BACKGROUND:Childhood maltreatment (CM), encompassing abuse and neglect, is highly prevalent and associated with elevated risk for major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and other related conditions. However, the extent to which neuroanatomical alterations in MDD and PTSD are attributable to CM is uncertain. METHODS:Here, we analyzed CM and whole-brain magnetic resonance imaging (MRI) data from 3711 participants in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) MDD and PTSD Working Groups (25 sites; mean age = 33.3 ± 13.0 years; 59.9% female). Normative modeling estimated deviation z scores for 14 subcortical volume, 68 cortical thickness (CT), and 68 surface area (SA) measures. To identify transdiagnostic effects, associations between CM and brain deviation scores were evaluated across all participants (patients and healthy control participants) stratified by sex and 3 age bins (pediatric, young adult, older adult). RESULTS:In young adults (ages 18-35), abuse was associated with larger volumes in the thalamus and pallidum, thinner isthmus cingulate and middle frontal regions, and thicker medial orbitofrontal cortex; there were no significant effects in pediatric (≤18 years) participants. The strongest effects were observed in young female adults (|β| = 0.07-0.22, q < .05): Greater abuse and neglect were correlated with smaller hippocampus and putamen volumes, thinner entorhinal cortex, and smaller SA in fusiform/inferior parietal regions and with larger SA in the orbitofrontal and occipital cortices. In males, abuse had widespread effects on CT and SA (|β| = 0.1-0.18, q < .05); effects for neglect were minimal. CONCLUSIONS:Our findings of age- and sex-specific instantiations of CM on brain morphometry highlight the importance of developmental context in understanding how adverse experiences shape neurobiological vulnerability to MDD and PTSD.

Dronabinol, the pharmaceutical form of Δ9-tetrahydrocannabinol, shows promise in the treatment of nightmares related to post-traumatic stress disorder (PTSD), but additional studies are needed to confirm safety and efficacy.

Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = -0.26, pBON = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = -1.01, pBON = 0.04) and arousal (β = -0.9, pBON = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = -0.1, pBON = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = -0.31, pBON = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, pBON = 9 × 10-3) and neglect (β = 0.29, pBON = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.

Generalizable neuroimaging biomarkers that detect cerebral cortical changes after traumatic brain injury (TBI) and predict patient outcomes are needed to improve care and to develop targeted therapies. We used morphometric inverse divergence (MIND) analysis of structural MRI to investigate cortical gray matter morphological networks cross-sectionally and longitudinally after TBI and correlate these with symptoms, disability and cognition six months after injury. Our findings support the Triple Network Model from functional MRI of post-traumatic alterations in the relationship between task-positive, default mode and salience networks. However, the strongest associations between early cortical similarity metrics and long-term patient outcomes involved the dorsal attention network and the limbic network as well as similarity metrics across Mesulam's hierarchy of laminar differentiation. Since MIND mapping of cortical gray matter networks only requires data that is a routine part of standard clinical MRI protocols and does not need image harmonization across different scanners, this work reports a promising new tool that is immediately available for advancing research and clinical care in TBI.

A substantial proportion of Veterans experience mental and physical health difficulties, including post-traumatic stress disorder and chronic pain, for which cannabis is sometimes medically authorized. However, relatively little is known about cannabis use among Canadian Veterans. Information on the prevalence of use, as well as the mental health profiles and help-seeking behaviours of Veterans who use cannabis, is important for developing more targeted prevention and intervention services and supports. The current study used data from Veteran respondents (n = 1992) of the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey. Descriptive statistics and logistic regression models were used to examine associations between past 12-month cannabis use and concurrent mental disorders, chronic pain conditions, use of other substances, suicide behaviours, perceived need for care, and help-seeking behaviours. Several participating Veterans (16.7

