No studies have investigated the effects of virtual reality (VR) on the persecutory idea of reference (IOR) or delusions of reference (DOR) in patients with psychosis. This study examined the efficacy and safety of VR therapy in stable outpatients with psychosis and explored relationships between primary outcomes and psychological factors using path analysis.

Seventy-eight patients were randomly assigned to either the VR-treatment (VR-T) or VR-control (VR-C) group. The VR-T group viewed three 360° 3D videos or four animated videos; the VR-C group viewed the same seven videos with muted voices or 11 360° 3D videos of natural scenes. Pre- and post-assessments were performed using the Psychotic Symptom Rating Scale-Delusions (PSYRATS-D) and Revised Green et al. Paranoid Thought Scale (R-GPTS) as a primary outcome measure. Several self-rating scales measuring schema, depression, brooding, negative evaluation, attribution bias, and self-esteem were administered. Safety was assessed after sessions 1 and 10, and path models were constructed.

Between-group analysis showed a significant improvement in PSYRATS-D scores in the VR-T group compared with the VR-C group. Regarding self-rating scales, the between-group analysis revealed a significant group × time interaction only for the Social and Occupational Functioning Assessment Scale (SOFAS) score. The frequency of VR sickness was high, but its severity was mild. Fear of Negative Evaluation Scale and Beck Depression Inventory scores were found to have mediating roles.

VR therapy effectively reduced delusions in young, stable psychosis patients with mild and tolerable side effects. Future studies should develop diverse VR content for older populations.

Individuals with long-term physical health conditions (LTCs) experience higher rates of depression and anxiety. Conventional self-report measures do not distinguish distress related to LTCs from primary mental health disorders. This difference is important as treatment protocols differ. We developed a transdiagnostic self-report measure of illness-related distress, applicable across LTCs.

The new Illness-Related Distress (IRD) scale was developed through thematic coding of interviews, systematic literature search, think-aloud interviews with patients and healthcare providers, and expert-consensus meetings. An internet sample (n = 1,398) of UK-based individuals with LTCs completed the IRD scale for psychometric analysis. We randomly split the sample (1:1) to conduct: (1) an exploratory factor analysis (EFA; n = 698) for item reduction, and (2) iterative confirmatory factor analysis (CFA; n = 700) and exploratory structural equation modeling (ESEM). Here, further item reduction took place to generate a final version. Measurement invariance, internal consistency, convergent, test–retest reliability, and clinical cut-points were assessed.

EFA suggested a 2-factor structure for the IRD scale, subsequently confirmed by iteratively comparing unidimensional, lower order, and bifactor CFAs and ESEMs. A lower-order correlated 2-factor CFA model (two 7-item subscales: intrapersonal distress and interpersonal distress) was favored and was structurally invariant for gender. Subscales demonstrated excellent internal consistency, very good test–retest reliability, and good convergent validity. Clinical cut points were identified (intrapersonal = 15, interpersonal = 12).

The IRD scale is the first measure that captures transdiagnostic distress. It may aid assessment within clinical practice and research related to psychological adjustment and distress in LTCs.

Second-generation antipsychotics (SGAs) cause metabolic side effects. However, patients’ metabolic profiles were influenced by time-invariant and time-varying confounders. Real-world evidence on the long-term, dynamic effects of SGAs (e.g. different treatment sequences) are limited. We employed advanced causal inference methods to evaluate the metabolic impact of SGAs in a naturalistic cohort.

We followed 696 Chinese patients with schizophrenia-spectrum disorders receiving SGAs. Longitudinal targeted maximum likelihood estimation (LTMLE) was used to estimate the average treatment effects (ATEs) of continuous SGA treatment versus ‘no treatment’ on metabolic outcomes, including total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), fasting glucose (FG), and body mass index (BMI), over 6–18 months at 3-month intervals. LTMLE accounted for time-invariant and time-varying confounders. Post-SGA discontinuation side effects were also assessed.

