Nadine Dougall, Nicola Maayan, Karla Soares-Weiser, Lisa M McDermott, Andrew McIntosh

People with schizophrenia often experience symptoms which fail to fully respond to antipsychotic medication. Transcranial magnetic stimulation (TMS) has been proposed as a new treatment for people with schizophrenia, especially those who experience persistent auditory hallucinations. To estimate the effects of TMS alone, compared with sham TMS or with 'standard management' and any other comparison interventions in reducing psychotic symptoms associated with schizophrenia. We searched the Cochrane Schizophrenia Group Trials Register (June 2006, June 2008, April 2013). This register is compiled by methodical searches of MEDLINE, EMBASE, BIOSIS, CINAHL, Dissertation abstracts, LILACS, PSYNDEX, PsycINFO, RUSSMED, and Sociofile, and is supplemented with handsearching of relevant journals and numerous conference proceedings. We included all randomised controlled trials recruiting at least five participants and comparing TMS with sham TMS or any other treatment for people with schizophrenia. We extracted data independently. For dichotomous data we calculated relative risks (RRs) and their 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MD) and 95% CI. We used a fixed-effect model. We assessed overall quality of the evidence using the GRADE approach. We included 41 studies with 1473 participants in the review. We found significant differences in favour of temporoparietal TMS compared to sham TMS for global state measured on the CGI scale (7 RCTs, n = 224, MD -0.5, 95% CI -0.76 to -0.23, very low-quality evidence) and positive symptoms measured on the PANSS scale (5 RCTs, n = 127, MD -6.09, 95% CI -10.95 to -1.22, very low-quality evidence). Participants experienced significantly more headaches in the temporoparietal TMS group (10 RCTs, n = 392, RR 2.65, 95% CI 1.56 to 4.50, very low-quality evidence). However, no more participants left the study early from the TMS group than from the sham group (very low-quality evidence). Cognitive state was assessed using 39 different measures, and all were equivocal (very low-quality evidence).We included only two trials which compared temporoparietal TMS with standard treatment. In both trials the participants received first- and second-generation antipsychotic medication in both treatment groups, therefore TMS was used an adjunctive therapy to medication. We found no significant differences in the number of participants that showed clinical improvement in global state (1 RCT, n = 100, RR 1.19, 95% CI 0.91 to 1.57) or left the study early (2 RCTs, n = 140, RR 0.33, 95% CI 0.08 to 1.46) (both very low-quality evidence). No studies reported on global state score, mental state, cognitive state and adverse effects.For prefrontal TMS compared to sham TMS, global state was measured on three different scales, all of which presented equivocal results (very low quality evidence). We could not pool data for mental state on the PANSS scale due to high heterogeneity. Cognitive state was assessed using 19 different measures, with 15/19 being equivocal (very low-quality evidence). Prefrontal TMS caused more headaches (6 RCTs, n = 164, RR 2.77, 95% CI 1.22 to 6.26, very low-quality evidence) but there was no difference in the number of participants leaving the study early (very low-quality evidence). No studies reported data for clinical improvement.We found a significant difference in favour of prefrontal theta burst stimulation TMS compared to sham TMS for mental state on the PANNS scale (3 RCTs, n = 108, MD -5.71, 95% CI -9.32 to -2.10, very low evidence). We found no difference for clinical improvement, cognitive state, number of headaches, and leaving the study early (very low-quality evidence).None of the included studies reported satisfaction with care. Based on this review, there is insufficient evidence to support or refute the use of TMS to treat symptoms of schizophrenia. Although some evidence suggests that TMS, and in particular temporoparietal TMS, may improve certain symptoms (such as auditory hallucinations and positive symptoms of schizophrenia) compared to sham TMS, the results were not robust enough to be unequivocal across the assessment measures used. There was insufficient evidence to suggest any added benefit with TMS used as an adjunctive therapy to antipsychotic medication.The overall quality of evidence was graded as very low due to risk of bias, and this was accompanied by an imprecision in estimates due to the relatively small number of participants in the studies. Thus, consideration is required in improving the quality of trial processes, as well as the quality of reporting of ongoing and future TMS trials, so as to facilitate accurate future judgements in assessing risk of bias. Differences in TMS techniques in relation to stimulation intensity, stimulation length, brain areas stimulated and variations in the design of sham TMS all contributed to the heterogeneity of study findings and limited the interpretation and applicability of the results. In addition, the trials assessed their outcomes with a variety of scales, and usable data were limited. Therefore, to better evaluate the treatment effects of TMS in people with schizophrenia, we favour the use of standardised treatment protocols and outcome measures.