Schema therapy versus any control group for adult mental health disorders: a protocol for a systematic review with meta-analysis and trial sequential analysis

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P. Arendt, Sophie Juul, Carsten Hjorthøj, Michiel van Vreeswijk, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6570797/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background Mental health disorders are among the heaviest global health burdens. While many psychotherapies are effective for mental health disorders, some patients may require more specialized psychotherapies. Schema therapy, a transdiagnostic psychotherapy, addresses childhood adversity and personality characteristics which have been shown to predict and maintain more ingrained mental health disorders. The effects of schema therapy have previously been assessed in systematic reviews, but these suffered from methodological shortcomings and did not include the most recent trials. This systematic review with meta-analysis aims to synthesize the evidence of beneficial and harmful effects of schema therapy for a broad array of mental health disorders, taking into account the risk of both systematic errors, random errors, and certainty of evidence. Methods This systematic review with meta-analysis will contain a comprehensive search for relevant published and unpublished trials in major clinical databases and clinical trial registries. We will include randomized clinical trials comparing schema therapy to a control group for adult mental health disorders including attention deficit hyperactivity disorder, autism spectrum disorders, psychotic disorders, dissociative identity disorder, depressive disorders, bipolar disorders, anxiety disorders, obsessive-compulsive disorder, substance abuse, trauma- and stressor-related disorders, eating disorders, and personality disorders. Primary outcomes will be symptom severity and quality of life. Secondary outcomes will be serious adverse events, level of functioning, and treatment dropout. Risk of bias will be assessed with the Cochrane Risk of Bias tool version 2, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, the risk of random errors will be assessed with Trial Sequential Analysis, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Discussion Schema therapy is a promising intervention for more severe cases of mental health disorders, but the certainty of evidence for benefits and harms of schema therapy is still unclear. This review will inform clinical guidelines, thus expanding the possible choices of treatments in clinical practice. Further, the review will provide a comprehensive overview of the literature and highlight research gaps to inform future research. Systematic review registration PROSPERO, CRD420251015725 Schema therapy psychotherapy depression personality disorders obsessive-compulsive disorder anxiety disorders post-traumatic stress disorder psychotic disorders autism spectrum disorders attention deficit hyperactivity disorder Background Mental health disorders are a global problem, with an estimated point prevalence in 2019 of 970 million or 12.5% worldwide (REF LANCET), and a life time prevalence in Europe of 26%(1). Mental health disorders account for substantial costs for the individual and for society(2, 3) and account for 123 million Disability-Adjusted Life Years globally(4), which places them among the five highest ranking non-communicable diseases regarding disease burden (5). A mental health disorders is defined in the Diagnostic and Statistical Manual of Mental Disorders , 5th edition (DSM-5) as ‘a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning […] usually associated with significant distress in social, occupational, or other important activities’. Mental health disorders can be broadly categorized into Neurodevelopmental disorders, Schizophrenia Spectrum and other Psychotic disorders, Bipolar and related disorders, Depressive disorders, Anxiety disorders, Obsessive-Compulsive and related disorders, Trauma- and stressor-related disorders, Dissociative disorders, Somatic Symptom and related disorders, Feeding and Eating disorders, Elimination disorders, Sleep-Wake disorders, Sexual dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control and Conduct disorders, Substance-Related and Addictive disorders, Neurocognitive disorders, Personality disorders, and Paraphilic disorders (6) . Pharmacological interventions are often used to treat mental health disorders, including, e.g., antipsychotics, antidepressants, and mood stabilizers(7-11) . However, psychotherapy is often recommended either as an adjunctive to pharmacological interventions or as stand-alone treatment for a wide selection of mental health disorders(7-11). While most established psychotherapies have been found effective on mental disorders at a general level, evidence suggests that more specialized treatments could be warranted for more severe and/or complex cases of mental health problems(12). Description of the intervention Schema therapy is one such specialized form of psychotherapy. It was developed by Jeffrey Young and colleagues to address mental health issues that do not respond to first line treatments, often due to more fundamental problems rooting in childhood adversity and characterological challenges(13). Drawing on theories and methods from cognitive behavioral, psychodynamic, emotion-focused and gestalt therapies, schema therapy has a distinct experiential focus with hallmark methods such as imagery rescripting, chair exercises and role play. Further, the therapeutic relationship is used actively as a means to ameliorate adverse childhood events ( limited reparenting ) and to call out and change dysfunctional behavior ( empathic confrontation )(13, 14). Schema therapy can be delivered in a group and in an individual format(15), in person and in online formats(16, 17). Schema therapy can be applied in in-patient and out-patient contexts(17-19), including forensic settings(20), and to both adults, adolescents, and children (14, 21). As schema therapy is transdiagnostic by nature, it can be applied and adapted to many, more ingrained mental health disorders(22). The therapy is often delivered in a longer format (e.g., 30 sessions or longer), as this is necessary to capture and change more ingrained cognitive structures and behaviors. How the intervention might work In schema therapy, it is hypothesized that mental health disorders result from early developed cognitive structures, so-called early maladaptive schemas, which direct and potentially distort perception and emotions(13). Schemas, when triggered, activate schema modes, whichare (most often dysfunctional) behavioral and emotional coping responses. In schema therapy, the therapist ultimately seeks to ameliorate early maladaptive schemas and the dysfunctional modes. Importantly, the mode Vulnerable Child , a representation of genuine sadness and unmet personal needs, is sought to be soothed and have its needs met, while the mode Healthy Adult , representing the wise, healthy and resourceful part of the individual, is supported to grow and gradually assume greater autonomy from the therapist’s guidance(14). Working with childhood adversity and its consequences, not only on the level of current maintaining factors, but also on fundamentally modifying cognitive and emotional dysfunction originating in individual learning history, schema therapy is thought to create longer-lasting, positive changes in the patient’s psychological make-up and behavior. Further, schema therapy works trans-diagnostically and can simultaneously address both mental disorders thought of as a ‘state’ (e.g., depression, anxiety) and ‘traits’ such as personality disorders, accentuated personality traits, or other idiosyncratic, maladaptive patterns of thought and behavior. Why is it important to do this review Research on schema therapy has accumulated in recent years(23), but the empirical status of its effects remains unclear. We have identified seven systematic reviews to date (whereof two include a meta-analysis) on the effects of schema therapy. The characteristics and results of the previous systematic reviews are summarized in Table 1 [Additional File 1].While the reviews encompass both the effects of schema therapy as a whole and on important selected disorders, they also exhibited shortcomings, both in regard to a narrow focus on only mental health symptoms as outcome, and in the use of inconsistent methodology, as we will now present. Out of the seven reviews, three reviews assessed the effects of schema therapy for a wide range of mental health disorders. One was a systematic review of the effects of schema therapy on all outcomes (as reported by the included trials) for treatments lasting at least ten psychotherapy sessions(24). The review included ten studies, out of which three were randomized controlled trials comparing schema therapy to standard treatments and two were head-to head randomized trials. Only one high quality study was found, and it was concluded that schema therapy seems effective, but that there was too little evidence of high quality to make conclusions or clinical recommendations. A second systematic review(25) was an update of the above review(24), now including trials from 2011 to 2015. An additional 9 studies were identified, out of which one was a three-arm randomized trial comparing schema therapy to clarification-oriented therapy and Treatment As Usual (TAU), one was a randomized controlled trial comparing schema therapy to TAU, and one was a randomized head-to-head trial. The results were again found inconclusive regarding the effects of schema therapy due to scarcity of high-quality evidence. The third was a systematic review of the effects of schema therapy on both symptom change and schema or schema mode change(26). Twelve studies were included, out of which one was a randomized controlled trial comparing the effect of schema therapy with or without additional telephonic crisis support. Regarding symptom change, the study concluded that there is some evidence to suggest effectiveness of schema therapy on personality disorders, but too scarce evidence to make conclusions for other mental disorders. These reviews were limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, meaning that interpretations and recommendations for clinical practice were subject to subjective interpretation(24-26). The studies included a variety of trial designs, such as head-to-head trials, non-controlled and non-randomized trials, and case series(24-26), which means that results were based on evidence of varying quality and risk of bias. Further, the studies did not investigate harmful effects or other patient-relevant effects of schema therapy(24-26). Moreover, the latter study did not search all relevant databases, and it excluded twelve trials that did not report both change in symptom levels and schemas or schema modes, thus potentially excluding trials that could have provided additional data on the effectiveness of schema therapy(26). We have also identified four systematic reviews which investigated distinct mental health disorders. Two reviews investigated personality disorders(27, 28). One review with meta-analysis investigated the effect of schema therapy on personality disorder symptoms, quality of life, and schema change(28). It included 16 studies, out of which nine were RCTs, with five trials comparing schema therapy to TAU, one trial comparing schema therapy to transference-focused psychotherapy, one trial comparing schema therapy with or without access to telephonic crisis support, and two were three-arm trials comparing schema therapy to Dialectical Behavior Therapy and placebo, and clarification-oriented psychotherapy and TAU, respectively. It was concluded that schema therapy significantly reduces symptoms of personality disorders and improves quality of life and schemas(28). The other review was a network meta-analysis of the effect of all psychotherapies for symptoms of borderline personality disorder, suicidal behavior, and dropout rates (27). It included three trials on schema therapy(27), of which two trials were RCTs comparing schema therapy to TAU, and one RCT compared schema therapy to transference-focused psychotherapy. The review concluded that schema therapy might be equal to or superior over some other psychotherapies regarding symptom change and dropout rates. The two reviews were limited by also including head-to head trials(when not doing network meta-analysis), non-controlled and non-randomized trials, and case series(28), by not employing trial sequential analysis methods to control for random errors(27, 28), not investigating harmful or other patient-relevant effects of schema therapy(27, 28), and not assessing the certainty of evidence using GRADE(27, 28). We identified one systematic review on eating disorders, investigation eating disorder symptoms in addition to various other outcomes reported by the studies (29). The review included four studies on various kinds of eating disorders, out of which one was an RCT comparing schema therapy to traditional cognitive behavior therapy and appetite-focused cognitive behavior therapy. It was concluded that schema therapy seems effective on eating disorders symptoms. The review was limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, not publishing a protocol before the literature search began, by also including head-to head trials, non-randomized trials, case series, and case reports, not assessing harmful or other patient-relevant effects, and not assessing the certainty of evidence using GRADE. Finally, we identified one systematic review on the effect of schema therapy on symptom change and changes in diagnosis status for post-traumatic stress disorder, anxiety, and obsessive–compulsive disorder(30). Six trials were included, whereof one was a head-to-head non-randomized controlled trial comparing schema therapy to cognitive behavior therapy for post-traumatic stress disorder, one was a three-arm RCT