Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST).

BACKGROUND: About one third of patients with depression are in a condition that can be termed as "difficult-to-treat". Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector. METHODS: In this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed. DISCUSSION: This trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Short-Term versus Long-Term Mentalization-Based Therapy for Borderline Personality Disorder: A Randomized Clinical Trial (MBT-RCT).

INTRODUCTION: Borderline personality disorder (BPD) is a severe and prevalent psychiatric disorder. Mentalization-based therapy (MBT) is an evidence-based intervention for BPD, and several countries offer treatment programs for BPD lasting for years, which is resource demanding. No previous trial has compared short-term with long-term MBT. OBJECTIVE: The aim of the study was to assess the efficacy and safety of short-term versus long-term MBT for outpatients with BPD. METHODS: Adult outpatients (≥18 years) with subthreshold or diagnosed BPD were randomly assigned (1:1) to short-term MBT (5 months) or long-term MBT (14 months). The primary outcome was BPD symptoms assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes were functional impairment, quality of life, global functioning, and severe self-harm. All outcomes were primarily assessed at 16 months after randomization. This trial was prospectively registered at ClinicalTrials.gov, NCT03677037. RESULTS: Between October 4, 2018, and December 3, 2020, we randomly assigned 166 participants to short-term MBT (n = 84) or long-term MBT (n = 82). Regression analyses showed no evidence of a difference when assessing BPD symptoms (MD 0.99; 95% CI: -1.06 to 3.03; p = 0.341), level of functioning (MD 1.44; 95% CI: -1.43 to 4.32; p = 0.321), quality of life (MD -0.91; 95% CI: -4.62 to 2.79; p = 0.626), global functioning (MD -2.25; 95% CI: -6.70 to 2.20; p = 0.318), or severe self-harm (RR 1.37; 95% CI: 0.70-2.84; p = 0.335). More participants in the long-term MBT group had a serious adverse event compared with short-term MBT (RR 1.63; 95% CI: 0.94-3.07; p = 0.088), primarily driven by a difference in psychiatric hospitalizations (RR 2.03; 95% CI: 0.99-5.09; p = 0.056). CONCLUSION: Long-term MBT did not lead to lower levels of BPD symptoms, nor did it influence any of the secondary outcomes compared with short-term MBT.

The difference between shorter- versus longer-term psychotherapy for adult mental health disorders: a systematic review with meta-analysis.

BACKGROUND: The optimal psychotherapy duration for mental health disorders is unclear. Our aim was to assess the beneficial and harmful effects of shorter- versus longer-term psychotherapy for adult mental health disorders. METHOD: We searched relevant databases and websites for published and unpublished randomised clinical trials assessing different durations of the same psychotherapy type before June 27, 2022. Our methodology was based on Cochrane and an eight-step procedure. Primary outcomes were quality of life, serious adverse events, and symptom severity. Secondary outcomes were suicide or suicide-attempts, self-harm, and level of functioning. RESULTS: We included 19 trials randomising 3,447 participants. All trials were at high risk of bias. Three single trials met the required information size needed to confirm or reject realistic intervention effects. One single trial showed no evidence of a difference between 6 versus 12 months dialectical behavioral therapy for borderline personality when assessing quality of life, symptom severity, and level of functioning. One single trial showed evidence of a beneficial effect of adding booster sessions to 8 and 12 weeks of internet-based cognitive behavioral therapy for depression and anxiety when assessing symptom severity and level of functioning. One single trial showed no evidence of a difference between 20 weeks versus 3 years of psychodynamic psychotherapy for mood- or anxiety disorders when assessing symptom severity and level of functioning. It was only possible to conduct two pre-planned meta-analyses. Meta-analysis showed no evidence of a difference between shorter- and longer-term cognitive behavioural therapy for anxiety disorders on anxiety symptoms at end of treatment (SMD: 0.08; 95% CI: -0.47 to 0.63; p = 0.77; I2 = 73%; four trials; very low certainty). Meta-analysis showed no evidence of a difference between shorter and longer-term psychodynamic psychotherapy for mood- and anxiety disorders on level of functioning (SMD 0.16; 95% CI -0.08 to 0.40; p = 0.20; I2 = 21%; two trials; very low certainty). CONCLUSIONS: The evidence for shorter versus longer-term psychotherapy for adult mental health disorders is currently unclear. We only identified 19 randomised clinical trials. More trials at low risk of bias and at low risk of random errors assessing participants at different levels of psychopathological severity are urgently needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128535.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Mentalizing the therapist - Therapist experiences with short-term mentalization-based therapy for borderline personality disorder: A qualitative study.

