Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.

To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.

This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists.

The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI −0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = −0.53, 95% CI −0.86 to −0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms.

This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.

There are ethnic differences, including differences related to indigeneity, in the incidence of first episode psychosis (FEP) and pathways into care, but research on ethnic disparities in outcomes following FEP is limited.

In this study we examined social and health outcomes following FEP diagnosis for a cohort of Māori (Indigenous people of New Zealand) and non-Māori (non-Indigenous) young people. We have focused on understanding the opportunities for better outcomes for Māori by examining the relative advantage of non-Māori with FEP.

Statistics New Zealand's Integrated Data Infrastructure was accessed to describe mental health and social service interactions and outcomes for a retrospective FEP cohort comprising 918 young Māori and 1275 non-Māori aged 13 to 25 at diagnosis. Logistic regression models were used to examine whether social outcomes including employment, benefit receipt, education and justice involvement in year 5 differed by indigeneity.

Non-Māori young people were more likely than Māori to have positive outcomes in the fifth year after FEP diagnosis, including higher levels of employment and income, and lower rates of benefit receipt and criminal justice system involvement. These patterns were seen across diagnostic groups, and for both those receiving ongoing mental healthcare and those who were not.

Non-Māori experience relative advantage in outcomes 5 years after FEP diagnosis. Indigenous-based social disparities following FEP urgently require a response from the health, education, employment, justice and political systems to avoid perpetuating these inequities, alongside efforts to address the disadvantages faced by all young people with FEP.

Suboptimal treatment outcomes contribute to the high disease burden of mood, anxiety or psychotic disorders. Clinical prediction models could optimise treatment allocation, which may result in better outcomes. Whereas ample research on prediction models is performed, model performance in other clinical contexts (i.e. external validation) is rarely examined. This gap hampers generalisability and as such implementation in clinical practice.

Systematically appraise studies on externally validated clinical prediction models for estimated treatment outcomes for mood, anxiety and psychotic disorders by (1) reviewing methodological quality and applicability of studies and (2) investigating how model properties relate to differences in model performance.

The review and meta-analysis protocol was prospectively registered with PROSPERO (registration number CRD42022307987). A search was conducted on 8 November 2021 in the databases PubMED, PsycINFO and EMBASE. Random-effects meta-analysis and meta-regression were conducted to examine between-study heterogeneity in discriminative performance and its relevant influencing factors.

Twenty-eight studies were included. The majority of studies (n = 16) validated models for mood disorders. Clinical predictors (e.g. symptom severity) were most frequently included (n = 25). Low methodological and applicability concerns were found for two studies. The overall discrimination performance of the meta-analysis was fair with wide prediction intervals (0.72 [0.46; 0.89]). The between-study heterogeneity was not explained by number or type of predictors but by disorder diagnosis.

Few models seem ready for further implementation in clinical practice to aid treatment allocation. Besides the need for more external validation studies, we recommend close examination of the clinical setting before model implementation.

The clinical high risk for psychosis (CHR-p) syndrome enables early identification of individuals at risk of schizophrenia and related disorders. We differentiate between the stigma associated with the at-risk identification itself (‘labelling-related’ stigma) versus stigma attributed to experiencing mental health symptoms (‘symptom-related’ stigma) and examine their relationships with key psychosocial variables.

We compare labelling- and symptom-related stigma in rates of endorsement and associations with self-esteem, social support loss and quality of life.

We assessed stigma domains of shame-related emotions, secrecy and experienced discrimination for both types of stigma. Individuals at CHR-p were recruited across three sites (N = 150); primary analyses included those who endorsed awareness of psychosis risk (n = 113). Paired-sample t-tests examined differences in labelling- versus symptom-related stigma; regressions examined associations with psychosocial variables, controlling for covariates, including CHR-p symptoms.

Respondents reported greater symptom-related shame, but more labelling-related secrecy. Of the nine significant associations between stigma and psychosocial variables, eight were attributable to symptom-related stigma, even after adjusting for CHR-p symptoms.

Stigma attributed to symptoms had a stronger negative association with psychosocial variables than did labelling-related stigma among individuals recently identified as CHR-p. That secrecy related to the CHR-p designation was greater than its symptom-related counterpart suggests that labelling-related stigma may still be problematic for some CHR-p participants. To optimise this pivotal early intervention effort, interventions should address the holistic ‘stigmatising experience’ of having symptoms, namely any harmful reactions received as well as participants’ socially influenced concerns about what their experiences mean, in addition to the symptoms themselves.

One of the ‘critical goals’ for psychiatric liaison services is reducing hospitalisation. Psychotropic medication is a treatment for psychosis, although research determining the efficacy of early medication administration is lacking.

To determine whether commencing psychotropic medication within 2 days of psychiatric liaison input in the accident and emergency (A&E) department is correlated with length of in-patient psychiatric admissions for patients with psychosis.

We gathered data on patients presenting to A&E sites covered by South London and Maudsley (SLaM) National Health Service Trust, who were subsequently admitted to and discharged from SLaM psychiatric in-patient wards with discharge diagnosis of psychosis between 2015 and 2020. The analysis set comprised 228 patients waiting in the A&E department under psychiatric liaison care for ≥2 days, of which 140 were started on medication within those 2 days (group A) and 88 were not (group B). Group A was divided into A1 (patients restarted on previous psychotropic medication taken within 1 week) and A2 (others, including those new to psychotropic medication or with past usage).

