Social determinants of health (SDoHs) are increasingly recognized as important contributors to the development, course, and outcomes of psychiatric disorders. However, their integration into clinical psychiatry and mecha...Social determinants of health (SDoHs) are increasingly recognized as important contributors to the development, course, and outcomes of psychiatric disorders. However, their integration into clinical psychiatry and mechanistic models remains limited. This overview synthesizes emerging evidence on the biopsychosocial mechanisms through which SDoHs influence mental health. There is a need to distinguish between individual-level, clinically actionable health-related social needs and family-, community-, and society-level structural SDoHs, and to consider both adverse and protective social factors. Converging research demonstrates that social experiences are biologically embedded through interacting pathways, including exposomics, epigenetics, allostatic load, accelerated inflammaging, immune dysregulation, and gut-brain-microbiome signaling. These mechanisms influence neural circuitry underlying stress regulation, reward processing, and social cognition. Psychological processes-including individual differences in resilience, wisdom, compassion, and purpose in life-shape responses to SDoHs and are supported by identifiable neurobiological substrates. Social connection has emerged as a central, potentially modifiable SDoH that is strongly associated with whole health and longevity. Loneliness and social isolation have become major global public health challenges. The authors propose a biopsychosocial framework that integrates social exposures, biological mechanisms, neural systems, and psychological processes to better understand the risk, course, and prevention of mental illnesses. Clinical and public health implications include the need for routine assessment of SDoHs, incorporation of protective factors at individual and societal levels, and development of pragmatic, multidomain interventions. Finally, rapidly evolving digital technologies, including artificial intelligence, offer new opportunities but also require careful governance. Advancing toward human-centered "artificial wisdom" may enhance the capacity of technology to promote whole health in individuals with mental illnesses globally.
Forsyth JK, Zhu J, Chavannes AS
… +34 more, Trevorrow ZH, Hyat M, Sievertsen SA, Ferreira-Ianone S, Conomos MP, Nuechterlein KH, Asarnow RF, Green MF, Karlsgodt KH, Perkins DO, Cannon TD, Addington JM, Cadenhead KS, Cornblatt BA, Keshavan MS, Mathalon DH, Stone WS, Tsuang MT, Walker EF, Woods SW, Narr KL, McEwen SC, Schleifer CH, Yee CM, Diehl CK, Guha A, Miller GA, Alexander-Bloch AF, Sha Z, Glessner J, Seidlitz J, Bethlehem RAI, Ophoff RA, Bearden CE
Am J Psychiatry
· 2026 Jun · PMID 42337417
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OBJECTIVE: Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSDs). However, i...OBJECTIVE: Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSDs). However, it is unclear how known risk CNVs and broader genome-wide CNVs influence clinical variability. Furthermore, whether biological annotation of CNV scores can improve power for patient stratification is unknown. This study therefore investigated the relationships between severe SSD-related phenotypes and varied CNV metrics, including CNV burden affecting genes involved in different aspects of neurodevelopment. METHODS: This study of 617 individuals with SSDs examined associations of two severe phenotypes-childhood-onset psychosis and borderline intellectual functioning (IQ)-with 1) known risk CNVs, 2) genome-wide deletion burden scores, and 3) novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene sets, representing distinct aspects of neurodevelopment. Associations with borderline IQ were assessed for replicability in 233 relatives of SSD patients, 581 control subjects, and 9,930 youths from the Adolescent Brain Cognitive Development (ABCD) Study. RESULTS: Known SSD-risk CNVs (odds ratio=7.07, 95% CI=1.60, 31.32) and neurodevelopmental disorder (NDD)-risk CNVs (odds ratio=4.56, 95% CI=1.48, 14.10) were associated with borderline IQ in SSDs. Furthermore, beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline IQ across SSD cases and noncases (odds ratio=2.57, 95% CI=1.44, 4.60) and in the ABCD cohort (odds ratio=1.33, 95% CI=1.00, 1.76). Exploratory structural MRI-based analyses showed associations between fetal gene regulatory gene deletions and altered gray matter volume (b=0.09, 95% CI=0.004, 0.17) and cortical thickness (b=0.14, 95% CI=0.05, 0.24) across SSD cases and noncases. CONCLUSIONS: The study results confirm contributions of known risk CNVs to severe phenotypes in SSDs, implicate disrupted fetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes.