Background: Mentalization-Based Therapy (MBT) was originally developed as a structured psychotherapy approach developed to treat borderline personality disorder (BPD) lasting up to 18 months in outpatient settings. However, a short-term (5 months) MBT program has recently been developed. No studies have investigated how MBT therapists experience the shift towards conducting short-term MBT for BPD. Objective: The objective of this study was to explore therapist experiences with conducting short-term MBT for outpatients with BPD in the Danish mental health services. Methods: Semi-structured qualitative interviews were conducted with seven therapists about their experiences with short-term MBT after a one-year pilot phase. The interviews were verbatim transcribed and analyzed using thematic analysis. Results: The following four major themes from the therapists' experiences with short-term MBT were found in the qualitative analysis: (1) The longer the better, (2) Change processes can be intellectual or experiential, (3) Short-term therapy is hard work, and (4) Termination is more challenging in short-term MBT. Conclusion: Most therapists were overall reluctant towards changing from long-term to short-term MBT. These therapist experiences could inform implementation of short-term MBT in mental health settings in the future.

The risks of adverse events with venlafaxine and mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder: a protocol for two separate systematic reviews with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the effects seem small and may not be important to the average patient. Moreover, previous reviews have not systematically assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder in two separate systematic reviews. METHODS: This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the effects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will be assessed with the Cochrane risk-of-bias tool version 2, clinical significance will be assessed using our eight-step procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine or mirtazapine with 'active placebo', placebo, or no intervention for adults with major depressive disorder. The primary outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. DISCUSSION: Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022315395.

Adapting Short-Term Mentalization-Based Therapy to ICD-11 Personality Disorder in Adolescents.

Following the introduction of the 11th revision of the International Classification of Diseases (ICD-11), adolescents can now be diagnosed with a personality disorder based on severity ranging from mild to moderate to severe. This dimensional model has potential implications for treatment, as it allows clinicians and researchers to search for effective treatments targeting adolescents at different severity levels rather than offering all patients the same treatment. In this conceptual paper, we propose that the short-term mentalization-based therapy (MBT) program, originally developed to treat adults with borderline personality disorder (BPD), has potential clinical advantages for adolescents with ICD-11 personality disorder at the mild to moderate severity level. The short-term MBT program is a 5-month structured treatment approach including individual therapy, combined psychotherapy with the individual therapist also being one of the group therapists, and closed-group therapy to enhance cohesion and a feeling of security. The purpose of this paper is to make a case for the use of this format, as opposed to the traditional long-term MBT format, for adolescents with BPD. Future research should include large-scale randomized clinical trials powered to assess patient-important outcomes.

Melatonin for sleep disorders in children with neurodevelopmental disorders: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

INTRODUCTION: Neurodevelopmental disorders are a group of disorders thought to be associated with the functioning of the brain and the nervous system. Children with neurodevelopmental disorders often have sleep-related comorbidities that may negatively affect quality of life for both the children and their families. Melatonin is one of the most used interventions in children with neurodevelopmental disorders and sleep disorders. Previous reviews have investigated the effects of melatonin for sleep disorders in children with neurodevelopmental disorders, but these had important limitations, such as inadequate analysis of adverse effects, small sample sizes and short follow-up. METHODS AND ANALYSIS: This is a protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials. The protocol is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We will search for published and unpublished trials in the Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, PsycINFO, ClinicalTrials.gov and the International Clinical Trials Registry Platform. We will search the databases from their inception without language restrictions. We will also request clinical study reports from regulatory authorities and pharmaceutical companies. Review authors working in pairs will screen reports, extract data and conduct risk of bias assessments using the Cochrane Risk of Bias tool. We will include randomised clinical trials comparing melatonin versus placebo or no intervention for sleep disorders in children with neurodevelopmental disorders. Primary outcomes will be total sleep time and adverse effects. Secondary outcomes will be quality of life of the child and caregivers and sleep onset latency. Data will be analysed using random-effects and fixed-effect meta-analyses. Certainty of evidence will be assessed with Grading of Recommendations, Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethical approval was not required for this protocol. The systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022337530.

