Working memory deficit, a key feature of schizophrenia, is a heritable trait shared with unaffected siblings. It can be attributed to dysregulation in transitions from one brain state to another.

Using network control theory, we evaluate if defective brain state transitions underlie working memory deficits in schizophrenia.

We examined average and modal controllability of the brain's functional connectome in 161 patients with schizophrenia, 37 unaffected siblings and 96 healthy controls during a two-back task. We use one-way analysis of variance to detect the regions with group differences, and correlated aberrant controllability to task performance and clinical characteristics. Regions affected in both unaffected siblings and patients were selected for gene and functional annotation analysis.

Both average and modal controllability during the two-back task are reduced in patients compared to healthy controls and siblings, indicating a disruption in both proximal and distal state transitions. Among patients, reduced average controllability was prominent in auditory, visual and sensorimotor networks. Reduced modal controllability was prominent in default mode, frontoparietal and salience networks. Lower modal controllability in the affected networks correlated with worse task performance and higher antipsychotic dose in schizophrenia (uncorrected). Both siblings and patients had reduced average controllability in the paracentral lobule and Rolandic operculum. Subsequent out-of-sample gene analysis revealed that these two regions had preferential expression of genes relevant to bioenergetic pathways (calmodulin binding and insulin secretion).

Aberrant control of brain state transitions during task execution marks working memory deficits in patients and their siblings.

Psychotic-like experiences (PLEs) are subclinical phenomena that often precede the onset of psychosis and occur in various mental disorders. Social determinants of psychosis and PLEs are important and have been operationalized within the social defeat (SD) hypothesis. The SD hypothesis posits that low social status and exposure to repeated humiliation can lead to imbalanced dopamine neuron activity, and thus increased risk of psychosis. We aimed to assess the role of dynamic interactions between SD components in shaping the occurrence of PLEs using a network analysis.

A total of 2241 non-clinical, young adults were assessed at baseline and invited for reassessment after a 6-month follow-up. Self-reports recording the occurrence of PLEs, aberrant salience (AS), depressive, and anxiety symptoms as well as SD characteristics (socioeconomic status, minority status, humiliation, perceived constraints, and domain control) were administered. Two networks were analyzed (the first one covering all baseline measures and the second one with the baseline SD components and follow-up measures of AS and psychopathology).

The SD components were not directly connected to the measures of PLEs in both networks. However, in both networks, SD components were connected to PLEs through a mediating effect of AS. Among SD components, humiliation had the highest bridge centrality across three predefined communities of variables (SD; depressive and anxiety symptoms; AS, and PLEs).

The findings indicate that SD might make individuals vulnerable to develop PLEs through the mediating effects of AS. Among SD components, humiliation might play the most important role in the development of PLEs.

Low- and middle-income countries (LMICs) bear a disproportionate burden of mental illness, with limited access to biomedical care. This study examined pathways to care for psychosis in rural Uganda, exploring factors influencing treatment choices.

We conducted a mixed-methods study in Buyende District, Uganda, involving 67 in-depth interviews and 4 focus group discussions (data collection continued until thematic saturation was reached) with individuals with psychotic disorders, family members, and local leaders. Structured questionnaires were administered to 41 individuals with psychotic disorders.

Three main themes emerged: (1) Positive attitudes towards biomedical providers, (2) Barriers to accessing biomedical care (3) Perceived etiologies of mental illness that influenced care-seeking behaviors. While 81% of participants eventually accessed biomedical care, the median time to first biomedical contact was 52 days, compared to 7 days for any care modality.

Despite a preference for biomedical care, structural barriers and diverse illness perceptions led many to seek pluralistic care pathways. Enhancing access to biomedical services and integrating traditional and faith healers could improve mental health outcomes in rural Uganda.

Stigma of mental health conditions hinders recovery and well-being. The Honest, Open, Proud (HOP) program shows promise in reducing stigma but there is uncertainty about the feasibility of a randomized trial to evaluate a peer-delivered, individual adaptation of HOP for psychosis (Let's Talk).

A multi-site, Prospective Randomized Open Blinded Evaluation (PROBE) design, feasibility randomised controlled trial (RCT) comparing the peer-delivered intervention (Let's Talk) to treatment as usual (TAU). Follow-up was 2.5 and 6 months. Randomization was via a web-based system, with permuted blocks of random size. Up to 10 sessions of the intervention over 10 weeks were offered. The primary outcome was feasibility data (recruitment, retention, intervention attendance). Primary outcomes were analyzed by intention to treat. Safety outcomes were reported by as treated status. The study was prospectively registered: https://doi.org/10.1186/ISRCTN17197043.