The ATEs of continuous SGA treatment on BMI and TG showed an inverted U-shaped pattern, peaking at 12 months and declining afterwards. Similar patterns were observed for TC and LDL, albeit the ATEs peaked at 15 months. For FG and HDL, the ATEs peaked at ~6 months. The adverse impact of SGAs on BMI persisted even after medication discontinuation, yet other metabolic parameters did not show such lingering side effects. Clozapine and olanzapine exhibited greater metabolic side effects compared to other SGAs.

Our real-world study suggests that metabolic side effects may stabilize with prolonged continuous treatment. Clozapine and olanzapine confer higher cardiometabolic risks than other SGAs. The side effects of SGAs on BMI may persist after drug discontinuation. These insights may guide antipsychotic choice and improve management of metabolic side effects.

Antisocial behavior (ASB) is relatively common in childhood and adolescence. While it harms victims, perpetrators are at increased risk of disadvantageous adult outcomes. Developmental heterogeneity is well documented; distinctions have been drawn between early-onset persistent, adolescent-onset, and childhood-limited pathways. We examine whether individuals in some pathways face worse mid-life outcomes than others and whether the pattern differs across sexes.

The 1970 British Cohort Study assessed parent-reported ASB measures at ages 5, 10, and 16. We classified developmental pathways using the Rutter A scale conduct questions. We categorized children scoring in the top 10% of the distribution as showing high ASB, separately at each assessment. Approximately 6000 individuals were classified into low (73%), childhood-limited (11%), adolescent-onset (9%), and early-onset persistent (7%) groups. We tested associations of ASB grouping with age 46 social, economic, and health outcomes, controlling for a range of covariates.

The childhood-limited group showed little mid-life difficulty. The early-onset persistent and adolescent-onset groups both showed a pattern of worse midlife outcomes for boys and girls.

The results highlight that ASB in young people is not transient and that prevention and treatment during early childhood and adolescence are warranted.

Functional Somatic Disorders (FSD) and Internalizing Psychiatric Disorders (IPD) are frequently comorbid and likely share familial/genetic risk factors.

We performed a Common Factor Multivariate Analysis of 2 FSDs, Fibromyalgia (FM) and Irritable Bowel Syndrome (IBS), and two IPDs, Major Depression (MD) and Anxiety Disorders (AD), in five kinds of Swedish female–female relative pairs: monozygotic (n = 8,052) dizygotic (n = 7216), full siblings (n = 712,762), half-siblings reared together (n = 23,623), and half-siblings reared apart (n = 53,873). Model fitting was by full information maximum likelihood using OpenMx.

The best-fit model included genetic, shared environmental, and unique environmental factors. The common factor, ~50% heritable with a small shared environmental effect, loaded more strongly on the two IPDs (~0.80) than the 2 FSDs (0.40). Disorder-specific genetic effects were larger for the 2 FSDs (~0.30) than the 2 IPDs (~0.03). Estimated genetic correlations were high for MD and AD (+0.91), moderate between IBS and IPDs (+0.62), and intermediate between FM and MD (+0.54), FM and AD (+0.28), and FM and IBS (+0.38). Shared environmental influences on all disorders were present but small.

In women, FSDs and IPDs shared a moderate proportion of their genetic risk factors, greater for IBS than for FM. However, the genetic sharing between IBS and FM was less than between MD and AD, suggesting that FSDs do not form a highly genetically coherent group of disorders. The shared environment made a modest contribution to the familial aggregation of FSDs and IPDs.

Functional disorders (FDs) are characterized by persistent somatic symptoms and are highly comorbid with internalizing disorders (IDs). To provide much-needed insight into FD etiology, we evaluated FD and ID familial coaggregation and shared familiality.

Lifelines is a three-generation cohort study, which assessed three FDs (myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS], irritable bowel syndrome [IBS], and fibromyalgia [FM]) and six IDs (major depressive disorder [MDD], dysthymia [DYS], generalized anxiety disorder [GAD], agoraphobia [AGPH], social phobia [SPH], and panic disorder [PD]) according to diagnostic criteria. Based on 153,803 individuals, including 90,397 with a first-degree relative in Lifelines, we calculated recurrence risk ratios (λRs) and tetrachoric correlations to evaluate familial aggregation and coaggregation of these disorders in first-degree relatives. We then estimated their familiality and familial correlations.

