Introduction Mindfulness-based interventions are widely used, yet concerns about potential negative effects—particularly those related to mindfulness meditation practice—have gained increasing attention. Individuals with difficult-to-treat depression (DTD) represent a population of particular relevance due to heightened vulnerability, but comparative evidence on clinically relevant negative outcomes of mindfulness-based cognitive therapy (MBCT) versus established alternative psychotherapies in this group is lacking. This protocol describes a systematic review and individual participant data (IPD) network meta-analysis to assess and compare the incidence of clinically relevant negative outcomes associated with MBCT and the cognitive behavioural analysis system of psychotherapy (CBASP), an established individual psychotherapy for DTD. Methods and analysis Randomised controlled trials of MBCT and CBASP for adults with DTD were identified through systematic searches of major databases. Eligible studies must compare MBCT or CBASP (alone or with treatment as usual) to each other or to control groups. The primary outcome is clinically significant deterioration, defined as a ≥6-point increase on the Patient Health Questionnaire-9 or equivalent. Secondary outcomes are suicidality and treatment dropout. IPD will be requested from trial investigators; aggregate data will be used when IPD is unavailable. One-stage random-effects IPD network meta-analyses will be conducted to integrate direct and indirect evidence and to examine participant-level moderators of deterioration. Adverse events reported in the included trials will be summarised descriptively at the study level. Ethics and dissemination No local ethical review was required following consultation with the Swedish Ethical Review Authority. Primary trial investigators obtained local ethical approval and will share pseudonymised IPD. Findings will inform clinical decision-making and guideline development by strengthening the evidence base on potential negative effects of MBCT and CBASP in adults with DTD, including identification of subgroups at increased risk. Results will be disseminated through peer-reviewed publication and accessible summaries for relevant stakeholders. PROSPERO registration number CRD42022332039
Niemi et al. (Wed,) studied this question.