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.

Limited longitudinal research examining developmental changes in visuospatial working memory (WM) among children and adolescents with autism spectrum disorder (ASD) has prompted our investigation.

We assessed 123 autistic children and adolescents and 145 typically developing controls (TDC) using the Cambridge Neuropsychological Test Automated Battery at baseline (Time 1 [mean age ± SD]: ASD: 13.04 ± 2.86; TDC: 11.53 ± 2.81) and 2–9 years later (Time 2: ASD: 18.08 ± 3.17; TDC: 16.41 ± 3.09) to measure changes of visuospatial (working) memory over time. The linear mixed model was used to compare the differences between ASD and TDC and estimate the effect of changes over time, age, ASD diagnosis, and interactions of Time×Age×ASD. The overall Age×ASD effect was calculated in the spline regression.

Autistic children and adolescents exhibited significantly poorer performance on all spatial tasks and some visual tasks than their TDC counterparts at Time 1 and Time 2, after adjusting for sex, age, attention deficit/hyperactivity disorder (ADHD), and full-scale intelligence quotient. There was an overall improvement from Time 1 to Time 2 across all tasks with significant Age×Time interactions. Significant Age×ASD interactions were observed in the delayed matching to sample, pattern recognition memory (PRM), spatial span (SSP), and spatial working memory (SWM) tasks with no significant Time×ASD interactions. In the quadratic nonlinear model, Age×ASD interactions were significant in PRM and SSP.

Despite significant improvements during the follow-up period, autistic children and adolescents continue to experience persistent deficits in SWM, with a weaker age-related improvement in visuospatial WM than TDC.

Most cognitive studies of bipolar disorder (BD) have examined case–control differences on cognitive tests using measures of central tendency, which do not consider intraindividual variability (IIV); a distinct cognitive construct that reliably indexes meaningful cognitive differences between individuals. In this study, we sought to characterize IIV in BD by examining whether it differs from healthy controls (HCs) and is associated with other cognitive measures, clinical variables, and white matter microstructure.

Two hundred and seventeen adults, including 100 BD outpatients and 117 HCs, completed processing speed, sustained attention, working memory, and executive function tasks. A subsample of 55 BD participants underwent diffusion tensor imaging. IIV was operationalized as the individual standard deviation in reaction time on the Continuous Performance Test-Identical Pairs version.

BD participants had significantly increased IIV compared to age-matched controls. Increased IIV was associated with poorer mean performance scores on processing speed, sustained attention, working memory, and executive function tasks, as well as two whole-brain white matter indices: fractional anisotropy and radial diffusivity.

IIV is increased in BD and appears to correlate with other cognitive variables, as well as white matter measures that index reduced structural integrity and demyelination. Thus, IIV may represent a neurobiologically informative cognitive measure for BD research that is worthy of further investigation.

The premorbid phase of treatment-resistant schizophrenia (TRS) may reveal underlying mechanisms and inform early interventions. According to the neurodevelopmental hypothesis, treatment resistance may be linked to pronounced developmental impairments. We examined school grades and attendance trajectories in children who later developed TRS.

This case-control study analyzed school grade point average and attendance among all individuals born after 1990 and started on clozapine in Chile’s public health system as a proxy for TRS. Control groups included children later diagnosed with treatment-responsive schizophrenia, bipolar disorder, and unaffected classmates. Linear mixed models accounted for individual and school-level confounders.

We included 1072 children (9929 observations, 29.3% female) subsequently diagnosed with TRS, 323 (2802 observations, 25.7% female) with schizophrenia, 175 (1784 observations, 53.8% female) bipolar disorder, and 273,260 (533,335 observations, 47% female) unaffected classmates. Children who later developed TRS had worse grades across levels than their classmates (−0.26 SD [−0.2, −0.4]), but not treatment-responsive schizophrenia. All severe mental illness groups showed grade declines in later school levels, with TRS showing steeper linear decline than treatment-responsive schizophrenia (group×age of −0.03; 95%CI −0.04, −0.01) and steeper quadratic decline than bipolar disorder (group×age2 of −0.005; −0.01, −0.001). Attendance declined over time in the two groups developing schizophrenia compared to their classmates. Those developing TRS experienced the sharpest drop (group×age compared to schizophrenia −0.03; −0.05, −0.01 and bipolar disorder −0.027; −0.049, −0.006).