Familial aggregation was observed across disorders, with λR ranging from 1.45 to 2.23 within disorders and from 1.17 to 1.94 across disorders. Familiality estimates ranged from 22% (95% confidence interval [CI]: 16–29) for IBS to 42% (95% CI: 33–50) for ME/CFS. Familial correlations ranged from +0.37 (95% CI: 0.24–0.51) between FM and AGPH to +0.97 (95% CI: 0.80–1) between ME/CFS and FM. The highest familial correlation between an ID and FD was +0.83 (95% CI: 0.66–0.99) for MDD and ME/CFS.

There is a clear familial component to FDs, which is partially shared with IDs. This suggests that IDs and FDs share both genetic and family-environmental risk factors. Of the FDs, ME/CFS is most closely related to IDs.

Many studies have highlighted the detrimental effect of childhood maltreatment (CM) on depression severity and the course of illness in major depressive disorder (MDD). Yet our understanding of how CM influences the dynamic symptom change throughout a patient’s trajectory remains limited. Hence, we investigated the impact of CM on depression severity in MDD with a focus on various treatment phases during inpatient treatment and after discharge (1 or 2 years later) and validated findings in a real-world setting.

We used longitudinal data from a cohort study sample (n = 567) and a clinical routine sample (n = 438). CM was measured with the Childhood Trauma Questionnaire (CTQ), and depression severity was assessed using Beck’s Depression Inventory (BDI). The long-term clinical trajectory was assessed using the Life Chart Interview.

Our analyses revealed that CM significantly increased depression severity before, during, and after inpatient therapy in both samples. Although CM was associated with higher depression severity at the beginning of inpatient treatment and lower remission rates upon discharge, no discernible impact of CM was evident on the relative change in symptoms over time during inpatient treatment. CM consistently predicted higher relapse rates and lower rates of full remission after discharge during long-term follow-up in both samples.

Our findings affirm the link between CM and the development of more severe and persistent clinical trajectories within real-world clinical settings. Furthermore, conventional psychiatric treatments may not lead to comparable outcomes for individuals with a history of CM, underscoring the necessity for tailored therapeutic interventions.

Mental health problems are the major cause of disability among adolescents. Personalized prevention may help to mitigate the development of mental health problems, but no tools are available to identify individuals at risk before they require mental health care.

We identified children without mental health problems at baseline but with six different clinically relevant problems at 1- or 2-year follow-up in the Adolescent Brain Cognitive Development (ABCD) study. We used machine learning analysis to predict the development of these mental health problems with the use of demographic, symptom and neuroimaging data in a discovery (N = 3236) and validation (N = 3851) sample. The discovery sample (N = 168–513 per group) consisted of participants with MRI data and were matched with healthy controls on age, sex, IQ, and parental education level. The validation sample (N = 84–231) consisted of participants without MRI data.

Subclinical symptoms at 9–10 years of age could accurately predict the development of six different mental health problems before the age of 12 in the discovery and validation sample (AUCs = 0.71–0.90). The additive value of neuroimaging in the discovery sample was limited. Multiclass prediction of the six groups showed considerable misclassification, but subclinical symptoms could accurately differentiate between the development of externalizing and internalizing problems (AUC = 0.79).

These results suggest that machine learning models can predict conversion to mental health problems during a critical period in childhood using subclinical symptoms. These models enable the personalization of preventative interventions for children at increased risk, which may reduce the incidence of mental health problems.

Adolescence is a key developmental period associated with an increased risk of experiencing cannabis-related problems. Identifying modifiable risk factors prior to the onset of cannabis use could help inform preventative interventions.

Analysis nested within a UK prospective birth cohort study, the Avon Longitudinal Study of Parents and Children. Participants (n = 6,049) provided data on cannabis use and symptoms of cannabis problems using the Cannabis Abuse Screening Test at two or more time points between the ages of 15–24 years. Risk factors included internalizing and externalizing disorders assessed at age 10 years, and cognitive function assessed at age 8 years via short-term memory, emotion recognition, divided attention, and listening comprehension.

