Studies that examined sex differences in first-episode patients consistently show that males compared to females have poor premorbid adjustment, earlier age of onset, worse clinical characteristics, and poorer outcomes. However, little is known about potential mediators that could explain these sex differences.

Our sample consisted of 137 individuals with first episode schizophrenia (males, n = 105; 77%) with a mean age of 22.1(s.d. = 4.1) years and mean education of 12.5(s.d. = 1.7) years. At entry, patients were within 2 years of their first psychotic episode onset. Baseline assessments were conducted for premorbid adjustment, symptoms, cognitive functioning, insight, and at 6-months for role and social functioning.

Males as compared to females had poorer premorbid adjustment across several key developmental periods (p < 0.01), an earlier age of onset [M = 20.3(3.3) v. 22.8(5.6), p = 0.002], more negative symptoms (p = 0.044), poorer insight (p = 0.031), and poorer baseline and 6-month role (p = 0.002) and social functioning (p = 0.034). Several of these variables in which males showed impairment were significant predictors of 6-month role and social functioning. Premorbid adjustment and insight mediated the relationship between sex and role and social functioning at 6-months, but not negative symptoms.

Males compared to females were at lower levels across several key premorbid and clinical domains which are strongly associated with functional outcome supporting the hypothesis that males might have a more disabling form of schizophrenia. The relationship between sex with role and social functioning was mediated through premorbid adjustment and insight suggesting pathways for understanding why females might have a less disabling form of schizophrenia.

Previous research has examined the role of parental religious belief in offspring mental health, but has revealed inconsistent results, and suffered from a number of limitations. The aim of this study is to examine the prospective relationship between maternal religiosity and offspring mental health and psychosocial outcomes.

We used latent classes of religious belief (Highly religious, Moderately religious, Agnostic, Atheist) in mothers from the Avon Longitudinal Study of Parents and Children from 1990, and examined their association with parent-reported mental health outcomes and self-reported psychosocial outcomes in their children at age 7–8 (n = 6079 for mental health outcomes and n = 5235 for psychosocial outcomes). We used inverse probability weighted multivariable logistic regression analysis adjusted for maternal mental health, adverse childhood experience, and socioeconomic variables.

There was evidence for a greater risk of internalising problems among the offspring of the Highly religious and Moderately religious classes [e.g. for depression; OR 1.40. 95% CI (1.07–1.85), OR 1.48, 95% CI (1.17–1.87)], and greater risk of externalising problems in the offspring of the Atheist class [e.g. for ADHD; OR 1.41, 95% CI (1.08–1.85)], compared to the offspring of the Agnostic class.

These novel findings provide evidence associations between maternal religiosity and offspring mental health differ when examined using a person-centred approach, compared to the previously used variable-centred approaches. Our findings also suggest that differences may exist in the relationship between religious (non)belief and mental health variables when comparing the UK and US.

This study tested whether the dissonance-based Body Project eating disorder prevention program reduced onset of subthreshold/threshold anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and purging disorder (PD) over long-term follow-up.

Data were combined from three prevention trials that targeted young women at high-risk for eating disorders (N = 1092; M age = 19.3). Participants were randomized to Body Project groups led by peer educators or expressive writing/educational controls and completed masked diagnostic interviews over 2- to 4-year follow-ups. Logistic regressions tested whether onset of each eating disorder over follow-up differed between Body Project and control participants.

Peer-led Body Project groups produced a 46% reduction in onset of subthreshold/threshold BN and a 62% reduction in onset of PD relative to controls over follow-up. Rates of onset of subthreshold/threshold AN and BED did not significantly differ between peer-led Body Project participants and control participants.

Results support the dissemination of the peer-led Body Project for reducing future onset of BN and PD. This study and recent research suggest that thin-ideal internalization, the risk factor for eating disorders targeted in the Body Project, may be more relevant for predicting onset of BN and PD compared to AN and BED. Findings support the development of a version of the Body Project aimed to reduce risk factors that have predicted future onset of all four types of eating disorders (e.g. overvaluation of weight/shape, fear of weight gain), which may more effectively prevent all eating disorder types.

