To improve early intervention and personalise treatment for individuals early on the psychosis continuum, a greater understanding of symptom dynamics is required. We address this by identifying and evaluating the movement between empirically derived attenuated psychotic symptomatic substates—clusters of symptoms that occur within individuals over time.

Data came from a 90-day daily diary study evaluating attenuated psychotic and affective symptoms. The sample included 96 individuals aged 18–35 on the psychosis continuum, divided into four subgroups of increasing severity based on their psychometric risk of psychosis, with the fourth meeting ultra-high risk (UHR) criteria. A multilevel hidden Markov modelling (HMM) approach was used to characterise and determine the probability of switching between symptomatic substates. Individual substate trajectories and time spent in each substate were subsequently assessed.

Four substates of increasing psychopathological severity were identified: (1) low-grade affective symptoms with negligible psychotic symptoms; (2) low levels of nonbizarre ideas with moderate affective symptoms; (3) low levels of nonbizarre ideas and unusual thought content, with moderate affective symptoms; and (4) moderate levels of nonbizarre ideas, unusual thought content, and affective symptoms. Perceptual disturbances predominantly occurred within the third and fourth substates. UHR individuals had a reduced probability of switching out of the two most severe substates.

Findings suggest that individuals reporting unusual thought content, rather than nonbizarre ideas in isolation, may exhibit symptom dynamics with greater psychopathological severity. Individuals at a higher risk of psychosis exhibited persistently severe symptom dynamics, indicating a potential reduction in psychological flexibility.

Population-level preventive interventions are urgently needed and may be effective for psychosis due to social determinants. We tested three syndemic models along pathways from childhood adversity (CA) to psychotic spectrum disorder (PSD) and their implications for prevention.

Cross-sectional data from 7461 British men surveyed in 5 population subgroups. We tested interactions on both additive and multiplicative scales for a syndemic of violence/criminality (VC), sexual behavior (SH), and substance misuse (SM) according to the presence of CA and adult traumatic life events; mediation analysis of path models; and partial least squares path modeling, with PSD as outcome.

Multiplicative synergistic interactions were found between VC, SH, and SM among men, who experienced CA and traumatic adult life events. However, when disaggregated, only SM mediated the pathway from CA to PSD. Path modeling showed traumatic life events acted on PSD through the syndemic and had no direct effect on PSD. Higher syndemic scores and living in areas of deprivation characterized men with PSD and CA.

Our findings support a broad division of PSD into cases due to (i) biological/inherent causes, and (ii) social determinants, the latter including a syndemic pathway determined by CA. Preventive strategies should focus primarily on preventing adverse effects of CA on developmental pathways which result in PSD. Single component prevention strategies may prevent triggering effects of SM on PSD during adolescence/early adulthood among vulnerable individuals due to CA. Future research should determine applicability and transferability of interventions based on these findings to different populations, specifically those experiencing syndemics.

Data from an RCT of IAPT Norway (“Prompt Mental Health Care” [PMHC]) were linked to several administrative registers up to five years following the intervention. The aims were to (1) examine the effects of PMHC compared to treatment-as-usual (TAU) on work-related outcomes and health care use, (2) estimate the cost–benefit of PMHC, and (3) examine whether clinical outcomes at six-month follow-up explained the effects of PMHC on work−/cost–benefit-related outcomes.

RCTs with parallel assignment were conducted at two PMHC sites (N = 738) during 2016/2017. Eligible participants were considered for admission due to anxiety and/or depression. We used Bayesian estimation with 90% credibility intervals (CI) and posterior probabilities (PP) of effects in favor of PMHC. Primary outcome years were 2018–2022. The cost–benefit analysis estimated the overall economic gain expressed in terms of a benefit–cost ratio and the differences in overall public sector spending.

The PMHC group was more likely than the TAU group to be in regular work without receiving welfare benefits in 2019–2022 (1.27 ≤ OR ≤ 1.43). Some evidence was found that the PMHC group spent less on health care. The benefit–cost ratio in terms of economic gain relative to intervention costs was estimated at 5.26 (90%CI $ - $1.28, 11.8). The PP of PMHC being cost-beneficial for the economy as a whole was 85.9%. The estimated difference in public sector spending was small. PMHC effects on work participation and cost–benefit were largely explained by PMHC effects on mental health.

The results support the societal economic benefit of investing in IAPT-like services.

Obsessive-compulsive symptoms (OCS) emerge in a significant proportion of clozapine-treated schizophrenia patients, affecting social functioning and increasing depressive symptoms. This study investigates the underexplored cognitive mechanisms of clozapine-induced OCS, particularly focusing on dysfunctional checking behavior.

Clinical and cognitive profiles of OCS and their relationship to dysfunctional checking were investigated using a novel checking paradigm (image verification task or IVT) in four groups: clozapine-treated schizophrenia patients with clozapine-induced OCS (SCZ-OCS, n = 21) and without (SCZ-only, n = 15), patients with obsessive-compulsive disorder (OCD, n = 32) and IQ-matched healthy volunteers (HV, n = 30).

