Psychological Medicine

Background: Participants in the ReINVEST randomised placebo-controlled trial of sertraline, conducted among men with high trait impulsivity and histories of violent offending, received structured clinical contact throughout the trial, including psychiatric assessments, nursing consultations, crisis support, and referrals to mental health and external services. We estimated the effect of placebo trial participation, compared with non-participation after baseline and single-blind run-in, on violent and domestic-violence reoffending. Methods: This prespecified secondary analysis included men from the ReINVEST trial pathway who completed baseline assessment and entered the single-blind run-in phase but did not proceed to randomisation, to inform the counterfactual. Violent and domestic-violence offences were identified from linked administrative records over 12- and 24-month follow-up periods. The adjusted difference in offending was estimated using two independent analytical approaches accounting for baseline differences. Additional analyses examined whether the effect varied by baseline clinical and criminal-history characteristics, whether pre-randomisation external referrals explained selection into placebo participation, and whether post-randomisation external referrals accounted for any part of the estimated effect. Results: Placebo trial participation was associated with lower offending across both outcome domains and follow-up periods. Placebo-standardised mean count differences for violent offending were -0.19 (95% confidence interval [CI] -0.38, -0.04) at 12 months and -0.22 (95% CI -0.51, -0.05) at 24 months. Corresponding differences for domestic-violence offending were -0.37 (95% CI -0.81, -0.14) at 12 months and -0.49 (95% CI -0.92, -0.22) at 24 months. The association was more apparent among men with a documented psychiatric history and, for domestic-violence offending, among those with higher baseline anger, irritability and aggression. Pre-randomisation referrals did not explain selection into placebo participation or materially alter the estimates. Post-randomisation referrals were observed in both groups, remained more common in the placebo group, and did not account for the observed association. Conclusion: Placebo participation in this trial involved sustained clinical contact and psychosocial support beyond exposure to inactive medication, and these non-pharmacological components may have contributed to lower reoffending. In placebo-controlled trials involving populations with high psychiatric morbidity and limited continuity of coordinated care, the clinical content of placebo participation should be explicitly characterised in trial design and interpretation.

Background: Observational studies have consistently reported associations between social media use (SMU) and poorer mental health outcomes; however, such designs cannot establish causality. This study synthesised evidence from randomized experiments to estimate the effects of restricting SMU on mental health outcomes. Methods: A systematic search was conducted across MEDLINE, Embase, PsycINFO, and Cochrane CENTRAL to identify experimental trials evaluating interventions that constrained SMU for at least 24 hours and included an unconstrained control condition. Multilevel random-effects meta-analyses were used to synthesise effect estimates. Prespecified meta-regressions explored study-level moderators, and population-level impact fractions were estimated relative to global SMU prevalence. Results: From 7,784 screened records, 37 reports representing 35 distinct studies were included (pooled N = 7,160). Most interventions lasted one to three weeks and targeted college-aged youth. Pooled estimates favoured SMU constraints across outcomes, with magnitude and precision varying by domain. Confidence intervals were entirely above zero, consistent with a beneficial response for depressive symptoms (g = 0.22; 95% CI, 0.12 to 0.32), perceived stress (g = 0.15; 95% CI, 0.01 to 0.29), anxiety symptoms (g = 0.19; 95% CI, 0.05 to 0.34), fear of missing out/nomophobia (g = 0.14; 95% CI, 0.04 to 0.24), and well-being (g = 0.36; 95% CI, 0.10 to 0.63). Heterogeneity was substantial for several outcomes (I2 > 75%). In bivariate meta-regressions, higher baseline SMU was associated with larger effects for anxiety symptoms ({beta} = 0.13; 95% CI, 0.03 to 0.22), and longer interventions were associated with larger effects for depressive symptoms ({beta} = 0.16; 95% CI, 0.02 to 0.30). Inferences revealed that a short-term reduction in SMU globally could plausibly mitigate 17.5% and 15.4% of depressive and anxiety symptom cases, respectively. Conclusions: Experimental design-based evidence supports the causal case for an effect of SMU on mental health, with constraints producing improvements across multiple outcomes and no evidence of harm. Population-level inferences suggest that even individually modest effects may translate into meaningful public health benefits given the high prevalence of SMU exposure. These findings suggest that reducing SMU may represent a low-intensity, low-cost, scalable strategy to support mental health and improve well-being.