To determine, in a general population, how much rates of stress reactions (SR), major depression (MD), alcohol-use disorder (AUD) and drug-use disorder (DUD) increase after the death of close relatives.

SR, MD, AUD, and DUD registrations were assessed from national Swedish registries. From the population followed from 2000 to 2018, those exposed to death of a close relative in 2002–2016 were matched to unexposed controls and analyzed in males and females by a controlled pre-post design using a difference-in-difference method.

Substantial, brief increases in risk for SR and more modest prolonged increases in MD were observed after death of relatives in both men and women greatest with children, followed by spouses, parents, and siblings. Relatively long-lasting modest increases in AUD but not DUD were also observed following death of relatives. The absolute increases for SR and MD were greater in females than males and for AUD greater in males than females. However, logistic regression analyses showed most effects did not differ significantly by sex. Consistently larger increases in disorder risk were seen with the death of younger v. older parents, siblings, and spouses and with accidental v. non-accidental death in children.

Applying a matched cohort design to Swedish population registries, death of close relatives was associated with, and likely caused, substantial increases in rates of SR, MD, and AUD, consistent with smaller prior clinical investigations. Through such registries, we can, in large representative samples, integrate the impact of exposures to selected environmental adversities into disorder risk pathways.

The diagnostic concept of unipolar mania (UM), i.e. the lifetime occurrence of mania without major depressive episodes, remains a topic of debate despite the evidence accumulated in the last few years. We carried out a systematic review and meta-analysis of observational studies testing factors associated with UM as compared to bipolar disorder with a manic-depressive course (md-BD).

Studies indexed up to July 2022 in main electronic databases were searched. Random-effects meta-analyses of the association between UM and relevant correlates yielded odds ratio (OR) or standardized mean difference (SMD), with 95% confidence intervals (CIs).

Based on data from 21 studies, factors positively or negatively associated with UM, as compared to md-BD, were: male gender (OR 1.47; 95% CI 1.11–1.94); age at onset (SMD −0.25; 95% CI −0.46 to −0.04); number of hospitalizations (SMD 0.53; 95% CI 0.21–0.84); family history of depression (OR 0.55; 95% CI 0.36–0.85); suicide attempts (OR 0.25; 95% CI 0.19–0.34); comorbid anxiety disorders (OR 0.35; 95% CI 0.26–0.49); psychotic features (OR 2.16; 95% CI 1.55–3.00); hyperthymic temperament (OR 1.99; 95% CI 1.17–3.40). The quality of evidence for the association with previous suicide attempts was high, moderate for anxiety disorders and psychotic features, and low or very low for other correlates.

Despite the heterogeneous quality of evidence, this work supports the hypothesis that UM might represent a distinctive diagnostic construct, with peculiar clinical correlates. Additional research is needed to better differentiate UM in the context of affective disorders, favouring personalized care approaches.

Cumulative burden from vascular risk factors (VRFs) has been associated with an increased risk of depressive symptoms in mid- and later life. It has been hypothesised that this association arises because VRFs disconnect fronto-subcortical white matter tracts involved in mood regulation, which puts older adults at higher risk of developing depressive symptoms. However, evidence for the hypothesis that disconnection of white matter tracts underlies the association between VRF burden and depressive symptoms from longitudinal studies is scarce.

This preregistered study analysed longitudinal data from 6,964 middle-aged and older adults from the UK Biobank who participated in consecutive assessments of VRFs, brain imaging, and depressive symptoms. Using mediation modelling, we directly tested to what extend white matter microstructure mediates the longitudinal association between VRF burden and depressive symptoms.

VRF burden showed a small association with depressive symptoms at follow-up. However, there was no evidence that fractional anisotropy (FA) of white matter tracts mediated this association. Additional analyses also yielded no mediating effects using alternative operationalisations of VRF burden, mean diffusivity (MD) of single tracts, or overall average of tract-based white matter microstructure (global FA, global MD, white matter hyperintensity volume).