comparing schema therapy to neural-linguistic programming and to no treatment for generalized anxiety disorder, and four trials were single-arm trials with schema therapy for panic disorder/agoraphobia/cluster C personality traits, posttraumatic stress disorder/substance use disorder, and obsessive-compulsive disorder, respectively. It was concluded that only preliminary, scarce and low-quality evidence exists to support the effect of schema therapy on symptom change for these disorders. The review was limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, by also including head-to head trials, non-controlled trials and case series, and by not assessing harmful or other patient-relevant effects. Moreover, we identified a still ongoing review with meta-analysis on the effect of group schema therapy for mental health disorders or psychosocial problems on psychological symptoms, schemas, modes, and dropout (31). However, this review also includes quasi-experimental and naturalistic designs, thereby introducing more possibility for bias in the results. Further, there is no report of planning to employ trial sequential analysis methods to control random errors, assessment of adverse effects, nor assessment of the certainty of evidence using GRADE. Summing up, most reviews did not assess the certainty of evidence using GRADE, which means that clinical recommendations are idiosyncratic for each study and thus based on subjective interpretation. Further, the control group to which schema therapy is compared is important in relation to the conclusions that can be drawn: All reviews mixed evidence from studies investigating schema therapy compared to active treatments (such as cognitive behavior therapy) and schema therapy compared to control groups (such as TAU or waitlist). While head-to-head trials are important to evaluate the additional benefit of new treatments in relation to established treatments, they cannot report on the absolute effect of a treatment, i.e., whether schema therapy is an effective treatment per se. Therefore, evidence from head-to-head trials should be analyzed separately from non-active treatment groups (except in network meta-analyses). Also, with few exceptions most reviews investigate only mental health symptoms as outcomes. From a patient perspective, however, many other outcomes may be equally or more relevant(32), such as quality of life, level of functioning, and adverse events. And finally, none of the reviews with meta-analysis performed trial sequential analyses to control for random errors, meaning that there is a risk of lack of power to support conclusions on treatment effects. In addition to these points, there is a need for an updated review, as we have identified several recent, relevant randomized clinical trials which were not included in the abovementioned reviews (15, 19, 20, 33). Moreover, no systematic review has yet included a meta-analysis on the effects of schema therapy as intervention for a broader range of mental health disorders. Hence, a comprehensive and updated systematic review and meta-analysis of the evidence from randomized clinical trials is needed, which will assess absolute, patient-relevant beneficial and harmful effects of schema therapy for a broad selection of adult mental health disorders in comparison to non-bona fide control groups and consider the risk of both systematic and random errors as well as the certainty of findings. Our review will support informed decision making for clinicians, policy makers, and researchers regarding future investigation into and implementation of schema therapy. Methods The present protocol has been registered in the PROSPERO database (PROSPERO ID: CRD420251015725). The protocol is reported according to the guidelines provided in Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement(34, 35) (see PRISMA-P checklist in Additional file 2). Criteria for considering studies for this review Types of studies We will include randomized clinical trials irrespective of setting, publication year, status, or language of the articles. Types of participants Participants from 18 years of age will be included. Participants with the following primary mental health diagnoses will be included, as defined by the International Statistical Classification of Diseases and Related Health Problems (11th ed.; ICD-11)(36), DSM-5(6), or earlier versions: substance use disorders, psychosis disorders, depressive and bipolar disorders, anxiety disorders, post-traumatic stress disorder, dissociative identity disorder, obsessive-compulsive disorder, eating disorders, personality disorders, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD). Participants will be included irrespective of sex and psychiatric or physical comorbidities. Types of interventions Experimental group We will include any type of schema therapy when it is defined as schema therapy or schema-focused therapy by the authors and has the hallmark traits of schema therapy, i.e., a clear focus on work with schema and schema modes using experiential and other schema therapy interventions. Trials with therapy provided by non-humans, e.g., app formats or artificial intelligence (AI), will not be included. Trials investigating only selected of elements of schema therapy, e.g., imagery rescripting as a stand-alone treatment, will not be included. Trials where schema therapy is merged with other well-established treatments, e.g., Dialectical Behavior Therapy, in a way that means that it is not possible to discern the isolated effect of schema therapy, will not be included. Control group Treatment As Usual (TAU)(or similar terminology), attention control/’psychological placebo’, waitlist, or no intervention are accepted as control groups. Already recognized treatments such as cognitive behavior therapy can function as TAU if they are, a) defined as TAU or similar by trialist, b) described as already implemented and used routinely in the clinical setting of the trial, and, c) Not manualized and/or not undergoing rigorous adherence or quality control. Attention control/psychological placebo is defined as treatment that mimics only the non‐specific or shared components of psychotherapy, such as treatment exposure, human interaction, attending sessions, and patient expectations(37). Trials comparing schema therapy head-to-head to other established bona fide treatments explicitly defined as such and undergoing the same adherence and quality control (e.g., a trial comparing schema therapy to Cognitive Behavior Therapy) will not be included. Outcomes A predefined, prioritized order of outcome measurement instruments is presented in Additional File 3. This will be consulted when a trial measures the same outcome with more than one instrument, in which case results measured with the instrument mentioned first in the prioritized order will be used. Primary outcomes Symptom severity for the trial’s primary diagnosis assessed with a valid disorder-specific symptom scale (continuous data)(note that for ADHD and autism, primary disorder symptoms are not targets for treatment in schema therapy(38), therefore comorbid anxiety (first choice) and depression (second choice) have been chosen as symptom outcomes for ADHD and autism unless the trial specifies another more prevalent psychiatric comorbidity). Symptom severity will be analyzed separately for each disorder Quality of life as assessed on a valid scale (continuous data) Secondary outcomes The proportion of participants with one or more serious adverse events (dichotomous data). The definition of the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use—Good Clinical Practice (ICH-GCP) will be used, namely ‘ any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolonging of existing hospitalization and resulted in persistent or significant disability or jeopardized the participant’(39). This means that data on events that clearly fullfils this definition will be included. Further, data from trials where trialists themselves use the term ‘serious adverse event’ will be included. We will assess a range of serious adverse events separately as exploratory outcomes (see below) Level of functioning as assessed on a valid scale (continuous data) Proportion of participants with premature dropout from treatment as defined by trialists (i.e., not termination of treatment due to considerable bettering of the condition; dichotomous data). If the reason for dropout is not specified by the trialists, we will report the overall dropout rate Exploratory outcomes Proportion of participants with one or more acts of self-harm as defined by trialists (dichotomous data) Proportion of participants with a suicide or a suicide-attempt (dichotomous data) Proportion of participants with one or more psychiatric hospitalizations (dichotomous data) Changes in schemas as measured on the Young Schema Questionnaire or similar (any version) Changes in schema modes as measured on the Schema Mode Inventory or similar (any version) Assessment time points Our primary time point of interest will be at the end of treatment. Our secondary time point of interest will be at maximum follow-up. Search methods for identification of studies Electronic searches We will search Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), PubMed, PsycINFO, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index—Science (CPCI-S), Conference Proceedings Citation Index—Social Science & Humanities (CPCI-SSH), and the International Society for Schema Therapy database at https://schematherapy.omeka.net/ . We will search in all databases from their inception to the present date. For a detailed search strategy for all electronic databases, see Additional file 4. Searching other resources We will check the reference list of relevant trial publications for any unidentified clinical trials. We will contact the authors of included trials by email asking for unpublished randomized clinical trials. To further identify unpublished trials, we will search www.clinicaltrials.gov. We will consider grey literature for inclusion if we identify this. Relevant retraction statements and errata will be assessed for included trials. Data collection We will perform and report the review as recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement(34, 35). Analyses will be performed with Stata (StataCorp LLC, College Station, TX, USA)(40) and Trial Sequential Analysis(41, 42). Selection of randomized clinical trials Titles and abstracts will be screened independently by two review authors. After retrieval of all relevant full-text papers, two authors will independently screen the full texts and record reasons for exclusion of trials. In case of disagreement, a third author will be consulted. Data extraction and management Data will be extracted from included trials independently by two review authors and entered in a data extraction sheet developed for this study. In case of disagreement, a third author will be consulted. In the case of data not being reported in the papers, trial authors will be contacted to and asked if they can supply additional data. Trial characteristics Data will be extracted as follows: publication status, bias risk components (as defined below), trial design (parallel, factorial, or crossover), country, funding, for profit bias, preregistration (e.g., in clinicaltrials.gov), pre-published protocol, number of intervention arms, length of follow-up, sample size estimation, delivery setting, and inclusion and exclusion criteria. Participant characteristics Data will be extracted as follows: number of randomized participants, number of analyzed participants, number of participants lost to follow-up/withdrawal/crossover, dropout after randomization but before treatment initiation, age range (mean or median), sex ratio, primary mental disorder diagnosis and duration, frequency of comorbid personality disorder (when personality disorder is not the primary disorder being treated), other psychiatric and physical comorbidities, earlier received treatments, and proportion receiving psychotropic medicine. Experimental intervention characteristics Data will be extracted as follows: treatment duration in months, number of sessions, session lengths (minutes), number of sessions per week, adherence measured (yes/no), treatment format (e.g., individual, group therapy), and co-occurring interventions. Control intervention characteristics Data will be extracted as follows: type of control intervention, treatment duration in months, number of sessions, session lengths (minutes), number of sessions per week, treatment format, and co-occurring interventions. Outcomes For each outcome, we will identify if outcomes are missing, inadequately measured, or selectively reported - according to the Cochrane Risk of Bias - version 2 (RoB2) criteria(43) – in the bias domains of “missing outcome data”, “risk of bias in measurement of the outcome”, and “risk of bias in selection of the reported results”, as explained below. Conflicts of interest We will extract information about vested interests in relation to trial funding as well as notable conflicts of interest for all trial authors. Assessment of risk of bias in the included studies Thefollowing bias domains will be judged as per the Cochrane Handbook for Systematic Reviews of Interventions (43), with the risk-of-bias judgment options Low risk of bias, Some concerns, or High risk of bias for each domain: Bias arising from the randomization process This domain evaluates allocation sequence generation, concealment of the allocation sequence, and baseline differences between the trial arms that may be due to a problem in the randomization process. Bias due to deviation from intended interventions This domain evaluates whether study participants, care providers, and other personnel were aware of intervention groups during the trial as this can lead to protocol deviations such as patients seeking or clinicians administering the experimental or other treatments to the control group. Also, it evaluates whether participants were analyzed in the