Anhedonia is a multidimensional concept, and it is not known which aspects of it are linked to the heterogeneity of treatment responses in major depressive disorder (MDD). We examine the role of anhedonia dimensions in predicting response to antidepressant medication and adjunctive pharmacotherapy.

In CAN-BIND-1, 187 adults with MDD completed the Dimensional Anhedonia Rating Scale (DARS) and the Snaith–Hamilton Pleasure Scale (SHAPS) before undergoing 8 weeks of treatment with escitalopram. At week 8, 90 nonresponders received adjunctive treatment with aripiprazole for an additional 8 weeks. Mixed-effects models tested the hobbies, food, social, and sensory subscales and items of DARS and SHAPS as predictors of change in the Montgomery-Åsberg Depression Rating Scale (MADRS).

Of the four DARS subscales, sensory anhedonia predicted a worse treatment outcome with escitalopram (b = 1.14, 95%CI 0.08 to 2.20, p = 0.034) as did a three-item SHAPS sensory anhedonia subscale (b = 1.50, 95%CI 0.43 to 2.57, p = 0.006). A combined DARS–SHAPS sensory anhedonia subscale complemented the previously reported interest–activity symptom dimension to improve treatment outcome prediction. In contrast, food and social anhedonia dimensions predicted worse outcomes with adjunctive aripiprazole (b = 2.52, 95%CI 1.25 to 3.80, p < 0.001; b = 2.56, 95%CI 1.16 to 3.96, p < 0.001). Corresponding SHAPS items showed similar results.

The inability to enjoy sensory experiences and the lack of interest in food and social activities distinctly predict outcomes with serotonergic versus dopaminergic pharmacotherapy. These findings require replication and extension to other treatments.

Adults with intellectual disability (ID) experience marked mental health inequities, yet population-wide estimates that capture both primary- and specialist-care diagnoses remain scarce.

Using nationwide Swedish registries, including primary care, specialist, inpatient, prescription drug, criminal, and suspicion registers, we included all individuals born in Sweden between 1958 and 1997 (N = 3,970,600), including 38,818 individuals with ID diagnoses (0.98%; 49.1% mild, 13.3% moderate, and 9.6% severe/profound). Hazard ratios (HR) were calculated using Cox proportional hazards regression to estimate the relative risk of lifetime diagnoses of major depression, anxiety disorders (ANX), obsessive-compulsive disorder (OCD), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), drug use disorder, alcohol use disorder, schizophrenia, and other nonaffective psychosis. Additionally, cohort effects on psychiatric diagnosis risks in adults with intellectual disabilities versus the general population were evaluated.

People with ID were at higher risk for all psychiatric and substance use disorders, with HRs ranging from 1.7–2.0 for major depression and anxiety, drug and alcohol use disorders, 3.5–5.8 for BD, OCD and ADHD, and 10.9–12.7 for schizophrenia and other nonaffective psychosis. Higher prevalence was consistently seen among those with mild versus moderate or severe/profound intellectual disability. Relative risks narrowed modestly in successive birth cohorts, although absolute differences remained substantial.

Across six decades of follow-up, adults with ID faced markedly higher psychiatric and substance-use morbidity – most pronounced for psychotic disorders – than the general population. Whole-system mental-health screening and tailored interventions are required to address this persistent disparity.

Evidence regarding the effects of antipsychotic medication on cognitive functioning after a first-episode psychosis (FEP) remains inconclusive. This study examined whether dopamine D2 receptor occupancy, affinity, and antipsychotic dose are related to cognitive functioning in people in remission from FEP.

278 remitted FEP participants from the HAMLETT-trial were included. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia, 3–6 months after remission. D2 receptor occupancy was estimated based on antipsychotic type and dose. Antipsychotics were categorized into partial agonists, or antagonists with high or low D2 receptor affinity. Linear regression analyses were performed with inverse probability of treatment weighting to control for differences in characteristics between groups.

