Review articleRevisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis
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
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Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance
2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :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.