Childhood adversity increases risk for impaired social functioning later in life; however, neural pathways delineating this association are poorly understood. Different types of adverse interpersonal experiences (i.e., abuse, neglect) may impact neural pathways distinctly, resulting in unique consequences on social motivation and behavior in adulthood. Here, we investigated neural responses during the anticipation of social reward and punishment and their associations with childhood abuse and neglect in adults with a depressive and/or anxiety disorder and social impairment. Participants (N=57) completed an fMRI social incentive delay task. In region-of-interest analyses, we examined activation in striatal regions when participants anticipated receiving potential social reward or avoiding social punishment in relation to self-reported childhood abuse and neglect. Individuals endorsing greater neglect during childhood demonstrated increased activation in the caudate (β = .359, p = .006) and putamen (β = .454, p < .001) during anticipation of social reward, while participants reporting greater abuse during childhood showed decreased activation in the same regions (β = -.314, p = .024 and β = -.341, p = .014, respectively). No significant associations were observed between childhood trauma and activation during anticipation of social punishment. Findings reveal differential associations of childhood abuse and neglect with dorsal striatum activation during social reward anticipation in adults with anxiety and depression. Treatments targeting aberrant social reward processing may benefit patients who have experienced significant childhood adversity, and different approaches may be needed based on the type(s) of early adversity experienced.

Patients with traumatic brain injury (TBI) and Glasgow Coma Scale scores of 13-15 (historically called mild TBI [mTBI]) commonly experience changes in cognitive functioning, including processing speed, memory, and executive functioning. In a prospective sample (N = 523) of individuals of European descent who had been treated in a U.S. level 1 trauma center for mTBI, we examined the prognostic value of four polygenic risk scores (PRS) for cognitive outcomes at 6-months postinjury. To estimate the impact of mTBI on cognition, primary cognitive outcomes were scaled as z-scores reflecting changes in performance relative to predicted preinjury performance. The PRS examined were previously developed and validated to predict cognition-related outcomes of educational attainment (Education-PRS), intelligence (Intelligence-PRS), and Alzheimer's disease (AD-mild traumatic brain injury (APOE)-PRS and AD + APOE-PRS). Both the Education-PRS and Intelligence-PRS displayed bivariate associations with all four cognitive outcomes (β = 0.19-0.32), whereas neither Alzheimer's disease PRS was significantly associated with any outcome. After controlling for other factors known to predict cognitive outcomes of TBI (e.g., sex, education, mTBI severity defined by a combination of Glasgow Coma Scale scores and the presence/absence of acute intracranial findings on clinical neuroimaging), the Education-PRS and Intelligence-PRS remained independently predictive of verbal episodic memory (β = 0.10-0.16), whereas their associations with processing speed and executive functioning were mostly nonsignificant and were mediated through educational attainment. Looking across primary z-score and secondary raw score outcomes, cognitive outcomes 6 months post-mTBI were good on average, and PRS made small independent contributions to outcome prediction. The mediation model findings may support theories of cognitive reserve, which propose that individuals with stronger preinjury cognitive processing abilities (often estimated by educational history) can better compensate for TBI. Moreover, findings indicate that PRS may contribute modestly to multivariable models predicting cognitive function after TBI.

Migraine is a leading cause of disability 1 , yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies 2 . Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data 3 . We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1 4 . Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.

