Preexisting epidemiological studies suggest that early pubertal development in males is associated with externalizing (e.g. conduct problems, risky behavior, and aggression) and internalizing (e.g. depression and anxiety) traits and disorders. However, due to problems inherent to observational studies, especially of residual confounding, it remains unclear whether these associations are causal. Mendelian randomization (MR) studies take advantage of the random allocation of genes at conception and can establish causal relationships.

In this study, N = 76 independent genetic variants for male puberty timing (MPT) were derived from a large genome-wide association study (GWAS) on 205,354 participants and used as an instrumental variable in MR studies on 17 externalizing and internalizing traits and psychopathologies utilizing outcome GWAS with 16,400–1,045,957 participants.

In these MR studies, earlier MPT was significantly associated with higher scores for the overarching phenotype of ‘Externalizing Traits’ (b = −0.03, 95% CI [−0.06, −0.01]). However, this effect was likely driven by an earlier age at first sexual contact (b = −0.17, 95% CI [−0.21, −0.13]), without evidence for an effect on further externalizing phenotypes. Regarding internalizing phenotypes, earlier MPT was associated with higher levels of the ‘Depressed Affect’ subdomain of neuroticism (b = −0.04, 95% CI [−0.07, −0.01]). Late MPT was related to higher scores of internalizing traits in early life (b = 0.04, 95% CI [0.01, 0.08]).

This comprehensive MR study supports a causal effect of MPT on specific traits and behaviors. However, no evidence for an effect of MPT on long-term clinical outcomes (depression, anxiety disorders, alcohol dependency, cannabis abuse) was found.

Patients with chronic insomnia are characterized by alterations in default mode network and alpha oscillations, for which the medial parietal cortex (MPC) is a key node and thus a potential target for interventions.

Fifty-six adults with chronic insomnia were randomly assigned to 2 mA, alpha-frequency (10 Hz), 30 min active or sham transcranial alternating current stimulation (tACS) applied over the MPC for 10 sessions completed within two weeks, followed by 4- and 6-week visits. The connectivity of the dorsal and ventral posterior cingulate cortex (vPCC) was calculated based on resting functional MRI.

For the primary outcome, the active group showed a higher response rate (≥ 50% reduction in Pittsburgh Sleep Quality Index (PSQI)) at week 6 than that of the sham group (71.4% versus 3.6%) (risk ratio 20.0, 95% confidence interval 2.9 to 139.0, p = 0.0025). For the secondary outcomes, the active therapy induced greater and sustained improvements (versus sham) in the PSQI, depression (17-item Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale), and cognitive deficits (Perceived Deficits Questionnaire-Depression) scores. The response rates in the active group decreased at weeks 8–14 (42.9%–57.1%). Improvement in sleep was associated with connectivity between the vPCC and the superior frontal gyrus and the inferior parietal lobe, whereas vPCC-to-middle frontal gyrus connectivity was associated with cognitive benefits and vPCC-to-ventromedial prefrontal cortex connectivity was associated with alleviation in rumination.

Targeting the MPC with alpha-tACS appears to be an effective treatment for chronic insomnia, and vPCC connectivity represents a prognostic marker of treatment outcome.

Social anhedonia, indicating reduced pleasure from social interaction, is heightened in autistic youth and associated with increased internalizing symptoms transdiagnostically. The stability of social anhedonia over time and its longitudinal impact on internalizing symptoms in autism have never been examined.

Participants were 276 autistic children (Mage = 8.60, SDage = 1.65; 211 male) with IQ ≥ 60 (MIQ = 96.74, SDIQ = 18.19). Autism severity was measured using the Autism Diagnostic Observation Schedule, Second Edition. Caregivers completed the Child and Adolescent Symptom Inventory, Fifth Edition (CASI-5) at baseline, 6 weeks, and 6 months. The CASI-5 includes a social anhedonia subscale derived from relevant items across domains. ICC (Intraclass Correlation Coefficient) analysis assessed stability, while cross-lagged panel models examined associations among social anhedonia, depression, and social anxiety across time.

