Decades of research have identified a strong association between heavy cannabis use and schizophrenia (SCZ), with evidence of correlated genetic factors. However, many studies on the genetic relationship between cannabis use and psychosis have lacked data on both phenotypes within the same individuals, creating challenges due to unmeasured confounding. We aimed to address this by using multimodal data from the All of Us Research Program, which contains genetic data as well as information on SCZ diagnosis and cannabis use.

We tested the association between cannabis use disorder (CUD) and SCZ polygenic scores (PGSs) with SCZ and heavy cannabis use. We tested models where both CUD and SCZ PGSs were included as joint predictors of heavy cannabis use and SCZ case status. We defined three sets of cases based on comorbidities: relaxed (assessing for only the primary condition), strict (excluding comorbidity), and dual-comorbidity.

CUD and SCZ polygenic liability were independently associated with heavy cannabis use; the SCZ PGS effect was very modest. In contrast, both SCZ and CUD PGSs were independently associated with SCZ, with independent significant effects of CUD PGS. Polygenic liability to CUD was associated with SCZ in individuals without a documented history of cannabis use, suggesting widespread pleiotropy.

These findings underscore the need for comprehensive models that integrate genetic risk factors for heavy cannabis use to advance our understanding of SCZ etiology.

AVATAR therapy, a digitally supported intervention, utilises avatars to promote recovery in people who experience distressing auditory hallucinations. This approach was recently evaluated in a multicentre randomised controlled trial comparing brief (AV-BRF) and extended (AV-EXT) forms of therapy with treatment as usual (TAU). There was evidence for the effectiveness of therapy, particularly for AV-EXT. However, value for money needs to be assessed.

To compare separately the cost utility of the brief and extended forms of AVATAR therapy with TAU.

In a three-arm randomised controlled trial the use of health services was measured, and costs (2021/2022; pounds sterling) calculated from a health and social care perspective over a 28-week follow-up period. Quality-adjusted life years (QALYs; derived from the 5-level version of the EuroQol 5-Dimension questionnaire) were combined with costs.

AV-BRF resulted in extra costs of £319 (95% CI, −£1558 to £2496), and AV-EXT in lower costs of £1965 (95% CI, −£1912 to £1519), compared with TAU. Over the follow-up, AV-BRF resulted in 0.0159 (95% CI, −0.0103 to 0.0422) and AV-EXT in 0.0173 (95% CI, −0.0049 to 0.0395) more QALYs than TAU. The cost per QALY for AV-BRF compared with TAU was £20 016, while AV-EXT dominated TAU (lower costs and more QALYs).

Neither version of AVATAR had a substantial impact on QALYs. However, AV-EXT did result in reduced care costs − albeit not statistically significant − and was potentially cost-effective compared with TAU. AV-BRF had an incremental cost-effectiveness ratio that indicated lower potential cost-effectiveness. These findings are uncertain, but could still inform decision-making regarding interventions in this field.

Clinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline.

To investigate cortical volume longitudinal deviations in first-episode psychosis (FEP) using normative modelling, exploring their relationship with long-term cognitive and symptomatic outcomes, as well as their cytoarchitectural and neurobiological underpinnings.

We collected magnetic resonance imaging (MRI), cognitive and symptomatic data from 195 healthy controls and 357 drug-naïve or minimally medicated FEP individuals that were followed up 1, 3, 5 and 10 years following the first episode (1209 MRI scans and assessments in total). Using normative modelling, we derived subject-specific centile scores for cortical volume to investigate atypical deviations in FEP and their relationship to long-term cognitive and symptomatic deterioration. The resulting centile association maps were further characterised by examining their cytoarchitectural and neurobiological attributes using normative atlases.

FEP centiles demonstrated a widespread reduction at treatment initiation, with longitudinal analysis showing an increase during treatment time, indicating convergence towards normal maturation trajectories. Interestingly, this effect was reduced in highly medicated individuals. Additionally, we found that cognitive impairments experienced during early FEP stages worsened under long-term medication. Positive symptomatology was negatively associated with regional centiles, and individuals with higher centiles benefited most from treatment. Cytoarchitectural and neurobiological analyses revealed that regional centiles related to FEP, as well as to symptomatology, were associated with specific molecular features, such as regional serotonin and dopamine receptor densities.

