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.

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.

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.

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.

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.

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.

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.

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.

Self-injurious behaviors (SIB) are common in autistic people. SIB is mainly studied as a broad category, rather than by specific SIB types. We aimed to determine associations of distinct SIB types with common psychiatric, emotional, medical, and socio-demographic factors.

Participants included 323 autistic youth (~50% non−/minimally-speaking) with high-confidence autism diagnoses ages 4–21 years. Data were collected by the Autism Inpatient Collection during admission to a specialized psychiatric inpatient unit (www.sfari.org/resource/autism-inpatient-collection/). Caregivers completed questionnaires about their child, including SIB type and severity. The youth completed assessments with clinicians. Elastic net regressions identified associations between SIB types and factors.

No single factor relates to all SIB types. SIB types have unique sets of associations. Consistent with previous work, more repetitive motor movements and lower adaptive skills are associated with most types of SIB; female sex is associated with hair/skin pulling and self-rubbing/scratching. More attention-deficit/hyperactivity disorder symptoms are associated with self-rubbing/scratching, skin picking, hair/skin pulling, and inserts finger/object. Inserts finger/object has the most medical condition associations. Self-hitting against surface/object has the most emotion dysregulation associations.

Specific SIB types have unique sets of associations. Future work can develop clinical likelihood scores for specific SIB types in inpatient settings, which can be tested with large community samples. Current approaches for SIB focus on the behavior functions, but there is an opportunity to further develop interventions by considering the specific SIB type in assessment and treatment. Identifying factors associated with specific SIB types may aid with screening, prevention, and treatment of these often-impairing behaviors.

Externalizing and internalizing pathways may lead to the development of substance use behaviors (SUBs) and substance use disorders (SUDs), which are all heritable phenotypes. Genetic correlation studies have indicated differences in the genetic susceptibility between SUBs and SUDs. We investigated whether these substance use phenotypes are differently related to externalizing and internalizing problems at a genetic level.

We analyzed data from genome-wide association studies (GWAS) of four SUBs and SUDs, five externalizing traits, and five internalizing traits using the bivariate causal mixture model (MiXeR) to estimate genetic overlap beyond genetic correlation.

Two distinct patterns were found. SUBs demonstrated high genetic overlap but low genetic correlation of shared variants with internalizing traits, suggesting a pattern of mixed effect directions of shared genetic variants. Conversely, SUDs and externalizing traits exhibited considerable genetic overlap with moderate to high positive genetic correlation of shared variants, suggesting concordant effect direction of shared risk variants.

These results highlight the importance of the externalizing pathway in SUDs as well as the limited role of the internalizing pathway in SUBs. As MiXeR is not intended for the identification of specific genes, further studies are needed to reveal the underlying shared mechanisms of these traits.

Findings from contemporary clinical trials suggest that psychedelics are generally safe and may be effective in the treatment of various psychiatric disorders. However, less is known about the risks associated with psychedelic use outside of medically supervised contexts, particularly in populations that are typically excluded from participation in clinical trials.

Using a preregistered longitudinal observational research design with a purposive sample of US residents between 18 and 50 years old (N=21,990), we investigated associations between self-reported naturalistic psychedelic use and psychotic and manic symptoms, with emphasis on those with psychiatric histories of schizophrenia or bipolar I disorder.

The follow-up survey was completed by 12,345 participants (56% retention), with 505 participants reporting psychedelic use during the 2-month study period. In covariate-adjusted regression models, psychedelic use during the study period was associated with increases in the severity of psychotic and manic symptoms. However, such increases were only observed for those who reported psychedelic use in an illegal context. While increases in the severity of psychotic symptoms appeared to depend on the frequency of use and the intensity of challenging psychedelic experiences, increases in the severity of manic symptoms appeared to be moderated by a personal history of schizophrenia or bipolar I disorder and the subjective experience of insight during a psychedelic experience.

The findings suggest that naturalistic psychedelic use specifically in illegal contexts may lead to increases in the severity of psychotic and manic symptoms. Such increases may depend on the frequency of use, the acute subjective psychedelic experience, and psychiatric history.

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.

Recent studies have increasingly utilized gradient metrics to investigate the spatial transitions of brain organization, enabling the conversion of macroscale brain features into low-dimensional manifold representations. However, it remains unclear whether alterations exist in the cortical morphometric similarity (MS) network gradient in patients with schizophrenia (SCZ). This study aims to examine potential differences in the principal MS gradient between individuals with SCZ and healthy controls and to explore how these differences relate to transcriptional profiles and clinical phenomenology.

MS network was constructed in this study, and its gradient of the network was computed in 203 patients with SCZ and 201 healthy controls, who shared the same demographics in terms of age and gender. To examine irregularities in the MS network gradient, between-group comparisons were carried out, and partial least squares regression analysis was used to study the relationships between the MS network gradient-based variations in SCZ, and gene expression patterns and clinical phenotype.

In contrast to healthy controls, the principal MS gradient of patients with SCZ was primarily significantly lower in sensorimotor areas, and higher in more areas. In addition, the aberrant gradient pattern was spatially linked with the genes enriched for neurobiologically significant pathways and preferential expression in various brain regions and cortical layers. Furthermore, there were strong positive connections between the principal MS gradient and the symptomatologic score in SCZ.

These findings showed changes in the principal MS network gradient in SCZ and offered potential molecular explanations for the structural changes underpinning SCZ.

Limited studies have examined the association between the whole range of parental psychopathology and offspring major depression (MD). No previous study has examined this association by age of onset of offspring MD, or restricting to parental psychiatric diagnoses before offspring birth.

This nested case–control study included 37,677 cases of MD and 145,068 controls, identified from Finnish national registers. Conditional logistic regression models examined the association between parental psychopathology and MD, adjusting for potential confounders.

Increased risk of MD, expressed as adjusted odds ratio and 95% confidence interval (aOR [95% CI]) were most strongly observed for maternal diagnoses of schizophrenia and schizoaffective disorders (2.51 [2.24–2.82]) and depression (2.19 [2.11–2.28]), and paternal diagnoses of schizophrenia and schizoaffective disorders (2.0 [1.75–2.29]) and conduct disorders (1.90 [1.40–2.59]). The aORs for any psychiatric diagnosis were (2.66 [2.54–2.78]) for mothers, (1.95 [1.86–2.04]) for fathers, and (4.50 [4.24–4.79]) for both parents. When both parents had any psychiatric diagnosis, the highest risk was for MD diagnosed at the age of 5–12 years (7.66 [6.60–8.89]); versus at 13–18 years (4.13 [3.85–4.44]) or 19–25 years (3.37 [2.78–4.07]). A stronger association with parental psychopathology and offspring MD was seen among boys than girls, especially among 13–19 years and 19–25 years.

Parental psychiatric disorders, including those diagnosed before offspring birth, were associated with offspring MD, indicating potential genetic and environmental factors in the development of the disorder.