D2 receptor occupancy was negatively related to global cognition (β = −0.18), verbal fluency (β = −0.22), and attention and processing speed (β = −0.17, all p < 0.003). The interaction between daily dose and D2 receptor affinity category was significant for global cognition (p = 0.0046) and working memory (p = 0.0019), but not for verbal fluency after correction for multiple testing (p = 0.029). Interactions showed that higher daily dose was related to lower cognitive functioning, with significantly stronger negative effects in high-affinity antagonists compared to other antipsychotics.

The current findings underscore the importance of antipsychotic D2 receptor occupancy and affinity for cognitive functioning and suggest better cognitive functioning in users of partial agonists and low D2 receptor affinity antipsychotics. This can be important when selecting antipsychotics for individuals with FEP.

While prenatal exposure to tobacco has been associated with adolescent suicide attempt, little is known about the mechanisms explaining this association. This study aims to explore the mediating roles of internalizing symptoms, externalizing behaviors, and peer problems across childhood in the association between prenatal exposure to tobacco and adolescent suicide attempt.

We analyzed data from N = 8,861 participants from the Millennium Cohort Study followed from ages 9 months to 17 years. Binary logistic regression models were used to investigate the total association between exposure to tobacco in pregnancy and suicide attempt, and mediation analyses were conducted using structural equation models to investigate the direct and indirect associations.

In models adjusted for key covariates, we found a significant association between prenatal tobacco exposure and increased risk of adolescent suicide attempts (odds ratio = 2.08, 95% confidence interval = [1.68, 2.56]), partly mediated through internalizing problems, externalizing behaviors, and peer problems from ages 3 to 14 years (accounting for 37% of the total association, that is, 16%, 12%, and 9%, respectively).

These findings suggest that interventions targeting mental health symptoms and peer problems may maximize suicide prevention efforts among children who were prenatally exposed to tobacco, thus potentially reducing the long-term risk of suicide attempt.

Cumulative stress exposure is extensively involved in carcinogenesis. However, cancer risk associated with allostatic load (AL), a valid measure of chronic stress, has not been comprehensively evaluated in large cohorts, and the combined effect of AL and personality trait on cancer risk remains unknown.

This prospective cohort study was conducted based on 245,683 participants from the UK Biobank, with a median follow-up of 13.5 years. The AL score was calculated based on 11 biomarkers. Personality traits were constructed and categorized into two clusters. Multivariable Cox regression model was used to assess the risk of incident cancer according to AL and personality clusters, and multiplicative and additive interactions were evaluated.

High AL was associated with an increased cancer risk compared to low AL (hazard ratio [HR] = 1.06, 95% confidence interval [CI]: 1.04–1.09), particularly for cancers of stomach, liver, kidney, esophageal, lung, colorectal, breast, and leukemia (HR ranged from 1.08 to 1.43). Personality clusters was associated with risk of lung cancer (HR = 1.14, 95% CI: 1.05–1.23), but not overall cancer. Significant synergistic interaction was observed between high AL and ‘nervous-dominant’ personality for overall cancer risk, with the strongest association observed for liver cancer (HR = 1.58, 95% CI: 1.24–2.02).

High AL was related to higher risks of overall cancer and site-specific cancers, particularly when combined with nervous-dominant personality, highlighting the interplay between chronic physiological stress and psychological factors in cancer development.

Girls with predispositions for disordered eating (DE) may select into weight-conscious peer groups (i.e. peer groups that emphasize body weight/shape). However, factors driving selection into these peer groups remain unknown, as genetic and/or environmental predisposition to DE may lead girls to select weight-conscious peers. To explore what may drive selection, the present study investigated whether genetic or shared environmental influences underlie associations between DE and exposure to weight-conscious peers and whether effects differ by pubertal status.

Participants included 833 female twins (ages 8–15) from the Michigan State University Twin Registry. Bivariate twin models were conducted to explore etiologic overlap between DE and exposure to weight-conscious peers. Separate models were run for pre-early pubertal girls and mid-late pubertal girls given past research demonstrates differences in genetic and environmental contributions underlying eating pathology by pubertal status.