Collectively, these findings underscore the potential use of centile-based normative modelling for a better understanding of how atypical cortical development contributes to the long-term clinical progression of neurodevelopmental conditions.

According to existing evidence, during menopause transition, women with psychosis may present with exacerbated psychiatric symptoms, due to age-related hormonal changes.

We aimed to (a) replicate this evidence, using age as a proxy for peri/menopausal status; (b) investigate how clinical presentation is affected by concomitant factors, including hyperprolactinaemia, dose and metabolism of prescribed antipsychotics using cross-sectional and longitudinal analyses.

Secondary analysis on 174 women aged 18–65, from the IMPaCT (Improving physical health and reducing substance use in psychosis) randomised controlled trial. We compared women aged below (N = 65) and above 40 (N = 109) for (a) mental health status with the Positive and Negative Syndrome Scale (PANSS) and Montgomery Asberg Depression Rating Scale; (b) current medications and (c) prolactin levels, at baseline and at follow-up (12/15 months later).

Women aged above 40 showed higher baseline PANSS total score (mean ± s.d. = 53.4 ± 14.1 v. 48.0 ± 13.0, p = 0.01) and general symptoms scores (28.0 ± 7.4 v. 25.7 ± 7.8, p = 0.03) than their younger counterparts. Progressive sub-analysis revealed that this age-related difference was observed only in women with non-affective psychosis (n = 93) (PANSS total score: 57.1 ± 13.6 v. 47.0 ± 14.4, p < 0.005) and in those prescribed antipsychotic monotherapy with olanzapine or clozapine (n = 25) (PANSS total score: 63 ± 16.4 v. 42.8 ± 10.9, p < 0.05).

Among all women with hyperprolactinaemia, those aged above 40 also had higher PANSS positive scores than their younger counterparts. No longitudinal differences were found between age groups.

Women aged above 40 showed worse psychotic symptoms than younger women. This difference seems diagnosis-specific and may be influenced by antipsychotics metabolism. Further longitudinal data are needed considering the menopause transition.

Insight into psychosis is a multidimensional construct involving awareness of illness, attribution of symptoms, and perceived need for treatment. Despite extensive research, substantial variability in how insight is conceptualized and measured continues to hinder clinical assessment and cross-study comparisons.

Following Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines and a registered International Prospective Register of Systematic Reviews protocol (CRD42024558386), we conducted a systematic search across five databases (n = 2,184). Twenty-nine studies met the inclusion criteria, comprising 15 primary scale development papers and 10 independent validation studies. We included instruments explicitly designed to assess insight in schizophrenia-spectrum, and evaluated them using the COnsensus-based Standards for the selection of health Measurement INstruments Risk of Bias checklist. Psychometric domains assessed included content validity, structural validity, construct validity, criterion validity, internal consistency, reliability, responsiveness, and interpretability.

Fifteen distinct insight scales were identified, comprising nine clinician-rated instruments, five self-report tools, and one hybrid format. Most demonstrated adequate content and structural validity, with 11 achieving ‘very good’ reliability ratings. Four scales showed the strongest overall psychometric support. However, responsiveness to clinical change was rarely tested, and cross-cultural validation remained limited. Earlier instruments primarily emphasized clinician-rated illness awareness, whereas more recent tools incorporated cognitive, neurocognitive, and subjective dimensions. Discrepancies between self-report and clinician ratings were common and often clinically meaningful. These findings underscore the need for multidimensional, psychometrically robust, and context-sensitive tools to advance both clinical assessment and research on insight in psychotic disorders.

The nosology of mania has long been a conundrum. Prior studies have alternately concluded that it is an internalizing disorder, a thought disorder, or a unique condition. Unfortunately, nearly all existing studies assessed symptoms cross-sectionally. This is problematic for syndromes that follow a more episodic course, such as mania. Here, we test whether including a history of episodes, not simply current symptoms, can help resolve the placement of mania in the meta-structure of psychopathology.