At baseline, social anhedonia correlated with autism severity, as well as parent-reported social anxiety and depression. Social anhedonia showed relative stability (ICC = 0.763) over 6 months, with a significant decline between baseline and 6 weeks (β = −0.52, p < .001). Cross-lagged models revealed a bidirectional relationship between social anhedonia and depression over time, while social anxiety displayed concurrent, but not predictive, associations across time.

Social anhedonia demonstrated stability over 6 months, suggesting that it may be a relatively stable characteristic in autistic children. Concurrent relationships were observed between social anhedonia and depression, as well as social anxiety and attention-deficit/hyperactivity disorder. Only depression demonstrated a bidirectional longitudinal association with social anhedonia. This bidirectional relationship aligns with developmental models linking early negative social experiences to subsequent internalizing symptoms in autistic children, underscoring the clinical significance of social anhedonia assessment in this population.

Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Critically, self-injury and suicide attempts in BPD are often precipitated by interpersonal discord. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of socioemotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period.

Eighty-six adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflicting or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We examined whether BPD symptom dimensions were associated with alterations in facial emotion processing. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task.

Emotion-related impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, emotion-related impulsivity in adolescents, but not young adults, was further associated with a lower decision boundary – resulting in fast but inaccurate decisions.

Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial emotion expressions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.

As the use of guided digitally-delivered cognitive-behavioral therapy (GdCBT) grows, pragmatic analytic tools are needed to evaluate coaches’ implementation fidelity.

We evaluated how natural language processing (NLP) and machine learning (ML) methods might automate the monitoring of coaches’ implementation fidelity to GdCBT delivered as part of a randomized controlled trial.

Coaches served as guides to 6-month GdCBT with 3,381 assigned users with or at risk for anxiety, depression, or eating disorders. CBT-trained and supervised human coders used a rubric to rate the implementation fidelity of 13,529 coach-to-user messages. NLP methods abstracted data from text-based coach-to-user messages, and 11 ML models predicting coach implementation fidelity were evaluated.

Inter-rater agreement by human coders was excellent (intra-class correlation coefficient = .980–.992). Coaches achieved behavioral targets at the start of the GdCBT and maintained strong fidelity throughout most subsequent messages. Coaches also avoided prohibited actions (e.g. reinforcing users’ avoidance). Sentiment analyses generally indicated a higher frequency of coach-delivered positive than negative sentiment words and predicted coach implementation fidelity with acceptable performance metrics (e.g. area under the receiver operating characteristic curve [AUC] = 74.48%). The final best-performing ML algorithms that included a more comprehensive set of NLP features performed well (e.g. AUC = 76.06%).

NLP and ML tools could help clinical supervisors automate monitoring of coaches’ implementation fidelity to GdCBT. These tools could maximize allocation of scarce resources by reducing the personnel time needed to measure fidelity, potentially freeing up more time for high-quality clinical care.

Individuals with a psychiatric inpatient admission in adolescence have a high risk of schizophrenia-spectrum disorders (SSDs) when followed to adulthood. Whether psychotic symptoms predict subsequent SSDs in inpatient cohorts, however, is an important unanswered question.

The sample consisted of adolescents (aged 13–17) admitted to psychiatric inpatient care (Oulu, Finland) from April 2001 to March 2006. Psychotic symptoms were assessed with the Schedule for Affective Disorders and Schizophrenia. Specialized health care use and diagnoses were followed up in national health care registers until June 2023. Cox regression was used to predict SSDs by the presence of baseline psychotic symptoms.

