Mental disorders affect nearly one billion people worldwide, posing major challenges to public health. While conventional treatments like psychotherapy and pharmacotherapy are effective for many patients, they are often associated with adverse effects and high non-response rates, underscoring the need for alternative approaches. Non-invasive brain stimulation techniques such as transcranial magnetic stimulation, transcranial electric stimulation and transcranial focused ultrasound stimulation are increasingly used to treat psychiatric conditions. Although these methods show promising efficacy, data on their adverse effects remain fragmented and inconsistently reported. This meta-analysis aims to systematically compare the type and frequency of adverse effects, tolerability, and acceptability across different brain stimulation techniques and mental disorders. The findings will help improve safety monitoring and support more personalised, well-tolerated treatment strategies.

A systematic literature search of the Embase, MEDLINE(R), AMED (Allied and Complementary Medicine) and APA PsycINFO via OVID will be performed. Eligible studies include randomised controlled trials (RCTs) that compare active treatments or an active treatment with sham control, including both parallel group and cross-over studies, as well as prospective non-randomised studies such as case–control studies and pre–post studies investigating adverse effects of non-invasive brain stimulation in psychiatric populations. Included studies report on the frequency of adverse effects in a standardised manner. Primary outcomes comprise the incidence of specific adverse effects, dropout rates due to adverse effects (tolerability) and overall dropout rates (acceptability). Risk of bias will be assessed using the Cochrane RoB 2.0 tool for RCTs and the NHLBI quality assessment tool for pre–post studies. The quality of case–control studies will be assessed using the Newcastle-Ottawa scale. Provided that sufficient data are available and the network of comparisons is adequately connected, a network meta-analysis will be conducted to compare adverse effects and tolerability across interventions.

No ethical approval is needed to conduct this work. The findings will be submitted for publication in peer-reviewed journals and presented at scientific meetings.

CRD420251164554

Major depressive disorder (MDD) is a major global healthcare challenge. This is, in part, due to the lack of treatment response and chronic course of MDD. Such a course of illness is often termed treatment-resistant depression (TRD) and is seen in over one-third of people with MDD. Reasons for treatment resistance are not well established, nor is the definition of TRD. Duration and severity of depression, however, are associated with TRD and are also associated with cognitive deficits. Thus, TRD could be particularly prone to cognitive deficits and at heightened risk for neuroprogression. While the cognitive profile of MDD has been investigated in several systematic reviews, no systematic review of cognition in TRD exists to date. The present study will fill this gap in the literature. It is expected that TRD will show more severe cognitive deficits than generally reported in MDD and deficits in all cognitive functions are expected.

A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be performed of the databases Embase, Pubmed/MEDLINE, PsychINFO and Cochrane including peer-reviewed studies on humans using standardised cognitive tests. Pilot searching was performed in January 2025 and the full search will be commenced in June 2025, with additional searches following completion. Where sufficient data are reported, a meta-analysis comparing deficits in TRD with MDD and healthy control participants will be performed; alternatively, effects based on norms will be calculated. Meta-regression, subgroup and sensitivity analyses will be conducted to explore moderators that are sufficiently reported in the literature. The quality of studies will be assessed by the Newcastle-Ottawa Scale.

Ethical approval is not necessary to perform the study, and results will be presented at a suitable conference and published in a peer-reviewed journal.

CRD42024538898.