First-admission patients with psychosis from the Suffolk County Mental Health Project (N = 337) were followed across 20 years. Internalizing, thought disorder, and mania symptoms were assessed at year 20, whereas corresponding episodes (i.e. depressive, psychotic, and manic) were assessed across three intervals spanning the previous 20 years. We tested five models to determine whether mania (current and past) loaded onto the internalizing factor, the thought disorder factor, or an independent factor. A final model was validated against established markers of bipolar disorder.

For depression and psychosis, current and past markers were congruent in loading onto internalizing and thought disorder factors, respectively. However, current and past markers of mania diverged: current mania was most strongly related to the thought disorder dimension, whereas past mania formed an independent factor. Classic correlates of mania – including family history, genetic risk, and neuropsychological function – were associated only with the history of mania dimension.

Including illness course in structural models of psychopathology suggests that mania is distinguished from internalizing and thought disorder factors, whereas assessments of current symptoms place it with psychosis. These findings require independent validation, but if replicated, they would support a separate spectrum of mania defined by the occurrence of episodes across the lifetime.

Adolescence is a critical period for brain maturation, influenced by stress and hormonal changes. Chronic stress can lead to increased allostatic load (AL), a cumulative measure of multisystem dysregulation, and insulin resistance (IR), both of which are linked to mental health disorders. We hypothesized that heightened AL and IR during adolescence (age 17) would predict the emergence of mood and psychotic symptoms in young adults.

This study used data from the Avon Longitudinal Study of Parents and Children, a population cohort from Bristol, United Kingdom.

Our results showed that elevated AL at age 17 was significantly associated with the development of mood disorder symptoms (MDS) and psychotic disorder symptoms (PDS) and the co-occurrence of mood and psychotic disorder symptoms (MPDS) at age 24 (p < 0.001). Mean AL increased progressively across these symptom groups, indicating a dose–response relationship between physiological dysregulation and mental health burden (MDS = 3.67, PDS = 3.89, and MPDS = 4.03). We also observed that IR was significantly elevated in the MDS, PDS, and MPDS groups compared to healthy controls (HCs). IR was most prevalent in the PDS group, suggesting a possible association between metabolic dysfunction and psychosis risk.

This study demonstrated that multisystem dysregulation in late adolescence precedes the onset of mood and psychotic symptoms in early adulthood. These results support the use of AL and metabolic markers as early indicators of psychiatric vulnerability and highlight the potential for early intervention targeting systemic dysregulation to prevent the onset of mental health disorders.

The treatment response for the negative symptoms of schizophrenia is not ideal, and the efficacy of antidepressant treatment remains a matter of considerable controversy. This systematic review and meta-analysis aimed to assess the efficacy of adjunctive antidepressant treatment for negative symptoms of schizophrenia under strict inclusion criteria.

A systematic literature search (PubMed/Web of Science) was conducted to identify randomized, double-blind, effect-focused trials comparing adjuvant antidepressants with placebo for the treatment of negative symptoms of schizophrenia from database establishment to April 16, 2025. Negative symptoms were examined as the primary outcome. Data were extracted from published research reports, and the overall effect size was calculated using standardized mean differences (SMD).

A total of 15 articles, involving 655 patients, were included in this review. Mirtazapine (N = 2, n = 48, SMD −1.73, CI −2.60, −0.87) and duloxetine (N = 1, n = 64, SMD −1.19, CI −2.17, −0.21) showed significantly better efficacy for negative symptoms compared to placebo. In direct comparisons between antidepressants, mirtazapine showed significant differences compared to reboxetine, escitalopram, and bupropion, but there were no significant differences between other antidepressants or between antidepressants and placebo. No publication bias for the prevalence of this condition was observed.

These findings suggest that adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment. Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration.

Schizophrenia is a chronic severe mental illness affecting 24-million people globally, associated with a life expectancy 15 years shorter than the general population. Approximately 70% of people with schizophrenia experience auditory verbal hallucinations (AVHs), i.e. ‘hearing voices’. Current treatment approaches remain unsuccessful in up to 30% of cases.

This systematic review and meta-analysis evaluated randomised controlled trials (RCTs) of non-pharmacological treatments for AVHs in schizophrenia spectrum disorders, assessing emerging treatment effectiveness and identifying research gaps.