Participants were mostly female (59.1%) and white (95.73%). Five patterns of adolescent cannabis use problems were identified using longitudinal latent class analysis: stable-no problems (n = 5,157, 85%), early-onset high (n = 104, 2%), late-onset high (n = 153, 3%), early onset low (n = 348, 6%), and late-onset low (n = 287, 5%). In adjusted models, externalizing disorders were associated with early-onset high [RR, 95% CI: 2.82 (1.72, 4.63)], late-onset high [RR, 95% CI: 1.62 (1.02, 2.57)], and early-onset low [RR, 95% CI: 1.82 (1.30, 2.55)] compared to the stable-no problems class. Internalizing disorders were associated with late-onset low only [RR, 95% CI: .50 (.26, .96)], and short-term memory with late-onset high only [RR, 95% CI: 1.09 (1.01, 1.18) compared to the stable-no problems class.

Childhood externalizing disorders were consistently associated with increased risk of problematic patterns of cannabis use over adolescence, particularly early-onset and high levels of problems.

Offspring of parents with bipolar disorder (BD offspring) face elevated risks for emotional dysregulation and cognitive deficits, particularly in working memory. This study investigates working memory deficits and their neural correlates in BD offspring.

We assessed 41 BD offspring and 25 age-matched healthy controls (HCs) using a spatial N-back task and task-related functional magnetic resonance imaging (fMRI).

Compared to HCs, BD offspring exhibit reduced accuracy and lower signal-detection sensitivity (d′) on the 1-back task. fMRI reveals hyperactivation in the right intracalcarine cortex/lingual gyrus (ICC/LG) in BD offspring, particularly during the 1-back condition. Psychophysiological interaction (PPI) analyses show reduced connectivity between the right ICC/LG and the left postcentral gyrus in BD offspring as task load increases from 0-back to 1-back. This connectivity positively correlates with 1-back task performance in HCs but not in BD offspring. Additionally, using bilateral dorsolateral prefrontal cortex (DLPFC) as regions of interest, PPI analyses show diminished condition-dependent connectivity between the left DLPFC and the left superior frontal gyrus/paracingulate cortex, and between the right DLPFC and the left postcentral gyrus/precentral gyrus in BD offspring as the task load increases.

These findings suggest that BD offspring exhibit working memory deficits and impaired neural connectivity involving both sensory processing and higher-order cognitive systems. Such deficits may emerge at a genetically predisposed stage of bipolar disorder, underscoring the significance of early identification and intervention strategies.

The relationship between emotional symptoms and cognitive impairments in major depressive disorder (MDD) is key to understanding cognitive dysfunction and optimizing recovery strategies. This study investigates the relationship between subjective and objective cognitive functions and emotional symptoms in MDD and evaluates their contributions to social functioning recovery.

The Prospective Cohort Study of Depression in China (PROUD) involved 1,376 MDD patients, who underwent 8 weeks of antidepressant monotherapy with assessments at baseline, week 8, and week 52. Measures included the Hamilton Depression Rating Scale (HAMD-17), Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), Chinese Brief Cognitive Test (C-BCT), Perceived Deficits Questionnaire for Depression-5 (PDQ-D5), and Sheehan Disability Scale (SDS). Cross-lagged panel modeling (CLPM) was used to analyze temporal relationships.

Depressive symptoms and cognitive measures demonstrated significant improvement over 8 weeks (p < 0.001). Baseline subjective cognitive dysfunction predicted depressive symptoms at week 8 (HAMD-17: β = 0.190, 95% CI: 0.108–0.271; QIDS-SR16: β = 0.217, 95% CI: 0.126–0.308). Meanwhile, baseline depressive symptoms (QIDS-SR16) also predicted subsequent subjective cognitive dysfunction (β = 0.090, 95% CI: 0.003-0.177). Recovery of social functioning was driven by improvements in depressive symptoms (β = 0.384, p < 0.0001) and subjective cognition (β = 0.551, p < 0.0001), with subjective cognition contributing more substantially (R2 = 0.196 vs. 0.075).