OBJECTIVES:To investigate the relationship between alcohol consumption and dementia. DESIGN:Prospective cohort and case-control analyses combined with linear and non-linear Mendelian randomisation. SETTING:Two large-scale population-based cohorts: the US Million Veteran Programme and the UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS). PARTICIPANTS:559 559 adults aged 56-72 years at baseline were included in observational analyses (mean follow-up: 4 years in the US cohort; 12 years in the UK cohort). Genetic analyses used summary data from multiple large GWAS consortia (2.4 million participants). MAIN OUTCOME MEASURES:Incident all-cause dementia, determined through health record linkage, and genetic proxies. RESULTS:During follow-up, 14 540 participants developed dementia and 48 034 died. Observational phenotype-only analyses revealed U-shaped associations between alcohol and dementia risk: higher risk was observed among non-drinkers, heavy drinkers (>40 drinks per week; HR 1.41, 95% CI 1.15 to 1.74), and those with alcohol use disorder (AUD) (HR 1.51, 95% CI 1.42 to 1.60) compared with light drinkers. In contrast, Mendelian randomisation genetic analysis identified a monotonic increase in dementia risk with greater alcohol consumption. A 1 SD increase in log-transformed drinks per week was associated with a 15% dementia increase (inverse-variance weighted (IVW) OR 1.15, 95% CI 1.03 to 1.27). A twofold increase in AUD prevalence was associated with a 16% increase in dementia risk (IVW OR 1.16, 95% CI 1.03 to 1.30). Alcohol intake increased dementia, but individuals who developed dementia also experienced a decline in alcohol intake over time, suggesting reverse causation-where early cognitive decline leads to reduced alcohol consumption-underlies the supposed protective alcohol effects in observational studies. CONCLUSIONS:These findings provide evidence for a relationship between all types of alcohol use and increased dementia risk. While correlational observational data suggested a protective effect of light drinking, this could be in part attributable to reduced drinking seen in early dementia; genetic analyses did not support any protective effect, suggesting that any level of alcohol consumption may contribute to dementia risk. Public health strategies that reduce the prevalence of alcohol use disorder could potentially lower the incidence of dementia by up to 16%.

Abstract Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (N cases =33,977, N controls =675,392) in four broad ancestry groups: European (EUR) (N cases =22,564, N controls =624,672), African (AFR) (N cases =7,574, N controls =34,189), Admixed American (AMR) (N cases =3,657, N controls =15,698), and East Asian (EAS) (N cases =182, N controls =833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2 *rs5794864, P =7.32×10 −10 , one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5 *rs55781567, P =3.27×10 −9 , two in a male-only meta-analysis, including FTO *rs8057044, P =9.50×10 −9 , and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (N EUR =18,841, N AFR =12,263, N AMR =9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1 , BSN ). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (r g =0.94, P =5.43×10 −237 ) and opioid use disorder (r g =1.01, P =4.40×10 −107 ), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.

Abstract Background Type 2 diabetes mellitus (T2DM) shares multiple modifiable and non-modifiable risk factors across populations, yet it is unclear whether these risk profiles differ in adults with depression—a group with elevated baseline metabolic risk. Objective To identify clinical, behavioral, and sociodemographic predictors of incident T2DM among adults with depression and determine their implications for endocrine prevention and screening strategies. Methods We conducted a retrospective cohort analysis of 40,585 adults with a documented depression diagnosis but no prior T2DM in the All of Us Research Program (median follow-up = 8.15 years). Incident T2DM was defined using electronic health record–based diagnosis codes. Cox proportional hazards models estimated adjusted hazard ratios (HRs) for T2DM as a function of gender, race, ethnicity, age, body mass index (BMI per 10 kg/m²), and household income. Sensitivity analyses incorporated cigarette smoking and multiple imputation for BMI. Results Higher BMI (HR = 1.76 per 10 kg/m²; 95% CI: 1.69–1.83), older age (HR = 1.03 per year; 95% CI: 1.027–1.032), male gender (HR = 1.38; 95% CI: 1.27–1.49), Black race (HR = 1.79; 95% CI: 1.64–1.95), and non-Hispanic ethnicity (HR = 1.37; 95% CI: 1.10–1.71) were independently associated with greater T2DM risk, while higher household income was protective (HR = 0.47 for >$150k vs. <$35k; 95% CI: 0.39–0.58), demonstrating a clear socioeconomic gradient. Associations were robust to smoking adjustment and multiple imputation, and were directionally consistent with patterns reported in prior general-population studies. Conclusions Traditional demographic, socioeconomic, and clinical risk factors were associated with incident T2DM among adults with depression, supporting attention to established diabetes risk factors in psychiatric and endocrine prevention settings. Aggressive implementation of weight management, risk stratification, and early screening—particularly among socioeconomically disadvantaged patients—may reduce the burden of T2DM in psychiatric populations. Clinical trial number Not applicable.