group they were allocated to by randomization (rather than in the group with the intervention they actually received) and whether any deviations from the protocol were likely to have an impact on the outcome. Bias due to missing outcome data This domain evaluates the extent of missing data, and the robustness of the effect estimate to missing data, i.e., the missing data was not thought to impact the outcome (missing at random). Bias in measurement of the outcome This domain evaluates whether outcome assessors where blinded to and/or non-biased by the randomization status of the participant, whether the method of outcome measurements was appropriate, and whether the measurement could have differed between intervention groups. Bias arising from selective reporting of results This domain evaluates whether the trial was reported in accordance with a pre-specified plan, whether the reporting of specific data could have been selected to portray a specific desired result, and whether results could have been chosen selectively from multiple analyses of the data. Overall assessment of risk of bias The study is judged to be overall at low risk of bias if all domains are at low risk of bias. The judgment of ‘Some concerns’ will be given for the study overall if some concerns are raised in one or more domains, while the judgment for the overall study at ‘High risk of bias’ is given if multiple domains are evaluated to raise ‘Some concerns’, or at least one domain is evaluated to have ‘High risk of bias’. We will make subgroup analyses on the intervention effect of trials at low risk of bias compared with trials at high risk of bias. Our primary conclusions will be based on the results of our primary outcome results, taking into consideration the risk of bias in the individual studies on those outcomes. Both results of our primary and secondary outcomes will be presented and discussed. Differences between protocol and the review Any deviations from this protocol in the final systematic review will be reported in the main article. Measurement of treatment effect Dichotomous outcomes We will calculate risk ratios (RRs) with 95% confidence interval (CI) and Trial Sequential Analysis-adjusted CI (see description below) for dichotomous outcomes. Continuous outcomes We will calculate the mean differences (MDs) with 95% CI and Trial Sequential Analysis-adjusted CI for continuous outcomes that are identical across trials. We will consider calculating the standardized mean difference (SMD) with 95% CI if comparable, but non-identical continuous outcomes are reported across trials. Dealing with missing data Before statistical handling of missing data, we will contact trial authors to obtain relevant missing data for data extraction and for assessment of risk of bias. We will use intention-to-treat data if this is provided in the original report, and otherwise we will use per-protocol data. Dichotomous outcomes The primary analysis will not contain imputations, but we will impute missing data in sensitivity analyses. Continuous outcomes The primary analysis will not contain imputations, but we will impute missing data in best-worst/worst-best scenarios (see below). We will primarily analyze scores assessed at the end of treatment time point. In case only changes from baseline scores are reported, we will analyze these results together with mean end of treatment scores(43). If standard deviations (SDs) are not reported, we will calculate the SDs using trial data, if possible. Assessment of heterogeneity First, we will visually assess heterogeneity in forest plots. Second, we will assess statistical heterogeneity by the chi 2 test (threshold P < 0.10) and measure the quantities of heterogeneity by the I 2 statistic(43-45). We will also investigate possible heterogeneity through subgroup analyses. In the case of substantial heterogeneity, we may decide not to perform a meta-analysis(43). Assessment or reporting biases We will visually inspect funnel plots to assess the risk of reporting bias if ten or more trials are included(43). For dichotomous outcomes, we will test asymmetry with the Harbord test if τ 2 is less than 0.1(46) and with the Rücker test if τ 2 is more than 0.1(43). For continuous outcomes, we will use the regression asymmetry test(47) and the adjusted rank correlation(48). Unit of analysis issues Where multiple trial arms are reported in a single trial, we will only analyze the relevant arms, i.e., schema therapy and a control intervention as specified above. If several formats or versions of schema therapy occur in the same trial, we will divide the number of events (e.g., number of suicides or suicide attempts) and the sample size for the control group by the number of schema therapy groups for dichotomous data to avoid double-counting, and for continuous data we will keep the average main score for the control group as the comparison to schema therapy(43). For cluster-randomized trials, we will adjust the original sample size of the trial to its effective sample size, using the intra-cluster correlation coefficient from the ‘design effect’(43). For trials using a crossover design, only data from the first period will be included(43, 49). This means that unit of analysis issues will not occur. Data synthesis Meta-analysis We will undertake the meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions(43) and Keus et al.(50). For statistical analyses, we will use the statistical software Stata(40). To obtain a more valid assessment of results, the eight-step procedure suggested by Jakobsen et al.(51) will be followed, comprised of the following steps: (1) obtain the 95% confidence intervals and the P values from both fixed-effect and random-effects meta-analyses and report the most conservative results as the main results; (2) explore the reasons behind substantial statistical heterogeneity using subgroup and sensitivity analyses (see step 6); (3) adjust the thresholds for significance according to the number of primary outcomes to take account of problems with multiplicity; (4) calculate required information sizes (≈ the a priori required number of participants for a meta-analysis to be conclusive) for all outcomes and analyze each outcome with Trial Sequential Analysis. Report whether the trial sequential monitoring boundaries for benefit, harm, or futility are crossed; (5) calculate Bayes factors for all primary outcomes; (6) use subgroup analyses and sensitivity analyses to assess the potential impact of bias on the review results; (7) assess the risk of publication bias; (8) assess the clinical significance of the statistically significant review results(51). We will assess the intervention effects for each comparison separately with both random-effects meta-analyses(52) and fixed-effect meta-analyses(53) and report the most conservative results of the two as the main result(51). We will assess a total of two primary outcomes and therefore consider a P value < 0.025 as the threshold for statistical significance for the primary outcomes(51). Secondary and exploratory outcomes will be considered hypothesis-generating only; therefore, we will use a threshold of P < 0.05 for non-primary outcomes. As a primary analysis, we will report the effects of schema therapy separately for each mental health disorder. As an exploratory analysis, we will report the effects of schema therapy for longer lasting disorders (i.e., personality disorders, ADHD, autism, and other disorders lasting more than 2 years) pooled versus acute disorders (i.e., other disorders lasting less than 2 years) pooled. Our primary conclusion will be based on results with low risk of bias(51). If no low risk of bias trials are identified, we will base our primary conclusion on all trials. If quantitative synthesis is not appropriate due to considerable heterogeneity or a small number of included trials for each mental disorder, we will report the results narratively. Trial Sequential Analysis In traditional meta-analyses, there is a risk of random errors due to sparse data or repetitive testing of accumulating data when updating reviews. We wish to control the risks of both type I errors and type II errors by performing Trial Sequential Analysis on all outcomes(54). This will calculate the required information size for each outcome in the meta-analysis (that is, the number of participants needed to detect or reject a certain intervention effect) and the cumulative Z -curve’s breach of relevant trial sequential monitoring boundaries(41, 42, 55-61) (for a more detailed description, see the Trial Sequential Analysis manual(42) and http://www.ctu.dk/tsa/). For dichotomous outcomes, we will estimate the required information size based on the observed proportion of patients with an outcome in the control group (the cumulative proportion of patients with an event in the control groups relative to all patients in the control groups), a relative risk reduction of 20%, an alpha of 2.5% for the primary outcomes and 5% for the remaining outcomes, a beta of 20%, and the observed diversity as suggested by the trials in the meta-analysis. In a Trial Sequential Analysis for continuous outcomes, we will use the observed standard deviation (SD), a mean difference equal to the observed SD/2, an alpha of 2.5% for the primary outcomes and 5% for the remaining outcomes, a beta of 20%, and the observed diversity as suggested by the trials in the meta-analysis. Subgroup analysis and integration of heterogeneity Subgroup analysis We will perform the following subgroup analyses when analyzing the primary outcomes (symptom severity, quality of life): Trials at high risk of bias compared with trials at low risk of bias Psychotherapy formats (e.g., group, individual) Types of comparators (i.e., no intervention/waitlist, specialized TAU (i.e., interventions that are the best available treatments already implemented at the study site(s)) but still live up to the above criteria for TAU), attention control/non-specific TAU (e.g., supportive counselling) Longer lasting disorders (i.e., personality disorders, ADHD, autism, and other disorders lasting more than 2 years) pooled versus acute disorders (i.e., other disorders lasting less than 2 years) pooled We will use the formal test for subgroup interactions in Stata(40). Sensitivity analysis To assess the potential impact of missing data, we will perform the two following sensitivity analyses on the dichotomous outcomes: “ Best - worst - case ” scenario : We will assume that all participants lost to follow-up in the schema therapy group had neither a suicide, a suicide attempt, attempted self-harm, nor a psychiatric hospitalization or dropped out of treatment, and that all participants lost to follow-up in the control group had a suicide or suicide attempt, attempted self-harm, had a psychiatric hospitalization, and dropped out of treatment. “ Worst - best - case ” scenario : We will assume that all participants lost to follow-up in the control group had a suicide or suicide attempt, attempted self-harm, had a psychiatric hospitalization, and dropped out of treatment, and that all participants lost to follow-up in the schema therapy group had neither a suicide or suicide attempt, attempted self-harm, nor a psychiatric hospitalization or dropped out of treatment. To assess the potential impact of missing data for the continuous outcomes, we will perform the same sensitivity analysis, where a “beneficial outcome” will be defined as the group mean plus two standard deviations (SDs) (we will secondly use one SD in another sensitivity analysis) of the group mean and a “harmful outcome” will be defined as the group mean minus two SDs (we will secondly use one SD in another sensitivity analysis) of the group mean(51). Where SDs are missing and it is not possible to calculate them, we will impute SDs from trials with similar populations and low risk of bias. If we find no such trials, we will impute SDs from trials with a similar population. As the final option, we will impute SDs from all trials. We will present results of all these scenarios in our review. Other post hoc sensitivity analyses might be warranted if unexpected clinical or statistical heterogeneity is identified during the analysis of the review results, in which case these analyses will be presented clearly as post hoc and exploratory(51). Summary of findings table We will report findings in a table for each comparison (schema therapy vs. no intervention/waitlist, vs TAU, or vs. attention control/’psychological placebo’) including each of the prespecified outcomes (symptom severity, quality of life, level of functioning, self-harm, suicidal behavior, dropout, schemas, schema modes). We will use the five GRADE considerations (risk of bias in the trials, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence(51, 62-64). We will assess imprecision using Trial Sequential Analysis, and downgrade imprecision in GRADE by two levels if the accrued number of participants is below 50% of the diversity-adjusted required information size (DARIS), and one level if it is between 50 and 100% of DARIS. We will not downgrade if the cumulative Z -curve crosses the monitoring boundaries for benefit, harm, or futility, or DARIS is reached. We will justify all decisions to downgrade the quality of studies. Firstly, we will present our results in the summary of findings table based on the results from the trials with an overall low risk of bias, and secondly, we will present the results based on all trials. Discussion This systematic review with meta-analyses and Trial Sequential Analysis aims to assess the beneficial and harmful effects of schema therapy versus treatment as usual, attention control, or waitlist for the most commonly treated mental health disorders. Primary outcomes will be symptom severity and quality of life. Secondary outcomes will serious adverse events, level of functioning, and premature dropout from treatment. Exploratory outcomes will be self-harm, suicide or suicide-attempts, psychiatric hospitalizations, and changes in schemas and schema modes. This protocol has a particular strength in the comprehensive, state-of-the-art methodology. The risk of both random and systematic errors will be considered, using the methodology by Keus et al.