Subjective cognitive dysfunction is more strongly associated with depressive symptoms and plays a significant role in social functioning recovery, highlighting the need for targeted interventions addressing subjective cognitive deficits in MDD.

Genetic and environmental factors, including adverse childhood experiences (ACEs), contribute to substance use disorders (SUDs). However, the interactions between these factors are poorly understood.

We examined associations between SUD polygenic scores (PGSs), ACEs, and the initiation of use and severity of alcohol (AUD), opioid use disorder (OUD), and cannabis use disorder (CanUD) in 10,275 individuals (43.5% female, 47.2% African-like ancestry [AFR], and 52.8% European-like ancestry [EUR]). ACEs and SUD severity were modeled as latent factors. We conducted logistic and linear regressions within ancestry groups to examine the associations of ACEs, PGS, and their interaction with substance use initiation and SUD severity.

All three SUD PGS were associated with ACEs in EUR individuals, indicating a gene–environment correlation. Among EUR individuals, only the CanUD PGS was associated with initiating use, whereas ACEs were associated with initiating use of all three substances in both ancestry groups. Additionally, a negative gene-by-environment interaction was identified for opioid initiation in EUR individuals. ACEs were associated with all three SUD severity latent factors in EUR individuals and with AUD and CanUD severity in AFR individuals. PGS were associated with AUD severity in both ancestry groups and with CanUD severity in AFR individuals. Gene-by-environment interactions were identified for AUD and CanUD severity among EUR individuals.

Findings highlight the roles of ACEs and polygenic risk in substance use initiation and SUD severity. Gene-by-environment interactions implicate ACEs as moderators of genetic susceptibility, reinforcing the importance of considering both genetic and environmental influences on SUD risk.

Previous evidence has reported associations of a polygenic risk score for schizophrenia (PRSSCZ) with negative developmental outcomes, such as psychiatric symptoms, adverse health behaviors, and reduced everyday functioning. We now investigated the relationship of PRSSCZ with subjectively experienced well-being.

Participants (n = 1866) came from the prospective population-based Young Finns Study (YFS). Subjective well-being in adulthood was assessed in terms of life satisfaction, optimism, and self-acceptance (when participants were 20–50 years old). A PRSSCZ was calculated based on the most recent genome-wide association study on schizophrenia. Covariates included age, sex, early family environment, adulthood socioeconomic factors, and adulthood health behaviors.

The PRSSCZ did not predict any domain of subjective well-being, including life satisfaction, optimism, and self-acceptance. After adding covariates in a stepwise manner or including/excluding participants with diagnosed non-affective psychotic disorders, all the associations remained non-significant. Age- and sex-interaction analyses showed that PRSSCZ was not associated with subjective well-being in either sex or in any age between 20 and 50 years.

While high PRSSCZ has been linked to multiple adversities in previous studies, we did not find any association between high PRSSCZ and subjective measures of life satisfaction, optimism, and self-acceptance.

Nutraceuticals have been taken as an alternative and add-on treatment for depressive disorders. Direct comparisons between different nutraceuticals and between nutraceuticals and placebo or antidepressants are limited. Thus, it is unclear which nutraceuticals are the most efficacious.

We conducted a network meta-analysis to estimate the comparative efficacy and tolerability of nutraceuticals for the treatment of depressive disorder in adults. The primary outcome was the change in depressive symptoms, as measured by the standard mean difference (SMD). Secondary outcomes included response rate, remission rate, and anxiety. Tolerability was defined as all-cause discontinuation and adverse events. Frequentist random-effect NMA was conducted.