During pre-early puberty, shared and non-shared environmental correlations accounted for the overlap between DE and weight-conscious peer group exposure. Furthermore, shared environmental and non-shared environmental influences underlying DE contributed to 33.3% and 20.0% of the individual differences in weight-conscious peer group membership, respectively. In mid-late puberty, the genetic and non-shared environmental correlations accounted for the overlap between DE and weight-conscious peer group exposure. Genetic and non-shared environmental influences underlying DE contributed to 37.5% and 19.4% of the variance in weight-conscious peer group membership, respectively.

While selection effects may exist across development, these effects may be driven by variance in DE due to shared environment in pre-early puberty and genes in mid-late puberty.

Exercise improves stress perception and sleep quality and reduces repetitive negative thinking in patients with various mental disorders. However, it is unclear whether changes in these processes mediate treatment effects on psychopathology in a transdiagnostic sample.

Physically inactive adult outpatients with depressive disorders, agoraphobia, panic disorder, post-traumatic stress disorder, and/or nonorganic primary insomnia were randomly allocated to ImPuls – a 6-month transdiagnostic group exercise intervention – plus treatment-as-usual (n = 198), or to a treatment-as-usual alone control group (n = 201) at 10 study sites between March 2021 and May 2022. The primary outcome was global symptom severity; perceived stress, repetitive negative thinking, and sleep quality were included as mediators. All variables were assessed at baseline, 6 months, and 12 months using validated rating scales. As a secondary analysis of an RCT, intention-to-treat analyses were performed using structural equation modeling to test whether changes in stress perception, repetitive negative thinking, and sleep quality mediate treatment effects on changes in global symptom severity in two path models (from baseline to 6 and 12 months, respectively).

Treatment effects on global symptom severity were fully mediated by changes in perceived stress (6 months: β = −0.99, p = .024; 12 months: β = −1.28, p = .014) and repetitive negative thinking (6 months: β = −1.34, p = .004; 12 months: β = −0.94, p = .024).

Our results suggest that changes in perceived stress and repetitive negative thinking may be key transdiagnostic mechanisms underlying the treatment effect of exercise on global symptom severity.

The results of a previous randomized trial showed that mentalization-based treatment for psychotic disorder (MBTp) was associated with greater improvement than treatment as usual (TAU) in social functioning up to 6 months after treatment. The purpose of the present study is to examine the effect after 5 years.

The researchers tried to find all patients who had participated in the trial (n = 84) and to assess, blind to previous treatment status, their social functioning and mentalizing capacity. Social functioning was measured using the Social Functioning Scale, mentalizing using the Social Cognition and Object Relations Scale and the Hinting Task.

Twenty-three MBTp patients and 23 TAU patients collaborated. There was no evidence of selective drop-out. A complete case, repeated measure analysis of variance on the basis of intention-to-treat showed that, 5 years post-treatment, MBTp patients still scored better on social functioning compared to baseline [ηp2 = .25, p = .01], whereas TAU patients did not [ηp2 = .01, p = .67], with a significant difference between the conditions [ηp2 = .10, p = .03]. A sensitivity analysis with linear mixed models, however, showed weaker evidence for an additive effect of MBTp over TAU on social functioning 5 years post-treatment, F = 3.731, p = .06. MBT patients also showed a greater improvement in one aspect of mentalizing, understanding of social causality [ηp2 = 0.17, p = .04], but not other aspects of mentalizing.

The results suggest a durable effect of MBTp.

Auditory verbal hallucinations (AVH) in schizophrenia spectrum disorders (SSDs) may arise from misattributed inner speech. However, it is unclear if inner speech frequency and phenomenology differ in schizophrenia-spectrum voice-hearers compared with healthy individuals, and how different inner speech varieties relate to AVH and affect. Using experience sampling methodology (ESM), this study examined the moment-to-moment dynamics between inner speech varieties, AVH, and affect.

Participants completed 6 days of ESM on an electronic device, responding to 10 daily prompts on inner speech varieties (i.e. dialogic, evaluative, other people, condensed, and positive), AVH, and affect. Responses from 32 individuals with SSDs with current AVH (‘SSD’) and 34 healthy controls (‘HC’) were analyzed using linear mixed modeling.