Background: Internet-based cognitive behavioral therapy (iCBT) is efficacious for panic disorder (PD), yet the mechanisms of change remain underspecified. Anxiety sensitivity (AS) is theoretically central to PD maintenance, but its role as a mediator has not been formally tested in Spanish-speaking populations using minimal-contact formats. This study evaluates the efficacy of the "Free from Anxiety" iCBT program and examines AS as a mediator of clinical outcomes. Methods: In a randomized controlled trial, 95 adults meeting DSM-IV-TR criteria for PD were assigned to an 8-week iCBT program with optional email support (n = 49) or a waiting-list control (n = 46). Primary outcome was PD severity (PDSS); secondary outcomes included anxiety sensitivity (ASI-3), general anxiety (BAI), and depression (BDI-II). Mediation was assessed via Baron and Kenny's framework with bootstrapping (5,000 resamples) to estimate the indirect effect of ASI-3 change on PDSS reduction. Results: The treatment group showed significant improvements across all measures compared to controls (PDSS: d = 0.76, 95% CI [0.10, 1.42]; mean d = 1.30). Mediation analysis confirmed that ASI-3 change partially mediated the treatment effect on PDSS (indirect effect = 1.85, 95% CI [0.36, 3.70]), accounting for 27.4% of the total effect. The direct effect remained significant (b = 4.89, p < .001). Intent-to-treat (ITT) analyses supported robustness (d = 0.47 to 1.47). Gains were maintained at 6-month follow-up (d = 1.19 to 1.26). Conclusions: iCBT reduces anxiety sensitivity as a partial mechanism of change, aligning with cognitive models of panic. These findings support Free from Anxiety as an evidence-based, viable first-step intervention for Spanish-speaking clinical populations within stepped-care pathways.

Mental illness poses a substantial global burden, yet existing psychotherapies and psychopharmacologies often produce limited outcomes. Psychedelic assisted therapies have emerged as potential transdiagnostic interventions. In particular, 3,4 methylenedioxymethamphetamine assisted therapy (MDMA AT) has generated interest for its rapid psychological effects and potential to enhance psychotherapy outcomes. However, the incremental efficacy of MDMA AT relative to control interventions across transdiagnostic outcomes remains unclear. Further, there have been emerging concerns regarding harm reporting quality in MDMA AT clinical trials. We conducted a systematic review and meta analysis of MDMA AT randomized controlled trials. Eleven publications representing eight controlled trials with 10 analyzed subgroups (n = 295 participants) were included in meta-analyses. Two additional secondary publications were included for harm reporting syntheses (k = 13 total). Across 114 extracted effect sizes, MDMA AT demonstrated a significant moderate-to-large incremental reduction in psychopathology relative to controls (g = 1.03, 95% CI [0.46, 1.60]), though heterogeneity was high (I squared = 76%). Incremental effects were larger versus inert placebos (g = 1.27) than active controls (g = 0.75). Symptom specific analyses indicated strong incremental effects for trauma reduction (g=1.46 [95% CI: 0.67, 2.25]) and smaller non-significant effects for depression (g=0.51 [95% CI: -0.06, 1.08]). Harm reporting quality synthesis showed only 23% of publications met high-quality reporting standards. Overall, MDMA AT demonstrates potential transdiagnostic efficacy, but small samples, confounding factors, and mediocre harm reporting highlight the need for larger more transparent clinical trials.

