In the treatment of obsessive-compulsive disorder (OCD) with antidepressant medication, the earliest reliable indication of treatment failure remains uncertain. We investigated if non-improvement following 4 weeks of treatment predicts nonresponse at the end of the trial.

We conducted a random-effects bivariate diagnostic accuracy study using individual patient data from industry-sponsored short-term trials of adults with OCD receiving selective serotonin reuptake inhibitors or clomipramine, submitted for marketing approval. The primary outcome was accuracy of non-improvement (<25% reduction on the Yale–Brown Obsessive Compulsive Scale [YBOCS] after 4 weeks) in predicting nonresponse (<35% YBOCS reduction at trial endpoint [10–13 weeks]). Secondary outcomes were accuracy of non-improvement after 6 weeks, nonresponse after 8 weeks, and inclusion of Clinical Global Impression Scale – Improvement in definitions of improvement and response. We performed meta-regressions for sex, age, severity, trial duration, dosing regimen, and compound.

In 11 studies totaling 1,753 patients, non-improvement at week 4 predicted subsequent nonresponse (positive predictive value, PPV) in 86% of cases (95% confidence interval [CI] = 83–88%). Sensitivity was 78%, specificity was 70%, and the negative predictive value was 60%. Secondary outcomes showed similar PPV after 6 weeks and a PPV of 93% for nonresponse after 8 weeks. Predictive accuracy was significantly higher in men relative to women (β = −0.64, 95% CI = −1.12 to −0.16, p = 0.0089).

Patients with OCD who do not improve after 4 weeks of antidepressants will likely not respond to short-term treatment. Thus, a change in strategy should be considered after 4 weeks without treatment benefits.

Chronic pain activates the HPA axis stress response resulting in the release of cortisol, although empirical associations are often contradictory. Quantile regression models of hair cortisol may help us measure HPA-axis dysregulation more accurately and establish more robust associations with chronic pain. We also examined whether people with chronic pain characterised by HPA-axis dysregulation are at risk of future mental ill-health.

This study examined data from the English Longitudinal Study of Ageing (ELSA, n = 4,560) and the UK Household Longitudinal Survey-Innovation Panel (UKHLS-IP, n = 473) to assess whether quantile regression methods enable us to assess more robust associations between hair cortisol and chronic pain, and whether older adults with chronic pain characterised by HPA-axis dysregulation are at risk of future mental ill-health.

In ELSA, chronic pain was associated with a 15% (CI: 6%–23%) increase in cortisol at the 10th percentile of the hair cortisol distribution among older adults and a 19% (CI: 2%–37%) increase at the 80th percentile, but no association was found at the 30th or 40th percentiles. Having a low cortisol response to chronic pain protected against the recurrence of depression. These patterns of association were replicated in the UKHLS-IP sample.

The associations demonstrated across two longitudinal population surveys from the UK indicate that quantile regression analysis of hair cortisol may be useful in identifying individuals resilient to chronic pain. Hair cortisol is a promising biomarker that can be measured in population studies to quantify the stress response and resilience to future mental ill-health.

Depression and anxiety are prevalent mental health disorders. While sleep duration has been extensively studied, sleep regularity may play a critical role. We aimed to examine associations between objectively measured sleep regularity and incident depression and anxiety and to investigate whether meeting recommended sleep duration modifies these associations.

In 79,666 UK Biobank participants without baseline depression or anxiety, wrist accelerometers worn for 7 days yielded a sleep regularity index (SRI) and average sleep duration. SRI was categorized as irregular (≤51), moderately irregular (52–70), or regular (≥71). Sleep duration was classified by age-specific recommendations (7–9 hours for ages 18–64 years; 7–8 hours for over 65 years). Cox regression models assessed associations between sleep parameters and mental health outcomes.

During a median follow-up of 7.5 years, 1,646 participants developed depression, and 2,097 developed anxiety. Compared to irregular sleepers, regular sleepers had a 38% lower depression risk (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.52–0.73) and a 33% lower anxiety risk (HR, 0.67; 95%CI, 0.58–0.77). Participants with both irregular sleep and nonrecommended duration exhibited the highest risks (depression HR, 1.91; 95%CI, 1.55–2.35; anxiety HR, 1.61; 95%CI, 1.35–1.93). Notably, irregular sleepers who met duration guidelines still faced elevated risks (depression HR, 1.48; 95%CI, 1.18–1.86; anxiety HR, 1.35; 95%CI, 1.11–1.64).