(50), the eight-step procedure by Jakobsen et al.(51), and Trials Sequential Analysis(41). The GRADE framework will be used to assess the certainty of the evidence(62-64). Further, we will search for and include data from both published and unpublished trials to minimize the risk of publication bias. However, this protocol also has limitations: First, there is a risk of identifying only few eligible randomized trials. Schema therapy is still in a preliminary stage when it comes to evidence, meaning that many applications of the therapy have primarily been tested in a smaller and less methodologically strict format, e.g., case series and single-arm trials. As schema therapy has been developed out of cognitive behavioral and other therapies, many trialists performing randomized trials have chosen to test the additional effect of schema therapy against established therapies (e.g., (65-68)). While we are aware of the existence of such trials, we have chosen only to include randomized trials comparing schema therapy to TAU, consisting of non-manualized treatments under little control and waitlist/no intervention, as this gives the possibility to establish the general, absolute effects of schema therapy, rather than the effects relative to other, established psychotherapies. As the number of high-quality trials on schema therapy will hopefully accrue in the future, it will be possible to conduct a network meta-analysis including all randomized controlled trials to establish both the absolute and relative effects of schema therapy. In the case that the number of included trials is so low that meta-analysis is not possible to conduct for some mental health disorders, we will report the results narratively. A third limitation the inherent problem regarding blinding in psychotherapy research, where it is almost impossible to blind all parties(69). We expect that participants and clinicians delivering treatment will not be blinded, but we will attempt to estimate the extent to which other relevant parties have been blinded when reporting bias in the trials. Also, we expect to find many trials with other sources of bias risks, including large proportions of missing data(70). This will potentially influence the strength of conclusions and GRADE recommendations. Finally, a limitation is the potentially numerous comparisons when analyzing results for all included mental health disorders separately, increasing the risk for false positives (type I errors). We have adjusted the threshold for significance according to the number of primary outcomes, but not to the number of mental health diseases, and not for the subgroup analyses. Also, lack of data and statistical power for all planned subgroup analyses are likely. We will consider this when reporting and concluding on the findings. Conclusion Schema therapy is a promising intervention for severe mental health disorders, but the certainty of evidence for benefits and harms of schema therapy is still unclear. This review will inform clinical guidelines, thus expanding the possible choices of treatments in clinical practice. Further, the review will provide a comprehensive overview of the literature and highlight research gaps to inform future research. Abbreviations ADHD: Attention-Deficit/Hyperactivity Disorder AI: Artificial Intelligence CENTRAL: Cochrane Central Register of Controlled Trials CI: Confidence Interval CPCI-S: Conference Proceedings Citation Index – Science CPCI-SSH: Conference Proceedings Citation Index – Social Sciences & Humanities CRD: Centre for Reviews and Dissemination DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th edition EMBASE: Excerpta Medica database GRADE: Grading of Recommendations Assessment, Development and Evaluation ICD-11: International Statistical Classification of Diseases and Related Health Problems, 11th edition ICH-GCP: International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use – Guideline for Good Clinical Practice MEDLINE: Medical Literature Analysis and Retrieval System Online PROSPERO: The International Prospective Register of Systematic Reviews PRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analysis -Protocols RCT: Randomized Clinical Trial RoB2: Cochrane Risk of Bias – version 2 RR: Risk Ratio SCI-EXPANDED: Science Citation Expanded SD: Standard Deviation SMD: Standardized Mean Difference SSCI: Social Sciences Citation Index TAU: Treatment As Usual Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable Conflicts of interest IMTPA is a member of International Society for Schema Therapy (ISST) and has received funding for and published research on ST. SJ and CH have no conflict of interest to declare. MV provides workshops and lectures on Schema Therapy (ST). He is also on the executive board of the ISST 2024-2026, where he gets a fee for the voluntary work and is a part of the Dutch Society of Schema Therapy (VST). Furthermore, MV has received funding for and published research on ST and are getting publishing fees for books about ST. MV is a practitioner of ST and works at a clinic that provides ST. JK has provided workshops and lectures on ST and has received funding for and published research on ST. BB is a practitioner of ST and works in a clinic that provides ST. BB has received publishing fees for books about ST. Furthermore, BB has received funding for and published research on ST. AA has provided workshops and lectures on ST and received fees from societies that are promoting ST. AA has received publishing fees for books about ST and has received funding for and published research on ST. Furthermore, he is a practitioner of ST. SBM has received funding for and published research on ST and is a member of the International Society for Schema Therapy (ISST). Funding This study is funded by Trygfonden (award number: 149726) (see Additional file 5). The fund is not involved in the study conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. Authors’ contributions IMTPA and SBM conceptualized this research project. IMTPA is the guarantor of the project. IMTPA, SJ and SBM developed the methodology. IMTPA administrated the project and wrote the first draft of the protocol supervised by SBM and SJ. 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Tables Table 1 is available in the Supplementary Files section. Supplementary Files Trygfondenfundingstatement.pdf Additional file 5 Pdf-format Funding statement from Trygfonden Searchstrategies.pdf Additional file 4 Word-format (.doxc) Search strategies: search strings for all included databases OutcomehierarchyFINALversion2.docx Additional file 3 Word-format (.doxc) Outcome hierarchy Contains a prioritized order of continuous outcome measurement instruments which will be consulted in case a trial reports results from more than one instrument measuring the same outcome ATabel1Reviews.docx Additional file 1 Word-format (.doxc) Table 1. Characteristics of previous systematic reviews of schema therapy. Contains the most important characteristics of a range of systematic reviews of the effect of schema therapy that have been made up to the date of submission of the present article SYSRS2500841.pdf Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Trygfonden\u003c/p\u003e","description":"","filename":"Trygfondenfundingstatement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6570797/v1/46e5e7e65fb067b65a8574eb.pdf"},{"id":104973077,"identity":"68cd0080-0dd8-4f6c-8439-377e0c9d6fdf","added_by":"auto","created_at":"2026-03-19 11:27:10","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":193439,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWord-format (.doxc)\u003c/p\u003e\n\u003cp\u003eSearch strategies: search strings for all included databases\u003c/p\u003e","description":"","filename":"Searchstrategies.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6570797/v1/5633d87b913f1aac1f683164.pdf"},{"id":104973040,"identity":"75e04615-2164-4b60-b8a8-ae13c0f4a055","added_by":"auto","created_at":"2026-03-19 11:26:48","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":45726,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWord-format (.doxc)\u003c/p\u003e\n\u003cp\u003eOutcome hierarchy\u003c/p\u003e\n\u003cp\u003eContains a prioritized order of continuous outcome measurement instruments which will be consulted in case a trial reports results from more than one instrument measuring the same outcome\u003c/p\u003e","description":"","filename":"OutcomehierarchyFINALversion2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6570797/v1/6a4cc0c15ed6c3730644e6f1.docx"},{"id":104973130,"identity":"86071c8f-3223-4b61-82be-43d319314b47","added_by":"auto","created_at":"2026-03-19 11:27:25","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":22404,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWord-format (.doxc)\u003c/p\u003e\n\u003cp\u003eTable 1. Characteristics of previous systematic reviews of schema therapy.\u003c/p\u003e\n\u003cp\u003eContains the most important characteristics of a range of systematic reviews of the effect of schema therapy that have been made up to the date of submission of the present article\u003c/p\u003e","description":"","filename":"ATabel1Reviews.docx","url":"https://assets-eu.researchsquare.com/files/rs-6570797/v1/767fa43d0cd4a51d13c18b76.docx"},{"id":104973103,"identity":"ae0ffddf-ccab-4553-96be-38a6f5571ec0","added_by":"auto","created_at":"2026-03-19 11:27:16","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":2340516,"visible":true,"origin":"","legend":"","description":"","filename":"SYSRS2500841.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6570797/v1/d63aca9e3e01fab937314b12.pdf"}],"financialInterests":"","formattedTitle":"Schema therapy versus any control group for adult mental health disorders: a protocol for a systematic review with meta-analysis and trial sequential analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eMental health disorders are a global problem, with an estimated point prevalence in 2019 of 970 million or 12.5% worldwide (REF LANCET), and a life time prevalence in Europe of 26%(1). Mental health disorders account for substantial costs for the individual and for society(2, 3) and account for 123 million Disability-Adjusted Life Years globally(4), which places them among the five highest ranking non-communicable diseases regarding disease burden (5).\u003c/p\u003e\n\u003cp\u003eA mental health disorders is defined in the \u003cem\u003eDiagnostic and Statistical Manual of Mental Disorders\u003c/em\u003e, \u003cem\u003e5th edition\u003c/em\u003e (DSM-5) as ‘a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning […] usually associated with significant distress in social, occupational, or other important activities’. Mental health disorders can be broadly categorized into \u003cem\u003eNeurodevelopmental disorders, Schizophrenia Spectrum and other Psychotic disorders, Bipolar and related disorders, Depressive disorders, Anxiety disorders, Obsessive-Compulsive and related disorders, Trauma- and stressor-related disorders, Dissociative disorders, Somatic Symptom and related disorders, Feeding and Eating disorders, Elimination disorders, Sleep-Wake disorders, Sexual dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control and Conduct disorders, Substance-Related and Addictive disorders, Neurocognitive disorders, Personality disorders, and Paraphilic disorders\u003c/em\u003e\u003cem\u003e(6)\u003c/em\u003e\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePharmacological interventions are often used to treat mental health disorders, including, e.g., antipsychotics, antidepressants, and mood stabilizers(7-11) . However, psychotherapy is often recommended either as an adjunctive to pharmacological interventions or as stand-alone treatment for a wide selection of mental health disorders(7-11). While most established psychotherapies have been found effective on mental disorders at a general level, evidence suggests that more specialized treatments could be warranted for more severe and/or complex cases of mental health problems(12).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eDescription of the intervention\u003c/h2\u003e\n\u003cp\u003eSchema therapy is one such specialized form of psychotherapy. It was developed by Jeffrey Young and colleagues to address mental health issues that do not respond to first line treatments, often due to more fundamental problems rooting in childhood adversity and characterological challenges(13). Drawing on theories and methods from cognitive behavioral, psychodynamic, emotion-focused and gestalt therapies, schema therapy has a distinct experiential focus with hallmark methods such as \u003cem\u003eimagery rescripting, chair exercises\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;role play.\u0026nbsp;\u003c/em\u003eFurther, the therapeutic relationship is used actively as a means to ameliorate adverse childhood events (\u003cem\u003elimited reparenting\u003c/em\u003e) and to call out and change dysfunctional behavior (\u003cem\u003eempathic confrontation\u003c/em\u003e)(13, 14).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSchema therapy can be delivered in a group and in an individual format(15), in person and in online formats(16, 17). Schema therapy can be applied in in-patient and out-patient contexts(17-19), including forensic settings(20), and to both adults, adolescents, and children (14, 21). As schema therapy is transdiagnostic by nature, it can be applied and adapted to many, more ingrained \u0026nbsp;mental health disorders(22). The therapy is often delivered in a longer format (e.g., 30 sessions or longer), as this is necessary to capture and change more ingrained cognitive structures and behaviors.