Deep brain stimulation for neurological disorders: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

BACKGROUND: Deep brain stimulation has been used since the 1980s for neurological disorders and the USA and Europe have now approved it for Parkinson's disease, essential tremor, dystonia, and epilepsy. Previous reviews have assessed the effects of deep brain stimulation on different neurological disorders. These reviews all had methodological limitations. METHODS: This is a protocol for a systematic review based on searches of major medical databases (e.g. MEDLINE, EMBASE, CENTRAL) and clinical trial registries. Two review authors will independently extract data and conduct risk of bias assessment. We will include published and unpublished randomised clinical trial comparing deep brain stimulation versus no intervention, usual care, sham stimulation, medical treatment, or resective surgery for Parkinson's disease, essential tremor, dystonia, or epilepsy. The effects of deep brain stimulation will be analysed separately for each of the different diagnoses. Primary outcomes will be all-cause mortality, disease-specific symptoms, and serious adverse events. Secondary outcomes will be quality of life, depressive symptoms, executive functioning, level of functioning, and non-serious adverse events. Data will be analysed using fixed-effect and random-effects meta-analyses and Trial Sequential Analysis. Risk of bias will be assessed with the Cochrane Risk of Bias tool-version 2, an eight-step procedure to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE). DISCUSSION: Deep brain stimulation is increasingly being used for different neurological diseases, and the effects are unclear based on previous evidence. There is a need for a comprehensive systematic review of the current evidence. This review will provide the necessary background for weighing the benefits against the harms when assessing deep brain stimulation as intervention for individual neurological disorders. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 306,556.

A clinical illustration of short-term mentalization-based therapy for borderline personality disorder.

OBJECTIVE: Mentalization-based therapy (MBT) is an evidence-supported, long-term psychotherapy program developed to treat borderline personality disorder (BPD). A short-term, 20-week adaptation to the original MBT format including case formulation, psychoeducation, and group and individual therapy has recently been proposed. The current case material will illustrate how the recent adaptation to the mentalization-based practice can enhance personality functioning using a short-term format. METHODS: Case material is presented to demonstrate the clinical application of short-term MBT in the treatment of a young woman diagnosed with BPD who has a history of failed treatment attempts and who showed signs of affective dysregulation, unstable relationships, and intense abandonment anxiety. RESULTS: The case illustration shows how short-term MBT can facilitate improvement in personality functioning, specifically targeting situations in which the patient lost her temper and became overwhelmed by abandonment anxiety. By continuously employing therapeutic shifts toward greater autonomy and agency, and by maintaining a balanced empathetic therapeutic stance, the therapists were able to enhance the patients mentalizing and personality functioning. CONCLUSIONS: Short-term MBT can be effectively implemented to enhance the mentalizing capacity and personality functioning in outpatients with BPD.

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Treating Avoidant Personality Disorder With Combined Individual Metacognitive Interpersonal Therapy and Group Mentalization-Based Treatment: A Pilot Study.

ABSTRACT: Avoidant personality disorder (AvPD) is a severe but understudied condition. The current pilot project reports data on acceptability and outcomes of a novel treatment combining biweekly individual metacognitive interpersonal therapy (MIT) and weekly mentalization-based therapy (MBT) group therapy. A total of 30 patients with AvPD were consecutively included in the program. The primary outcome was AvPD-specific personality functioning measured by self-report after treatment. Secondary outcomes were symptom distress, interpersonal problems, quality of life, and psychosocial functioning. Twenty-two patients completed treatment, with a mean duration of 13 months. On the primary outcome, effect sizes were generally moderate to large (effect size range: 0.59-1.10). On secondary outcomes, effect sizes were large (effect size range: 0.77-2.3). Both in terms of acceptability and outcomes, results are promising for the combination of MIT and MBT for AvPD. The approach is a strong candidate for further investigation in future large-scale randomized controlled trial.