Of 404 adolescent inpatients admitted with non-psychotic mental disorders, 28% (n = 113) reported psychotic symptoms: 17% (n = 68) subthreshold and 11% (n = 45) full threshold. By the end of follow-up, 23% of the total cohort went on to be diagnosed with an SSD. Subthreshold psychotic symptoms did not differentiate patients who would subsequently develop SSDs (cumulative incidence 24%; HR = 1.42, 95%CI = 0.81–2.50). Full-threshold psychotic symptoms, on the other hand, were associated with an increased risk of subsequent SSDs (cumulative incidence 33%; HR = 2.00, 95%CI = 1.12–3.56). Most subsequent SSDs (83%), however, occurred in individuals who had not reported threshold psychotic symptoms during inpatient admission.

There was a high risk of subsequent SSDs among adolescent psychiatry inpatients when followed over time. SSDs were not predicted by subthreshold psychotic symptoms. Full-threshold psychotic symptoms were associated with an increased risk of subsequent SSDs, though with low sensitivity.

Older people with depression exhibit better response to electroconvulsive therapy (ECT). We aimed to measure the total effect of age on ECT response and investigate whether this effect is mediated by psychotic features, psychomotor retardation, psychomotor agitation, age of onset, and episode duration.

We pooled data from four prospective Irish studies where ECT was administered for a major depressive episode (unipolar or bipolar) with baseline score ≥21 on the 24-item Hamilton Depression Rating Scale (HAM-D). The primary outcome was change in HAM-D between baseline and end of treatment. The estimands were total effect of age, estimated using linear regression, and the indirect effects for each putative mediator, estimated using causal mediation analyses.

A total of 256 patients (mean age 57.8 [SD = 14.6], 60.2% female) were included. For every additional 10 years of age, HAM-D was estimated to decrease by a further 1.74 points over the ECT period (p < 0.001). Age acted on all putative mediators. Mechanistic theories, whereby a mediator drives treatment response, were confirmed for all putative mediators except age of onset. Consequently, mediation of the effect of age on change in HAM-D could be demonstrated for psychotic features, psychomotor retardation, psychomotor agitation, and episode duration but not for age of onset.

A total of 43.1% of the effect of older age on increased ECT response was explained by the mediators. Treatment planning could be improved by preferentially offering ECT to older adults, especially if presenting with psychotic features, greater severity of psychomotor disturbance, and earlier in the episode.

Emerging evidence indicates that gene–environment interactions (GEIs) are important underlying mechanisms for the development of schizophrenia (SZ). We investigated the associations of polygenic risk score for SZ (PRS-SZ), environmental measures, and their interactions with case–control status and clinical phenotypes among patients with schizophrenia spectrum disorders (SSDs).

The PRS-SZ for 717 SSD patients and 356 healthy controls (HCs) were calculated using the LDpred model. The Korea-Polyenvironmental Risk Score-I (K-PERS-I) and Early Trauma Inventory-Self Report (ETI-SR) were utilized as environmental measures. Logistic and linear regression analyses were performed to identify the associations of PRS-SZ and two environmental measures with case–control status and clinical phenotypes.

The PRS-SZ explained 8.7% of SZ risk. We found greater associations of PRS-SZ and total scores of the K-PERS-I with case–control status compared to the ETI-SR total score. A significant additive interaction was found between PRS-SZ and K-PERS-I. With the subdomains of the K-PERS-I and ETI-SR, we identified significant multiplicative or additive interactions of PRS-SZ and parental socioeconomic status (pSES), childhood adversity, and recent life events in association with case–control status. For clinical phenotypes, significant interactions were observed between PRS-SZ and the ETI-SR total score for negative-self and between PRS-SZ and obstetric complications within the K-PERS-I for negative-others.

Our findings suggest that the use of aggregate scores for genetic and environmental measures, PRS-SZ and K-PERS-I, can more accurately predict case–control status, and specific environmental measures may be more suitable for the exploration of GEIs.

Elevated maternal interleukin 6 (IL-6) during pregnancy has been associated with adverse fetal brain development and neurodevelopmental disorders, which often involve executive functioning (EF) impairments. However, the association between maternal IL-6 levels during pregnancy and EF remains largely unexplored.

