , 2013, Early intervention in psychiatry.

[40]  H. Möller.  Management of the Negative Symptoms of Schizophrenia , 2012, CNS drugs.

[41]  Raquel E. Gur,et al.  journal homepage: www. elsevier.com/locate/schres Development and psychometric validation of the Clinical Assessment Interview for Negative Symptoms (CAINS) , 2022 .

[42]  A. Sack,et al.  Changes in negative symptoms and EEG in schizophrenic patients after repetitive Transcranial Magnetic Stimulation (rTMS): an open-label pilot study , 2004, Journal of Neural Transmission.

[43]  G. Remington,et al.  Schizophrenia as a disorder of too little dopamine: implications for symptoms and treatment , 2011, Expert review of neurotherapeutics.

[44]  A. Yung,et al.  Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years , 2011, Psychological Medicine.

[45]  A. Malla,et al.  Determinants of quality of life in first‐episode psychosis , 2004, Acta psychiatrica Scandinavica.

[46]  A. Summerfelt,et al.  The negative symptom assessment: a new instrument to assess negative symptoms of schizophrenia. , 1989, Psychopharmacology bulletin.

[47]  R. Rosenthal.  The file drawer problem and tolerance for null results , 1979 .

[48]  S. Lisanby,et al.  High-Frequency Prefrontal Repetitive Transcranial Magnetic Stimulation for the Negative Symptoms of Schizophrenia: A Case Series , 2011, The journal of ECT.

[49]  P. Czobor,et al.  Basic neuropsychological dimensions in schizophrenia , 2003, Schizophrenia Research.

[50]  J. Valls-Solé,et al.  Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study , 1999, Journal of neurology, neurosurgery, and psychiatry.

[51]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[52]  A. L. Schneider,et al.  Repetitive transcranial magnetic stimulation (rTMS) as an augmentation treatment for the negative symptoms of schizophrenia: A 4-week randomized placebo controlled study , 2008, Brain Stimulation.

[53]  D. Weinberger,et al.  Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. IV. Further evidence for regional and behavioral specificity. , 1988, Archives of general psychiatry.

[54]  Hans-Jürgen Möller,et al.  Clinical evaluation of negative symptoms in schizophrenia , 2007, European Psychiatry.

[55]  S. Kapur,et al.  Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: Analysis of CATIE data , 2012, Schizophrenia Research.

[56]  Juan Carlos Espinosa,et al.  Comprehensive Meta-Analysis , 2004 .

[57]  S. Rossi,et al.  Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research , 2009, Clinical Neurophysiology.

[58]  B. Langguth,et al.  High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study , 2004, Psychological Medicine.

[59]  A. Cohen,et al.  The structure of negative symptoms within schizophrenia: implications for assessment. , 2006, Schizophrenia bulletin.

[60]  H. Emrich,et al.  High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients , 2000, Neuroreport.

[61]  J. Rabinowitz,et al.  Trajectories and antecedents of treatment response over time in early-episode psychosis. , 2010, Schizophrenia bulletin.

[62]  F. Španiel,et al.  The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: negative results. , 2006, Neuro endocrinology letters.

[63]  M. Holi,et al.  Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia. , 2004, Schizophrenia bulletin.

[64]  G. Juckel,et al.  Social skills and behavioral problems in schizophrenia: The role of mental state attribution, neurocognition and clinical symptomatology , 2011, Psychiatry Research.

[65]  J. Haro,et al.  Neurocognitive performance and negative symptoms: Are they equal in explaining disability in schizophrenia outpatients? , 2006, Schizophrenia Research.

[66]  R. Kerwin,et al.  Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia. , 1997, The American journal of psychiatry.

[67]  Jay Brand,et al.  File Drawer Problem , 2022, The SAGE Encyclopedia of Research Design.

[68]  V. Bowden,et al.  The Journal of Neuropsychiatry and Clinical Neurosciences , 1992 .

[69]  S. Leucht,et al.  How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials , 2009, Molecular Psychiatry.

[70]  D. Weinberger,et al.  Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. , 1988, Archives of general psychiatry.

[71]  Cindy L. Hovington,et al.  Identifying persistent negative symptoms in first episode psychosis , 2012, BMC Psychiatry.

[72]  Tyrone D. Cannon,et al.  The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample , 2009, Schizophrenia Research.

[73]  A. Aleman,et al.  Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. , 2010, The Journal of clinical psychiatry.

[74]  John-Paul Taylor,et al.  Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: A randomized controlled pilot study , 2007, Schizophrenia Research.