149 patients were referred to the study and 70 were recruited. 35 were randomly assigned to intervention + TAU and 35 to TAU. Recruitment was 93% of the target sample size. Retention rate was high (81% at 2.5 months primary endpoint), and intervention attendance rate was high (83%). 21% of 33 patients in Let's talk + TAU had an adverse event and 16% of 37 patients in TAU. One serious adverse event (pre-randomization) was partially related and expected.

This is the first trial to show that it is feasible and safe to conduct a RCT of HOP adapted for people with psychosis and individual delivery. An adequately powered trial is required to provide robust evidence.

Cognitive behavioural therapy (CBT) is one of the best-evidenced psychosocial interventions for psychosis and is recommended by the National Institute for Health and Care Excellence and the American Psychiatric Association. CBT was developed and derived from Western cultural values, which may not be appropriate for non-Western cultures. Trials of CBT in Western countries have indicated that participants from ethnic minority groups demonstrate low rates of engagement, retention, and recruitment. This indicates that the principles underlying CBT may conflict with individual beliefs and cultural values in non-Western countries. Therefore, we interviewed 15 people diagnosed with schizophrenia and 15 with their family members to explore the beliefs and attitudes of people diagnosed with schizophrenia and their family members concerning the proposed CBT intervention for psychosis in the Saudi context. The findings revealed that most participants accepted the proposed intervention. Important factors that influenced participants’ engagement and motivation in the CBT intervention were related to the therapist’s qualities (sex, empathy, and competence), family involvement, religion, and the number and format of CBT sessions for psychosis.

1. (1) To explore the beliefs and attitudes of people diagnosed with schizophrenia concerning the proposed CBT intervention for psychosis and how to improve it to make it more appropriate for their needs and cultures.

2. (2) To explore the beliefs and attitudes of family members of people diagnosed with schizophrenia concerning the proposed CBT intervention for psychosis and how to improve it to make it more appropriate to their needs and culture.

Clinical characteristics of psychosis in HIV infection have been described, but there have been limited comparative studies in HIV-endemic low-resource regions.

To compare clinical characteristics of psychosis in HIV-positive and HIV-negative patients at the main psychiatric referral units in Uganda.

Patients with psychosis were consecutively recruited and completed a standardised demographic questionnaire and psychiatric and laboratory assessments including an HIV test. The Mini International Neuropsychiatric Interview was used to diagnose psychiatric illness. Psychosis symptoms were compared between HIV-positive and HIV-negative individuals using bivariate methods. A logistic regression model was used to assess the effects of age, gender and HIV status on different types of psychosis.

There were 478 patients enrolled, of which 156 were HIV positive and 322 were HIV negative. The mean age was 33.2 years (95% CI 31.8–34.5) for the HIV-positive group and 29.6 years (95% CI 28.7–30.5) for the HIV-negative group (P < 0.001). Female patients had a higher proportion of seropositivity 40.6% (95% CI 34.8–46.4) compared with males 21.8% (95% CI 16.1–27.5) (P < 0.001). Psychotic disorder not otherwise specified occurred more in the HIV-positive individuals (88% (95% CI 82.9–93.1) v. 12% (95% CI 8.4–15.5), P < 0.001). Motor activity, irritability, emotional withdrawal, feelings of guilt, mannerisms and posturing, grandiosity, suspiciousness, unusual thoughts, blunted affect, excitement and disorientation were associated with HIV seropositivity.

The presentation of psychosis in patients with HIV is unique to this HIV endemic setting. Characterisation of the symptomatology of patients presenting with psychosis is important for proper diagnosis and care.

Cannabis use severely affects the outcome of people with psychotic disorders, yet there is a lack of treatments. To address this, in 2019 the National Health Service (NHS) Cannabis Clinic for Psychosis (CCP) was developed to support adults suffering from psychosis to reduce and/or stop their cannabis use.

Examine outcome data from the first 46 individuals to complete the CCP's intervention.

The sample (N = 46) consisted of adults (aged ≥ 18) with psychosis under the care of the South London and Maudsley NHS Foundation Trust, referred to the CCP between January 2020 and February 2023, who completed their intervention by September 2023. Clinical and functional measures were collected before (T0) and after (T1) the CCP intervention (one-to-one sessions and peer group attendance). Primary outcomes were changes in the Cannabis Use Disorders Identification Test-Revised (CUDIT-R) score and pattern of cannabis use. Secondary outcomes included T0–T1 changes in measures of delusions, paranoia, depression, anxiety and functioning.

A reduction in the mean CUDIT-R score was observed between T0 (mean difference = 17.10, 95% CI = 15.54–18.67) and T1, with 73.91% of participants achieving abstinence and 26.09% reducing the frequency and potency of their use. Significant improvements in all clinical and functional outcomes were observed, with 90.70% being in work or education at T1 compared with 8.70% at T0. The variance in CUDIT-R scores explained between 34 and 64% of the variance in our secondary measures.