SSD reported significantly more inner speech moments and higher momentary intensity of evaluative, other people, condensed, and positive inner speech compared with HC, but not for dialogic inner speech. Within SSD, higher momentary intensities of dialogic, evaluative, other people, and condensed inner speech were associated with higher AVH levels. Momentary negative affect (NA) moderated the association between evaluative inner speech and AVH, with a stronger association at higher NA levels.

SSDs with current AVH experience more frequent inner speech and exhibit a distinct phenomenological profile compared with healthy individuals. Several inner speech varieties are associated with AVH severity momentarily, supporting the hypothesis that inner speech contributes to AVH at the phenomenological level. This study highlights the emotional state as an important moderator of the inner speech–AVH relationship and as a potential therapeutic target.

Cognitive and behavioral symptoms of major depressive disorder (MDD) are linked to aberrant changes in the controllability of brain networks. However, previous studies examined network controllability using white matter tractography, neglecting the contributions of gray matter. We aimed to examine differences in the controllability of morphometric networks between patients with MDD and demographic-matched healthy controls and identify the associated neurobiological signatures.

Based on the structural and diffusion MRI data from two independent cohorts, we calculated the controllability of morphometric similarity networks for each participant. A generalized additive model was used to investigate the case–control differences in regional controllability and their cognitive and behavioral associations. We investigated the associations between imaging-derived controllability and neurotransmitters, brain metabolism, and gene transcription profiles using multivariate linear regression and partial least squares regression analyses.

In both cohorts, depression-related abnormalities of morphometric network controllability were primarily located in the prefrontal, cingulate, and visual cortices, contributing to memory, sensation, and perception processes. These abnormalities in network controllability were spatially aligned with the distributions of serotonergic transmission pathways as well as with altered oxygen and glucose metabolism. In addition, these abnormalities spatially overlapped with differentially expressed genes enriched in annotations related to protein catabolism and mitochondria in neuronal cells and were disproportionately located on chromosome 22.

Collectively, neuroimaging evidence revealed aberrant morphometric network controllability underlying MDD-related cognitive and behavioral deficits, and the associated genetic and molecular signatures may help identify the neurobiological mechanisms underlying MDD and provide feasible therapeutic targets.

Parenthood is consistently identified as a protective factor for suicidal behavior. However, it remains unclear whether this relationship varies as a function of sex, age, time since birth, number of children, and other risk/protective factors.

We used Cox proportional hazards models to describe the relationship between the birth of up to four children and suicide attempt (SA) risk in Swedish individuals born between 1960 and 1980. Models were stratified by sex and controlled for a range of covariates. We tested whether the relationship between parenthood and SA risk varies based on age at first birth and explored whether SA risk differed based on education, genetic liability, cohabitation with one’s co-parent, and geographic proximity to one’s mother (the child’s grandmother).

The first year following childbirth was associated with reduced SA risk in mothers (hazard ratios [HRs] = 0.34–0.64) and fathers (HRs = 0.60–0.86). However, later time periods following the birth of one’s third and fourth children were associated with elevated risk (HRs = 1.02–1.26). Moreover, age at first birth moderated the association between parenthood and SA: individuals who became parents at age 15 exhibited increased risk for SA (HRs = 2.81–5.30), while individuals with an older age at first birth (30+ years) experienced a reduction in risk (HRs = 0.31–0.92). The effect of parenthood also varied based on cohabitation and proximity to one’s mother.

These findings underscore the complexity of the relationship between parenthood and SA, indicating that there are some subgroups for whom the transition to parenthood is not protective. Clinical outreach may be warranted as a preventative measure.

Subjective cognitive complaints are poor predictors of neurodegenerative disease and future dementia. Errors in metacognition, positive or negative differences between actual and perceived performance, may partially explain this. We aimed to assess whether hypothesized indicators of underlying neurodegenerative factors (e.g. hippocampal atrophy) in mild cognitive impairment (MCI) were associated with overestimation of actual cognitive performance, and hypothesized non-degenerative factors (e.g. depression) were associated with underestimation of performance.