The COPSYCH study is based on the prospective COPSAC2010 birth cohort of 700 mother-child pairs, recruited during pregnancy. The children’s executive functioning was assessed at age 10 using: (i) the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) parental questionnaire, and (ii) a comprehensive neuropsychological test battery. Maternal blood levels of IL-6 and hs-CRP were measured at gestational week 24. Associations between IL-6 (main analysis) and hs-CRP (secondary analysis) and EF in children at age 10 were investigated with regression models with extensive confounder adjustment.

Six hundred and four children (86% of the cohort) completed the 10-year follow-up. Higher maternal IL-6 levels were significantly associated with less efficient parental-rated executive functioning in the children: BRIEF-2 Global Executive Composite score (p = 0.003), Behavior Regulation Index (p = 0.005), Emotion Regulation Index (p=0.04), and Cognitive Regulation Index (p=0.007). Interaction analysis with sex was significant (p-value=0.01) and exploratory analyses showed that IL-6 associations to BRIEF-2 were solely driven by boys. Associations between IL-6 and neuropsychological tests, as well as associations between hs-CRP and EF outcomes, were non-significant.

IL-6 during pregnancy was associated with less efficient everyday EF in children at age 10. If replicated, preventive strategies targeting inflammation in pregnancy may ameliorate adverse cognitive outcomes in offspring.

Major depressive disorder (MDD) tends to emerge during adolescence; however, neurobiological research in adolescents has lagged behind that in adults. This study aimed to characterize gray matter (GM) structural alterations in adolescents with MDD using comprehensive morphological analyses.

This study included 93 adolescent MDD patients and 77 healthy controls. Voxel-based morphometry (VBM), deformation-based morphometry (DBM), and surface-based morphometry (SBM) methods were used to analyze GM morphological alterations in adolescent MDD patients. Sex-by-group and age-by-group interactions, as well as the relationships between altered GM structure and clinical characteristics were also analyzed.

Whole-brain VBM and DBM analyses revealed GM atrophy in the left thalamus and bilateral midbrain in adolescent MDD patients. Whole-brain SBM analysis revealed that adolescent MDD patients, relative to controls, showed decreased thickness in the left postcentral gyrus and left precentral gyrus; increased thickness in the bilateral superior temporal gyrus, left parahippocampal gyrus and right lateral orbitofrontal gyrus; and decreased fractal dimension in the right lateral occipital gyrus. A significant sex-by-group interaction effect was found in the fractal dimension of the left lateral occipital gyrus. The volume of the left thalamus and the thickness of the left superior temporal gyrus were correlated with the duration of disease in adolescent MDD patients.

This study suggested that adolescent MDD had GM morphological abnormalities in the frontal-limbic, subcortical, perceptual network and midbrain regions, with some morphological abnormalities associated with disease duration and sex differences. These findings provide new insight into the neuroanatomical substrates underlying adolescent MDD.

Prediction models that can detect the onset of psychotic experiences are a key component of developing Just-In-Time Adaptive Interventions (JITAI). Building these models on passively collectable data could substantially reduce user burden. In this study, we developed prediction models to detect experiences of auditory verbal hallucinations (AVH) and paranoia using ambulatory sensor data and assessed their stability over 12 weeks.

Fourteen individuals diagnosed with a schizophrenia-spectrum disorder participated in a 12-day Ecological Momentary Assessment (EMA) study. They wore ambulatory sensors measuring autonomic arousal (i.e., electrodermal activity, heart rate variability) and completed questionnaires assessing the intensity/distress of AVHs and paranoia once every hour. After 12 weeks, participants repeated the EMA for four days for a follow-up assessment. We calculated prediction models to detect AVHs, paranoia, and AVH-/paranoia-related distress using random forests within nested cross-validation. Calculated prediction models were applied to the follow-up data to assess the stability of prediction models.

Prediction models calculated with physiological data achieved high accuracy both for AVH (81%) and paranoia (69%–75%). Accuracy increased by providing models with baseline information about psychotic symptom levels (AVH: 86%; paranoia: 80%–85%). During the follow-up EMA accuracy dropped slightly throughout all models but remained high (73%–84%).

