Elsevier

Psychiatry Research

Volume 215, Issue 3, 30 March 2014, Pages 505-513
Psychiatry Research

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

https://doi.org/10.1016/j.psychres.2013.12.019Get rights and content

Abstract

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.

Introduction

Negative symptoms in schizophrenia constitute a heterogeneous syndrome that comprises flattened affect, poor communication, avolition, apathy, anhedonia, asociality, psychomotor retardation and impaired attention (Blanchard and Cohen, 2006, Moller, 2007). Among these, the two consensus components are affective flattening and diminished motivation (Blanchard and Cohen, 2006, Moller, 2007). Negative symptoms have been found to be the major predictor of functional outcome in patients with schizophrenia (Brune et al., 2011, Gonzalez-Blanch et al., 2010, Rabinowitz et al., 2012, Shamsi et al., 2011, Villalta-Gil et al., 2006) and are important for their ultimate qualify of life and functional recovery (Alvarez-Jimenez et al., 2012, Gorecka and Czernikiewicz, 2004).

Treatment of negative symptoms in patients with schizophrenia, however, remains unsatisfactory. Current treatment of negative symptoms is mainly limited to second generation antipsychotics (SGA), which have been found to be better than first generation antipsychotics (FGA) in that SGAs had fewer side effects such as extrapyramidal symptoms and sedation than FGAs. Although SGAs appear to be more effective than placebo in alleviating negative symptoms, the effect sizes are only small to moderate (Buchanan et al., 2010, Erhart et al., 2006, Leucht et al., 2009). Various adjunctive therapies, such as selective serotonin reuptake inhibitors (SSRIs), glutamatergic compounds, oestrogen and acetylcholinesterase inhibitors, have also been used to alleviate negative symptoms, but their efficacies have been unimpressive (Erhart et al., 2006, Moller, 2003).

Recently, repetitive transcranial magnetic stimulation (rTMS) has been used for the treatment of various psychiatric disorders, such as obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorders, schizophrenia and depression (Rossi et al., 2009). The Food and Drug Administration (FDA) in the United States has recently approved the use of rTMS to treat refractory depression. Repetitive TMS was tested for the treatment of auditory hallucinations and negative symptoms of schizophrenia, while experiences with catatoniac symptoms are limited. It has been suggested that negative symptoms in schizophrenia may be related to a lack of dopamine at the prefrontal cortex and hypofrontality (Hill et al., 2004, Remington et al., 2011). It has also been found that high frequency rTMS may be able to increase cortical excitability and modulate dopamine release (Eisenegger et al., 2008, Pell et al., 2011). This has led to the hypothesis that high frequency rTMS applied at the prefrontal cortex may be an effective treatment of negative symptoms in schizophrenia. Apart from this, rTMS could change the expression of glutamic acid decarboxylase, which is the synthetic enzyme of the precursor of γ-aminobutyric acid (GABA). This may be important as negative symptom scores have been found to be inversely related to benzodiazepine receptor binding in the medial frontal region (Busatto et al., 1997, Trippe et al., 2009).

To date two meta-analyses have been conducted to specifically examine the therapeutic effects of rTMS on negative symptoms in schizophrenia (Dlabac-de Lange et al., 2010, Freitas et al., 2009). However, the results of these two meta-analyses are different due to the inclusion of different number of studies. Freitas et al. (2009) concluded that there were significant and moderate effects of rTMS on negative symptoms when outcome was defined by comparing the baseline and endpoint negative symptoms scores. However, when the analysis was limited to five sham controlled studies, the results became non-significant, which suggest that placebo effect should be taken into account. On the contrary, by comparing the mean changes of negative symptoms scores in pre- to post-treatment between active and sham controlled groups in nine studies, Dlabac-de Lange et al. (2010) reported a small but significant effect size supporting the efficacy of rTMS in treating negative symptoms. Another meta-analysis reported the efficacy of rTMS in a variety of psychiatric disorders. Only seven of the studies included examined the efficacy of rTMS on negative symptoms in schizophrenia, and the results showed that its effect size was small and non-significant (Slotema et al., 2010).

A number of factors may modulate the efficacy of rTMS on negative symptoms. These include the assessment tool used, baseline psychopathology, duration of illness (DOI), rTMS frequency, motor threshold (MT), stimulus location, total stimulus strength, and duration of stimulus. These factors have not been thoroughly analyzed in the two aforementioned meta-analyses. In addition, the number of studies included in these meta-analyses is small (eight and nine respectively). Because of this, further research taking into account the effect of possible moderators is needed to determine the efficacy of rTMS treatment on negative symptoms in schizophrenia. The present meta-analysis aimed to clarify the effects of rTMS on the treatment of negative symptoms in schizophrenia and to provide a comprehensive review on the possible moderators of rTMS treatment efficacy on negative symptoms in schizophrenia.

Section snippets

Selection of studies

Four data bases, namely, PubMed, Web of science, Elsevier and EBSCO, were used to identify relevant studies and the search period was from 1st January 1998 to 30th June 2013. The keywords used were: “schizophrenia” and “transcranial magnetic stimulation” or “TMS” or “rTMS”. In addition, reference lists in systematic reviews and meta-analyses were also examined.