Our results lend no support to the hypothesis that disconnection of white matter tracts underlies the association between VRF burden and depressive symptoms, while highlighting the relevance of using longitudinal data to directly test pathways linking vascular and mental health.

Dynamic interpersonal therapy (DIT) is a brief, structured psychodynamic psychotherapy with demonstrated efficacy in treating major depressive disorder (MDD). The aim of the study was to determine whether DIT is an acceptable and efficacious treatment for MDD patients in China.

Patients were randomized to 16-week treatments with either DIT plus antidepressant medication (DIT + ADM; n = 66), general supportive therapy plus antidepressant medication (GST + ADM; n = 75) or antidepressant medication alone (ADM; n = 70). The Hamilton Depression Rating Scale (HAMD) administered by blind raters was the primary efficacy measure. Assessments were completed during the acute 16-week treatment and up to 12-month posttreatment.

The group × time interaction was significant for the primary outcome HAMD (F = 2.900, df1 = 10, df2 = 774.72, p = 0.001) in the acute treatment phase. Pairwise comparisons showed a benefit of DIT + ADM over ADM at weeks 12 [least-squares (LS) mean difference = −3.161, p = 0.007] and 16 (LS mean difference = −3.237, p = 0.004). Because of the unexpected high attrition during the posttreatment follow-up phase, analyses of follow-up data were considered exploratory. Differences between DIT + ADM and ADM remained significant at the 1-, 6-, and 12-month follow-up (ps range from 0.001 to 0.027). DIT + ADM had no advantage over GST + ADM during the acute treatment phase. However, at the 12-month follow-up, patients who received DIT remained less depressed.

Acute treatment with DIT or GST in combination with ADM was similarly efficacious in reducing depressive symptoms and yielded a better outcome than ADM alone. DIT may provide MDD patients with long-term benefits in symptom improvement but results must be viewed with caution.

Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms.

We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition.

Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31–40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found.

We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.

Vaccine-preventable conditions cause preventable illness and may increase mortality in people living with mental illness. We examined how risks of hospitalisation for a wide range of vaccine-preventable conditions varied by age and sex among mental health (MH) service users.

Linked population data from New South Wales (NSW), Australia were used to identify vaccine-preventable hospitalisations (VPH) for 19 conditions from 2015 to 2020. Adult MH service users (n = 418 915) were compared to other NSW residents using incidence rates standardised for age, sex and socioeconomic status. Secondary analyses examined admissions for COVID-19 to September 2021.

We identified 94 180 VPH of which 41% were influenza, 33% hepatitis B and 10% herpes zoster. MH service users had more VPH admissions [adjusted incidence rate ratio (aIRR) 3.2, 95% CI 3.1–3.3]. Relative risks were highest for hepatitis (aIRR 4.4, 95% CI 4.3–4.6), but elevated for all conditions including COVID-19 (aIRR 2.0, 95% CI 1.9–2.2). MH service users had a mean age of 9 years younger than other NSW residents at first VPH admission, with the largest age gap for vaccine-preventable pneumonias (11–13 years younger). The highest relative risk of VPH was among MH service users aged 45–65.

MH service users have increased risk of hospitalisation for many vaccine-preventable conditions. This may be due to reduced vaccination rates, more severe illness requiring hospitalisation, greater exposure to infectious conditions or other factors. People living with mental illness should be prioritised in vaccination strategies.

The aetiology of dual harm (co-occurring self-harm and violence towards others) is poorly understood because most studies have investigated self-harm and violence separately. We aimed to examine childhood risk factors for self-harm, violence, and dual harm, including the transition from engaging in single harm to dual harm.

Data from the Avon Longitudinal Study of Parents and Children, a UK-based birth cohort study, were used to estimate prevalence of self-reported engagement in self-harm, violence, and dual harm at ages 16 and 22 years. Risk ratios were calculated to indicate associations across various self-reported childhood risk factors and risks of single and dual harm, including the transition from single harm at age 16 years to dual harm at age 22.