\u003c/p\u003e\n\u003ch2\u003eHow the intervention might work\u003c/h2\u003e\n\u003cp\u003eIn schema therapy, it is hypothesized that mental health disorders result from early developed cognitive structures, so-called \u003cem\u003eearly maladaptive schemas,\u0026nbsp;\u003c/em\u003ewhich direct and potentially distort perception and emotions(13). Schemas, when triggered, activate \u003cem\u003eschema modes,\u0026nbsp;\u003c/em\u003ewhichare (most often dysfunctional) behavioral and emotional coping responses. In schema therapy, the therapist ultimately seeks to ameliorate early maladaptive schemas and the dysfunctional modes. Importantly, the mode \u003cem\u003eVulnerable Child\u003c/em\u003e, a representation of genuine sadness and unmet personal needs, is sought to be soothed and have its needs met, while the mode \u003cem\u003eHealthy Adult\u003c/em\u003e, representing the wise, healthy and resourceful part of the individual, is supported to grow and gradually assume greater autonomy from the therapist’s guidance(14).\u003c/p\u003e\n\u003cp\u003eWorking with childhood adversity and its consequences, not only on the level of current maintaining factors, but also on fundamentally modifying cognitive and emotional dysfunction originating in individual learning history, schema therapy is thought to create longer-lasting, positive changes in the patient’s psychological make-up and behavior. Further, schema therapy works trans-diagnostically and can simultaneously address both mental disorders thought of as a ‘state’ (e.g., depression, anxiety) and ‘traits’ such as personality disorders, accentuated personality traits, or other idiosyncratic, maladaptive patterns of thought and behavior.\u003c/p\u003e\n\u003ch2\u003eWhy is it important to do this review\u003c/h2\u003e\n\u003cp\u003eResearch on schema therapy has accumulated in recent years(23), but the empirical status of its effects remains unclear.\u003c/p\u003e\n\u003cp\u003eWe have identified seven systematic reviews to date (whereof two include a meta-analysis) on the effects of schema therapy. The characteristics and results of the previous systematic reviews are summarized in Table 1 [Additional File 1].While the reviews encompass both the effects of schema therapy as a whole and on important selected disorders, they also exhibited shortcomings, both in regard to a narrow focus on only mental health symptoms as outcome, and in the use of inconsistent methodology, as we will now present.\u003c/p\u003e\n\u003cp\u003eOut of the seven reviews, three reviews assessed the effects of schema therapy for a wide range of mental health disorders.\u003c/p\u003e\n\u003cp\u003eOne was a systematic review of the effects of schema therapy on all outcomes (as reported by the included trials) for treatments lasting at least ten psychotherapy sessions(24). The review included ten studies, out of which three were randomized controlled trials comparing schema therapy to standard treatments and two were head-to head randomized trials. Only one high quality study was found, and it was concluded that schema therapy seems effective, but that there was too little evidence of high quality to make conclusions or clinical recommendations.\u003c/p\u003e\n\u003cp\u003eA second systematic review(25) was an update of the above review(24), now including trials from 2011 to 2015. An additional 9 studies were identified, out of which one was a three-arm randomized trial comparing schema therapy to clarification-oriented therapy and Treatment As Usual (TAU), one was a randomized controlled trial comparing schema therapy to TAU, and one was a randomized head-to-head trial. The results were again found inconclusive regarding the effects of schema therapy due to scarcity of high-quality evidence.\u003c/p\u003e\n\u003cp\u003eThe third was a systematic review of the effects of schema therapy on both symptom change and schema or schema mode change(26). Twelve studies were included, out of which one was a randomized controlled trial comparing the effect of schema therapy with or without additional telephonic crisis support. Regarding symptom change, the study concluded that there is some evidence to suggest effectiveness of schema therapy on personality disorders, but too scarce evidence to make conclusions for other mental disorders.\u003c/p\u003e\n\u003cp\u003eThese reviews were limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, meaning that interpretations and recommendations for clinical practice were subject to subjective interpretation(24-26). The studies included a variety of trial designs, such as head-to-head trials, non-controlled and non-randomized trials, and case series(24-26), which means that results were based on evidence of varying quality and risk of bias. Further, the studies did not investigate harmful effects or other patient-relevant effects of schema therapy(24-26). Moreover, the latter study did not search all relevant databases, and it excluded twelve trials that did not report both change in symptom levels \u003cem\u003eand\u003c/em\u003e schemas or schema modes, thus potentially excluding trials that could have provided additional data on the effectiveness of schema therapy(26).\u003c/p\u003e\n\u003cp\u003eWe have also identified four systematic reviews which investigated distinct mental health disorders.\u003c/p\u003e\n\u003cp\u003eTwo reviews investigated personality disorders(27, 28). One review with meta-analysis investigated the effect of schema therapy on personality disorder symptoms, quality of life, and schema change(28). \u0026nbsp;It included 16 studies, out of which nine were RCTs, with five trials comparing schema therapy to TAU, one trial comparing schema therapy to transference-focused psychotherapy, one trial comparing schema therapy with or without access to telephonic crisis support, and two were three-arm trials comparing schema therapy to Dialectical Behavior Therapy and placebo, and clarification-oriented psychotherapy and TAU, respectively. It was concluded that schema therapy significantly reduces symptoms of personality disorders and improves quality of life and schemas(28).\u003c/p\u003e\n\u003cp\u003eThe other review was a network meta-analysis of the effect of all psychotherapies for symptoms of borderline personality disorder, suicidal behavior, and dropout rates (27). It included three trials on schema therapy(27), of which two trials were RCTs comparing schema therapy to TAU, and one RCT compared schema therapy to transference-focused psychotherapy. The review concluded that schema therapy might be equal to or superior over some other psychotherapies regarding symptom change and dropout rates. The two reviews were limited by also including head-to head trials(when not doing network meta-analysis), non-controlled and non-randomized trials, and case series(28), by not employing trial sequential analysis methods to control for random errors(27, 28), not investigating harmful or other patient-relevant effects of schema therapy(27, 28), and not assessing the certainty of evidence using GRADE(27, 28).\u003c/p\u003e\n\u003cp\u003eWe identified one systematic review on eating disorders, investigation eating disorder symptoms in addition to various other outcomes reported by the studies (29). The review included four studies on various kinds of eating disorders, out of which one was an RCT comparing schema therapy to traditional cognitive behavior therapy and appetite-focused cognitive behavior therapy. It was concluded that schema therapy seems effective on eating disorders symptoms. The review was limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, not publishing a protocol before the literature search began, by also including head-to head trials, non-randomized trials, case series, and case reports, not assessing harmful or other patient-relevant effects, and not assessing the certainty of evidence using GRADE.\u003c/p\u003e\n\u003cp\u003eFinally, we identified one systematic review on the effect of schema therapy on symptom change and changes in diagnosis status for post-traumatic stress disorder, anxiety, and obsessive–compulsive disorder(30). Six trials were included, whereof one was a head-to-head non-randomized controlled trial comparing schema therapy to cognitive behavior therapy for post-traumatic stress disorder, one was a three-arm RCT comparing schema therapy to neural-linguistic programming and to no treatment for generalized anxiety disorder, and four trials were single-arm trials with schema therapy for panic disorder/agoraphobia/cluster C personality traits, posttraumatic stress disorder/substance use disorder, and obsessive-compulsive disorder, respectively. It was concluded that only preliminary, scarce and low-quality evidence exists to support the effect of schema therapy on symptom change for these disorders. The review was limited by primarily reporting narratively and not including a meta-analysis or an assessment of the certainty of evidence using GRADE, by also including head-to head trials, non-controlled trials and case series, and by not assessing harmful or other patient-relevant effects.\u003c/p\u003e\n\u003cp\u003eMoreover, we identified a still ongoing review with meta-analysis on the effect of group schema therapy for mental health disorders or psychosocial problems on psychological symptoms, schemas, modes, and dropout (31). However, this review also includes quasi-experimental and naturalistic designs, thereby introducing more possibility for bias in the results. Further, there is no report of planning to employ trial sequential analysis methods to control random errors, assessment of adverse effects, nor assessment of the certainty of evidence using GRADE.\u003c/p\u003e\n\u003cp\u003eSumming up, most reviews did not assess the certainty of evidence using GRADE, which means that clinical recommendations are idiosyncratic for each study and thus based on subjective interpretation. Further, the control group to which schema therapy is compared is important in relation to the conclusions that can be drawn: All reviews mixed evidence from studies investigating schema therapy compared to active treatments (such as cognitive behavior therapy) and schema therapy compared to control groups (such as TAU or waitlist). While head-to-head trials are important to evaluate the additional benefit of new treatments in relation to established treatments, they cannot report on the absolute effect of a treatment, i.e., whether schema therapy is an effective treatment per se. Therefore, evidence from head-to-head trials should be analyzed separately from non-active treatment groups (except in network meta-analyses).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlso, with few exceptions most reviews investigate only mental health symptoms as outcomes. From a patient perspective, however, many other outcomes may be equally or more relevant(32), such as quality of life, level of functioning, and adverse events. And finally, none of the reviews with meta-analysis performed trial sequential analyses to control for random errors, meaning that there is a risk of lack of power to support conclusions on treatment effects.\u003c/p\u003e\n\u003cp\u003eIn addition to these points, there is a need for an updated review, as we have identified several recent, relevant randomized clinical trials which were not included in the abovementioned reviews (15, 19, 20, 33). Moreover, no systematic review has yet included a meta-analysis on the effects of schema therapy as intervention for a broader range of mental health disorders.\u003c/p\u003e\n\u003cp\u003eHence, a comprehensive and updated systematic review and meta-analysis of the evidence from randomized clinical trials is needed, which will assess absolute, patient-relevant beneficial and harmful effects of schema therapy for a broad selection of adult mental health disorders in comparison to non-bona fide control groups and consider the risk of both systematic and random errors as well as the certainty of findings. Our review will support informed decision making for clinicians, policy makers, and researchers regarding future investigation into and implementation of schema therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe present protocol has been registered in the PROSPERO database (PROSPERO ID: CRD420251015725). The protocol is reported according to the guidelines provided in Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement(34, 35) (see PRISMA-P checklist in Additional file 2).\u003c/p\u003e\n\u003ch2\u003eCriteria for considering studies for this review\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will include randomized clinical trials irrespective of setting, publication year, status, or language of the articles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants from 18 years of age will be included. Participants with the following primary mental health diagnoses will be included, as defined by the \u003cem\u003eInternational Statistical Classification of Diseases and Related Health Problems\u003c/em\u003e (11th ed.; ICD-11)(36), DSM-5(6), or earlier versions: substance use disorders, psychosis disorders, depressive and bipolar disorders, anxiety disorders, post-traumatic stress disorder, dissociative identity disorder, obsessive-compulsive disorder, eating disorders, personality disorders, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD). Participants will be included irrespective of sex and psychiatric or physical comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of interventions\u003c/strong\u003e\u003c/p\u003e\n\u003ch4\u003eExperimental group\u003c/h4\u003e\n\u003cp\u003eWe will include any type of schema therapy when it is defined as schema therapy or schema-focused therapy by the authors \u003cem\u003eand\u0026nbsp;\u003c/em\u003ehas the hallmark traits of schema therapy, i.e., a clear focus on work with schema and schema modes using experiential and other schema therapy interventions. Trials with therapy provided by non-humans, e.g., app formats or artificial intelligence (AI), will not be included. Trials investigating only selected of elements of schema therapy, e.g., imagery rescripting as a stand-alone treatment, will not be included. Trials where schema therapy is merged with other well-established treatments, e.g., Dialectical Behavior Therapy, in a way that means that it is not possible to discern the isolated effect of schema therapy, will not be included.