Abstract We explore the genetic mechanisms underlying fibromyalgia, a chronic heritable syndrome. We conduct genome-wide association studies (GWAS) of fibromyalgia in European, African, and Latin American ancestry subjects, combining data from several cohorts (85,139 cases; 1,642,433 controls). We also conduct a multi-trait analysis of GWAS (MTAG), leveraging pain GWAS to enhance power for fibromyalgia analyses. We apply a series of methods to analyze genetic association between fibromyalgia and psychological and physiological phenotypes. We find 10 genomic loci that are associated with fibromyalgia in European ancestry subjects, one in African, 12 cross-ancestry, and 45 in the European ancestry MTAG; most of these were previously associated with pain, cognitive function, autoimmune response, or general health measures. We show a moderate negative genetic correlation between fibromyalgia and physical activity, and strong genetic correlations with chronic pain, post-traumatic stress disorder, and depression (r g ≥0.69). Genomic structural equation modeling places fibromyalgia in the context of psychiatric, medical, and lifestyle phenotypes, mostly as pain- and autoimmune-related trait. Local genetic correlations and genetic causality point to neuronal mechanisms that provide a strong basis for some of the main characteristics of fibromyalgia and its comorbidities. These findings provide potential targets for future studies to improve diagnosis and treatment of fibromyalgia.

BACKGROUND:The impact of combat injury on the development of chronic pain and mental health concerns in combat-exposed populations is unknown. This study examined associations of combat injury and injury-related pain with pain-related factors and mental health outcomes, and potential mediation of the relation between combat injury and mental health outcomes by pain-related factors. METHODS:Pain interference, pain catastrophizing, pain intensity, post-traumatic stress disorder (PTSD), and major depressive episode (MDE) were assessed in (1) a probability sample of US Army soldiers and veterans cross-sectionally and (2) US Army soldiers before and 1, 3, and 9 months after deployment to Afghanistan. Associations among these variables were modeled using logistic regression and multiple mediation analyses. RESULTS:Among 5003 service members with cross-sectional data, combat injury-related pain was associated with increased odds of clinically significant pain intensity (OR=2.69), pain interference (OR=3.69), MDE (OR=2.17), and PTSD (OR=3.96) relative to pain from other injuries and conditions. Among 4645 service members assessed pre- and post-deployment, combat injury was associated with increased odds of new-onset pain interference (OR=2.78), pain catastrophizing (OR=2.75), PTSD (OR=4.06), and MDE (OR=2.56) 3 months post-deployment, and PTSD (OR=2.86) and MDE (OR=1.74) 9 months post-deployment. Pain-related factors mediated the relations of combat injury with post-deployment PTSD and MDE. CONCLUSIONS:Combat injury is associated with greater odds of pain interference, pain catastrophizing, PTSD, and MDE compared to other sources of pain in a cohort of US service members. Efforts to address pain-related factors following combat injury may mitigate the risk of subsequent chronic pain and mental health disorders.

Anhedonia, which is characterized by a loss of pleasure and engagement in rewarding activities, is prevalent across diagnostic groups and is associated with worse clinical and treatment outcomes. Existing evidence-based treatments have only modest effects on improving anhedonia. Reward learning (RL) is an important driver of reward-responsive behavior, which could be leveraged to improve reward sensitivity - a candidate mechanism underlying anhedonia. Individuals (N = 50) with at least moderate anhedonia and clinical levels of depression and/or anxiety were randomized to either an active RL training (high variance of reward rates to promote reward exploration and maximization) or a sham version. Before and after training, they completed an assessment RL task while undergoing functional neuroimaging as well as ratings of current affect. Computational modeling was used to assess change in reward learning and sensitivity, as well as associated neural activity. Participants assigned to the active condition exhibited greater increases in learning-based reward maximization, i.e., the propensity to choose options predicted to be most rewarding, and reductions in anterior cingulate cortex activation to reward prediction errors (discrepancies between expected and observed rewards), consistent with optimization of reward learning and performance. In exploratory analyses, learning-based reward maximization during training mediated increase in positive affect associated with the active condition. Our results underscore the potential of RL-informed computerized trainings to improve RL and associated goal-directed reward behavior in anhedonic individuals. Future research is needed to determine whether the proposed training can successfully transfer to real-world settings and produce long-term affective and clinical improvements (ClinicalTrials.gov: NCT05383248).