At age 16 years, 18.1% of the 4176 cohort members had harmed themselves, 21.1% had engaged in violence towards others and 3.7% reported dual harm. At age 22 the equivalent prevalence estimates increased to 24.2, 25.8 and 6.8%, respectively. Depression and other mental health difficulties, drug and alcohol use, witnessing self-harm and being a victim of, or witnessing, violence were associated with higher risks of transitioning from self-harm or violence at age 16 to dual harm by age 22.

Prevalence of dual harm doubled from age 16 to 22 years, highlighting the importance of early identification and intervention during this high-risk period. Several childhood psychosocial risk factors associated specifically with dual harm at age 16 and with the transition to dual harm by age 22 have been identified.

A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations.

Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE.

In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI.

The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome.

157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS−).

We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS− group. Neurocognitive performance was generally comparable in PS+ and PS− groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS− counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change.

Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN.

Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147).

In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected.

A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Little has been done to comprehensively study the relationships between multiple well-being constructs at a time. Even less is known about whether child maltreatment and major depressive disorder (MDD) impact different well-being constructs. This study aims to examine whether maltreated or depressed individuals have specific impacts on well-being structures.

Data analyzed were from the Montreal South-West Longitudinal Catchment Area Study (N = 1380). The potential confounding of age and sex was controlled by propensity score matching. We used network analysis to assess the impact of maltreatment and MDD on well-being. The centrality of nodes was estimated with the ‘strength’ index and a case-dropping bootstrap procedure was used to test network stability. Differences in the structure and connectivity of networks between different studied groups were also examined.

Autonomy and daily life and social relations were the most central nodes for the MDD and maltreated groups [MDD group: strength coefficient (SC)autonomy = 1.50; SCdaily life and social relations = 1.34; maltreated group: SCautonomy = 1.69; SCdaily life and social relations = 1.55]. Both maltreatment and MDD groups had statistical differences in terms of the global strength of interconnectivity in their networks. Network invariance differed between with and without MDD groups indicating different structures of their networks. The non-maltreatment and MDD group had the highest level of overall connectivity.

We discovered distinct connectivity patterns of well-being outcomes in maltreatment and MDD groups. The identified core constructs could serve as potential targets to maximize the effectiveness of clinical management of MDD and also advance prevention to minimize the sequelae of maltreatment.

Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings.

Case–control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST).

Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99–2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10–3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77–12.47), early age of first use (adj. OR 1.83, 95% CI 1.03–3.27). Cannabis use in the other two settings was too rare to examine associations.

In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.

Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct.

In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e).

An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26–39% of total phenotypic variance; 69–74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance.

Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.

Accumulating evidence suggests that positive and negative emotions, as well as emotion regulation, play key roles in human health and disease. Recent work has shown the gut microbiome is important in modulating mental and physical health through the gut–brain axis. Yet, its association with emotions and emotion regulation are understudied. Here we examined whether positive and negative emotions, as well as two emotion regulation strategies (i.e. cognitive reappraisal and suppression), were associated with the gut microbiome composition and functional pathways in healthy women.

Participants were from the Mind-Body Study (N = 206, mean age = 61), a sub-study of the Nurses' Health Study II cohort. In 2013, participants completed measures of emotion-related factors. Two pairs of stool samples were collected, 6 months apart, 3 months after emotion-related factors measures were completed. Analyses examined associations of emotion-related factors with gut microbial diversity, overall microbiome structure, and specific species/pathways and adjusted for relevant covariates.

Alpha diversity was negatively associated with suppression. In multivariate analysis, positive emotions were inversely associated with the relative abundance of Firmicutes bacterium CAG 94 and Ruminococcaceae bacterium D16, while negative emotions were directly correlated with the relative abundance of these same species. At the metabolic pathway level, negative emotions were inversely related to the biosynthesis of pantothenate, coenzyme A, and adenosine.

These findings offer human evidence supporting linkages of emotions and related regulatory processes with the gut microbiome and highlight the importance of incorporating the gut microbiome in our understanding of emotion-related factors and their associations with physical health.