The Short Version of the Metacognitive Anger Processing Scale (MAP-SV) - initial psychometric testing.

BACKGROUND: The 26-item version of the Metacognitive Anger Processing Scale (MAP) has shown good psychometric properties in previous studies. However, there is a need for a shorter version of the scale. AIMS: The aim of the present study is to psychometrically evaluate the 9-item Metacognitive Anger Processing Scale - Short Version (MAP-SV) in comparison with the original, 26-item version. METHOD: The 26-item MAP includes three subscales: rumination, positive beliefs and negative beliefs. Three items from each subscale were selected based on clinical validity to constitute the 9-item MAP-SV. A previous sample used for validation of the 26-item MAP was used for clinimetric testing. The sample included psychiatric patients (n = 88) and male forensic inpatients (n = 54). The MAP-SV was assessed according to scalability, convergent validity with general metacognition, and concurrent validity with anger measures. RESULTS: The scalability of the 9-item MAP-SV was comparable to that of the original 26-item MAP in most psychometric tests. The Loevinger's coefficient of homogeneity for the total score of the MAP-SV items was 0.29 for the combined sample compared with 0.36 in the original MAP, indicating close to acceptable scalability. The alpha coefficient for the MAP-SV total score was 0.79. For the combined sample, Pearson inter-correlations between the subscales of the MAP-SV were highly correlated with the MAP-SV total score (ranging from .66 to .84). CONCLUSIONS: The 9-item MAP-SV showed good psychometric properties and can be used as a reliable tool for assessing self-reported metacognitive anger processing.

Mentalizing the patient-Patient experiences with short-term mentalization-based therapy for borderline personality disorder: A qualitative study.

Background: Mentalization-based therapy (MBT) is an evidence-supported psychotherapy approach for borderline personality disorder (BPD) that has been implemented in mental health services worldwide. Originally, MBT was developed as an 18-months program for BPD. However, a short-term (5 months) MBT program has been developed. Research into patient experiences with long-term MBT for BPD is scarce, and no studies have investigated patient experience with short-term MBT for BPD. Objective: The objective of this study was to explore patient experience with short-term MBT for BPD in the Danish mental health services. Methods: Semi-structured qualitative interviews were conducted with 12 outpatients diagnosed with BPD, who attended short-term MBT for 5 months. The interviews were verbatim transcribed and analyzed using thematic analysis with double coding. Results: The analysis resulted in four subordinate themes: (1) Treatment duration - too short or appropriately short?, (2) The group as a "safe space," (3) Bad experiences impacted treatment negatively, and (4) My life has changed for the better. Conclusion: The results suggest that most of the patients were overall satisfied with short-term MBT, which they experienced as having a positive impact on their lives. However, a subgroup of patients wanted more therapy. This study highlighted the strengths and limitations of short-term MBT for BPD as experienced by the patients, and points to barriers in developing service-user informed short-term treatment options for BPD.

Tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder. METHODS: This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool-version 2, our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with 'active placebo', placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosulepin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. DISCUSSION: Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021226161 .

Detailed statistical analysis plan for the short-term versus long-term mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder randomised clinical trial (MBT-RCT).

BACKGROUND: Psychotherapy for borderline personality disorder is often extensive and resource-intensive. Mentalisation-based therapy is a psychodynamically oriented treatment option for borderline personality disorder, which includes a case formulation, psychoeducation, and group and individual therapy. The evidence on short-term compared with long-term mentalisation-based therapy is currently unknown. METHODS/DESIGN: The Short-Term MBT Project (MBT-RCT) is a single-centre, parallel-group, investigator-initiated, randomised clinical superiority trial in which short-term (20 weeks) will be compared with long-term (14 months) mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder. Outcome assessors, data managers, the data safety and monitoring committee, statisticians, and decision-makers will be blinded to treatment allocation. Participants will be assessed before randomisation and at 8, 16, and 24 months after randomisation. The primary outcome will be the severity of borderline symptomatology assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes will be functional impairment (Work and Social Adjustment Scale), quality of life (Short-Form Health Survey 36-mental component), global functioning (Global Assessment of Functioning), and proportion of participants with severe self-harm. In this paper, we present a detailed statistical analysis plan including a comprehensive explanation of the planned statistical analyses, methods to handle missing data, and assessments of the underlying statistical assumptions. Final statistical analyses will be conducted independently by two statisticians following the present plan. DISCUSSION: We have developed this statistical analysis plan before unblinding of the trial results in line with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice Guidelines, which should increase the validity of the MBT-RCT trial by mitigation of analysis bias. TRIAL REGISTRATION: ClinicalTrials.gov NCT03677037 . Registered on 19 September 2018.