Greater sleep regularity is independently associated with lower depression and anxiety risk regardless of sleep duration, suggesting that sleep–wake consistency should be considered in mental health promotion strategies alongside traditional sleep duration recommendations.

We investigate whether, in Swedish national registers, social and psychiatric outcomes for six major psychiatric and substance disorders – drug use disorder (DUD), alcohol use disorder (AUD), major depression (MD), bipolar disorder (BD), anxiety disorder (AD), and schizophrenia (SZ) – reflect the primary genetic risk for each disorder and the level of genetic heterogeneity.

We utilize Genetic Risk Ratios – defined as the ratio of the genetic risk for secondary disorders to the genetic risk for the primary disorder – derived from Family Genetic Risk Scores. Poor social outcome was defined by a common factor of four variables: receipt of social welfare, sick leave, early retirement pension, and residence in a socially deprived area. Psychiatric outcome was defined as days of inpatient psychiatric hospitalization.

With poorer social outcomes, the primary genetic risks rose robustly for all disorders except SZ, as did the secondary genetic risks for DUD, AUD, and attention-deficit hyperactivity disorder. With poorer psychiatric outcomes, available only for BD and SZ, the primary genetic risks increased sharply. Overall, MD, AD, and BD became substantially more genetically heterogenous as their social outcomes became poorer, while for AUD, DUD, and SZ, the increase in heterogeneity was more modest. By contrast, with poorer psychiatric outcome, genetic risks for SZ became substantially more genetically homogeneous, with a similar but less robust trend seen for BD.

Despite important differences between our primary disorders, social and psychiatric outcomes are often robust indices of genetic risk and can reflect the levels of genetic heterogeneity.

Functional disorders (FDs) are associated with internalizing disorders (IDs). Studies investigating the nature of these associations over time are limited. We tested the direction of causation between measures of IDs (major depressive disorder [MDD], generalized anxiety disorder [GAD]) and FDs (fibromyalgia [FM] and myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) measured across two waves of longitudinal data (N = 108,034 and N = 73,590).

The Lifelines Cohort Study is a large prospective population-based cohort study in the northeast of the Netherlands. We tested competing causal models for the longitudinal association between IDs and FDs and, to follow-up results from the model with all IDs and FDs, tested the direction of causation between MDD and FM.

FDs were more stable over time than IDs. Initial model comparisons support a bidirectional relationship between most IDs and FDs. Follow-up analyses support a unidirectional model where FM predicts MDD over time (β = 0.14, 95% confidence interval = [0.11, 0.18]), but not vice versa.

The cross-time associations between ME/CFS, MDD, and GAD appear bidirectional (causal in both directions). Our results are consistent with, but not demonstrative of, a causal relationship from FM to MDD. The consequences of specific FDs vary, underscoring the value of studying these conditions as distinct constructs.

In psychiatry, there is a drive to reduce institutionalization, the risk of which starts with the index admission. In first-episode psychosis (FEP), the proportion of people admitted to hospital at initial presentation is still unknown.

This systematic review aimed to determine the proportion of people with FEP who are admitted at initial presentation (within 30 days from point of first contact with psychiatry) and the influence of individual, clinical, and service factors on admission risk. Four databases were searched from inception until June 2023: PubMed, Embase, PsycINFO, and CINAHL. The pooled proportion of people admitted was calculated using a random-effects model. Analyses were further stratified according to individual, clinical, and service factors.

Of 7,455 abstracts screened, 18 studies with 19,854 participants were included. The proportion of people admitted overall was 51% (k = 18, 95% confidence interval [CI]: 37–65%; I2: 99.56%). The proportion admitted involuntarily was 31% (k = 6, 95% CI: 23–40%; I2: 95.26%). Sub-analyses for sex, diagnosis, and early intervention service access did not show significant differences between groups. The proportion of people with a short duration of untreated psychosis (DUP) admitted was 59% (k = 2, 95% CI: 56–63%) vs. 37% (k = 2, 95% CI: 33–41%) for long DUP, which was significant (p < 0.001). High inter-study heterogeneity was observed.

Results demonstrate that over half of the people are hospitalized when initially presenting for FEP, a high proportion, with consequences for individuals and health services at large. First, service contact must be prioritized as an opportunity for appropriate intervention, to either avoid unwarranted hospitalizations or if hospitalization is required, to ensure the application of focused therapeutic objectives within intended timeframes.

Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Childhood trauma is a well-established risk factor for psychosis, paranoia, and substance use, with cannabis being a modifiable environmental factor that exacerbates these vulnerabilities. This study examines the interplay between childhood trauma, cannabis use, and paranoia using standard tetrahydrocannabinol (THC) units as a comprehensive measure of cannabis exposure.