Background Multimorbidity is increasingly prevalent, and associated with worse clinical and psychosocial burdens. Interoception, the brain's ability to sense and interpret internal bodily signals, may contribute to multimorbidity, through its link with health behaviors, stress regulation, and mental health. This study examines whether self-reported interoceptive accuracy and attention is associated with multimorbidity, by identifying multimorbid subgroups and their interoceptive profiles. Methods Morbidity classes were identified through latent class analyses in two Dutch survey datasets, focusing on depression and alexithymia (DA-dataset; N = 671) and lifestyle factors (L-dataset; N = 1022). Linear regression analyses were used to assess interoceptive accuracy and attention (by the Interoceptive Accuracy Scale and Interoceptive Attention Scale respectively) among different subgroups. Results Multimorbid subgroups were characterized by older age, low socioeconomic position, and elevated physical, psychological, and behavioral problems. Multimorbid classes exhibited lower interoceptive accuracy (DA-dataset: B = -1.14, 95% CI = [-2.89, 0.62]; L-dataset: B = -2.36, 95% CI = [-3.83, -0.89]) and higher attention (DA-dataset: B = 3.62, 95% CI = [0.97, 6.27]; L-dataset: B = 1.07, 95% CI = [-1.42, 3.56]) compared to healthier classes. Conclusion Multimorbid populations demonstrated lower interoceptive accuracy and higher interoceptive attention. This highlights the psychosocial complexity of multimorbid populations which may impact their self-management and health behavior. These findings underscore the need to expand treatments to include psychosocial domains for multimorbid patients.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).

Hoarding disorder (HD) affects approximately 2-3% of adults and is associated with substantial functional disability and limited access to evidence-based care. The aim of the current analysis was to examine the naturalistic effectiveness of therapist-delivered video cognitive-behavioral therapy (CBT) for HD in a large real-world sample, and to characterize individual-level treatment response, time-to-response, and moderators of outcome. This retrospective, observational analysis examined clinical data from 305 adults diagnosed with HD who received therapist-delivered video CBT through an online specialty therapy platform between September 2021 and February 2026. Hoarding symptom severity was assessed using the Hoarding Rating Scale-Self Report (HRS-SR). Linear mixed models examined symptom change from baseline to three timepoints: session 10, session 20, and each patient's final session. HRS-SR scores decreased from M = 22.4 (SD = 7.6) at baseline to M = 16.4 (SD = 8.2) at final session (Hedges' g = 0.81, 95% CI: 0.68-0.94). By the final session, median percent improvement was 25.0% [IQR: 3.0-46.7%]. A total of 39.3% of patients achieved [&ge;]35% HRS-SR reduction, 27.4% of patients who began above the clinical threshold achieved remission, 36.4% demonstrated reliable improvement, and 22.9% of eligible patients achieved clinically significant change. Among patients who achieved and maintained [&ge;]35% reduction through their final session (n = 120), median time to first response was session 9, with 54.2% responding within 10 sessions. Analyses of secondary outcomes showed significant improvements in clutter severity, depressive and anxiety symptoms, stress, quality of life, and functional disability (Hedges' g = 0.21-0.47). Greater baseline severity, more sessions, and longer treatment duration significantly moderated outcomes; prior OCD treatment history did not. Findings suggest that therapist-delivered video CBT for HD, delivered remotely in a real-world setting, produces outcomes consistent with controlled trials and may be a clinically effective and scalable approach for a condition historically underserved by mental health systems.

Impaired learning that both novel and previously dangerous stimuli are safe (safety and extinction learning, respectively) are long standing, robust, and heritable features of anxiety disorders, representing potential endophenotypes. The computational mechanisms underpinning them have demonstrated associations with anxiety severity in recent studies. We undertook a pre-registered replication in a tenfold larger independent sample of twins (n = 925). Extinction learning rates were associated with anxiety severity ({rho}replication = -0.14, BFr0 = 1189. 67) but safety learning rates were not. Conversely, although safety learning rates showed modest heritability (h2safety = 0.16), extinction learning rates were not heritable. Accordingly, we were unable to identify genetic overlap between anxiety and either learning rate. Although this suggests neither learning rate is an anxiety endophenotype, we confirmed a cognitive-behavioral mechanism underpinning a robust marker of anxiety severity. Furthermore, we demonstrated heritability of a computationally modelled learning parameter, a key step towards establishing its biological basis.