A literature search was performed between 2013-2024 across five databases: PubMed, Embase, PsycINFO, Medline, and Web of Science. The meta-analysis included 45 studies based on predefined criteria and bias assessment. Effect sizes (Hedge’s g) were calculated using a random effects model with 95% confidence intervals. The study followed PRISMA guidelines and was pre-registered (PROSPERO ID: CRD42024598615).

Our sample included 2,314 patients and fourteen interventions. The overall mean effect size was -0.298 (95% CI, [-0.470, -0.126]), representing a medium, statistically significant effect. Subgroup analyses revealed medium, statistically significant effects for both AVATAR therapy and cognitive behavioural therapy (CBT). Conversely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) showed small, non-significant effects.

AVATAR therapy has the strongest evidence for treating AVHs, highlighting the need for large-scale RCTs and integration into treatment guidelines. CBT requires methodological standardisation. Acceptance and commitment therapy shows promise but needs further high-quality RCTs. Non-invasive brain stimulation techniques require additional trials before clinical implementation.

Insight assessment in psychosis remains challenging in practice-oriented research.

To develop and validate a proxy measure for insight based on information from electronic health records (EHR). For that purpose, we used data on the Scale to Assess Unawareness of Mental Disorder (SUMD) and data from EHR notes of patients in an early psychosis intervention programme (Programa de Atención a Fases Iniciales de Psicosis, Santander, Spain).

Junior and senior clinicians examined 134 clinical notes from 106 patients to explore criterion and content validity between SUMD and a clinician-rated proxy measure, using three SUMD items.

In terms of criterion validity, SUMD scores correlated with the proxy (r = 0.61, P < 0.001), even after adjusting for the following confounders: type of psychotic disorder, clinical remission status and rater experience (r = 0.58, P < 0.001); and the proxy predicted good insight status (odds ratio 20.95, 95% CI 7.32–59.91, P < 0.001). Regarding content validity, the three main SUMD subscores correlated with the proxy (r = 0.55–0.60, P < 0.005). There were no significant differences in age, gender or other clinical variables, i.e. discriminant validity, and the proxy significantly correlated with validated psychometric instruments, i.e. external validity. Intraclass correlation coefficient (i.e. interrater reliability) was 0.88 (95% CI 0.59–1.00, P < 0.05).

This SUMD-based proxy measure was shown to have good to excellent validity and reliability, which may offer a reliable and efficient alternative for assessing insight in real-world clinical practice, EHR-based research and management. Future studies should explore its applicability across different healthcare contexts and its potential for automation, using natural language-processing techniques.

The functional outcome of patients with psychotic disturbances is associated with several overlapping premorbid, societal, neuropsychological, and clinical factors. Extracting the factors associated with functional outcomes is important for designing effective mental health interventions.

In a naturalistic prospective European multicentre study, we analysed the effects of sociodemographic, preadmission, admission, and postadmission precursors on functional outcomes in 296 patients with recent-onset psychosis (ROP) and 262 patients at clinically high risk of psychosis (CHR-P). Functioning was assessed with the Global Assessment of Functioning—symptoms and deficits version—at baseline and at the 9- and 18-month follow-ups.

In the overall sample, male sex, childhood adversities, poor sociability, scholastic problems, neurocognitive deficits, and greater severity of baseline and follow-up symptoms were associated with poor functional outcomes. In contrast, a favourable work/educational situation and preadmission treatment for nonpsychotic disorders were associated with better functional outcomes. Among ROP patients, neurocognitive deficits and the severity of baseline and follow-up affective and psychotic symptoms were strongly associated with functional outcomes. Among CHR-P patients, premorbid sociability, previous treatment for affective disorders, and follow-up affective symptoms played more significant roles.

To improve functioning in patients in the early stages of psychosis, several factors should be considered, such as sex, childhood adversities, psychosocial development, baseline neurocognitive deficits, work/educational situation, clinical presentations, and follow-up symptoms. Personalized and integrated treatment and rehabilitation measures should be actively continued beyond the first admission period, with a particular focus on addressing both baseline and follow-up affective disturbances.