Hundred and ninety-two trials involving 17,437 patients and 44 nutraceuticals were eligible for inclusion. Adjunctive nutraceuticals consistently showed better efficacy than antidepressants (ADT) alone in outcomes including SMD, remission, and response. Notable combinations were Eicosapentaenoic acid + Docosahexaenoic Acid plus ADT (EPA + DHA + ADT) (SMD 1.04, 95% confidence interval 0.64–1.44), S-Adenosyl Methionine (SAMe) + ADT (0.99, 0.31–1.68), curcumin + ADT (1.03, 0.55–1.51), Zinc + ADT (1.59, 0.63–2.55), tryptophan + ADT (1.24, 0.32–2.16), and folate + ADT (0.64, 0.17–1.10). Additionally, four nutraceutical monotherapies demonstrated superior efficacy compared to ADT: EPA + DHA (0.6, 0.32–0.88), SAMe (0.52, 0.18–0.87), curcumin (0.62, −0.17 to 1.40) and saffron (0.69, 0.34–1.04). It is noted that EPA + DHA, SAMe, and curcumin showed strong performance as either monotherapies or adjuncts to ADT. Most nutraceuticals showed comparable tolerability to placebo.

This extensive systematic review and NMA of nutraceuticals for treating depressive disorders indicated a number of nutraceuticals that could offer benefits, either as adjuncts or monotherapies.

The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology. We used a multi-omics approach to examine how HiTOP’s psychopathology spectra (externalizing [EXT], internalizing [INT], and shared EXT + INT) map onto RDoC’s units of analysis.

We conducted analyses across five RDoC units of analysis: genes, molecules, cells, circuits, and physiology. Using genome-wide association studies from the companion Part I article, we identified genes and tissue-specific expression patterns. We used drug repurposing analyses that integrate gene annotations to identify potential therapeutic targets and single-cell RNA sequencing data to implicate brain cell types. We then used magnetic resonance imaging data to examine brain regions and circuits associated with psychopathology. Finally, we tested causal relationships between each spectrum and physical health conditions.

Using five gene identification methods, EXT was associated with 1,759 genes, INT with 454 genes, and EXT + INT with 1,138 genes. Drug repurposing analyses identified potential therapeutic targets, including those that affect dopamine and serotonin pathways. Expression of EXT genes was enriched in GABAergic, cortical, and hippocampal neurons, while INT genes were more narrowly linked to GABAergic neurons. EXT + INT liability was associated with reduced gray matter volume in the amygdala and subcallosal cortex. INT genetic liability showed stronger causal effects on physical health – including chronic pain and cardiovascular diseases – than EXT.

Our findings revealed shared and distinct pathways underlying psychopathology. Integrating genomic insights with the RDoC and HiTOP frameworks advanced our understanding of mechanisms that underlie EXT and INT psychopathology.

There is considerable comorbidity between externalizing (EXT) and internalizing (INT) psychopathology. Understanding the shared genetic underpinnings of these spectra is crucial for advancing knowledge of their biological bases and informing empirical models like the Research Domain Criteria (RDoC) and Hierarchical Taxonomy of Psychopathology (HiTOP).

We applied genomic structural equation modeling to summary statistics from 16 EXT and INT traits in individuals genetically similar to European reference panels (EUR-like; n = 16,400 to 1,074,629). Traits included clinical (e.g. major depressive disorder, alcohol use disorder) and subclinical measures (e.g. risk tolerance, irritability). We tested five confirmatory factor models to identify the best fitting and most parsimonious genetic architecture and then conducted multivariate genome-wide association studies (GWAS) of the resulting latent factors.

A two-factor correlated model, representing EXT and INT spectra, provided the best fit to the data. There was a moderate genetic correlation between EXT and INT (r = 0.37, SE = 0.02), with bivariate causal mixture models showing extensive overlap in causal variants across the two spectra (94.64%, SE = 3.27). Multivariate GWAS identified 409 lead genetic variants for EXT, 85 for INT, and 256 for the shared traits.

The shared genetic liabilities for EXT and INT identified here help to characterize the genetic architecture underlying these frequently comorbid forms of psychopathology. The findings provide a framework for future research aimed at understanding the shared and distinct biological mechanisms underlying psychopathology, which will help to refine psychiatric classification systems and potentially inform treatment approaches.

Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs.

Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration.

Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience.

Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.