Data were derived from the Cannabis&Me study, an observational, cross-sectional, online survey of 4,736 participants. Childhood trauma was assessed using a modified Childhood Trauma Screen Questionnaire, while paranoia was measured via the Green Paranoid Thoughts Scale. Cannabis use was quantified using weekly standard THC units. Structural equation modeling (SEM) was employed to evaluate direct and indirect pathways between trauma, cannabis use, and paranoia.

Childhood trauma was strongly associated with paranoia, particularly emotional, and physical abuse (β = 16.10, q < 0.001; β = 16.40, q < 0.001). Cannabis use significantly predicted paranoia (β = 0.009, q < 0.001). Interactions emerged between standard THC units and both emotional abuse (β = 0.011, q < 0.001) and household discord (β = 0.011, q < 0.001). SEM revealed a small but significant indirect effect of trauma on paranoia via cannabis use (β = 0.004, p = 0.017).

These findings highlight childhood trauma as a primary driver of paranoia, with cannabis use amplifying its effects. While trauma had a strong direct impact, cannabis played a significant mediating role. Integrating standard THC units into psychiatric research and clinical assessments may enhance risk detection and refine intervention strategies, particularly for childhood trauma-exposed individuals.

The management of persistent physical symptoms poses a challenge in many healthcare settings, including primary care. Psychological treatments that involve exposure have shown promise for several conditions where patients suffer from persistent physical symptoms and unwanted responses to these. It is unclear, however, to what extent exposure therapy has effects beyond existing routine care interventions and who benefits the most.

A randomized controlled trial at a primary care center in Stockholm, Sweden compared 10 weeks of internet-delivered exposure therapy (n = 80) to healthy lifestyle promotion (HLP; n = 81) for patients bothered by at least one persistent physical symptom. The primary outcome was the mean reduction in subjective somatic symptom burden (Patient Health Questionnaire 15) as measured week-by-week up to the post-treatment assessment. Secondary outcomes included symptom preoccupation, anxiety, depression symptoms, and functional impairment.

Patients contributed 1544 datapoints during treatment. The primary analysis showed no significant advantage of exposure therapy versus HLP in the reduction of mean somatic symptom burden (d = 0.14; p = 0.220). In secondary analyses, exposure showed superiority in the reduction of symptom preoccupation (d = 0.31; p = 0.033) but not anxiety, depression symptoms, or functional impairment. A higher somatic symptom burden or symptom preoccupation before treatment was predictive of a larger advantage of exposure versus HLP.

Exposure therapy does not appear to show noteworthy average benefit over HLP, with the exception of symptom preoccupation. Substantial benefits are seen in patients with very high symptom burden or symptom preoccupation.

Deep brain stimulation (DBS) is being investigated as a treatment for patients with refractory major depressive disorder (MDD). However, little is known about how DBS exerts its antidepressive effects. Here, we investigated whether ventral anterior limb of the internal capsule stimulation modulates a limbic network centered around the amygdala in patients with treatment-resistant MDD.

Nine patients underwent resting state functional magnetic resonance scans before DBS surgery and after 1 year of treatment. In addition, they were scanned twice within 2 weeks during the subsequent double-blind cross-over phase with active and sham treatment. Twelve matched controls underwent scans at the same time intervals to account for test–retest effects. The imaging data were investigated with functional connectivity (FC) analysis and dynamic causal modelling.

Results showed that 1 year of DBS treatment was associated with increased FC of the left amygdala with precentral cortex and left insula, along with decreased bilateral connectivity between nucleus accumbens and ventromedial prefrontal cortex. No changes in FC were observed during the cross-over phase. Effective connectivity analyses using dynamic causal models revealed widespread amygdala-centric changes between presurgery and 1 year follow-up, while the cross-over phase was associated with insula-centric changes between active and sham stimulation.

These results suggest that ventral anterior limb of the internal capsule DBS results in complex rebalancing of the limbic network involved in emotion, reward, and interoceptive processing.

Establishing appropriate action–outcome associations can allow animals and humans to control behavior and the environment in a goal-directed manner. Deficits in instrumental learning in psychosis have been widely reported in past studies, but the results remain elusive.

To explore the consistent neural representations of instrumental learning in functional magnetic resonance imaging (fMRI) in individuals with psychosis, a total of 18 studies (458 individuals with psychosis and 454 controls) were included in our coordinate-based meta-analysis.

