An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol  link ), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

OBJECTIVES: Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. METHODS: Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. RESULTS: The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. CONCLUSIONS: Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Efficacy and acceptability of psychosocial interventions in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence.

Psychosocial interventions are recommended in schizophrenia and first-episode psychosis/early psychosis (EP). Nevertheless, literature is heterogeneous and often contradictory. We conducted an umbrella review of (network) meta-analyses of randomized controlled trials (RCTs) comparing psychosocial interventions vs treatment as usual (TAU)/active interventions(ACTIVE)/MIXED controls. Primary outcome was total symptoms (TS); secondary outcomes were positive/negative/depressive symptoms (PS/NS/DS), cognition, functioning, relapse, hospitalization, quality of life (QoL), treatment discontinuation. Standardized mean difference (SMD)/odds ratio (OR)/risk ratio (RR) vs TAU/ACTIVE/MIXED were summarized at end-of-treatment (EoT)/follow-up (FU). Quality was rated as high/medium/low (AMSTAR-PLUS). Eighty-three meta-analyses were included (RCTs = 1246; n = 84,925). Against TAU, regarding TS, Early Intervention Services (EIS) were superior EoT/FU in EP (SMD = -0.32/-0.21), cognitive behavioral therapy (CBT) in schizophrenia EoT/FU (SMD = -0.38/-0.19). Regarding secondary outcomes, in EP, EIS were superior for all outcomes EoT except cognition, and at FU for PS/NS/QoL, specific family interventions (FI-s) prevented relapse EoT; in schizophrenia, superiority emerged EoT for CBT for PS/NS/relapse/functioning/QoL; psychoeducation (EDU)/any FI for relapse; cognitive remediation therapy (CRT) for cognition/functioning; and hallucination-focused integrative treatment for PS. Against ACTIVE, in EP, mixed family interventions (FI-m) were superior at FU regarding TS (SMD = -0.61) and for functioning/relapse among secondary outcomes. In schizophrenia, regarding TS, mindfulness and social skills training (SST) were superior EoT, CBT at FU; regarding secondary outcomes superiority emerged at EoT for computerized cognitive drill-and-practice training for PS/DS, CRT for cognition/functioning, EDU for relapse, individual placement and support (IPS) for employment; and at FU CBT for PS/NS. Against MIXED, in schizophrenia, CRT/EDU were superior for TS EoT (d = -0.14/SMD = -0.33), CRT regarding secondary outcomes EoT for DS/social functioning, both EoT/FU for NS/cognition/global functioning; compensatory cognitive interventions for PS/functioning EoT/FU and NS EoT; CBT for PS at FU, and EDU/SST for relapse EoT. In conclusion, mental health services should consider prioritizing EIS/any FI in EP and CBT/CRT/any FI/IPS for schizophrenia, but other interventions may be helpful for specific outcomes.

Brain stimulation and other biological non-pharmacological interventions in mental disorders: An umbrella review.

BACKGROUND: The degree of efficacy, safety, quality, and certainty of meta-analytic evidence of biological non-pharmacological treatments in mental disorders is unclear. METHODS: We conducted an umbrella review (PubMed/Cochrane Library/PsycINFO-04-Jul-2021, PROSPERO/CRD42020158827) for meta-analyses of randomized controlled trials (RCTs) on deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electro-convulsive therapy (ECT), and others. Co-primary outcomes were standardized mean differences (SMD) of disease-specific symptoms, and acceptability (for all-cause discontinuation). Evidence was assessed with AMSTAR/AMSTAR-Content/GRADE. RESULTS: We selected 102 meta-analyses. Effective interventions compared to sham were in depressive disorders: ECT (SMD=0.91/GRADE=moderate), TMS (SMD=0.51/GRADE=moderate), tDCS (SMD=0.46/GRADE=low), DBS (SMD=0.42/GRADE=very low), light therapy (SMD=0.41/GRADE=low); schizophrenia: ECT (SMD=0.88/GRADE=moderate), tDCS (SMD=0.45/GRADE=very low), TMS (prefrontal theta-burst, SMD=0.58/GRADE=low; left-temporoparietal, SMD=0.42/GRADE=low); substance use disorder: TMS (high frequency-dorsolateral-prefrontal-deep (SMD=1.16/GRADE=moderate), high frequency-left dorsolateral-prefrontal (SMD=0.77/GRADE=very low); OCD: DBS (SMD=0.89/GRADE=moderate), TMS (SMD=0.64/GRADE=very low); PTSD: TMS (SMD=0.46/GRADE=moderate); generalized anxiety disorder: TMS (SMD=0.68/GRADE=low); ADHD: tDCS (SMD=0.23/GRADE=moderate); autism: tDCS (SMD=0.97/GRADE=very low). No significant differences for acceptability emerged. Median AMSTAR/AMSTAR-Content was 8/2 (suggesting high-quality meta-analyses/low-quality RCTs), GRADE low. DISCUSSION: Despite limited certainty, biological non-pharmacological interventions are effective and safe for numerous mental conditions. Results inform future research, and guidelines. FUNDING: None.