Metacognitive error was estimated from paired subjective and objective cognitive assessments using the Multifactorial Memory Questionnaire and Addenbrooke’s Cognitive Examination – Revised, respectively. A normative model was developed with cognitively healthy older adults (n = 36), and applied to individuals with suspected MCI due to Alzheimer’s disease (AD) or MCI with Lewy bodies (total n = 88). Theorized predictors of subjective overestimation or underestimation of performance (metacognitive error) were assessed, including demographics, AD biomarkers, and mental and physical ill health. Metacognitive error was also assessed as a predictor of conversion to dementia.

Underestimation of cognitive function was associated with depressive symptoms, anxiety, and self-reported autonomic symptoms. Overestimation of cognitive function was associated with age, hippocampal atrophy, plasma glial fibrillary acidic protein, and subsequent dementia conversion.

Underestimation of cognitive function may reflect functional cognitive changes linked to mental and physical ill health, while overestimation of function may be a marker of neurodegenerative changes. Quantifying metacognitive error may provide a noninvasive screening tool for progressive MCI, requiring investigation in an independent sample.

Anhedonia and rumination, a form of repetitive negative thinking (RNT), are key features of depression associated with poor treatment outcomes, chronic disease progression, and an increased risk of suicidality. Although their interaction is thought to sustain depressive states, the state-level mechanisms linking these symptoms remain poorly understood.

In this multilevel, randomized within-subjects study, 62 individuals (n = 38 females) with varying levels of depressive symptoms completed the Probabilistic Reward Task (PRT) under two conditions: experimentally induced RNT and an active control. Concurrent electroencephalography was employed to assess electroencephalographic markers of reward functioning.

RNT significantly attenuated both reward response bias and feedback-related positivity (FRP) amplitudes, with the most pronounced effects in individuals with more severe depressive symptoms. These effects were not attributable to differences in task difficulty or perceptual cortical processing of PRT stimuli, supporting the specificity of RNT’s impact on reward-related processes.

RNT may transiently disrupt behavioral and neural indicators of reward functioning. These findings suggest that cognitive states such as RNT can exacerbate or reveal the latent reward-processing deficits typically observed in individuals with anhedonia. This state-dependent sensitivity highlights the potential utility of targeting RNT to restore reward processing in depression.

Cognitive fatigue is a prevalent and disabling symptom in neurological and post-viral conditions, including multiple sclerosis (MS) and Long COVID. Assessment relies largely on self-report, and no validated objective biomarker exists, limiting reliable diagnosis and treatment monitoring. The aperiodic exponent of the Electroencephalogram (EEG) power spectrum, reflecting the excitation/inhibition (E/I) balance, is a promising candidate biomarker. We examined whether aperiodic exponent values can objectively identify pathological fatigue and assessed their classification accuracy.

We conducted a cross-sectional study, including 119 participants: 36 healthy controls, 33 with Long COVID-related fatigue (LCOF), and 50 with MS (23 fatigued and 27 nonfatigued). Resting-state EEGs were analyzed, and associations with fatigue ratings and group differences were assessed. Logistic mixed-effects regression models evaluated classification accuracy for fatigue status.

Lower frontal aperiodic exponents were associated with higher cognitive fatigue across participants. Fatigued individuals, regardless of diagnosis, showed reduced frontal exponent values compared with nonfatigued groups, while no differences emerged in occipital regions. Logistic regression confirmed that frontal exponent values significantly predicted fatigue status, improving classification accuracy beyond age and depression, with good sensitivity and specificity.

The frontal aperiodic exponent is a regionally specific biomarker of cognitive fatigue across MS and LCOF. Mechanistic interpretation suggests an altered prefrontal E/I balance, which could inform the development of targeted interventions to alleviate cognitive fatigue. It offers a clinically accessible tool to complement self-report, support trial stratification, and enable objective treatment monitoring. Importantly, its presence across distinct disorders highlights its value as a transdiagnostic marker of fatigue.