Only SCZ-OCS patients showed a distinctive pattern of dysfunctional checking on the IVT. Compared with SCZ-OCS, SCZ-only patients exhibited functional checking while having equivalent deficits in executive cognition, clozapine dose, and treatment duration, though with less severe positive and depressive symptoms. In SCZ-OCS, dysfunctional checking was positively correlated with clozapine dose and working memory performance. By contrast, OCD patients’ checking was positively related to intolerance of uncertainty. Checking in the OCD and SCZ-OCS groups was positively correlated with YBOCS-compulsion.

This study is the first to compare the distinct cognitive and clinical profiles of SCZ-OCS, SCZ-only, and OCD, with a focus on checking behavior, a major symptom in clozapine-treated patients. We introduced a novel and sensitive measure for checking, which showed dysfunctional checking only in SCZ-OCS patients treated with clozapine. These findings indicate that a subset of patients with schizophrenia with more severe positive symptoms and cognitive deficits are especially susceptible to OCD symptoms when treated with clozapine.

Major depressive disorder (MDD) is marked by significant changes to the local synchrony of spontaneous neural activity across various brain regions. However, many methods for assessing this local connectivity use fixed or arbitrary neighborhood sizes, resulting in a decreased capacity to capture smooth changes to the spatial gradient of local correlations. A newly developed method sensitive to classical anatomo-functional boundaries, Iso-Distant Average Correlation (IDAC), was therefore used to examine depression associated alterations to the local functional connectivity of the brain.

One-hundred and forty-seven adolescents and young adults with MDD and 94 healthy controls underwent a resting-state functional magnetic resonance imaging (fMRI) scan. Whole-brain functional connectivity maps of intracortical neural activity within iso-distant local areas (5–10, 15–20, and 25–30 mm) were generated to characterize local fMRI signal similarities.

Across all spatial distances, MDD participants demonstrated greater local functional connectivity of the bilateral posterior hippocampus, retrosplenial cortex, dorsal insula, fusiform gyrus, and supplementary motor area. Local connectivity alterations in short and medium distances (5–10 and 15–20 mm) in the mid insula cortex were additionally associated with expressive suppression use, independent of depressive symptom severity.

Our study identified increased synchrony of the neural activity in several regions commonly implicated in the neurobiology of depression. These effects were relatively consistent across the three distances examined. Longitudinal investigation of this altered local connectivity will clarify whether these differences are also found in other age groups and if this relationship is modified by increased disease chronicity.

Access to “big data” is a boon for researchers, fostering collaboration and resource-sharing to accelerate advancements across fields. Yet, disentangling complex datasets has been hindered by methodological limitations, calling for alternative, interdisciplinary approaches to parse manifold multi-directional pathways between clinical features, particularly for highly heterogeneous autism spectrum disorder (ASD). Despite a long history of male-bias in ASD prevalence, no consensus has been reached regarding mechanisms underlying sex-related discrepancies.

Applying a novel network-theory-based approach, we extracted data-driven, clinically-relevant insights from a well-characterized sample (http://sfari.org/simons-simplex-collection) of autistic males (N = 2175, Age = 8.9 ± 3.5 years) and females (N = 334, Age = 9.2 ± 3.7 years). Expert clinical review of exploratory factor analysis (EFA) results yielded factors of interest in sensory, social, and restricted and repetitive behavior domains. To offset inherent confounds of sample imbalance, we identified a comparison subgroup of males (N = 331) matched to females (by age, IQ). We applied data-driven causal discovery analysis (CDA) using Greedy Fast Causal Inference (GFCI) on three groups (all females, all males, matched males). Structural equation modeling (SEM) extracted measures of model-fit and effect sizes for causal relationships between sex, age-at-enrollment, and IQ on EFA-determined factors.

We identified potential targets for intervention at nodes with mediating or indirect effects. For example, in the female and matched male groups, analyses suggest mitigating RRB domain behaviors may lead to downstream reductions in oppositional and self-injurious behaviors.

Our investigation unveiled sex-specific directional relationships that inform our understanding of differing needs and outcomes associated with biological sex in autism and may serve to further development of targeted interventions.

Childhood and adolescence are vulnerable periods for mental disorders, and the COVID-19 pandemic has exacerbated mental health challenges in this population. We aimed to estimate changes in the global burden of mental disorders among children and adolescents before and during the pandemic.

Using data from the Global Burden of Diseases Study 2021, we analyzed incidence, prevalence, and years lived with disability (YLDs) for mental disorders in individuals aged 5–24. Annual percent changes in age-standardized rates were calculated, and a Bayesian age–period–cohort model estimated the expected and additional burden based on pre-pandemic trends.

In 2021, an estimated 123.0 million new cases of mental disorders were reported among children and adolescents, with an 11.8% average annual increase in the age-standardized incidence rate during the pandemic. Anxiety disorders, which previously ranked third, became the leading cause of nonfatal disability (12.9 million [8.0–19.3] YLDs), while depressive disorders rose to fourth place (10.9 million [6.8–16.5] YLDs). The burden grew in most regions, especially among females, those aged 15–24, and in high sociodemographic index (SDI) areas. Based on pre-pandemic data, we estimated an additional burden of 795.0, 165.9, and 622.8 new cases per 100,000 population for total mental disorders, anxiety disorders, and depressive disorders globally in 2021, respectively. Spearman correlation analysis showed a significant positive correlation between additional burden and SDI levels.