Efficacy of neurostimulation across mental disorders: systematic review and meta-analysis of 208 randomized controlled trials.

Non-invasive brain stimulation (NIBS), including transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS), is a potentially effective treatment strategy for a number of mental conditions. However, no quantitative evidence synthesis of randomized controlled trials (RCTs) of TMS or tDCS using the same criteria including several mental conditions is available. Based on 208 RCTs identified in a systematic review, we conducted a series of random effects meta-analyses to assess the efficacy of NIBS, compared to sham, for core symptoms and cognitive functioning within a broad range of mental conditions. Outcomes included changes in core symptom severity and cognitive functioning from pre- to post-treatment. We found significant positive effects for several outcomes without significant heterogeneity including TMS for symptoms of generalized anxiety disorder (SMD = -1.8 (95% CI: -2.6 to -1), and tDCS for symptoms of substance use disorder (-0.73, -1.00 to -0.46). There was also significant effects for TMS in obsessive-compulsive disorder (-0.66, -0.91 to -0.41) and unipolar depression symptoms (-0.60, -0.78 to -0.42) but with significant heterogeneity. However, subgroup analyses based on stimulation site and number of treatment sessions revealed evidence of positive effects, without significant heterogeneity, for specific TMS stimulation protocols. For neurocognitive outcomes, there was only significant evidence, without significant heterogeneity, for tDCS for improving attention (-0.3, -0.55 to -0.05) and working memory (-0.38, -0.74 to -0.03) in individuals with schizophrenia. We concluded that TMS and tDCS can benefit individuals with a variety of mental conditions, significantly improving clinical dimensions, including cognitive deficits in schizophrenia which are poorly responsive to pharmacotherapy.

Awareness of illness moderates self-assessment of psychotic symptoms.

OBJECTIVE: Self-reports or patient-reported outcome measures are seldom used in psychosis due to concerns about the ability of patients to accurately report their symptomatology, particularly in cases of low awareness of illness. The aim of this study was to assess the effect of insight on the accuracy of self-reported psychotic symptoms using a computerized adaptive testing tool (CAT-Psychosis). METHODS: A secondary analysis of data drawn from the CAT-Psychosis development and validation study was performed. The Brief Psychiatric Rating Scale and the Scale of Unawareness of Mental Disorders were administered by clinicians. Patients completed the self-reported version of the CAT-Psychosis. Patients were median-split regarding their insight level to compare the correlation between the two psychosis severity measures. A subgroup sensitivity analysis was performed only on patients with schizophrenia spectrum disorders. RESULTS: A total of 159 patients with a psychotic disorder who completed both CAT-Psychosis and Scale of Unawareness of Mental Disorders were included. For the whole sample, CAT-Psychosis scores showed convergent validity with Brief Psychiatric Rating Scale ratings (r = 0.517, 95% confidence interval = [0.392, 0.622], p < 0.001). Insight was found to moderate this correlation (ß = -0.511, p = 0.005), yet agreement between both measures remained statistically significant for both high (r = 0.621, 95% confidence interval = [0.476, 0.733], p < 0.001) and low insight patients (r = 0.408, 95% confidence interval = [0.187, 0.589], p < 0.001), while psychosis severity was comparable between these groups (for Brief Psychiatric Rating Scale: U = 3057, z = -0.129, p = 0.897; disorganization: U = 2986.5, z = -0.274, p = 0.784 and for CAT-Psychosis: U = 2800.5, z = -1.022, p = 0.307). Subgroup of patients with schizophrenia spectrum disorders showed very similar results. CONCLUSIONS: Insight moderates the correlation between self-reported and clinician-rated severity of psychosis, yet CAT-Psychosis remains valid in patients with both high and low awareness of illness.