\u003c/p\u003e\n\u003ch4\u003eControl group\u003c/h4\u003e\n\u003cp\u003eTreatment As Usual (TAU)(or similar terminology), attention control/’psychological placebo’, waitlist, or no intervention are accepted as control groups. Already recognized treatments such as cognitive behavior therapy can function as TAU if they are, a) defined as TAU or similar by trialist, b) described as already implemented and used routinely in the clinical setting of the trial, and, c) Not manualized and/or not undergoing rigorous adherence or quality control. Attention control/psychological placebo is defined as treatment that mimics only the non‐specific or shared components of psychotherapy, such as treatment exposure, human interaction, attending sessions, and patient expectations(37).\u003c/p\u003e\n\u003cp\u003eTrials comparing schema therapy head-to-head to other established bona fide treatments explicitly defined as such and undergoing the same adherence and quality control (e.g., a trial comparing schema therapy to Cognitive Behavior Therapy) will not be included.\u003c/p\u003e"},{"header":"Outcomes","content":"\u003cp\u003eA predefined, prioritized order of outcome measurement instruments is presented in Additional File 3. This will be consulted when a trial measures the same outcome with more than one instrument, in which case results measured with the instrument mentioned first in the prioritized order will be used.\u003c/p\u003e\n\u003ch4\u003ePrimary outcomes\u003c/h4\u003e\n\u003col\u003e\n \u003cli\u003eSymptom severity for the trial\u0026rsquo;s primary diagnosis assessed with a valid disorder-specific symptom scale (continuous data)(note that for ADHD and autism, primary disorder symptoms are not targets for treatment in schema therapy(38), therefore comorbid anxiety (first choice) and depression (second choice) have been chosen as symptom outcomes for ADHD and autism unless the trial specifies another more prevalent psychiatric comorbidity). Symptom severity will be analyzed separately for each disorder\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"2\" type=\"1\"\u003e\n \u003cli\u003eQuality of life as assessed on a valid scale (continuous data)\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch4\u003eSecondary outcomes\u003c/h4\u003e\n\u003col\u003e\n \u003cli\u003eThe proportion of participants with one or more serious adverse events (dichotomous data). The definition of the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use\u0026mdash;Good Clinical Practice (ICH-GCP) will be used, namely \u0026lsquo; any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolonging of existing hospitalization and resulted in persistent or significant disability or jeopardized the participant\u0026rsquo;(39). This means that data on events that clearly fullfils this definition will be included. Further, data from trials where trialists themselves use the term \u0026lsquo;serious adverse event\u0026rsquo; will be included. We will assess a range of serious adverse events separately as exploratory outcomes (see below)\u003c/li\u003e\n \u003cli\u003eLevel of functioning as assessed on a valid scale (continuous data)\u003c/li\u003e\n \u003cli\u003eProportion of participants with premature dropout from treatment as defined by trialists (i.e., not termination of treatment due to considerable bettering of the condition; dichotomous data). If the reason for dropout is not specified by the trialists, we will report the overall dropout rate\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch4\u003eExploratory outcomes\u003c/h4\u003e\n\u003col\u003e\n \u003cli\u003eProportion of participants with one or more acts of self-harm as defined by trialists (dichotomous data)\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"2\" type=\"1\"\u003e\n \u003cli\u003eProportion of participants with a suicide or a suicide-attempt (dichotomous data)\u003c/li\u003e\n \u003cli\u003eProportion of participants with one or more psychiatric hospitalizations (dichotomous data)\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Changes in schemas as measured on the Young Schema Questionnaire or similar (any version)\u003c/li\u003e\n \u003cli\u003eChanges in schema modes as measured on the Schema Mode Inventory or similar (any version)\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch3\u003eAssessment time points\u003c/h3\u003e\n\u003cp\u003eOur primary time point of interest will be at the end of treatment. Our secondary time point of interest will be at maximum follow-up.\u003c/p\u003e\n\u003ch2\u003eSearch methods for identification of studies\u003c/h2\u003e\n\u003ch3\u003eElectronic searches\u003c/h3\u003e\n\u003cp\u003eWe will search Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), PubMed, PsycINFO, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index\u0026mdash;Science (CPCI-S), Conference Proceedings Citation Index\u0026mdash;Social Science \u0026amp; Humanities (CPCI-SSH), and the International Society for Schema Therapy database at https://schematherapy.omeka.net/ . We will search in all databases from their inception to the present date. For a detailed search strategy for all electronic databases, see Additional file 4.\u003c/p\u003e\n\u003ch3\u003eSearching other resources\u003c/h3\u003e\n\u003cp\u003eWe will check the reference list of relevant trial publications for any unidentified clinical trials. We will contact the authors of included trials by email asking for unpublished randomized clinical trials. To further identify unpublished trials, we will search www.clinicaltrials.gov. We will consider grey literature for inclusion if we identify this. Relevant retraction statements and errata will be assessed for included trials.\u003c/p\u003e\n\u003ch2\u003eData collection\u003c/h2\u003e\n\u003cp\u003eWe will perform and report the review as recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement(34, 35). Analyses will be performed with Stata (StataCorp LLC, College Station, TX, USA)(40) and Trial Sequential Analysis(41, 42).\u003c/p\u003e\n\u003ch3\u003eSelection of randomized clinical trials\u003c/h3\u003e\n\u003cp\u003eTitles and abstracts will be screened independently by two review authors. After retrieval of all relevant full-text papers, two authors will independently screen the full texts and record reasons for exclusion of trials. In case of disagreement, a third author will be consulted.\u003c/p\u003e\n\u003ch3\u003eData extraction and management\u003c/h3\u003e\n\u003cp\u003eData will be extracted from included trials independently by two review authors and entered in a data extraction sheet developed for this study. In case of disagreement, a third author will be consulted.\u003c/p\u003e\n\u003cp\u003eIn the case of data not being reported in the papers, trial authors will be contacted to and asked if they can supply additional data.\u003c/p\u003e\n\u003ch3\u003eTrial characteristics\u003c/h3\u003e\n\u003cp\u003eData will be extracted as follows: publication status, bias risk components (as defined below), trial design (parallel, factorial, or crossover), country, funding, for profit bias, preregistration (e.g., in clinicaltrials.gov), pre-published protocol, number of intervention arms, length of follow-up, sample size estimation, delivery setting, and inclusion and exclusion criteria.\u003c/p\u003e\n\u003ch3\u003eParticipant characteristics\u003c/h3\u003e\n\u003cp\u003eData will be extracted as follows: number of randomized participants, number of analyzed participants, number of participants lost to follow-up/withdrawal/crossover, dropout after randomization but before treatment initiation, age range (mean or median), sex ratio, primary mental disorder diagnosis and duration, frequency of comorbid personality disorder (when personality disorder is not the primary disorder being treated), other psychiatric and physical comorbidities, earlier received treatments, and proportion receiving psychotropic medicine.\u003c/p\u003e\n\u003ch3\u003eExperimental intervention characteristics\u003c/h3\u003e\n\u003cp\u003eData will be extracted as follows: treatment duration in months, number of sessions, session lengths (minutes), number of sessions per week, adherence measured (yes/no), treatment format (e.g., individual, group therapy), and co-occurring interventions.\u003c/p\u003e\n\u003ch3\u003eControl intervention characteristics\u003c/h3\u003e\n\u003cp\u003eData will be extracted as follows: type of control intervention, treatment duration in months, number of sessions, session lengths (minutes), number of sessions per week, treatment format, and co-occurring interventions.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eFor each outcome, we will identify if outcomes are missing, inadequately measured, or selectively reported - according to the Cochrane Risk of Bias - version 2 (RoB2) criteria(43) \u0026ndash; in the bias domains of \u0026ldquo;missing outcome data\u0026rdquo;, \u0026ldquo;risk of bias in measurement of the outcome\u0026rdquo;, and \u0026ldquo;risk of bias in selection of the reported results\u0026rdquo;, as explained below.\u003c/p\u003e\n\u003ch3\u003eConflicts of interest\u003c/h3\u003e\n\u003cp\u003eWe will extract information about vested interests in relation to trial funding as well as notable conflicts of interest for all trial authors.\u003c/p\u003e\n\u003ch2\u003eAssessment of risk of bias in the included studies\u003c/h2\u003e\n\u003cp\u003eThefollowing bias domains will be judged as per the \u003cem\u003eCochrane Handbook for Systematic Reviews of Interventions\u003c/em\u003e(43), with the risk-of-bias judgment options \u003cem\u003eLow risk of bias, Some concerns,\u0026nbsp;\u003c/em\u003eor\u003cem\u003e\u0026nbsp;High risk of bias\u0026nbsp;\u003c/em\u003efor each domain:\u003c/p\u003e\n\u003ch3\u003eBias arising from the randomization process\u003c/h3\u003e\n\u003cp\u003eThis domain evaluates allocation sequence generation, concealment of the allocation sequence, and baseline differences between the trial arms that may be due to a problem in the randomization process.\u003c/p\u003e\n\u003ch3\u003eBias due to deviation from intended interventions\u003c/h3\u003e\n\u003cp\u003eThis domain evaluates whether study participants, care providers, and other personnel were aware of intervention groups during the trial as this can lead to protocol deviations such as patients seeking or clinicians administering the experimental or other treatments to the control group. Also, it evaluates whether participants were analyzed in the group they were allocated to by randomization (rather than in the group with the intervention they actually received) and whether any deviations from the protocol were likely to have an impact on the outcome.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eBias due to missing outcome data\u003c/h3\u003e\n\u003cp\u003eThis domain evaluates the extent of missing data, and the robustness of the effect estimate to missing data, i.e., the missing data was not thought to impact the outcome (missing at random).\u003c/p\u003e\n\u003ch3\u003eBias in measurement of the outcome\u003c/h3\u003e\n\u003cp\u003eThis domain evaluates whether outcome assessors where blinded to and/or non-biased by the randomization status of the participant, whether the method of outcome measurements was appropriate, and whether the measurement could have differed between intervention groups.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eBias arising from selective reporting of results\u003c/h3\u003e\n\u003cp\u003eThis domain evaluates whether the trial was reported in accordance with a pre-specified plan, whether the reporting of specific data could have been selected to portray a specific desired result, and whether results could have been chosen selectively from multiple analyses of the data. \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eOverall assessment of risk of bias\u003c/h3\u003e\n\u003cp\u003eThe study is judged to be overall at low risk of bias if all domains are at low risk of bias. The judgment of \u0026lsquo;Some concerns\u0026rsquo; will be given for the study overall if some concerns are raised in one or more domains, while the judgment for the overall study at \u0026lsquo;High risk of bias\u0026rsquo; is given if multiple domains are evaluated to raise \u0026lsquo;Some concerns\u0026rsquo;, or at least one domain is evaluated to have \u0026lsquo;High risk of bias\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003eWe will make subgroup analyses on the intervention effect of trials at low risk of bias compared with trials at high risk of bias.\u003c/p\u003e\n\u003cp\u003eOur primary conclusions will be based on the results of our primary outcome results, taking into consideration the risk of bias in the individual studies on those outcomes. Both results of our primary and secondary outcomes will be presented and discussed.\u003c/p\u003e\n\u003ch4\u003eDifferences between protocol and the review\u003c/h4\u003e\n\u003cp\u003eAny deviations from this protocol in the final systematic review will be reported in the main article.\u003c/p\u003e\n\u003ch2\u003eMeasurement of treatment effect\u003c/h2\u003e\n\u003ch3\u003eDichotomous outcomes\u003c/h3\u003e\n\u003cp\u003eWe will calculate risk ratios (RRs) with 95% confidence interval (CI) and Trial Sequential Analysis-adjusted CI (see description below) for dichotomous outcomes.\u003c/p\u003e\n\u003ch3\u003eContinuous outcomes\u003c/h3\u003e\n\u003cp\u003eWe will calculate the mean differences (MDs) with 95% CI and Trial Sequential Analysis-adjusted CI for continuous outcomes that are identical across trials. We will consider calculating the standardized mean difference (SMD) with 95% CI if comparable, but non-identical continuous outcomes are reported across trials.