Relying solely on physiological data to detect psychotic symptoms achieved substantial accuracy that remained sufficiently stable over 12 weeks. Experiences of AVHs can be predicted with higher accuracy and long-term stability than paranoia. The findings tentatively suggest that psychophysiology-based prediction models could be used to develop and enhance JITAIs for psychosis.

Pubertal development variations have consequences for adolescent internalizing problems, which likely continue into adulthood. Key questions concern the extent of these links between pubertal timing and adult symptoms, as well as the underlying mechanisms.

Longitudinal data were available for 475 female and 404 male participants. Pubertal timing was indicated by age at mid-puberty for both groups and age at menarche for female participants (both assessed continuously). Adult self-reported outcomes of recent and lifetime depression and anxiety were predicted from pubertal timing, also controlling for adolescent (then childhood) internalizing problems. Emerging adulthood self-esteem, body dissatisfaction, education level, and age at sexual initiation were examined as mediators of the pubertal timing-adult internalizing link. Multilevel models tested hypotheses.

Pubertal timing had persisting and sex-dependent psychological associations. Specifically, in female, but not male, adults, early puberty was associated with all adult internalizing outcomes, and for past year and lifetime depression symptoms, even after controlling for adolescent internalizing problems. Pubertal timing links with past-year depression symptoms were mediated by age at sexual initiation, while all other persisting pubertal timing links with adult symptoms were mediated by body dissatisfaction. Most findings concerning depression held when childhood internalizing problems were also a covariate.

Leveraging data spanning four developmental periods, findings highlight the associations between pubertal variations and adult internalizing symptoms by revealing underlying sex-dependent behavioral pathways. Only for female participants did pubertal timing affect depression and anxiety in established adulthood, with body dissatisfaction and age at sexual initiation as unique developmental mechanisms.

Compulsive cleaning is a characteristic symptom of a particular subtype of obsessive–compulsive disorder (OCD) and is often accompanied by intense disgust. While overgeneralization of threat is a key factor in the development of obsessive–compulsive symptoms, previous studies have primarily focused on fear generalization and have rarely examined disgust generalization. A systematic determination of the behavioral and neural mechanisms underlying disgust generalization in individuals with contamination concern is crucial for enhancing our understanding of OCD.

In this study, we recruited 27 individuals with high contamination concerns and 30 individuals with low contamination concerns. Both groups performed a disgust generalization task while undergoing functional magnetic resonance imaging (fMRI).

The results revealed that individuals with high contamination concern had higher disgust expectancy scores for the generalization stimulus GS4 (the stimulus most similar to CS+) and exhibited higher levels of activation in the left insula and left putamen. Moreover, the activation of the left insula and putamen were positively correlated with a questionnaire core of the ratings of disgust and also positively correlated with the expectancy rating of CS+ during the generalization stage.

Hyperactivation of the insula and putamen during disgust generalization neutrally mediates the higher degree of disgust generalization in subclinical OCD individuals. This study indicates that altered disgust generalization plays an important role in individuals with high contamination concerns and provides evidence of the neural mechanisms involved. These insights may serve as a basis for further exploration of the pathogenesis of OCD in the future.

Sleep problems are common in psychotic disorders and are associated with worse quality of life and disease prognosis. Genome-wide association studies (GWAS) have revealed genetic influences for schizophrenia and sleep, but polygenic scores (PGSs) for sleep traits have not been evaluated systematically in patients with psychotic disorders.

This study investigated the associations between PGSs for sleep traits (insomnia, PGSINS; sleep duration, PGSSD; short sleep duration, PGSSS; long sleep duration; PGSLS), diurnal preference (eveningness, PGSME), and schizophrenia (PGSSZ) with clinical features of psychotic disorders in the Finnish SUPER study comprising 8,232 patients with psychotic disorders. The measures included self-reported sleep and well-being, cognitive assessments, clozapine use, and functional outcomes. Using FinnGen data of 356,077 individuals, we analyzed the distributions of PGSs in psychotic and bipolar disorders and the general population.