Abstract Introduction: Over 30% of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) show an insufficient response to standard pharmacological treatments, which underscores the need for evidence-based alternative interventions. Methods: In this sham-controlled study, 30 adult outpatients with ADHD were randomized to 12 weeks of active or sham transcranial direct current stimulation (tDCS) as add-on to a digital cognitive behavioral therapy application (dCBT app). Participants received either active (2 mA, 20 min/day, 5 days/week) or sham tDCS with anodal (left) and cathodal (right) stimulation applied over the dorsolateral prefrontal cortex (DLPFC). In parallel, access to the dCBT app was provided for three months. ADHD symptoms were measured before and after treatment and after a three-month follow-up using the Adult Self-Report Scale (ASRS v1.1). Results: All scales showed an improvement over time with medium-to-large within-subjects effects (Cohens d: -.48 to -.75), irrespective of group allocation. Two additional sensitivity analyses including (1) participants with over 75% of planned (sham)-tDCS sessions and (2) those who logged into the dCBT app on at least 5 days (median split) confirmed results. Response was observed in 1/15 (6.7%) of the tDCS group and 2/15 (13.3%) of the sham-tDCS group, with no difference between groups (p = .543, phi = -.111). Compliance to (sham-)tDCS was high. tDCS usability was rated marginally lower in the tDCS group. Conclusions: tDCS as an add-on therapy could not produce additional improvement in ADHS symptoms. The results are discussed in terms of contextual and patient-related aspects. ClinicalTrials.gov Identifier: NCT06766214.

Background: While counterfactual thinking ('what could have been') guides adaptive decision-making, it remains unclear how this process is altered by the negative biases and motivational deficits characteristic of Major Depressive Disorder (MDD). Methods: We used a sequential economic decision-making task designed to emulate a volatile stock market to assess choice behavior in adults with or without MDD (Total N=178); a subset of these participants completed the task during functional MRI (N=53). The task allowed participants to make either positive ('invest') or negative ('short') bets, under either positive or negative contextual valence, defined by whether the immediately preceding stock price change was positive or negative. Fictive errors were defined as the difference between realized and best-possible outcomes. Results: Across the full cohort, group differences in behavioral adjustments to fictive error signals emerged exclusively under negative contextual valence, when stock prices decreased. Compared with controls, participants with MDD showed heightened sensitivity to invest-and-loss fictive errors, reflected in a greater reduction in subsequent bets (interaction beta = -0.63, p < .001), but blunted adjustment to short-and-gain fictive errors (beta = -0.86, p < .001). In the imaging cohort, blunted short-and-gain adjustment was accompanied by heightened anterior cingulate (ACC) activity and attenuated ventromedial prefrontal (vmPFC)-to-ACC coupling in MDD. vmPFC activity following negative market returns also tracked depression symptom severity. Conclusions: Depression selectively disrupts the use of counterfactual outcomes to guide adaptive choice under negative contextual valence, implicating altered frontocingulate function in maladaptive decision-making.

The ability to adjust to changing environments (cognitive flexibility) and optimal decision-making are pivotal brain functions that govern successful human behavior. Anxiety and depressive disorders are strongly pervasive psychiatric conditions across the lifespan that profoundly disrupt mechanisms of attention, working memory, and decision-making. Although existing task evidence documents impaired decision-making and flexibility outcomes for both anxiety and depression, there is a growing need to systematically evaluate the role of anxiety and depression and to quantitatively compare the effects of these disorders on these domains. In the present study, we conducted a meta-analysis of anxiety and depression on decision-making and cognitive flexibility. We utilized a random-effects approach, given that a large amount of between-subject heterogeneity was anticipated. Given the scope of this meta-analysis, we used the machine learning tool asReview to more efficiently conduct a meta-analytic search. Across all outcomes, results showed anxiety and depression were associated with reduced cognitive flexibility and decision-making. These effect sizes were then tested for significance using a fixed-effects (plural) model. Subgroup analyses revealed no significant differences between anxiety and depression for either decision-making or flexibility outcomes, consistent with a transdiagnostic perspective. Results are contextualized in light of the biopsychosocial model and potential transdiagnostic factors.