These findings highlight the increased burden of mental disorders among children and adolescents during the pandemic, emphasizing the need for targeted post-pandemic mental health support.

Because pediatric anxiety disorders precede the onset of many other problems, successful prediction of response to the first-line treatment, cognitive-behavioral therapy (CBT), could have a major impact. This study evaluates whether structural and resting-state functional magnetic resonance imaging can predict post-CBT anxiety symptoms.

Two datasets were studied: (A) one consisted of n = 54 subjects with an anxiety diagnosis, who received 12 weeks of CBT, and (B) one consisted of n = 15 subjects treated for 8 weeks. Connectome predictive modeling (CPM) was used to predict treatment response, as assessed with the PARS. The main analysis included network edges positively correlated with treatment outcome and age, sex, and baseline anxiety severity as predictors. Results from alternative models and analyses are also presented. Model assessments utilized 1000 bootstraps, resulting in a 95% CI for R2, r, and mean absolute error (MAE).

The main model showed a MAE of approximately 3.5 (95% CI: [3.1–3.8]) points, an R2 of 0.08 [−0.14–0.26], and an r of 0.38 [0.24–0.511]. When testing this model in the left-out sample (B), the results were similar, with an MAE of 3.4 [2.8–4.7], R2−0.65 [−2.29–0.16], and r of 0.4 [0.24–0.54]. The anatomical metrics showed a similar pattern, where models rendered overall low R2.

The analysis showed that models based on earlier promising results failed to predict clinical outcomes. Despite the small sample size, this study does not support the extensive use of CPM to predict outcomes in pediatric anxiety.

Borderline personality disorder (BPD) is a severe mental disorder characterized by emotional dysregulation, impulsive behaviors, and difficulties in interpersonal relationships. Despite the poor understanding of the underlying biological processes, the oxytocin (OXT) system may be involved in and mediate some of BPD’s symptomatic and behavioral aspects. To clarify OXT’s role in BPD, we assessed its plasma levels and modulations induced by psychotherapies in patients.

Fifty BPD patients and 28 healthy controls (HC) participated in the study; patients were randomly assigned to two psychotherapeutic treatments: metacognitive interpersonal therapy and structured clinical management. Clinical and psychometric measures were assessed, and plasma was collected at baseline (T0) and in patients after 6 (T6) and 12 (T12) months of treatment. OXT was quantified by a radioimmunoassay technique.

BPD patients showed lower plasma OXT at T0 than HC (p = 0.002), and a correlation was observed (r = −0.36, p = 0.017) between low OXT concentrations and high Attachment Style Questionnaire – Italian Version–Preoccupation with Relationships subscale scores. OXT changed significantly over time in patients (p = 0.049) with an increase particularly evident from baseline to T6 (p = 0.022), without significant difference between treatment groups. OXT changes (T0 − T12) inversely correlated with symptom improvement as changes in the Zanarini Rating Scale for borderline personality disorder (r = 0.387, p = 0.006) and the Difficulties in Emotion Regulation Scale (r = 0.387, p = 0.005) scores during treatment.

OXT alteration in BPD patients and the regularizing effect of long-term psychotherapies support an involvement of the OXT system in the disease and in treatment impact. More research is needed to fully understand the underlying causal mechanisms linking OXT with pathogenesis and psychotherapy outcomes.

Hallucinations are common and distressing symptoms in Parkinson’s disease (PD). Treatment response in clinical trials is measured using validated questionnaires, including the Scale for Assessment of Positive Symptoms-Hallucinations (SAPS-H) and University of Miami PD Hallucinations Questionnaire (UM-PDHQ). The minimum clinically important difference (MCID) has not been determined for either scale. This study aimed to estimate a range of MCIDs for SAPS-H and UM-PDHQ using both consensus-based and statistical approaches.

A Delphi survey was used to seek opinions of researchers, clinicians, and people with lived experience. We defined consensus as agreement ≥75%. Statistical approaches used blinded data from the first 100 PD participants in the Trial for Ondansetron as Parkinson’s Hallucinations Treatment (TOP HAT, NCT04167813). The distribution-based approach defined the MCID as 0.5 of the standard deviation of change in scores from baseline at 12 weeks. The anchor-based approach defined the MCID as the average change in scores corresponding to a 1-point improvement in clinical global impression-severity scale (CGI-S).

Fifty-one researchers and clinicians contributed to three rounds of the Delphi survey and reached consensus that the MCID was 2 points on both scales. Sixteen experts with lived experience reached the same consensus. Distribution-defined MCIDs were 2.6 points for SAPS-H and 1.3 points for UM-PDHQ, whereas anchor-based MCIDs were 2.1 and 1.3 points, respectively.

We used triangulation from multiple methodologies to derive the range of MCID estimates for the two rating scales, which was between 2 and 2.7 points for SAPS-H and 1.3 and 2 points for UM-PDHQ.

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.

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.

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.