Patients with psychosis presented increased activation in the left middle occipital gyrus, insula, and lingual and postcentral gyri; decreased activation in cortico-striato-thalamo-cortical (CSTC) networks, including the dorsal striatum, insula, thalamus, middle cingulate cortex, posterior cingulate cortex, dorsolateral, orbital, and medial prefrontal cortices (DLPFC, OFC, and mPFC), cerebellum, and associated sensory areas, during instrumental learning. Moreover, mPFC hypoactivation was negatively associated with the percentage of first-generation antipsychotic users, and insula hyperactivation was negatively associated with the percentage of medicated individuals.

Our study revealed that the CSTC circuit could facilitate action-based reward learning in psychosis and may help explain the neuropathological mechanisms underlying these deficits in this disorder.

Few studies have examined attention-deficit/hyperactivity disorder (ADHD) symptoms in middle- and older-aged adults. We aim to examine the phenotypic expression of ADHD symptoms in these age groups.

This study comprised a random sample (N = 1,562) from the US Health and Retirement Study 2016, a representative US sample aged 50 years and over. ADHD symptoms were assessed based on the Adult ADHD Self-Report Scale.

In the primary analysis, 10 competing confirmatory factor analytic models of ADHD symptoms in middle- and older-aged adults were compared. The best-fitting model was hierarchical with a general ADHD factor at the apex and underneath symptom factors of inattention, hyperactivity, and impulsivity (ꭓ2 = 319.34, df = 91.71, P = 0.00, TLI = 0.98, CFI = 0.96, RMSEA = 0.04, 95% CI = 0.04–0.05). In complementary analyses, this model was a satisfactory fit to the data: (1) in individuals without a history of cognitive impairment or dementia, and when the general ADHD factor was specified to load on (2) cognitive function, (3) depressive symptoms (which showed adequate fit), and (4) ADHD polygenic scores, (5) in middle- and older-aged adults, and (6) when weighted to represent the US population.

These results imply a hierarchical representation of ADHD symptoms in middle- and older-aged adults consisting of a general factor at the apex with neurocognitive and genetic correlates and underneath symptom factors of inattention, hyperactivity, and impulsivity. Collectively, this model offers a novel framework to study the mechanisms of ADHD symptoms in middle- and older-aged adults and points to treatment targets.

Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.

In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores from the Patient Health Questionnaire-9 (depression symptoms), Generalized Anxiety Disorder-7 (anxiety symptoms), and Work and Social Adjustment Scale (functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML.

The phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50–0.69). All three scales were found to be under low but significant genetic influence (single-nucleotide polymorphism-based heritability [h2SNP] = 0.11–0.19) with high genetic correlations between them (rg = 0.79–0.87).

Among individuals with lifetime depression or anxiety from the GLAD Study, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.

Physiological signals conveyed by the vagus nerve may generate quiescent psychological states conducive to contemplative practices. This suggests that vagal neurostimulation could interact with contemplative psychotherapies (e.g. mindfulness and compassion-based interventions) to augment their efficacy.

In a fully factorial experimental trial, healthy adults (n = 120) were randomized to transcutaneous vagus nerve stimulation (tVNS) plus Self-Compassion-Mental-Imagery Training (SC-MIT) or alternative factorial combinations of stimulation (tVNS or sham) plus mental imagery training (MIT: SC-MIT or Control-MIT). Primary outcomes were self-reported state self-compassion, self-criticism, and heart rate variability (HRV). Exploratory outcomes included state mindfulness and oculomotor attentional bias to compassion-expressing faces. Most outcomes were assessed acutely on session 1 at the pre-stimulation (T1), peri-stimulation (T2), and post-MIT + stimulation (T3) timepoints, and after daily stimulation+MIT sessions (eight sessions).

During session 1, a significant Timepoint × Stimulation × MIT interaction (p = 0.025) was observed, reflecting a larger acute T1→T3 increase in state self-compassion after tVNS+SC-MIT, with similar rapid effects on state mindfulness. Additionally, significant Session × MIT and Session × Stimulation interactions (p ≤ 0.027) on state mindfulness (but not self-compassion) suggested that tVNS+SC-MIT’s effects may accumulate across sessions for some outcomes. By contrast, changes in state self-criticism and compassion-related attentional bias were only moderated by MIT (not stimulation) condition. HRV was unaffected by stimulation or MIT condition.

tVNS augmented the effects of SC-MIT and might, therefore, be a useful strategy for enhancing meditation-based psychotherapies. Our findings also highlight the value of oculomotor attentional metrics as responsive markers of self-compassion training and the continued need for sensitive indices of successful vagal stimulation.