Objective: ADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

Hypomanic tendencies are associated with elevated goal-directed behavior, creativity, charisma, sociability, and entrepreneurial drive, but also with mood instability, irritability, impulsive persistence, and elevated risk for bipolar disorder and other psychopathology. Existing models often emphasize unidimensional constructs such as reward sensitivity or behavioral activation, yet these approaches incompletely capture the dynamic and often contradictory nature of the hypomanic temperament. We propose the Limbic Overload Hypothesis of Hypomanic Vulnerability, a dynamic biosocial framework suggesting that hypomanic tendencies reflect a persistent pattern of elevated engagement despite potential loss, coupled with reduced integration of negative emotional experience into subsequent behavioral regulation. Over time, this pattern may contribute to progressive "limbic overload," characterized by increasing emotional dysregulation, hypersensitivity to salient experiences, and vulnerability to psychopathology. Integrating evidence from personality research, affective neuroscience, and preliminary neuroimaging findings, we propose a dynamic cortico-limbic model linking prefrontal-limbic coordination, loss tolerance, emotional updating, and social reinforcement cycles. Preliminary pilot data suggest that individual differences in hypomanic tendencies are reflected not simply in baseline cortico-limbic organization, but in dynamic neural reconfiguration across pre-task resting-state [-&gt;] task [-&gt;] post-task resting-state transitions during loss-related decision making. Specifically, elevated hypomanic tendencies were associated with persistently elevated tolerance of potential losses and reduced integration of negative emotional information into subsequent behavioral regulation. We further propose that social connectedness and cognitive-emotional integration may mitigate progressive limbic overload and contribute to resilience. Together, this framework generates experimentally testable predictions regarding the neural, behavioral, and social processes underlying hypomanic vulnerability and resilience.

Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.

ImportancePrenatal exposure to gestational diabetes mellitus (GDM) has been associated with adverse metabolic, neurodevelopmental, and psychiatric outcomes in offspring. However, whether GDM-exposed youth exhibit heterogeneous neuroanatomical patterns remains unclear. ObjectiveTo identify distinct cortical thickness subtypes among GDM-exposed youth and examine their associations with anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures both cross-sectionally and longitudinally. Design, Setting, and ParticipantsThis cohort study used the Adolescent Brain Cognitive Development (ABCD)(R)data, a multisite longitudinal population study. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning framework, was applied to cross-sectional structural MRI data to identify cortical thickness patterns in 573 GDM-exposed youth and 2854 healthy controls. Posthoc longitudinal analyses included 1,853 observations from a subset of GDM-exposed youth with 1-, 2-, and 4-year follow-up visits to examine subtype differences in developmental trajectories over time. Exposure(s)Prenatal exposure to GDM. Main Outcome(s) and Measure(s)The primary outcomes included identification of cortical thickness subtypes and their inferred regional ordering patterns. Secondary outcomes included subtype-specific anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures. ResultsThe GDM-exposed sample had a mean age of 119.02 {+/-} 7.34 months and was 47.5% female. Two cortical thickness subtypes were identified. Between subtypes, Subtype 1 (63.2%) was characterized by earlier inferred insula involvement and was associated with greater height (d = 0.36, pFDR < 0.001) and weight (d = 0.26, pFDR = 0.007), whereas Subtype 2 exhibited earlier inferred frontal involvement and nominally higher Attention-Deficit/Hyperactivity Disorder (ADHD) prevalence (d = 0.08, p = 0.036), steeper longitudinal cortical thinning across all six cortical regions of interest ({beta} range: -0.05 to -0.13, all pFDR < 0.05), and a smaller decline in Obsessive-Compulsive Disorder (OCD) prevalence over time ({beta} = -1.02, pFDR = 0.049). Conclusions and RelevanceGDM exposure was associated with two distinct offspring cortical thickness subtypes, each showing different inferred regional ordering patterns and clinical associations. One subtype showed an insula-cingulate-predominant pattern associated with anthropometric measures, whereas the other showed a frontal-predominant pattern associated with nominally higher psychiatric measures and faster cortical thinning over time.