\u003c/p\u003e\n\u003ch3\u003eDealing with missing data\u003c/h3\u003e\n\u003cp\u003eBefore statistical handling of missing data, we will contact trial authors to obtain relevant missing data for data extraction and for assessment of risk of bias. We will use intention-to-treat data if this is provided in the original report, and otherwise we will use per-protocol data.\u003c/p\u003e\n\u003ch4\u003eDichotomous outcomes\u003c/h4\u003e\n\u003cp\u003eThe primary analysis will not contain imputations, but we will impute missing data in sensitivity analyses.\u003c/p\u003e\n\u003ch4\u003eContinuous outcomes\u003c/h4\u003e\n\u003cp\u003eThe primary analysis will not contain imputations, but we will impute missing data in best-worst/worst-best scenarios (see below). We will primarily analyze scores assessed at the end of treatment time point. In case only changes from baseline scores are reported, we will analyze these results together with mean end of treatment scores(43). If standard deviations (SDs) are not reported, we will calculate the SDs using trial data, if possible.\u003c/p\u003e\n\u003ch3\u003eAssessment of heterogeneity\u003c/h3\u003e\n\u003cp\u003eFirst, we will visually assess heterogeneity in forest plots. Second, we will assess statistical heterogeneity by the chi\u003csup\u003e2\u003c/sup\u003e test (threshold \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10) and measure the quantities of heterogeneity by the\u0026nbsp;\u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e statistic(43-45). We will also investigate possible heterogeneity through subgroup analyses. In the case of substantial heterogeneity, we may decide not to perform a meta-analysis(43).\u003c/p\u003e\n\u003ch3\u003eAssessment or reporting biases\u003c/h3\u003e\n\u003cp\u003eWe will visually inspect funnel plots to assess the risk of reporting bias if ten or more trials are included(43). For dichotomous outcomes, we will test asymmetry with the Harbord test if\u0026nbsp;\u003cem\u003e\u0026tau;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e is less than 0.1(46)\u0026nbsp;and with the R\u0026uuml;cker test if\u0026nbsp;\u003cem\u003e\u0026tau;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e is more than 0.1(43). For continuous outcomes, we will use the regression asymmetry test(47)\u0026nbsp;and the adjusted rank correlation(48).\u003c/p\u003e\n\u003ch3\u003eUnit of analysis issues\u003c/h3\u003e\n\u003cp\u003eWhere multiple trial arms are reported in a single trial, we will only analyze the relevant arms, i.e., schema therapy and a control intervention as specified above. If several formats or versions of schema therapy occur in the same trial, we will divide the number of events (e.g., number of suicides or suicide attempts) and the sample size for the control group by the number of schema therapy groups for dichotomous data to avoid double-counting, and for continuous data we will keep the average main score for the control group as the comparison to schema therapy(43). For cluster-randomized trials, we will adjust the original sample size of the trial to its effective sample size, using the intra-cluster correlation coefficient from the \u0026lsquo;design effect\u0026rsquo;(43). For trials using a crossover design, only data from the first period will be included(43, 49).\u003c/p\u003e\n\u003cp\u003eThis means that unit of analysis issues will not occur.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eData synthesis\u003c/h2\u003e\n\u003ch3\u003eMeta-analysis\u003c/h3\u003e\n\u003cp\u003eWe will undertake the meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions(43) and Keus et al.(50). For statistical analyses, we will use the statistical software Stata(40). To obtain a more valid assessment of results, the eight-step procedure suggested by Jakobsen et al.(51) will be followed, comprised of the following steps: (1) obtain the 95% confidence intervals and the \u003cem\u003eP\u003c/em\u003e values from both fixed-effect and random-effects meta-analyses and report the most conservative results as the main results; (2) explore the reasons behind substantial statistical heterogeneity using subgroup and sensitivity analyses (see step 6); (3) adjust the thresholds for significance according to the number of primary outcomes to take account of problems with multiplicity; (4) calculate required information sizes (\u0026asymp; the a priori required number of participants for a meta-analysis to be conclusive) for all outcomes and analyze each outcome with Trial Sequential Analysis. Report whether the trial sequential monitoring boundaries for benefit, harm, or futility are crossed; (5) calculate Bayes factors for all primary outcomes; (6) use subgroup analyses and sensitivity analyses to assess the potential impact of bias on the review results; (7) assess the risk of publication bias; (8) assess the clinical significance of the statistically significant review results(51).\u003c/p\u003e\n\u003cp\u003eWe will assess the intervention effects for each comparison separately with both random-effects meta-analyses(52) and fixed-effect meta-analyses(53) and report the most conservative results of the two as the main result(51). We will assess a total of two primary outcomes and therefore consider a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.025 as the threshold for statistical significance for the primary outcomes(51). Secondary and exploratory outcomes will be considered hypothesis-generating only; therefore, we will use a threshold of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for non-primary outcomes.\u003c/p\u003e\n\u003cp\u003eAs a primary analysis, we will report the effects of schema therapy separately for each mental health disorder. As an exploratory analysis, we will report the effects of schema therapy for longer lasting disorders (i.e., personality disorders, ADHD, autism, and other disorders lasting more than 2 years) pooled versus acute disorders (i.e., other disorders lasting less than 2 years) pooled.\u003c/p\u003e\n\u003cp\u003eOur primary conclusion will be based on results with low risk of bias(51). If no low risk of bias trials are identified, we will base our primary conclusion on all trials. If quantitative synthesis is not appropriate due to considerable heterogeneity or a small number of included trials for each mental disorder, we will report the results narratively.\u003c/p\u003e\n\u003ch3\u003eTrial Sequential Analysis\u003c/h3\u003e\n\u003cp\u003eIn traditional meta-analyses, there is a risk of random errors due to sparse data or repetitive testing of accumulating data when updating reviews. We wish to control the risks of both type I errors and type II errors by performing Trial Sequential Analysis on all outcomes(54). This will calculate the required information size for each outcome in the meta-analysis (that is, the number of participants needed to detect or reject a certain intervention effect) and the cumulative \u003cem\u003eZ\u003c/em\u003e-curve\u0026rsquo;s breach of relevant trial sequential monitoring boundaries(41, 42, 55-61) (for a more detailed description, see the Trial Sequential Analysis manual(42) and http://www.ctu.dk/tsa/). For dichotomous outcomes, we will estimate the required information size based on the observed proportion of patients with an outcome in the control group (the cumulative proportion of patients with an event in the control groups relative to all patients in the control groups), a relative risk reduction of 20%, an alpha of 2.5% for the primary outcomes and 5% for the remaining outcomes, a beta of 20%, and the observed diversity as suggested by the trials in the meta-analysis. In a Trial Sequential Analysis for continuous outcomes, we will use the observed standard deviation (SD), a mean difference equal to the observed SD/2, an alpha of 2.5% for the primary outcomes and 5% for the remaining outcomes, a beta of 20%, and the observed diversity as suggested by the trials in the meta-analysis.\u003c/p\u003e\n\u003ch3\u003eSubgroup analysis and integration of heterogeneity\u003c/h3\u003e\n\u003ch4\u003eSubgroup analysis\u003c/h4\u003e\n\u003cp\u003eWe will perform the following subgroup analyses when analyzing the primary outcomes (symptom severity, quality of life):\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eTrials at high risk of bias compared with trials at low risk of bias\u003c/li\u003e\n \u003cli\u003ePsychotherapy formats (e.g., group, individual)\u003c/li\u003e\n \u003cli\u003eTypes of comparators (i.e., no intervention/waitlist, specialized TAU (i.e., interventions that are the best available treatments already implemented at the study site(s)) but still live up to the above criteria for TAU), attention control/non-specific TAU (e.g., supportive counselling)\u003c/li\u003e\n \u003cli\u003eLonger lasting disorders (i.e., personality disorders, ADHD, autism, and other disorders lasting more than 2 years) pooled versus acute disorders (i.e., other disorders lasting less than 2 years) pooled\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWe will use the formal test for subgroup interactions in\u0026nbsp;Stata(40).\u003c/p\u003e\n\u003ch4\u003eSensitivity analysis\u003c/h4\u003e\n\u003cp\u003eTo assess the potential impact of missing data, we will perform the two following sensitivity analyses on the dichotomous outcomes:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u0026ldquo;\u003cem\u003eBest\u003c/em\u003e-\u003cem\u003eworst\u003c/em\u003e-\u003cem\u003ecase\u003c/em\u003e\u0026rdquo; \u003cem\u003escenario\u003c/em\u003e: We will assume that all participants lost to follow-up in the schema therapy group had neither a suicide, a suicide attempt, attempted self-harm, nor a psychiatric hospitalization or dropped out of treatment, and that all participants lost to follow-up in the control group had a suicide or suicide attempt, attempted self-harm, had a psychiatric hospitalization, and dropped out of treatment.\u003c/li\u003e\n \u003cli\u003e\u0026ldquo;\u003cem\u003eWorst\u003c/em\u003e-\u003cem\u003ebest\u003c/em\u003e-\u003cem\u003ecase\u003c/em\u003e\u0026rdquo; \u003cem\u003escenario\u003c/em\u003e: We will assume that all participants lost to follow-up in the control group had a suicide or suicide attempt, attempted self-harm, had a psychiatric hospitalization, and dropped out of treatment, and that all participants lost to follow-up in the schema therapy group had neither a suicide or suicide attempt, attempted self-harm, nor a psychiatric hospitalization or dropped out of treatment.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTo assess the potential impact of missing data for the continuous outcomes, we will perform the same sensitivity analysis, where a \u0026ldquo;beneficial outcome\u0026rdquo; will be defined as the group mean plus two standard deviations (SDs) (we will secondly use one SD in another sensitivity analysis) of the group mean and a \u0026ldquo;harmful outcome\u0026rdquo; will be defined as the group mean minus two SDs (we will secondly use one SD in another sensitivity analysis) of the group mean(51). Where SDs are missing and it is not possible to calculate them, we will impute SDs from trials with similar populations and low risk of bias. If we find no such trials, we will impute SDs from trials with a similar population. As the final option, we will impute SDs from all trials.\u003c/p\u003e\n\u003cp\u003eWe will present results of all these scenarios in our review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther post hoc sensitivity analyses might be warranted if unexpected clinical or statistical heterogeneity is identified during the analysis of the review results, in which case these analyses will be presented clearly as post hoc and exploratory(51).\u003c/p\u003e\n\u003ch3\u003eSummary of findings table\u003c/h3\u003e\n\u003cp\u003eWe will report findings in a table for each comparison (schema therapy vs. no intervention/waitlist, vs TAU, or vs. attention control/\u0026rsquo;psychological placebo\u0026rsquo;) including each of the prespecified outcomes (symptom severity, quality of life, level of functioning, self-harm, suicidal behavior, dropout, schemas, schema modes). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe will use the five GRADE considerations (risk of bias in the trials, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence(51, 62-64). We will assess imprecision using Trial Sequential Analysis, and downgrade imprecision in GRADE by two levels if the accrued number of participants is below 50% of the diversity-adjusted required information size (DARIS), and one level if it is between 50 and 100% of DARIS. We will not downgrade if the cumulative \u003cem\u003eZ\u003c/em\u003e-curve crosses the monitoring boundaries for benefit, harm, or futility, or DARIS is reached. We will justify all decisions to downgrade the quality of studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFirstly, we will present our results in the summary of findings table based on the results from the trials with an overall low risk of bias, and secondly, we will present the results based on all trials.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review with meta-analyses and Trial Sequential Analysis aims to assess the beneficial and harmful effects of schema therapy versus treatment as usual, attention control, or waitlist for the most commonly treated mental health disorders.\u003c/p\u003e\n\u003cp\u003ePrimary outcomes will be symptom severity and quality of life. Secondary outcomes will serious adverse events, level of functioning, and premature dropout from treatment. Exploratory outcomes will be self-harm, suicide or suicide-attempts, psychiatric hospitalizations, and changes in schemas and schema modes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis protocol has a particular strength in the comprehensive, state-of-the-art methodology. The risk of both random and systematic errors will be considered, using the methodology by Keus et al.(50), the eight-step procedure by Jakobsen et al.