TRS may stem from a more aggressive pathological process or pronounced late-maturation abnormality, rather than an early premorbid impairment, suggesting an intervention target.

Previous research has highlighted abnormalities in the pulvinar region of the brain among individuals diagnosed with obsessive-compulsive disorder (OCD). Nevertheless, given the pulvinar’s complex structure, comprising four distinct subnuclei (PuA, PuI, PuL, and PuM), inconsistencies persist regarding both structural and connectivity alterations within this region.

3D T1-weighted magnetic resonance imaging (MRI) and resting-state functional magnetic resonance imaging (rs-fMRI) were used on a cohort consisting of 41 healthy controls and 51 individuals with OCD in order to compare pulvinar connectivity and gray matter volume. Our aim was to compare both connectivity patterns and gray matter volume (GMV) within the PuA, PuI, PuL, and PuM subnuclei between the two groups. First, we examined resting-state connectivity differences in these subnuclei, followed by an analysis of GMV discrepancies to elucidate the potential neuropathological role of the pulvinar in OCD.

Our findings revealed significant connectivity differences in the left PuL, the right PuA, and the left PuA between OCD patients and healthy controls (p < 0.05). Furthermore, the left PuA exhibited both connectivity differences and increased GMV in the OCD group after applying multiple comparison corrections (p = 0.002).

Our study identified functional connectivity alterations within specific subnuclei, including the left and right PuA, and the left PuL, alongside GMV changes in the left PuA. These observations suggest that these distinct regions of the pulvinar may contribute to the pathophysiology of OCD through differences in both functional connectivity and GMV compared to healthy controls.

Mental ill-health has a major impact on young people, with pain often co-occurring. We estimated the prevalence and impact of pain in young people with mental ill-health.

Longitudinal data (baseline and three-month follow-up) of 1,107 Australian young people (aged 12–25 years) attending one of five youth mental health services. Multi-level linear mixed models estimated associations between pain characteristics (frequency, intensity, and limitations) and outcomes with false discovery rate (FDR) adjustment. Pain characteristics were baseline-centered to estimate if the baseline score (between-participant effect) and/or change from baseline (within-participant effect) was associated with outcomes.

At baseline, 16% reported serious pain more than 3 days, 51% reported at least moderate pain, and 25% reported pain-related activity limitations in the last week. Between participants, higher serious pain frequency was associated with greater anxiety symptoms (β[95%CI]: 0.90 [0.45, 1.35], FDR-p=0.001), higher pain intensity was associated with greater symptoms of depression (1.50 [0.71, 2.28], FDR-p=0.001), anxiety (1.22 [0.56, 1.89], FDR-p=0.002), and suicidal ideation (3.47 [0.98, 5.96], FDR-p=0.020), and higher pain limitations were associated with greater depressive symptoms (1.13 [0.63, 1.63], FDR-p<0.001). Within participants, increases in pain intensity were associated with increases in tobacco use risk (1.09 [0.48, 1.70], FDR-p=0.002), and increases in pain limitations were associated with increases in depressive symptoms (0.99 [0.54, 1.43], FDR-p<0.001) and decreases in social and occupational functioning (−1.08 [−1.78, −0.38], FDR-p=0.009).

One-in-two young people seeking support for mental ill-health report pain. Youth mental health services should consider integrating pain management.