Impaired theory of mind and emotion recognition in pediatric bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Social cognition is impaired in patients with severe mental disorders. We aimed to investigate impairments in social cognition in youth with pediatric bipolar disorder (PBD) through a systematic review of the literature and the meta-analysis. METHOD: Following the PRISMA guidelines, we searched in PubMed, Scopus, and Cochrane CENTRAL for studies reporting on the theory of mind (ToM) and emotion recognition (ER) abilities of patients with PBD compared to healthy controls (HC). We conducted a random-effects model meta-analysis for the contrast between PBD and HC. Subgroup and meta-regression analyses were conducted for demographic and clinical variables as appropriate. RESULTS: A total of thirteen studies involving 429 patients with PBD and 394 HC were included. Patients with PBD had significantly poorer social cognitive abilities (Hedges' g for ER, g = -0.74, CI = -0.91, -0.57; and for ToM, g = -0.98, CI = -1.41 to -0.55). Subgroup analysis also revealed significant impairment in ER for patients in a euthymic state (g = -0.75). Age, gender, sample size, the severity of mood symptoms, estimated IQ, the frequencies of bipolar-I disorder, attention-deficit hyperactivity disorder, medications, study quality and euthymia did not moderate the difference in meta-regression. Heterogeneity was low in all analyses and there was no evidence for publication bias. CONCLUSION: The results of this meta-analysis supported the notion that PBD is associated with a deficit in social cognitive abilities at a medium to a large level. Impairments in social cognition could be an illness-related trait of PBD. Meta-regression results did not find a moderator of the deficits in social cognition.

Longitudinal Course of Depressive, Anxiety, and Posttraumatic Stress Disorder Symptoms After Heart Surgery: A Meta-Analysis of 94 Studies.

OBJECTIVE: This study aimed to analyze the longitudinal course of depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms in patients with cardiac disease after heart surgery (HS). METHODS: We conducted a systematic review and random-effects meta-analysis of cohort studies in patients undergoing HS, measuring anxiety, depressive, and PTSD symptoms before and at least 30 days thereafter. Subgroup and meta-regression analyses, investigation of publication bias, and quality assessment were undertaken. RESULTS: We included 94 studies relating to 15,561 patients. HS included coronary artery bypass graft surgery, valve replacement, implantable cardioverter-defibrillator placement, left ventricular assist device placement, heart transplantation, and other types of HS. Across studies, symptoms of depression (g = 0.32; 95% confidence interval [CI] = 0.25 to 0.39; p < .001) and anxiety improved after HS (g = 0.52; 95% CI = 0.43 to 0.62; p < .001), whereas PTSD symptoms worsened (g = -0.42; 95% CI = -0.80 to -0.04; p = .032). The reduction of depression and anxiety levels was more pronounced for patients with underlying coronary artery disease and heart failure and persisted for 1 year after HS, whereas the increase in PTSD symptoms returned to baseline after 6 months. Depression improvement was inversely associated with older age, diabetes, hypertension, and dyslipidemia and positively with baseline heart failure. No additional clinical or demographic variables were associated with the course of anxiety symptoms. Quality of included studies was low overall. Publication bias was nonsignificant. CONCLUSIONS: Depressive and anxiety symptoms improve for 1 year after HS, whereas PTSD symptoms might worsen. Older patients and those with metabolic comorbidities, valve disease, or ventricular arrhythmias are at higher risk for continued depressive and anxiety symptoms and should be monitored closely.

Development and Validation of a Computerized Adaptive Assessment Tool for Discrimination and Measurement of Psychotic Symptoms.