(51), and Trials Sequential Analysis(41). The GRADE framework will be used to assess the certainty of the evidence(62-64). Further, we will search for and include data from both published and unpublished trials to minimize the risk of publication bias.\u003c/p\u003e\n\u003cp\u003eHowever, this protocol also has limitations: First, there is a risk of identifying only few eligible randomized trials. Schema therapy is still in a preliminary stage when it comes to evidence, meaning that many applications of the therapy have primarily been tested in a smaller and less methodologically strict format, e.g., case series and single-arm trials. As schema therapy has been developed out of cognitive behavioral and other therapies, many trialists performing randomized trials have chosen to test the additional effect of schema therapy against established therapies (e.g., (65-68)). While we are aware of the existence of such trials, we have chosen only to include randomized trials comparing schema therapy to TAU, consisting of non-manualized treatments under little control and waitlist/no intervention, as this gives the possibility to establish the general, absolute effects of schema therapy, rather than the effects relative to other, established psychotherapies. As the number of high-quality trials on schema therapy will hopefully accrue in the future, it will be possible to conduct a network meta-analysis including all randomized controlled trials to establish both the absolute and relative effects of schema therapy.\u003c/p\u003e\n\u003cp\u003eIn the case that the number of included trials is so low that meta-analysis is not possible to conduct for some mental health disorders, we will report the results narratively.\u003c/p\u003e\n\u003cp\u003eA third limitation the inherent problem regarding blinding in psychotherapy research, where it is almost impossible to blind all parties(69). We expect that participants and clinicians delivering treatment will not be blinded, but we will attempt to estimate the extent to which other relevant parties have been blinded when reporting bias in the trials. Also, we expect to find many trials with other sources of bias risks, including large proportions of missing data(70). This will potentially influence the strength of conclusions and GRADE recommendations.\u003c/p\u003e\n\u003cp\u003eFinally, a limitation is the potentially numerous comparisons when analyzing results for all included mental health disorders separately, increasing the risk for false positives (type I errors). We have adjusted the threshold for significance according to the number of primary outcomes, but not to the number of mental health diseases, and not for the subgroup analyses. Also, lack of data and statistical power for all planned subgroup analyses are likely. We will consider this when reporting and concluding on the findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSchema therapy is a promising intervention for severe mental health disorders, but the certainty of evidence for benefits and harms of schema therapy is still unclear. This review will inform clinical guidelines, thus expanding the possible choices of treatments in clinical practice. Further, the review will provide a comprehensive overview of the literature and highlight research gaps to inform future research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADHD: Attention-Deficit/Hyperactivity Disorder\u003c/p\u003e\n\u003cp\u003eAI: Artificial Intelligence\u003c/p\u003e\n\u003cp\u003eCENTRAL: Cochrane Central Register of Controlled Trials\u003c/p\u003e\n\u003cp\u003eCI: Confidence Interval\u003c/p\u003e\n\u003cp\u003eCPCI-S: Conference Proceedings Citation Index – Science\u003c/p\u003e\n\u003cp\u003eCPCI-SSH: Conference Proceedings Citation Index – Social Sciences \u0026amp; Humanities\u003c/p\u003e\n\u003cp\u003eCRD: Centre for Reviews and Dissemination\u003c/p\u003e\n\u003cp\u003eDSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th edition\u003c/p\u003e\n\u003cp\u003eEMBASE: Excerpta Medica database\u003c/p\u003e\n\u003cp\u003eGRADE: Grading of Recommendations Assessment, Development and Evaluation\u003c/p\u003e\n\u003cp\u003eICD-11: International Statistical Classification of Diseases and Related Health Problems, 11th edition\u003c/p\u003e\n\u003cp\u003eICH-GCP: International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use – Guideline for Good Clinical Practice\u003c/p\u003e\n\u003cp\u003eMEDLINE: Medical Literature Analysis and Retrieval System Online\u003c/p\u003e\n\u003cp\u003ePROSPERO: The International Prospective Register of Systematic Reviews\u003c/p\u003e\n\u003cp\u003ePRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analysis -Protocols\u003c/p\u003e\n\u003cp\u003eRCT: Randomized Clinical Trial\u003c/p\u003e\n\u003cp\u003eRoB2: Cochrane Risk of Bias – version 2\u003c/p\u003e\n\u003cp\u003eRR: Risk Ratio\u003c/p\u003e\n\u003cp\u003eSCI-EXPANDED: Science Citation Expanded\u003c/p\u003e\n\u003cp\u003eSD: Standard Deviation\u003c/p\u003e\n\u003cp\u003eSMD: Standardized Mean Difference\u003c/p\u003e\n\u003cp\u003eSSCI: Social Sciences Citation Index\u003c/p\u003e\n\u003cp\u003eTAU: Treatment As Usual\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u003c/h3\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch3\u003eConflicts of interest\u003c/h3\u003e\n\u003cp\u003e\u0026nbsp;IMTPA is a member of International Society for Schema Therapy (ISST) and has received funding for and published research on ST.\u003c/p\u003e\n\u003cp\u003eSJ and CH have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003eMV provides workshops and lectures on Schema Therapy (ST). He is also on the executive board of the ISST 2024-2026, where he gets a fee for the voluntary work and is a part of the Dutch Society of Schema Therapy (VST). Furthermore, MV has received funding for and published research on ST and are getting publishing fees for books about ST. MV is a practitioner of ST and works at a clinic that provides ST.\u003c/p\u003e\n\u003cp\u003eJK has provided workshops and lectures on ST and has received funding for and published research on ST.\u003c/p\u003e\n\u003cp\u003eBB is a practitioner of ST and works in a clinic that provides ST. BB has received publishing fees for books about ST. Furthermore, BB has received funding for and published research on ST.\u003c/p\u003e\n\u003cp\u003eAA has provided workshops and lectures on ST and received fees from societies that are promoting ST. AA has received publishing fees for books about ST and has received funding for and published research on ST. Furthermore, he is a practitioner of ST.\u003c/p\u003e\n\u003cp\u003eSBM has received funding for and published research on ST and is a member of the International Society for Schema Therapy (ISST).\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThis study is funded by Trygfonden (award number: 149726) (see Additional file 5). The fund is not involved in the study conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003ch3\u003eAuthors’ contributions\u003c/h3\u003e\n\u003cp\u003eIMTPA and SBM conceptualized this research project. IMTPA is the guarantor of the project. IMTPA, SJ and SBM developed the methodology. \u0026nbsp;IMTPA administrated the project and wrote the first draft of the protocol supervised by SBM and SJ. All authors read and commented on the manuscript draft and outcome hierarchy, both of which were then substantially revised by IMTPA based on the comments. All authors have read and approved the final manuscript before it was submitted for publication.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: We would like to thank Sarah Louise Klingenberg (Information Specialist, The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Copenhagen, Denmark) for making the search strategy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAlonso J, Angermeyer M, Bernert S, Bruffaerts R, Brugha T, Bryson H, et al. ESEMeD/MHEDEA 2000 investigators, European study of the epidemiology of mental disorders (ESEMeD) Project. Prevalence of mental disorders in Europe: results from the European study of the epidemiology of mental disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004;420:21-7. \u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller G, Bombana M, Heinzel-Gutenbrenner M, Kleindienst N, Bohus M, Lyssenko L, et al. 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Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology. 2008;61(8):763-9.\u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;nemann HJ, Best D, Vist G, Oxman AD, Group GW. Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations. Cmaj. 2003;169(7):677-80.\u003c/li\u003e\n\u003cli\u003eGuyatt GH, Oxman AD, Sch\u0026uuml;nemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380-2.\u003c/li\u003e\n\u003cli\u003eGuyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj. 2008;336(7650):924-6.\u003c/li\u003e\n\u003cli\u003eMcIntosh VVW, Jordan J, Carter JD, Frampton CMA, McKenzie JM, Latner JD, et al. Psychotherapy for transdiagnostic binge eating: A randomized controlled trial of cognitive-behavioural therapy, appetite-focused cognitive-behavioural therapy, and schema therapy. Psychiatry Res. 2016;240:412-20.\u003c/li\u003e\n\u003cli\u003eCarter JD, McIntosh VV, Jordan J, Porter RJ, Frampton CM, Joyce PR. Psychotherapy for depression: a randomized clinical trial comparing schema therapy and cognitive behavior therapy. J Affect Disord. 2013;151(2):500-5.\u003c/li\u003e\n\u003cli\u003eCockram DM, Drummond PD, Lee CW. Role and treatment of early maladaptive schemas in vietnam veterans with PTSD. Clin Psychol Psychother. 2010;17(3):165-82.\u003c/li\u003e\n\u003cli\u003eGiesen-Bloo J, van Dyck R, Spinhoven P, van Tilburg W, Dirksen C, van Asselt T, et al. Outpatient Psychotherapy for Borderline Personality Disorder: Randomized Trial of Schema-Focused Therapy vs Transference-Focused Psychotherapy. Archives of General Psychiatry. 2006;63(6):649-58.\u003c/li\u003e\n\u003cli\u003eJuul S, Gluud C, Simonsen S, Frandsen FW, Kirsch I, Jakobsen JC. Blinding in randomised clinical trials of psychological interventions: a retrospective study of published trial reports. BMJ Evidence-Based Medicine. 2021;26(3):109-.\u003c/li\u003e\n\u003cli\u003eJuul S, Faltermeier P, Petersen JJ, Olsen MH, Andersen RK, Kamp CB, et al. Missing outcome data in randomised clinical trials of psychological interventions: a review of published trial reports in major psychiatry journals. BMC Psychiatry. 2024;24(1):798.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Schema therapy, psychotherapy, depression, personality disorders, obsessive-compulsive disorder, anxiety disorders, post-traumatic stress disorder, psychotic disorders, autism spectrum disorders, attention deficit hyperactivity disorder","lastPublishedDoi":"10.21203/rs.3.rs-6570797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6570797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eMental health disorders are among the heaviest global health burdens. While many psychotherapies are effective for mental health disorders, some patients may require more specialized psychotherapies. Schema therapy, a transdiagnostic psychotherapy, addresses childhood adversity and personality characteristics which have been shown to predict and maintain more ingrained mental health disorders. The effects of schema therapy have previously been assessed in systematic reviews, but these suffered from methodological shortcomings and did not include the most recent trials. This systematic review with meta-analysis aims to synthesize the evidence of beneficial and harmful effects of schema therapy for a broad array of mental health disorders, taking into account the risk of both systematic errors, random errors, and certainty of evidence.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eThis systematic review with meta-analysis will contain a comprehensive search for relevant published and unpublished trials in major clinical databases and clinical trial registries. We will include randomized clinical trials comparing schema therapy to a control group for adult mental health disorders including attention deficit hyperactivity disorder, autism spectrum disorders, psychotic disorders, dissociative identity disorder, depressive disorders, bipolar disorders, anxiety disorders, obsessive-compulsive disorder, substance abuse, trauma- and stressor-related disorders, eating disorders, and personality disorders. Primary outcomes will be symptom severity and quality of life. Secondary outcomes will be serious adverse events, level of functioning, and treatment dropout. Risk of bias will be assessed with the Cochrane Risk of Bias tool version 2, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, the risk of random errors will be assessed with Trial Sequential Analysis, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE).\u003c/p\u003e\n\u003cp\u003eDiscussion\u003c/p\u003e\n\u003cp\u003eSchema therapy is a promising intervention for more severe cases of mental health disorders, but the certainty of evidence for benefits and harms of schema therapy is still unclear. This review will inform clinical guidelines, thus expanding the possible choices of treatments in clinical practice. Further, the review will provide a comprehensive overview of the literature and highlight research gaps to inform future research.\u003c/p\u003e\n\u003cp\u003eSystematic review registration\u003c/p\u003e\n\u003cp\u003ePROSPERO, CRD420251015725\u003c/p\u003e","manuscriptTitle":"Schema therapy versus any control group for adult mental health disorders: a protocol for a systematic review with meta-analysis and trial sequential analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 11:25:00","doi":"10.21203/rs.3.rs-6570797/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"667df909-9cc8-49bf-ac7c-d0c7c515c324","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-19T11:25:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 11:25:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6570797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6570797","identity":"rs-6570797","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}