Duloxetine versus 'active' placebo, placebo or no intervention for major depressive disorder; a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: Major depression significantly impairs quality of life, increases the risk of suicide, and poses tremendous economic burden on individuals and societies. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is a widely prescribed antidepressant. The effects of duloxetine have, however, not been sufficiently assessed in earlier systematic reviews and meta-analyses. METHODS/DESIGN: A systematic review will be performed including randomised clinical trials comparing duloxetine with 'active' placebo, placebo or no intervention for adults with major depressive disorder. Bias domains will be assessed, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed. We will conduct meta-analyses. Trial sequential analysis will be conducted to control random errors, and the certainty of the evidence will be assessed using GRADE. To identify relevant trials, we will search Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, PsycINFO, Science Citation Index Expanded, Social Sciences Citation Index, Conference Proceedings Citation Index-Science and Conference Proceedings Citation Index-Social Science & Humanities. We will also search Chinese databases and Google Scholar. We will search all databases from their inception to the present. Two review authors will independently extract data and perform risk of bias assessment. Primary outcomes will be the difference in mean depression scores on Hamilton Depression Rating Scale between the intervention and control groups and serious adverse events. Secondary outcomes will be suicide, suicide-attempts, suicidal ideation, quality of life and non-serious adverse events. DISCUSSION: No former systematic review has systematically assessed the beneficial and harmful effects of duloxetine taking into account both the risks of random errors and the risks of systematic errors. Our review will help clinicians weigh the benefits of prescribing duloxetine against its adverse effects and make informed decisions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016 CRD42016053931.

Beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder: a protocol for a systematic review of published and unpublished data with meta-analyses and trial sequential analyses.

BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder. METHODS/DESIGN: A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, 'active placebo', or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events. DISCUSSION: As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020220279.

Personality Functioning and Mentalizing in Patients With Subthreshold or Diagnosed Borderline Personality Disorder: Implications for ICD-11.

The 11th revision of the International Classification of Diseases for Mortality and Morbidity Statistics (ICD-11) defines personality disorder according to personality functioning, which relates to self- and interpersonal functioning. The aim of the present study was to assess the relationship between mentalizing and personality functioning in patients with subthreshold or diagnosed borderline personality disorder. A total of 116 eligible participants were included. Mentalizing was assessed using the Mentalization Questionnaire (MZQ), personality functioning (self- and interpersonal functioning) was assessed using the Level of Personality Functioning Scale-Brief Form 2.0 (LPFS-BF), and borderline severity was assessed using the Zanarini Rating Scale (ZAN-BPD). Mediation analysis was employed to test if mentalizing accounted for the relationship between borderline severity and self- and interpersonal functioning. We found a significant relationship between borderline severity and both subscales of the LPFS-BF. Mentalizing fully and significantly mediated the relationship between borderline severity and interpersonal functioning. However, mentalizing only partly mediated the relationship between borderline severity and self-functioning. Controlling for the covariates gender and age did not impact the results. Mentalizing is likely to be involved in the ICD-11 model of personality functioning, especially interpersonal functioning. This could emphasize the relevance of therapy aimed at strengthening mentalizing abilities when treating personality pathology in general and people with borderline personality disorder in particular. However, self-functioning may be more nuanced, as aspects other than mentalizing also influence self-functioning. The study is explorative in nature and has methodological limitations that require caution in the interpretation and generalizability.