Yeom JW, Jeong J, Moon E
… +13 more, Park YM, Lee MS, Yoon HK, Shin C, Yoon Y, Seo JY, Jeon S, Choi M, Cho CH, An H, Lee T, Lee JB, Lee HJ
Am J Psychiatry
· 2026 Jun · PMID 42337416
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OBJECTIVE: Preventing recurrence is essential for improving the clinical course of major depressive disorder (MDD) and bipolar disorder (BD). The authors developed the Circadian Rhythm for Mood (CRM) smartphone app, whic...OBJECTIVE: Preventing recurrence is essential for improving the clinical course of major depressive disorder (MDD) and bipolar disorder (BD). The authors developed the Circadian Rhythm for Mood (CRM) smartphone app, which provides individualized 3-day mood forecasts and delivers personalized circadian rhythm feedback using passive sensor data. This study tested the therapeutic efficacy of CRM in preventing mood episode recurrence compared with a sham app. METHODS: In a multicenter, double-blind, randomized clinical trial, 93 adults with MDD or BD were assigned in a 1:1 ratio to active CRM (N=47) or a sham app (N=46) for 12 months. Participants in the active CRM group received personalized circadian rhythm stabilization feedback generated by machine learning. Participants in the sham app group received nonactionable feedback from a dummy algorithm, designed not to influence circadian behavior, with a visually identical interface. The primary outcome was the number of recurrent mood episodes per participant during follow-up. RESULTS: In the modified intention-to-treat sample (N=80), the sham group (N=42) had a significantly higher recurrence rate than the active CRM group (N=38) (incidence rate ratio=3.39, 95% CI=1.86-6.17). Cumulative recurrent episode-days per person-year were greater in sham group (duration rate ratio=2.76, 95% CI=1.19-6.40), and time to recurrence favored active CRM (hazard ratio=3.03, 95% CI=1.58-5.81). No significant adverse effects were observed. CONCLUSIONS: The circadian rhythm stabilization app significantly reduced recurrence and improved the clinical course in MDD and BD. CRM has potential as an innovative, scalable digital chronotherapeutic adjunct to standard care.
Laursen AF, Bundgaard AF, Lawaetz Daugaard N
… +19 more, Birk M, Nielsen CS, Rohd SB, Wilms M, Schiavon M, Streymá DHB, Knudsen CB, Andreassen AK, Veddum L, Gregersen M, Krantz MF, Søndergaard A, Ueland T, Jepsen JRM, Nordentoft M, Mors O, Thorup AAE, Greve AN, Hemager N
Am J Psychiatry
· 2026 Jun · PMID 42337415
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OBJECTIVE: The course of neurocognitive development prior to the typical age of schizophrenia or bipolar disorder onset remains largely unexplored among offspring at familial high risk for these disorders. The authors so...OBJECTIVE: The course of neurocognitive development prior to the typical age of schizophrenia or bipolar disorder onset remains largely unexplored among offspring at familial high risk for these disorders. The authors sought to compare neurocognitive development in offspring at familial high risk of schizophrenia (FHR-SZ) or at familial high risk of bipolar disorder (FHR-BP) and a population-based control (PBC) group at ages 7, 11, and 15. METHODS: This study examined neurocognitive development in offspring at FHR-SZ, at FHR-BP, and in a PBC group who participated in the Danish High Risk and Resilience Study, a prospective, nationwide cohort study. Participants were assessed at ages 7 (N=520), 11 (N=451), and 15 (N=396) using a comprehensive neurocognitive battery. Mixed-effects models evaluated group differences in developmental trajectories across domains including intelligence, processing speed, attention, memory, planning, verbal fluency, and set-shifting. RESULTS: Offspring at FHR-SZ showed a significant developmental lag in processing speed between ages 11 and 15 (β=-3.82, 95% CI=-5.85, -1.78) and cross-sectional deficits at age 15 across multiple domains relative to the PBC group (Cohen's d range, 0.31-0.48). They also performed worse than the FHR-BP group in verbal working memory at age 15 (d=0.42). Offspring at FHR-BP showed normative development compared with the PBC group, despite a cross-sectional deficit in semantic verbal fluency at age 15 (d=0.36). CONCLUSIONS: Offspring at FHR-SZ showed aberrant neurocognitive developmental alterations, whereas those at FHR-BP largely followed normal trajectories, with emerging deficits only in semantic verbal fluency. Examination of distinct neurocognitive trajectories as potential predictors of conversion to schizophrenia or bipolar disorder is warranted.