Importance:The phase 2 data presented here support the development of TSND-201 for posttraumatic stress disorder (PTSD), a disorder for which there is a significant unmet need for rapid-acting and effective treatments. TSND-201 (methylone) is a highly selective, rapid-acting neuroplastogen that releases serotonin, norepinephrine, and dopamine without direct activity at 5-hydroxytryptamine (5-HT) 2A receptors that has shown rapid, robust, and long-lasting benefit for preclinical PTSD-related behaviors and has been well tolerated in phase 1 studies of healthy volunteers. Objective:To evaluate the efficacy and safety of TSND-201 vs placebo in adults with PTSD. Design, Setting, Participants:A Study to Assess the Use of Methylone in the Treatment of PTSD (IMPACT-1) part B was a phase 2, multicenter, double-blind, placebo-controlled, 10-week randomized clinical trial of TSND-201 in people with PTSD conducted between November 29, 2023, and February 19, 2025, across 16 sites in the US, UK, and Ireland. Adults aged 18 to 65 years who met DSM-5 criteria for current PTSD and 6 months or more of symptoms (Clinician-Administered PTSD Scales for DSM-5 [CAPS-5] ≥35) were eligible. Interventions:Participants were randomized 1:1 to receive TSND-201 or placebo. There were 4 once-weekly oral dosing sessions (150 mg followed by 100 mg or placebo). No psychotherapy was provided; however, dosing sessions were monitored by mental health professionals using a nondirective approach. Participants were followed up for 6 weeks after the last dose. Main Outcomes and Measures:The primary end point was change from baseline to day 64 in the CAPS-5 total severity score. Secondary end points included changes in PTSD Checklist for DSM-5 (PCL-5), Sheehan Disability Scale (SDS), and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Other measures included response (≥50% improvement from baseline), remission (≤11 total severity score), loss of PTSD diagnosis, changes in CAPS-5 symptom clusters, and incidence of treatment-emergent adverse events (TEAEs). Safety was assessed by monitoring adverse events, vital signs, and Columbia-Suicide Severity Rating Scale. Results:Among the 65 participants (mean [SD] age, 43.7 [10.5] years; 39 female [60.0%]), TSND-201 demonstrated significantly greater improvement in CAPS-5 total score than placebo (least-squares mean difference, 9.64; 90% CI, -16.48 to -2.80; P = .01). PCL-5 (-28.46 vs -19.47; LS mean treatment difference, -8.99; 90% CI, -17.81 to -0.17), SDS (-8.29 vs -3.57; LS mean treatment difference, -4.72; 90% CI, -8.84 to -0.61), and MADRS (-13.94 vs -7.73; LS mean treatment difference, -6.21; 90% CI, -12.41 to -0.27) scores were also improved. Common TEAEs in the TSND-201 group included headache, decreased appetite, nausea, dizziness, blood pressure increased, dry mouth, insomnia. Conclusions and Relevance:Results of this randomized clinical trial reveal that TSND-201 demonstrated statistically significant efficacy and was well tolerated, supporting its potential as a rapid-acting, durable treatment for PTSD. Trial Registration:ClinicalTrials.gov Identifier: NCT05741710.

