Croarkin, Paul E.

Importance Suicide is a leading cause of death among young people and an escalating public health crisis. Objective To assess the effectiveness and harms of available treatments for suicidal thoughts and behaviors among youths at heightened risk for suicide. Evidence Review A systematic review was conducted searching databases including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various gray literature sources from January 1, 2000, to September 26, 2024. We included randomized clinical trials, comparative observational studies, and before-after studies of psychosocial interventions, pharmacologic interventions, neurotherapeutics, emerging therapies, and combination therapies. Eligible patients were youths (aged 5-24 years) with heightened risk for suicide, adolescents from racial and ethnic minority groups known to be at increased risk of suicide, or those exposed to crime or violence. Pairs of independent reviewers selected and appraised studies. Findings This review included 65 studies (33 randomized clinical trials, 13 comparative observational studies, and 19 before-after studies) reporting on 14 534 patients (median age, 15.1 years; 75.1% female patients). Psychosocial interventions comprised psychotherapy interventions (33 studies; cognitive behavioral therapy, dialectical behavioral therapy, collaborative assessment and management of suicidality, dynamic deconstructive psychotherapy, attachment-based family therapy, and family-focused therapy), acute (ie, 1-4 sessions or contacts) psychosocial interventions (19 studies; safety planning, family-based crisis management, motivational interviewing crisis interventions, continuity of care after crisis, and brief adjunctive treatments), and school- or community-based psychosocial interventions (13 studies; social network interventions, school-based skills interventions, suicide awareness or gatekeeper programs, and community-based, culturally tailored adjunct programs). Dialectical behavior therapy showed moderate strength of evidence for reducing suicidal ideation. Other categories of psychosocial treatments showed insufficient to low strength of evidence for reducing suicidal outcomes. None of the studies evaluated adverse events. The evidence base on pharmacologic treatment for youths at risk of suicide was largely nonexistent. Conclusions and Relevance This systematic review found that the current evidence on available interventions targeting youths at heightened risk of suicide is uncertain. Medication, neurotherapeutics, and emerging therapies remain unstudied among this population. The limited evidence base calls for the development of novel, developmentally and trauma-informed treatments, as well as multilevel interventions to target the increasing suicide risk among youths.

ABSTRACT Major depressive disorder (MDD) is a substantial public health challenge. Pharmacogenomics (PGx), which identifies genetic variations that predict drug treatment outcomes, may have utility for clinical practice, but adequate representation of all populations is needed. As precision medicine in psychiatry moves towards the use of Artificial Intelligence (AI) and Machine Learning (ML) to predict treatment outcomes using PGx data, representation of diverse populations will be especially important in order to mitigate algorithmic bias and achieve equitable and generalizable findings. This work sought to quantify population diversity in pharmacogenomic studies of MDD through a systematic review. Data from 390 MDD antidepressant PGx studies were extracted from 5739 articles screened. Studies summarized were predominantly conducted in Europe, East Asia, and North America. Across all global studies, the study population comprised 57.3% White, 36.4% Asian, 1.7% Black, 3.5% Hispanic/Latino, and 0.1% Native American or Indigenous participants. Only sixty‐three (16.2%) studies included Black or Latino/Hispanic patients. Additionally, Black, Asian, Hispanic/Latino, and American Indian/Alaska Native populations were statistically underrepresented in U.S. study populations when compared to national census data, while Asian and Black populations were underrepresented in the United Kingdom. The overrepresentation of participants from a limited number of countries combined with the underrepresentation of Black and Hispanic/Latino populations could impact the extent to which pharmacogenomic testing and associated AI/ML‐based PGx tools could individualize antidepressant medication regimens for treating MDD.

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.

ABSTRACTPharmacogenetics is a promising strategy to facilitate individualized care for patients with Major Depressive Disorder (MDD). Research is ongoing to identify the optimal genetic markers for predicting outcomes to antidepressant therapies. The primary aim of this systematic review was to summarize antidepressant pharmacogenetic studies to enhance understanding of the genes, variants, datatypes/methodologies, and outcomes investigated in the context of MDD. The secondary aim was to identify clinical genetic panels indicated for antidepressant prescribing and summarize their genes and variants. Screening of N = 5793 articles yielded N = 390 for inclusion, largely comprising adult (≥ 18 years) populations. Top‐studied variants identified in the search were discussed and compared with those represented on the N = 34 clinical genetic panels that were identified. Summarization of articles revealed sources of heterogeneity across studies and low rates of replicability of pharmacogenetic associations. Heterogeneity was present in outcome definitions, treatment regimens, and differential inclusion of mediating variables in analyses. Efficacy outcomes (i.e., response, remission) were studied at greater frequency than adverse‐event outcomes. Studies that used advanced analytical approaches, such as machine learning, to integrate variants with complimentary biological datatypes were fewer in number but achieved higher rates of significant associations with treatment outcomes than candidate variant approaches. As large biological datasets become more prevalent, machine learning will be an increasingly valuable tool for parsing the complexity of antidepressant response. This review provides valuable context and considerations surrounding pharmacogenetic associations in MDD which will help inform future research and translation efforts for guiding antidepressant care.