Peterson BS, West AE, Weersing VR
… +21 more, Bansal R, Yu J, Findling RL, Marcelino CM, Smith K, Koebnick C, Ashen C, Snowdy C, Marcy SN, Hudson BO, Poulsen M, Arora BK, Perez M, Jurici M, Takata G, Chen I, Kipke MD, Mittman BS, Piantadosi S, Weisz JR, Mack WJ
Am J Psychiatry
· 2026 Jun · PMID 42337414
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OBJECTIVE: Clinicians treating pediatric anxiety disorders have inadequate information to decide which evidence-based treatment should initiate care and what strategies to adopt when initial care proves to be insufficien...OBJECTIVE: Clinicians treating pediatric anxiety disorders have inadequate information to decide which evidence-based treatment should initiate care and what strategies to adopt when initial care proves to be insufficient. The authors sought to determine whether beginning treatment with fluoxetine or exposure-based CBT yielded better outcomes, and, if 3 months of treatment failed to produce remission, whether optimizing the initial treatment or adding the other treatment modality (combination therapy) yielded better outcomes. METHODS: This 24-week single-blind sequential multiple assignment randomized trial (SMART), conducted in primary care and mental health clinics, employed two 12-week treatment stages: randomization to fluoxetine or cognitive-behavioral therapy (CBT) followed by randomization to either continued initial treatment or combination therapy. Eligibility criteria included a anxiety disorder; age 8-17; at least 2nd-grade reading level; and not receiving anxiety treatments. The primary outcome was score on the youth-report 41-item Screen for Child Anxiety Related Emotional Disorders (SCARED). Secondary outcomes were score on the parent-report SCARED and scores on the youth- and parent-report Child Anxiety Impact Scale. The authors hypothesized better outcomes from initial treatment with fluoxetine followed by combination treatment. RESULTS: A total of 316 youths with severe anxiety who had high levels of sociodemographic disadvantage and co-occurring diagnoses were randomized. Overall, youth-reported SCARED scores declined 31.7% over the 24-week trial. Improvement did not differ significantly by initial treatment, although CBT afforded a nonsignificant advantage over medication (24-week difference in mean group change: 1.45, 95% CI=-2.25, 5.16). In week-12 nonremitters, combination treatment did not yield superior week-24 improvement over continuing monotherapy (group difference in mean change from baseline: -2.74, 95% CI=-6.53, 1.05). Initial treatment with CBT followed by combination therapy significantly separated from other sequences on a subset of measures over 24 weeks. Non-Hispanic White youths benefited more from initiating treatment with fluoxetine and continuing it after week 12, whereas racial and ethnic minority youths benefited more from transitioning to combination therapy after week 12. CONCLUSIONS: This pragmatic SMART study shows that symptom reduction is similar for fluoxetine, CBT, their combination, and variations in sequencing when delivered to youths with anxiety disorders. Patients, families, and clinicians have a range of treatment options and may optimize outcomes by stakeholder preference.
Jayaraman P, Wortzel JR, Wei G
… +3 more, Christ RR, Sharma Y, Nugent NR
Am J Psychiatry
· 2026 Jun · PMID 42337413
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OBJECTIVE: The impact of higher ambient temperature on suicide is well documented in the general population, although it remains unclear in youths despite their particular biosocial vulnerability. In an ecological study,...OBJECTIVE: The impact of higher ambient temperature on suicide is well documented in the general population, although it remains unclear in youths despite their particular biosocial vulnerability. In an ecological study, the authors examined this relationship, focusing on seasonal differences. METHODS: The authors calculated monthly suicide rates in young people (ages 5-24) by county using data from the U.S. Centers for Disease Control and Prevention and the U.S. Census Bureau from 1980 to 2004 in the contiguous United States. Fixed-effects regression was used to estimate relative risk of suicide per 1°C change in average monthly temperature overall and by season, accounting for precipitation, region, county, month, and year. Age-stratified analysis (ages 4 to 65+) assessed whether effects were unique to young people. Heterogeneity models examined the impacts of legal sex, income, race, education, geographic division, and rurality. RESULTS: Averaged across seasons, suicide in young people increased 0.75% (95% CI=0.34, 1.16) per 1°C increase, comparable to the general population (0.73%, 95% CI=0.53, 0.93). This effect was significant only in summer, and it was substantially larger in summer (2.68% per 1°C; 95% CI=1.42, 3.94). Age stratification showed that 15- to 24-year-olds were uniquely vulnerable compared to other age groups (2.97% per 1°C; 95% CI=1.30, 4.65). Most geographic regions experienced this association, and no sociodemographic differences were identified. CONCLUSIONS: Summer heat is associated with higher suicide rates among late adolescents and young adults, who appear most at risk. This association likely reflects neurobiological and socioenvironmental conditions of young people that amplify heat-related mental health risk. These data highlight the need to study how ambient temperature impacts youth mental health and develop biosocially informed interventions as temperatures rise.
Gogtay N, Abi-Dargham A, Ajilore O
… +15 more, Alpert JE, Benton TD, Clarke DE, Compton WM, Drexler K, Fung KP, Kas MJH, Kumar A, Malaspina D, O'Keefe VM, Öngür D, Wainberg ML, Yonkers KA, Yousif L, Oquendo MA
Am J Psychiatry
· 2026 Jun · PMID 42310506
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