PGSINS associated with more sleep problems and worse well-being (e.g. worse health-related quality of life [β = −0.07, CI = −0.09, −0.05, p < .001]). High PGSSZ is associated with better sleep quality, worse clinical outcomes, and performance in cognitive tests (e.g. more errors in paired-associated learning [β = 0.07, CI = 0.04, 0.09, p < .001]). PGSINS was higher in affective psychotic and bipolar disorders, while PGSSD and PGSME were higher in schizophrenia as compared with individuals with no psychiatric disorders.

Genetic risks for sleep and diurnal preference vary between non-affective psychosis, affective psychosis, and the general population. The findings in this study emphasize the heterogeneity in genetic etiology of the objective features of disease severity and the more subjective measures related to well-being and self-reported measures of sleep.

The antidepressant mechanism of electroconvulsive therapy (ECT) remains not clearly understood. This study aimed to detect the changes in gray matter volume (GMV) in patients with major depressive disorder (MDD) caused by ECT and exploratorily analyzed the potential functional mechanisms.

A total of 24 patients with MDD who underwent eight ECT sessions were included in the study. Clinical symptom assessments and MRI scans were conducted and compared. Using whole-brain micro-array measurements provided by the Allen Human Brain Atlas (AHBA), regional gene expression profiles were calculated. The differential gene PLS1 was obtained through Partial Least Squares (PLS) regression analysis, and PLS1 was divided into positive contribution (PLS1+) and negative contribution (PLS1−) genes. Through gene function enrichment analysis, the functional pathways and cell types of PLS1 enrichment were identified.

Gray matter volume (GMV) in the somatosensory and motor cortices, occipital cortex, prefrontal cortex, and insula showed an increasing trend after ECT, while GMV in the temporal cortex, posterior cingulate cortex, and orbitofrontal cortex decreased. PLS1 genes were enriched in synapse- and cell-related biological processes and cellular components (such as ‘pre- and post-synapse’, ‘synapse organization’ etc.). A large number of genes in the PLS1+ list were involved in neurons (inhibitory and excitatory), whereas PLS1− genes were significantly involved in Astrocytes (Astro) and Microglia (Micro).

This study established a link between treatment-induced GMV changes and specific functional pathways and cell types, which suggests that ECT may exert its effects through synapse-associated functional and affect neurons and glial cells.

This study examines the prospective associations of alcohol and drug misuse with suicidal behaviors among service members who have left active duty. We also evaluate potential moderating effects of other risk factors and whether substance misuse signals increased risk of transitioning from thinking about to attempting suicide.

US Army veterans and deactivated reservists (N = 6,811) completed surveys in 2016–2018 (T1) and 2018–2019 (T2). Weights-adjusted logistic regression was used to estimate the associations of binge drinking, smoking/vaping, cannabis use, prescription drug abuse, illicit drug use, alcohol use disorder (AUD), and drug use disorder (DUD) at T1 with suicide ideation, plan, and attempt at T2. Interaction models tested for moderation of these associations by sex, depression, and recency of separation/deactivation. Suicide attempt models were also fit in the subgroup with ideation at T1 (n = 1,527).

In models controlling for socio-demographic characteristics and prior suicidality, binge drinking, cannabis use, prescription drug abuse, illicit drug use, and AUD were associated with subsequent suicidal ideation (AORs = 1.42–2.60, ps < .01). Binge drinking, AUD, and DUD were associated with subsequent suicide plan (AORs = 1.23–1.95, ps < .05). None of the substance use variables had a main effect on suicide attempt; however, interaction models suggested certain types of drug use predicted attempts among those without depression. Additionally, the effects of smoking/vaping and AUD differed by sex. Substance misuse did not predict the transition from ideation to attempt.

Alcohol and drug misuse are associated with subsequent suicidal behaviors in this population. Awareness of differences across sex and depression status may inform suicide risk assessment.