Efficacy and tolerability of transcranial electrical stimulation (tES) in schizophrenia: a systematic review, meta-analysis, and meta-regression analysis of sham response

Background

Schizophrenia is a severe mental disorder characterized by positive, negative, and cognitive symptoms that often persist despite optimized pharmacological treatment. Regardless of available pharmacological treatments, current therapeutic strategies for schizophrenia remain limited in terms of efficacy and tolerability, both as monotherapy or as add-on therapies with medications or with psychotherapy, emphasizing the need for novel, effective interventions. Transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS), alternating current stimulation (tACS), and random noise stimulation (tRNS), has emerged as a promising adjunct strategy.

Despite a decade of randomized controlled trials, findings remain heterogeneous. A significant methodological concern is the magnitude of the sham response, which may mask true therapeutic effects and remains poorly understood in the context of neuromodulation for schizophrenia. An updated synthesis is essential to quantify treatment effects and identify the clinical or technical moderators that drive both active and sham responses.

Methods

This systematic review and meta-analysis of RCTs follows PRISMA guidelines and is pre-registered with PROSPERO (CRD420261324259). We searched the Cochrane Schizophrenia Group’s specialized register for relevant records from inception through January 13, 2026. Study screening and selection were performed independently by two reviewers, with inclusion limited to assessor-blinded RCTs evaluating tES as a monotherapy or adjunct to antipsychotics. Data extraction and risk-of-bias assessments were conducted in duplicate, with discrepancies resolved through consensus.

The primary outcomes are changes in overall symptoms and negative symptoms of schizophrenia, measured by validated scales such as the Positive and Negative Syndrome Scale (PANSS). Secondary outcomes include positive symptoms, depressive symptoms, quality of life, cognition, attrition rates, and adverse events. Standardized mean differences (SMDs) will be calculated for between-group treatment effects, while standardized mean changes (SMCs) will quantify within-group sham and active responses. Pairwise meta-analyses will employ random-effects models. Furthermore, meta-regression will be used to explore potential moderators, such as stimulation intensity, session frequency, and baseline symptom severity. Finally, sensitivity and subgroup analyses will be conducted to ensure the robustness of the findings.

Main Objectives: The primary objective is to evaluate the efficacy and safety of tES compared to sham stimulation in schizophrenia. Additionally, the study aims to identify predictors of both active treatment response and sham response, thereby determining which variables significantly influence the statistical difference between active and sham conditions.

Results

Preliminary results from our systematic search identified 23,710 records, of which 38 RCTs met the inclusion criteria. Data extraction and quality assessments are currently underway. The final results will be presented at the ECNP conference in October 2026.

Conclusions

This meta-analysis will provide an estimate of tES efficacy, clarify the influence of the sham effect on clinical outcomes, and identify optimal stimulation parameters. These findings will have important implications for clinical decision-making and the design of future clinical trials in the field of psychiatry.

References

No references.