Comprehensive cognitive remediation improves cognitive and functional outcomes in people with serious mental illness, but the specific components required for effective programs are uncertain. The most common methods to improve cognition are facilitated computerized cognitive training with coaching and teaching cognitive self-management strategies. We compared these methods by dismantling the Thinking Skills for Work program, a comprehensive, validated cognitive remediation program that incorporates both strategies.

In a randomized controlled trial we assigned 203 unemployed people with serious mental illness in supported employment programs at two mental health agencies to receive either the full Thinking Skills for Work (TSW) program, which included computerized cognitive training (based on Cogpack software), or the program with cognitive self-management (CSM) but no computer training. Outcomes included employment, cognition, and mental health over 2 years. To benchmark outcomes, we also examined competitive work outcomes in a similar prior trial comparing the TSW program with supported employment only.

The TSW and CSM groups improved significantly on all outcomes, but there were no differences between the groups. Competitive work outcomes for both groups resembled those of the TSW program in a prior trial and were better than the supported employment-only group in that study, suggesting that participants in both groups benefited from cognitive remediation.

Providing facilitated computerized cognitive training improved neither employment nor cognitive outcomes beyond teaching cognitive self-management strategies in people receiving supported employment. Computerized cognitive training may not be necessary for cognitive remediation programs to improve cognitive and functional outcomes.

Obstetric complications (OCs) are associated with cognitive and brain abnormalities observed in patients with schizophrenia. Gyrification, a measure of cortical integrity sensitive to events occurring during the prenatal and perinatal periods, is also altered in first-episode psychosis (FEP). We examined the relationship between OCs and gyrification in FEP, as well as whether gyrification mediates the relationship between OCs and cognition.

We examined differences in the Local Gyrification Index (LGI) for the frontal, parietal, temporal, occipital, and cingulate cortices between 139 FEP patients and 125 healthy controls (HCs). Regression analyses explored whether OCs and diagnosis interact to explain LGI variation. Parametric mediation analyses were conducted to assess the effect of LGI on the relationship between OCs and cognition for FEP and HC.

Significant LGI differences were observed between FEP patients and HC in the left parietal and bilateral cingulate and occipital cortices. There was a significant interaction between OCs and diagnosis on the left cingulate cortex (LCC) that was specific to males (p = 0.04) and was driven by gestational rather than intrauterine OCs.

In HCs, OCs had a direct effect on working memory (WM) (p = 0.048) in the mediation analysis, whereas in FEP, we observed no significant effect of OCs on either verbal or WM.

OCs interact with diagnosis to predict LCC gyrification, such that males with FEP exposed to OCs exhibit the lowest LGI. OCs influence WM, and LCC gyrification may mediate this relation only in HC, suggesting a differential neurodevelopmental process in psychosis.

Providing psychotherapy at 50 sessions in a year (starting twice weekly) led to faster and greater improvements in depression and personality functioning compared to 25 sessions, starting weekly for patients with depression and personality disorder (PD). This study reports long-term dosage effects at 18 and 24 months.

In a pragmatic, double-randomized clinical trial, 246 outpatients with depression and PD were assigned to (1) 25 or 50 sessions and (2) Short-term Psychodynamic Supportive Psychotherapy (SPSP) or Schema Therapy (ST). Depression severity was assessed with the Beck Depression Inventory-II. Secondary outcomes included diagnostic remission of depression (MINI-plus), PD (SCID-II/SCID-5-P), and treatment-specific measures. Intention-to-treat analyses were conducted.

At 18 and 24 months, BDI-II means did not differ between dosage groups (19.0 for 25 sessions versus 19.1 for 50 sessions; d = −0.01; 95% CI = −0.35-0.37, p = 0.96). The lower-dosage group improved during follow-up (−2.6 BDI points, p = 0.031), which may be partly attributed to additional therapy received by a subgroup. Remission rates at 24 months were 66% for depression and 76% for PD, with no differences between conditions.