Adverse childhood experiences (ACEs) are associated with physical and mental health difficulties in adulthood. This study examines the associations of ACEs with functional impairment and life stress among military personnel, a population disproportionately affected by ACEs. We also evaluate the extent to which the associations of ACEs with functional outcomes are mediated through internalizing and externalizing disorders.

The sample included 4,666 STARRS Longitudinal Study (STARRS-LS) participants who provided information about ACEs upon enlistment in the US Army (2011–2012). Mental disorders were assessed in wave 1 (LS1; 2016–2018), and functional impairment and life stress were evaluated in wave 2 (LS2; 2018–2019) of STARRS-LS. Mediation analyses estimated the indirect associations of ACEs with physical health-related impairment, emotional health-related impairment, financial stress, and overall life stress at LS2 through internalizing and externalizing disorders at LS1.

ACEs had significant indirect effects via mental disorders on all functional impairment and life stress outcomes, with internalizing disorders displaying stronger mediating effects than externalizing disorders (explaining 31–92% vs 5–15% of the total effects of ACEs, respectively). Additionally, ACEs exhibited significant direct effects on emotional health-related impairment, financial stress, and overall life stress, implying ACEs are also associated with these longer-term outcomes via alternative pathways.

This study indicates ACEs are linked to functional impairment and life stress among military personnel in part because of associated risks of mental disorders, particularly internalizing disorders. Consideration of ACEs should be incorporated into interventions to promote psychosocial functioning and resilience among military personnel.

Depressive symptoms are highly prevalent in first-episode psychosis (FEP) and worsen clinical outcomes. It is currently difficult to determine which patients will have persistent depressive symptoms based on a clinical assessment. We aimed to determine whether depressive symptoms and post-psychotic depressive episodes can be predicted from baseline clinical data, quality of life, and blood-based biomarkers, and to assess the geographical generalizability of these models.

Two FEP trials were analyzed: European First-Episode Schizophrenia Trial (EUFEST) (n = 498; 2002–2006) and Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) (n = 404; 2010–2012). Participants included those aged 15–40 years, meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for schizophrenia spectrum disorders. We developed support vector regressors and classifiers to predict changes in depressive symptoms at 6 and 12 months and depressive episodes within the first 6 months. These models were trained in one sample and externally validated in another for geographical generalizability.

A total of 320 EUFEST and 234 RAISE-ETP participants were included (mean [SD] age: 25.93 [5.60] years, 56.56% male; 23.90 [5.27] years, 73.50% male). Models predicted changes in depressive symptoms at 6 months with balanced accuracy (BAC) of 66.26% (RAISE-ETP) and 75.09% (EUFEST), and at 12 months with BAC of 67.88% (RAISE-ETP) and 77.61% (EUFEST). Depressive episodes were predicted with BAC of 66.67% (RAISE-ETP) and 69.01% (EUFEST), showing fair external predictive performance.

Predictive models using clinical data, quality of life, and biomarkers accurately forecast depressive events in FEP, demonstrating generalization across populations.

Illicit drug use may lead to dependence on those drugs, is associated with various psychiatric disorders, and can have hazardous, sometimes life-threatening, consequences. We investigated the genetic architecture underlying the lifetime use (LU) of several drugs, individually and in combination.

We conducted genome-wide association studies of LU of cocaine, methamphetamine, inhalants, illegal opioids, prescription opioids, and prescription stimulants in European (EUR), African (AFR), and Latin American (AMR)-ancestry subjects (cases ranging from n = 4,900–21,850 [EUR], n = 519–9,802 [AFR], and n = 899–5,012 [AMR]; controls from n = 93,763–110,658 [EUR], n = 37,261–46,509 [AFR], and n = 31,412–35,501 [AMR]). We also investigated the use of illicit drugs of any kind and the total count of drugs a person has ever used. Then, we assessed the global and local genetic correlations between substance LU (SubLU) traits and their genetic correlations with other traits.

We found numerous genes that affect SubLU traits, with no overlap among the significant loci between traits, suggesting that unique genetic factors may differentially affect the use of different drugs. Nevertheless, the genetic correlations between SubLU traits were very strong; however, the phenotypic correlations were moderate. There were strong genetic correlations between various SubLU traits and psychiatric traits, most notably opioid use disorder, cannabis use disorder, problematic alcohol use, and suicidality.

Our findings provide insights into the genetic basis of substance use, identifying several novel genes associated with SubLU traits. This study can provide an improved understanding of the biology underlying SubLU and could potentially facilitate future risk assessments for the use of illicit and hazardous drugs.