INTRODUCTION:Adjustment disorder is the most common mental health diagnosis in the U.S. military and one of the most common globally, yet its patterns and predictors are rarely studied. Identifying career phases and characteristics associated with increased risk of first adjustment disorder (AD) diagnosis among U.S. Army soldiers can inform targeted prevention and intervention efforts. MATERIALS AND METHODS:This longitudinal, retrospective cohort study analyzed data from the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS). Administrative medical and personnel records from active duty Regular Army enlisted soldiers (2015-19) were used to identify all 118,735 person-months with a first AD diagnosis and a representative, stratified probability sample of control person-months with no history of AD diagnosis (n = 316,275). Risk of first AD diagnosis was estimated as function of time in service, stratified by sex and occupation. Logistic regression examined socio-demographic, service-related, and mental health risk factors for first AD diagnosis during periods of greatest risk. This study was approved by the Institutional Review Boards of STARRS-LS collaborating institutions. RESULTS:AD cases were 77.2% male, 54.9% ≤24 years old, and 51.0% White Non-Hispanic. For 63.7% of cases, AD was their first documented mental disorder during service. Of those, 25.5% had been diagnosed with a stressor or marital problem in the previous 12 months. Risk of first AD by time in service was bimodal, with elevated risk during the first 1-4 years ("early-career") and years 17-20 ("late-career"). This pattern was consistent across sex and occupational groups. Based on a sample size-adjusted alpha level, 12 of 13 multivariable risk factors were associated with early-career AD, whereas 7 of 13 were associated with late-career AD. Notable risk factors among early- and late-career soldiers were female sex (early-career: OR = 2.0; 95% CI = 1.9-2.0; late-career: OR = 1.4; 95% CI = 1.3-1.5), deployment status (early: never-deployed, OR = 2.0; 95% CI = 1.9-2.2, previously-deployed, OR = 1.6; 95% CI = 1.4-1.8; late: previously-deployed, OR = 1.7; 95% CI = 1.5-2.0), and recency of previous mental health diagnosis (early: past-month, OR = 3.7; 95% CI = 3.6-3.8; late: past-month, OR = 4.2; 95% CI = 3.9-4.5), stressor/marital problems (early: past-month, OR = 5.7; 95% CI = 5.5-5.8; late: past-month, OR = 4.1; 95% CI = 3.8-4.6), and postconcussive syndrome (early: past-month, OR = 3.0; 95% CI = 2.6-3.5; late: past 2-3-months, OR = 2.7; 95% CI = 1.5-4.8). Magnitudes of other significant ORs were more modest. Interactions indicated that associations of 9 risk factors differed for early versus late career soldiers. CONCLUSIONS:First AD risk is highest among soldiers either beginning their Army careers or approaching retirement eligibility. Differences in risk factors across groups highlight the importance of considering distinct military and life experiences/stressors when attempting to target and tailor interventions for those at risk of AD.

Neuroanatomical findings on panic disorder (PD) are typically difficult to replicate, with inconsistent effects. These concerns prompted a paradigm shift towards large-scale collaborations, focused on harmonized data extraction and processing for robust examination of PD brain correlates. Hence, leveraging the largest-ever multi-site neuroimaging database on PD (Age: 10–66 years; global sites: 28), compiled by the ENIGMA-Anxiety Working Group, we report on cortical and subcortical differences in individuals with PD (N = 1146) versus healthy controls (HC: N = 3778). The analyses revealed lower thickness and smaller cortical surface area within fronto-temporo-parietal regions in PD (Cohen’s ds: −0.08–0.13), along with lower thalamic and caudate volumes (Cohen’s ds: −0.07–0.12). Diagnosis-by-age2 interactions (Cohen’s ds: 0.07–0.12) revealed lower thickness in individuals with PD compared to HC in certain regions during adulthood (25–55 years), with relative absence of such differences during youth (<25 years) or late adulthood (>55 years). Finally, patient subgroup analyses showed that early disease onset (≤21 years) in PD was associated with larger lateral ventricles (Cohen’s ds: 0.31–0.38), whilst no medication, comorbidity, or severity effects were found. These findings lend support to neurocircuitry models of PD, which postulate differences within fronto-striato-limbic circuits and temporo-parietal regions. Moreover, findings highlight the potential importance of abnormal development and aging in neuroanatomical differences related to PD. Given its unprecedented scale, the current study is an important milestone towards identifying the structural brain correlates of PD.