OBJECTIVE: Time constraints limit the use of measurement-based approaches in research and routine clinical management of psychosis. Computerized adaptive testing (CAT) can reduce administration time, thus increasing measurement efficiency. This study aimed to develop and test the capacity of the CAT-Psychosis battery, both self-administered and rater-administered, to measure the severity of psychotic symptoms and discriminate psychosis from healthy controls. METHODS: An item bank was developed and calibrated. Two raters administered CAT-Psychosis for inter-rater reliability (IRR). Subjects rated themselves and were retested within 7 days for test-retest reliability. The Brief Psychiatric Rating Scale (BPRS) was administered for convergent validity and chart diagnosis, and the Structured Clinical Interview (SCID) was used to test psychosis discriminant validity. RESULTS: Development and calibration study included 649 psychotic patients. Simulations revealed a correlation of r = .92 with the total 73-item bank score, using an average of 12 items. Validation study included 160 additional patients and 40 healthy controls. CAT-Psychosis showed convergent validity (clinician: r = 0.690; 95% confidence interval [95% CI]: 0.610-0.757; self-report: r = .690; 95% CI: 0.609-0.756), IRR (intraclass correlation coefficient [ICC] = 0.733; 95% CI: 0.611-0.828), and test-retest reliability (clinician ICC = 0.862; 95% CI: 0.767-0.922; self-report ICC = 0.815; 95%CI: 0.741-0.871). CAT-Psychosis could discriminate psychosis from healthy controls (clinician: area under the receiver operating characteristic curve [AUC] = 0.965, 95% CI: 0.945-0.984; self-report AUC = 0.850, 95% CI: 0.807-0.894). The median length of the clinician-administered assessment was 5 minutes (interquartile range [IQR]: 3:23-8:29 min) and 1 minute, 20 seconds (IQR: 0:57-2:09 min) for the self-report. CONCLUSION: CAT-Psychosis can quickly and reliably assess the severity of psychosis and discriminate psychotic patients from healthy controls, creating an opportunity for frequent remote assessment and patient/population-level follow-up.

Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls.

People with severe mental illness (SMI) - schizophrenia, bipolar disorder and major depressive disorder - appear at risk for cardiovascular disease (CVD), but a comprehensive meta-analysis is lacking. We conducted a large-scale meta-analysis assessing the prevalence and incidence of CVD; coronary heart disease; stroke, transient ischemic attack or cerebrovascular disease; congestive heart failure; peripheral vascular disease; and CVD-related death in SMI patients (N=3,211,768) versus controls (N=113,383,368) (92 studies). The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4-13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross-sectional studies (odds ratio, OR=1.53, 95% CI: 1.27-1.83; 11 studies), and higher odds of coronary heart disease (OR=1.51, 95% CI: 1.47-1.55) and cerebrovascular disease (OR=1.42, 95% CI: 1.21-1.66). People with major depressive disorder were at increased risk for coronary heart disease, while those with schizophrenia were at increased risk for coronary heart disease, cerebrovascular disease and congestive heart failure. Cumulative CVD incidence in SMI patients was 3.6% (95% CI: 2.7-5.3) during a median follow-up of 8.4 years (range 1.8-30.0). Adjusting for a median of six confounders, SMI patients had significantly higher CVD incidence than controls in longitudinal studies (hazard ratio, HR=1.78, 95% CI: 1.60-1.98; 31 studies). The incidence was also higher for coronary heart disease (HR=1.54, 95% CI: 1.30-1.82), cerebrovascular disease (HR=1.64, 95% CI: 1.26-2.14), congestive heart failure (HR=2.10, 95% CI: 1.64-2.70), and CVD-related death (HR=1.85, 95% CI: 1.53-2.24). People with major depressive disorder, bipolar disorder and schizophrenia were all at increased risk of CVD-related death versus controls. CVD incidence increased with antipsychotic use (p=0.008), higher body mass index (p=0.008) and higher baseline CVD prevalence (p=0.03) in patients vs. CONTROLS: Moreover, CVD prevalence (p=0.007), but not CVD incidence (p=0.21), increased in more recently conducted studies. This large-scale meta-analysis confirms that SMI patients have significantly increased risk of CVD and CVD-related mortality, and that elevated body mass index, antipsychotic use, and CVD screening and management require urgent clinical attention.