Higher psychotherapy dosage led to faster initial improvements, but long-term outcomes were not superior to those achieved with a lower dosage. These results should be interpreted with caution, as unregulated treatment during follow-up reduced the power to detect significant dosage effects. Both SPSP and ST provide viable alternatives to treatments focused solely on depression.

Anhedonia, a transdiagnostic feature common to both Major Depressive Disorder (MDD) and Schizophrenia (SCZ), is characterized by abnormalities in hedonic experience. Previous studies have used machine learning (ML) algorithms without focusing on disorder-specific characteristics to independently classify SCZ and MDD. This study aimed to classify MDD and SCZ using ML models that integrate components of hedonic processing.

We recruited 99 patients with MDD, 100 patients with SCZ, and 113 healthy controls (HC) from four sites. The patient groups were allocated to distinct training and testing datasets. All participants completed a modified Monetary Incentive Delay (MID) task, which yielded features categorized into five hedonic components, two reward consequences, and three reward magnitudes. We employed a stacking ensemble model with SHapley Additive exPlanations (SHAP) values to identify key features distinguishing MDD, SCZ, and HC across binary and multi-class classifications.

The stacking model demonstrated high classification accuracy, with Area Under the Curve (AUC) values of 96.08% (MDD versus HC) and 91.77% (SCZ versus HC) in the main dataset. However, the MDD versus SCZ classification had an AUC of 57.75%. The motivation reward component, loss reward consequence, and high reward magnitude were the most influential features within respective categories for distinguishing both MDD and SCZ from HC (p < 0.001). A refined model using only the top eight features maintained robust performance, achieving AUCs of 96.06% (MDD versus HC) and 95.18% (SCZ versus HC).

The stacking model effectively classified SCZ and MDD from HC, contributing to understanding transdiagnostic mechanisms of anhedonia.

Lesbian, gay, and bisexual (LGB) individuals are more than twice as likely to experience anxiety and depression compared with heterosexuals. Minority stress theory posits that stigma and discrimination contribute to chronic stress, potentially affecting clinical treatment. We compared psychological therapy outcomes between LGB and heterosexual patients by gender.

Retrospective cohort data were obtained from seven NHS talking therapy services in London, from April 2013 to December 2023. Of 100,389 patients, 94,239 reported sexual orientation, 7,422 identifying as LGB. The primary outcome was reliable recovery from anxiety and depression. Secondary outcomes were reliable improvement, depression and anxiety severity, therapy attrition, and engagement. Analyses were stratified by gender and employed multilevel regression models, adjusting for sociodemographic and clinical covariates.

After adjustment, gay men had higher odds of reliable recovery (OR: 1.23, 95% CI: 1.13–1.34) and reliable improvement (OR: 1.16, 95% CI: 1.06–1.28) than heterosexual men, with lower attrition (OR: 0.88, 95% CI: 0.80–0.97) and greater reductions in depression (MD: 0.51, 95% CI: 0.28–0.74) and anxiety (MD: 0.45, 95% CI: 0.25–0.65). Bisexual men (OR: 0.67, 95% CI: 0.54–0.83) and bisexual women (OR: 0.84, 95% CI: 0.77–0.93) had lower attrition than heterosexuals. Lesbian and bisexual women, and bisexual men, attended slightly more sessions (MD: 0.02–0.03, 95% CI: 0.01–0.04) than heterosexual patients. No other differences were observed.

Despite significant mental health burdens and stressors, LGB individuals had similar, if not marginally better, outcomes and engagement with psychological therapy compared with heterosexual patients.

Methamphetamine (METH) dependence is a globally significant public health concern with no efficacious treatment. Trait impulsivity is associated with the initiation, maintenance, and recurrence of substance abuse. However, the presence of these associations in METH addiction, as well as the underlying neurobiological mechanisms, remains incompletely understood.