Depression is accompanied by considerable comorbidity and excess mortality. We examined multimorbidity data using the validated pharmacy-based Rx-Risk Comorbidity Index and examined healthcare costs associated with chronic illness burden in the Australian Genetics of Depression Study (AGDS). Australian Pharmaceutical Benefits Scheme (PBS) record linkage for 15,890 AGDS participants was available from 01/07/2013-31/12/2017. Forty-six health morbidities were inferred by mapping the prescription data using Anatomical Therapeutic Chemical Classification System codes and PBS Item Codes. Morbidity prevalence rates were then compared with an unselected 10% Australian representative population sample (10PCT) with PBS claims data available from 01/07/2010-31/12/2014. The average number of inferred comorbidities was higher among AGDS participants (4.6 {+/-} 2.9) than 10PCT individuals (3.0 {+/-} 3.0). Excluding depression, 89.1% of AGDS participants had one or more inferred comorbidity, most commonly pain (51.0%), inflammation/pain (40.3%), and anxiety (32.3%). In the AGDS, the number of comorbidities was higher among women compared to men and positively correlated with participant age, BMI, number of depressive episodes experienced, and annual health care costs. Compared to participants with no inferred comorbidities, the median annual health care costs were ~65% higher among those with 2-3 comorbidities. This study highlights the patterns of health morbidities experienced by individuals living with depression and shows that this chronic disease burden is significantly associated with increased health costs to the individual and the health system.

Background: Dissociative experiences encompass a variety of discontinuities in awareness and perception that are elevated in the dissociative disorders and associated with extensive comorbid symptomatology. Accumulating evidence points to developmental trauma and trait responsiveness to verbal suggestions (REVS) as factors that confer risk for severe dissociative symptoms, but they have typically been studied in isolation. This study integrated these measures using prediction modelling to better understand their predictive value for the risk of dissociative psychopathology. Method: 1,104 non-clinical participants completed measures of trauma, dissociation and trait REVS. The predictive model was developed using elastic net logistic regression, internally validated with 10-fold cross-validation, and assessed using receiver operating characteristic (ROC) curve and area under the ROC (AUROC). Variables entered into the model were components of REVS, trauma, age, and their interactions. Results: A dissociative psychopathology at-risk group (7%) was characterised by younger age, greater trauma and elevated REVS, particularly involuntariness during cognitive-perceptual suggestions. The prediction model retained nine of ten predictors, with an AUROC of .77 [95% CI: .73, .82], reflecting good discrimination with moderate sensitivity (78%) but modest specificity (67%). Conclusions: These findings reinforce trauma and trait REVS as risk factors for dissociative psychopathology and demonstrate that they can be integrated in a model that can identify at-risk individuals. Further validation and extension of the model is necessary to improve the identification of individuals at risk for severe dissociative symptomatology and the diagnosis of dissociative disorders with implications for outcome trajectories.

Background: The incidence of antidepressant withdrawal reactions in longer-term users and the influence of dosage is insufficiently understood. Objectives: Informed by neuropharmacological models and user surveys, this study examined symptom change during tapering and if increases were specifically associated with reductions below 75% of the minimum effective dose. Design: This was a prospective longitudinal cohort study with seven assessments over six months. Methods: Altogether 32 Swiss adult primary care patients who were on antidepressants for at least six months and in stable remission were assessed at baseline (week 0) before they started tapering and after 2, 4, 6, 8, 16, and 26 weeks. Withdrawal symptoms were measured repeatedly using an adapted version of the Discontinuation-Emergent Signs and Symptoms Scale (DESS) and the main outcome was intra-individual symptom change during intervals. Antidepressant dose was standardized relative to the minimum effective dose in the treatment of depressive and anxiety disorders. Results: Across intervals, reductions below 75% of the minimum effective dose were associated with symptom increases, while reductions above that threshold or no reductions were associated with symptom decreases. After adjusting for potential confounders, the rate of clinically relevant symptom increases contingent on dose reductions below 75% of the minimum effective dose was 33%, as compared to 13% during intervals with no dose reductions (OR=3.2, 1.4 to 7.4). We thus estimated that 60% of the risk of clinically relevant symptom increases was attributable to pharmacological withdrawal effects. The adjusted incidence rates for clinically relevant and severe withdrawal reactions were 32% and 11%, respectively. Conclusions: Consistent with neuropharmacological research findings, we found that antidepressant withdrawal symptoms emerge mostly following reductions below 75% of the minimum effective dose, affecting about one-third of patients. Even small reductions may trigger clinically relevant withdrawal reactions in this lowest dose-range, stressing the need for personalized tapering plans.