Selection criteria for the meta-analyses

The following inclusion criteria were used to select articles for the present meta-analysis: diagnosis of schizophrenia was ascertained

Results

Fig. 1 summarizes the process of selection of studies for the meta-analysis. Initially we obtained 117 peer-reviewed papers through PubMed, Web of science, Elsevier, and EBSCO databases. We excluded 37 studies because they were reviews, meta-analyses and abstracts. Through subsequent detailed screening, we further excluded 58 studies which did not focus on negative symptoms or when rTMS was not used as a therapeutic tool. Finally we excluded: three studies which assessed clinical symptoms using

Discussion

Our study yielded several findings. First, meta-analysis results from sham-controlled trials indicate that rTMS is effective in treating negative symptoms in schizophrenia, with a moderate effect size. Our results also revealed larger effect sizes for rTMS treatment effect on negative symptoms when the SANS rather than the PANSS was used as the assessment tool. In addition, the severity of negative symptoms at baseline predicted response to rTMS. Patients with more prominent negative symptoms

Acknowledgments

This study was supported by Grants from the Strategic Priority Research Programme (B) of the Chinese Academy of Sciences (XDB02030200), the National Science Fund China (81088001 and 91132701), the Project-Oriented Hundred Talents Programme (O7CX031003), a Grant from the Knowledge Innovation Project of the Chinese Academy of Sciences (KSCX2-EW-J-8), the National Key Project of Scientific and Technical Supporting Programs funded by Ministry of Science & Technology of China (No. 2007BAI17B04), the

References (73)

  • T.J. Huber et al.

    Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia

    Psychiatry Research

    (2003)
  • J. Jaeger et al.

    Basic neuropsychological dimensions in schizophrenia

    Schizophrenia Research

    (2003)
  • B. Kirkpatrick et al.

    The schedule for the deficit syndrome: an instrument for research in schizophrenia

    Psychiatry Research

    (1989)
  • E. Klein et al.

    Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study

    Biological Psychiatry

    (1999)
  • A. Mogg et al.

    Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: a randomized controlled pilot study

    Schizophrenia Research

    (2007)
  • H.J. Moller

    Clinical evaluation of negative symptoms in schizophrenia

    European Psychiatry: The Journal of the Association of European Psychiatrists

    (2007)
  • S.Y. Oh et al.

    Adjunctive treatment of bimodal repetitive transcranial magnetic stimulation (rTMS) in pharmacologically non-responsive patients with schizophrenia: a preliminary study

    Progress in Neuro-psychopharmacology and Biological Psychiatry

    (2011)
  • B. Olabi et al.

    Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies

    Biological Psychiatry

    (2011)
  • G.S. Pell et al.

    Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms

    Progress in Neurobiology

    (2011)
  • V. Peralta et al.

    Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia

    Psychiatry Research

    (1994)
  • R. Prikryl et al.

    Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study

    Schizophrenia Research

    (2007)
  • R. Prikryl et al.

    A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial

    Schizophrenia Research

    (2013)
  • J. Rabinowitz et al.

    Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data

    Schizophrenia Research

    (2012)
  • R. Rosenthal

    The “file drawer problem” and tolerance for null results

    Psychological Bulletin

    (1979)
  • S. Rossi et al.

    Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research

    Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology

    (2009)
  • P.M. 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

    Electroencephalography and Clinical Neurophysiology

    (1994)
  • G. Saba et al.

    Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: a double blind sham controlled study

    Journal of Psychiatric Research

    (2006)
  • 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

    Brain Stimulation

    (2008)
  • S. Shamsi et al.

    Cognitive and symptomatic predictors of functional disability in schizophrenia

    Schizophrenia Research

    (2011)
  • A.D. Stanford et al.

    High-frequency prefrontal repetitive transcranial magnetic stimulation for the negative symptoms of schizophrenia: a case series

    The Journal of ECT

    (2011)
  • V. Villalta-Gil et al.

    Neurocognitive performance and negative symptoms: are they equal in explaining disability in schizophrenia outpatients?

    Schizophrenia Research

    (2006)
  • E.F. Walker 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

    Schizophrenia Research

    (2009)
  • L.D. Alphs et al.

    The negative symptom assessment: a new instrument to assess negative symptoms of schizophrenia

    Psychopharmacology Bulletin

    (1989)
  • M. Alvarez-Jimenez et al.

    Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years

    Psychological Medicine

    (2012)
  • American Psychiatric Association, 1980,1987, 1994, 2000. Diagnostic and Statistical Manual of Mental Disorders, Third...
  • N.C. Andreasen

    Negative symptoms in schizophrenia. Definition and reliability

    Archives of General Psychiatry

    (1982)
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      Overall, we found a medium to large effect size (SMD = 0.54, 95% CI: 0.32, 0.75, P < 0.001; Fig. 2) across diagnostic groups. This indicates that noninvasive brain stimulation was on average more effective than sham and is in line with previous meta-analyses in depression (TMS: odds ratios between 1.69 and 7.44; Brunoni et al., 2017; Mutz et al., 2018; tDCS: odds ratio = 4.17; Mutz et al., 2018), schizophrenia (Hedges’ g between 0.39 and 0.63; Slotema et al., 2010; Shi et al., 2014), and OCD (Hedges’ g = 0.45; Trevizol et al., 2016). Further, we found a statistically significant inverse relationship of effect sizes and year of publication for the studies in patients with a schizophrenia spectrum diagnosis, but not for any of the other diagnostic groups (Supplementary Fig. 17).

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    indicates papers included in the current meta-analysis.

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