The CCP intervention is a feasible strategy to support cannabis use cessation/reduction and improve clinical and functional outcomes of people with psychotic disorders.

Suicide accounts for a proportion of the early mortality in people affected by psychotic disorders. The early phase of illness can represent a particularly high-risk time for suicide. Therefore, in a cohort of young people presenting with first-episode psychosis, this study aimed to determine: (i) the prevalence of suicidal ideation, intent with plan and self-harm and any associated demographic or clinical factors and (ii) the prevalence of depressive symptoms and any associated demographic or clinical factors.

Young people with a first episode of psychosis attending the Early Psychosis Prevention and Intervention Centre in Melbourne were included. Suicidal behaviours were recorded using a structured risk assessment – ‘Clinical Risk Assessment and Management in the Community’, and depressive symptoms were measured using the PHQ-9.

A total of 355 young people were included in the study. 57.2% were male, 95.4% were single and over one quarter were migrants. At the time of presentation, 34.6% had suicidal ideation, 6.2% had suicidal intent with a plan, and 21.4% had engaged in self-harm before their presentation. Combined, 39.7% (n = 141) presented with suicidal ideation, intent with plan or self-harm. A total of 71.5% (n = 118) had moderately severe or severe depressive symptoms, which was strongly associated with suicidal ideation or behaviours at the time of presentation (OR = 4.21, 95% C.I. 2.10–8.44).

Depressive symptoms, self-harm and suicidal behaviours are commonly present in the early phases of a psychotic disorder, which has important clinical implications for assessment and management.

The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.

Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.

In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08–8.43, p = 3.21 × 10−10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.

Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.

Cognitive impairment constitutes a prevailing issue in the schizophrenia spectrum, severely impacting patients' functional outcomes. A global cognitive score, sensitive to the stages of the spectrum, would benefit the exploration of potential factors involved in the cognitive decline.

First, we performed principal component analysis on cognitive scores from 768 individuals across the schizophrenia spectrum, including first-degree relatives of patients, individuals at ultra-high risk, who had a first-episode psychosis, and chronic schizophrenia patients, alongside 124 healthy controls. The analysis provided 10 g-factors as global cognitive scores, validated through correlations with intelligence quotient and assessed for their sensitivity to the stages on the spectrum using analyses of variance. Second, using the g-factors, we explored potential mechanisms underlying cognitive impairment in the schizophrenia spectrum using correlations with sociodemographic, clinical, and developmental data, and linear regressions with genotypic data, pooled through meta-analyses.

The g-factors were highly correlated with intelligence quotient and with each other, confirming their validity. They presented significant differences between subgroups along the schizophrenia spectrum. They were positively correlated with educational attainment and the polygenic risk score (PRS) for cognitive performance, and negatively correlated with general psychopathology of schizophrenia, neurodevelopmental load, and the PRS for schizophrenia.

The g-factors appeared as valid estimators of global cognition, enabling discerning cognitive states within the schizophrenia spectrum. Educational attainment and genetics related to cognitive performance may have a positive influence on cognitive functioning, while general psychopathology of schizophrenia, neurodevelopmental load, and genetic liability to schizophrenia may have an adverse impact.

Transition to psychosis rates within ultra-high risk (UHR) services have been declining. It may be possible to ‘enrich’ UHR cohorts based on the environmental characteristics seen more commonly in first-episode psychosis cohorts. This study aimed to determine whether transition rates varied according to the accumulated exposure to environmental risk factors at the individual (migrant status, asylum seeker/refugee status, indigenous population, cannabis/methamphetamine use), family (family history or parental separation), and neighborhood (population density, social deprivation, and fragmentation) level.

The study included UHR people aged 15–24 who attended the PACE clinic from 2012 to 2016. Cox proportional hazards models (frequentist and Bayesian) were used to assess the association between individual and accumulated factors and transition to psychosis. UHR status and transition was determined using the CAARMS. Benjamini–Hochberg was used to correct for multiple comparisons in frequentist analyses.

Of the 461 young people included, 55.5% were female and median follow-up was 307 days (IQR: 188–557) and 17.6% (n = 81) transitioned to a psychotic disorder. The proportion who transitioned increased incrementally according to the number of individual-level risk factors present (HR = 1.51, 95% CIs 1.19–1.93, p < 0.001, pcorr = 0.01). The number of family- and neighborhood-level exposures did not increase transition risk (p > 0.05). Cannabis use was the only specific risk factor significantly associated with transition (HR = 1.89, 95% CIs 1.22–2.93, pcorr = 0.03, BF = 6.74).

There is a dose–response relationship between exposure to individual-level psychosis-related environmental risk factors and transition risk in UHR patients. If replicated, this could be incorporated into a novel approach to identifying the highest-risk individuals within clinical services.