Objective. Persistent, distressing psychotic-like experiences (PLEs) are associated with neurobiological alterations and increased psychosis risk. We combined individual-level neuroimaging measures with effect sizes from large neuroimaging studies to create a summary score ('Psychosis Neuroscore') reflecting neuroanatomic liability for psychosis, and examined its ability to predict PLE trajectories in young adolescents. Method. Using latent growth mixture models, we estimated PLE trajectories from four annual visits of the Adolescent Brain Cognitive Development Study (N=9584, ages 9-10 at baseline). Using baseline T1-weighted and diffusion-weighted imaging data, we calculated Psychosis Neuroscores, as well as Neuroscores for two psychiatric disorders with late adolescent/adult onset (Major Depressive Disorder, Bipolar Disorder). We compared Psychosis Neuroscores to i) other psychiatric Neuroscores, ii) modifiable risk factors, and iii) established risk factors in predicting trajectory membership. Results. We identified four trajectories of distressing PLEs: Persistent Elevated (N=1,968, 21%), Gradual Decreasing (N=3,424, 36%), Rapid Decreasing (N=1,593, 17%) and Low/No Distress (N=2,599, 27%). Adolescents with Persistent Elevated PLEs had significantly higher Multimodal (combined T1 and diffusion-weighted) and T1-weighted Psychosis Neuroscores than all other trajectories (Odds Ratios [ORs] 1.27-1.34,pFDR<.01). Bipolar Disorder Neuroscores showed a similar pattern (ORs 1.16-1.23,pFDR<.01). Psychosis Neuroscores showed comparable associations with established risk factors in predicting trajectory membership, but smaller associations than modifiable risk factors, including screen time, physical activity, and sleep disturbances. Conclusion. Psychosis Neuroscores differentiate youth with persistent PLEs from those with decreasing, remitting or low PLEs, demonstrating their potential utility for early risk stratification. Integration with established risk factors may enhance psychosis risk prediction in youth.

AimsTo examine the longitudinal dynamic interactions of craving and drug use in the course of treatment of stimulant use disorders. DesignCross-lagged residual dynamic structural equation modeling (R-DSEM) was used to examine the reciprocal (bidirectional) longitudinal associations between craving and drug use. SettingPooled data from 11 randomized controlled trials of pharmacotherapies for methamphetamine and cocaine use disorders in the United States sponsored by the National Institute on Drug Abuse. Participants1,936 adults with cocaine or methamphetamine use disorder. MeasurementsCraving was measured using Brief Substance Craving Scale (BSCS), drug use was measured using Timeline Followback and urine drug screen (UDS). FindingsCraving and stimulant drug use were dynamically associated over time (within-person association). Daily craving significantly predicted drug use in subsequent days (estimate=0.092, 95% credible interval [CrI]=0.081, 0.103 for self-reported drug use and estimate=0.081, 95% CrI=0.069, 0.095 for UDS-ascertained drug use). In turn, drug use predicted subsequent craving (estimate=0.361, 95% CrI=0.325, 0.398 and estimate=0.060, 95% CrI=0.028, 0.094, respectively). There was substantial between-person heterogeneity in these cross-lagged effects, as reflected in the coefficients of variation ranging from 0.78 to 2.88. ConclusionsThere is a bidirectional interaction between stimulant drug craving and drug use. The heterogeneity in the interaction of craving with stimulant drug use may partly explain between-person variability in responses to anti-craving medications in treatment of stimulant use disorders.