We scanned 110 individuals with METH use disorder (MUDs) and 55 matched healthy controls (HCs) using T1-weighted imaging and assessed their drug use characteristics and trait impulsivity. Surface-based morphometry and graph theoretical analysis were used to investigate group differences in brain morphometry and network attributes. Partial correlations were conducted to investigate the relationships between brain morphometric changes, drug use parameters, and trait impulsivity. Mediation analyses examined how trait impulsivity and drug craving influenced the link between brain morphometric change and MUD severity in patients.

MUDs exhibited thinner thickness in the left fusiform gyrus and right pars opercularis, as well as diminished small-world properties in their structural covariance networks (SCNs) compared to HCs. Furthermore, reduced cortical thickness in the right pars opercularis was linked to motor impulsivity (MI) and MUD severity, and the association between the right pars opercularis thickness and MUD severity was significantly mediated by both MI and cue-induced craving.

These findings suggest that MUDs exhibit distinct brain structural abnormalities in both the cortical thickness and SCNs and highlight the critical role of impulse control in METH addiction. This insight may offer a potential neurobiological target for developing therapeutic interventions to treat addiction and prevent relapse.

Social disconnection, covering loneliness and social isolation, might be associated with the development of paranoid thoughts. Differential effects of loneliness and social isolation on the occurrence of paranoia have not been tested so far. Moreover, the role of cognitive mechanisms in these associations remains unknown. This study aimed to investigate differential associations of loneliness and social isolation with paranoid thoughts in the general population, considering the role of cognitive mechanisms.

Altogether, 3,275 individuals, enrolled from the general population, completed baseline and follow-up assessments spanning 6–7 months. Cognitive biases (rejection sensitivity, attributional biases, and safety behaviors), social cognitive problems, and subjective cognitive problems were measured. The cross-lagged panel network (CLPN) analysis was performed, controlling for the effects of sociodemographic characteristics, psychiatric treatment, substance use, depressive, and anxiety symptoms. Additionally, mediation was tested for the CLPN paths linking social disconnection with paranoid ideation, with one intermediary node representing cognitive processes.

Loneliness was the most important node in terms of predicting other network variables. It was bidirectionally associated with paranoid thoughts. Cognitive processes mediated these associations (partial mediation for ideas of reference and full mediation for ideas of persecution). In turn, social isolation predicted paranoid thoughts through the effects on loneliness. It was also predicted by paranoid thoughts through attributional biases.

Social disconnection might be bidirectionally associated with paranoid thoughts. However, loneliness is more closely tied to paranoid thoughts compared to social isolation. Cognitive processes might mediate the association of social disconnection with paranoid thoughts.

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.

Major depressive disorder (MDD) and psychostimulant use disorder (PUD) are common, disabling psychopathologies that pose a major public health burden. They share a common behavioral phenotype: deficits in inhibitory control (IC). However, whether this is underpinned by shared neurobiology remains unclear. In this meta-analytic study, we aimed to define and compare brain functional alterations during IC tasks in MDD and PUD.

We conducted a systematic literature search on IC task-based functional magnetic resonance imaging studies in MDD and PUD (cocaine or methamphetamine use disorder) in PubMed, Web of Science, and Scopus. We performed a quantitative meta-analysis using seed-based d mapping to define common and distinct neurofunctional abnormalities.

We identified 14 studies comparing IC-related brain activation in a total of 340 MDD patients with 303 healthy controls (HCs), and 11 studies comparing 258 PUD patients with 273 HCs. MDD showed disorder-differentiating hypoactivation during IC tasks in the median cingulate/paracingulate gyri relative to PUD and HC, whereas PUD showed disorder-differentiating hypoactivation relative to MDD and HC in the bilateral inferior parietal lobule. In conjunction analysis, hypoactivation in the right inferior/middle frontal gyrus was common to both MDD and PUD.

The transdiagnostic neurofunctional alterations in prefrontal cognitive control regions may underlie IC deficits shared by MDD and PUD, whereas disorder-differentiating activation abnormalities in midcingulate and parietal regions may account for their distinct features associated with disturbed goal-directed behavior.

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.