Although Kaplan–Meier survival curves with log-rank tests demonstrated no statistically significant difference of in-patient admission duration between groups A and B or groups B1 and B2, further analysis revealed that subgroup A1 had statistically significant shorter admissions than group B (P = 0.05).

Restarting patients with psychosis on medication they were taking within the week before A&E department attendance, within 2 days of arrival at the A&E department, is associated with statistically significant shorter admissions. The limitation is a relatively small sample size.

Breast cancer is a major global health issue, especially among women. Previous research has indicated a possible association between psychiatric conditions, particularly schizophrenia, and an increased risk of breast cancer. However, the specific risk of breast cancer in women with schizophrenia, compared with those with other psychiatric disorders and the general population, remains controversial and needs further clarification.

To estimate the risk of breast cancer among people with schizophrenia compared with people with other psychiatric disorders and people in the general population.

We utilised medical claims data of women aged 18 to 80 years in the Korean National Health Information Database from 2007 to 2018. Individuals with schizophrenia were defined as women with ICD-10 codes F20 or F25 (n = 224 612). The control groups were defined as women with other psychiatric disorders (n = 224 612) and women in the general Korean population (n = 449 224). Cases and controls were matched by index date and age, in a 1:1:2 ratio. We estimated the hazard of breast cancer using the Cox proportional hazards model, adjusting for insurance premiums and medical comorbidities. Among the people with schizophrenia, we used the landmark method to estimate the association between duration of antipsychotic medication use and the incidence of breast cancer.

In multivariable Cox regression models, the hazard rate of breast cancer was 1.26 times higher in the people with schizophrenia than in the general population (95% CI: 1.20–1.32). In comparison with the psychiatric patient group, the hazard ratio was 1.17 (95% CI: 1.11–1.28). Among women with schizophrenia, the hazard of breast cancer was greater among those who took antipsychotic medications for 1 year or more compared with those who took antipsychotics for less than 6 months.

Women with schizophrenia have an elevated risk of breast cancer, and long-term use of antipsychotics is associated with an increased risk of breast cancer.

Research on schizophrenia and life expectancy has mainly focused on premature mortality.

This study investigates factors associated with longevity in patients with schizophrenia receiving long-term care and identifies shared traits among these individuals.

A retrospective cross-sectional study analysing the clinical records of 138 patients with schizophrenia who died between 2015 and 2017 in a psychiatric long-term care facility was conducted. Longevity was defined by life tables drawn from the national health database. Variables were compared between longevity and control groups to determine predictors of longer lifespans. Cluster analysis was employed to identify shared traits among individuals with longevity. Causes of death by age were compared.

In the long-term care setting, of the 138 participants, 45 were in the longevity group. This group had more males, lower antipsychotic doses, but more mobility issues. Significant predictors of longevity included older age at onset, longer length of stay, lower activities of daily living scores and a hypertension diagnosis. Cluster analysis revealed two patterns, suggesting that poorer health indicators did not necessarily lead to shorter lives. Fatalities caused by pneumonia were associated with a higher age, compared to those from cancer and choking.

Addressing modifiable risk factors enhances life expectancy in patients with schizophrenia, especially for males, while the age at onset may play a significant role. An integrated long-term care model with close monitoring and timely provision of mental and general healthcare may help extend lifespans. Further research is needed to balance long-term residential care and community-based care for elderly patients with schizophrenia.

People with severe mental illness (SMI) have worse physical health than the general population. There is evidence that support from volunteers can help the mental health of people with SMI, but little evidence regarding the support they can give for physical health.

To evaluate the feasibility of an intervention where volunteer ‘Health Champions’ support people with SMI in managing their physical health.

A feasibility hybrid randomised controlled trial conducted in mental health teams with people with SMI. Volunteers delivered the Health Champions intervention. We collected data on the feasibility of delivering the intervention, and clinical and cost-effectiveness. Participants were randomised by a statistician independent of the research team, to either having a Health Champion or treatment as usual. Blinding was not done.

We recruited 48 participants: 27 to the intervention group and 21 to the control group. Data were analysed for 34 participants. No changes were found in clinical effectiveness for either group. Implementation outcomes measures showed high acceptability, feasibility and appropriateness, but with low response rates. No adverse events were identified in either group. Interviews with participants found they identified changes they had made to their physical health. The cost of implementing the intervention was £312 per participant.

The Health Champion intervention was feasible to implement, but the implementation of the study measures was problematic. Participants found the intervention acceptable, feasible and appropriate, and it led them to make changes in their physical health. A larger trial is recommended, with tailored implementation outcome measures.

Clozapine is the most effective medication for treatment-resistant psychoses, but the balance of benefits and risks is understudied in real-world settings.

To examine the relative re-hospitalisation rates for mental health relapse and adverse events associated with clozapine and other antipsychotics in adult and child/youth cohorts.

Data were obtained from the Canadian Institute of Health Information for adults (n = 45 616) and children/youth (n = 1476) initially hospitalised for mental health conditions in British Columbia, Manitoba and Saskatchewan from 2008 to 2018. Patient demographics and hospitalisations were linked with antipsychotic prescriptions dispensed following the initial visit. Recurrent events survival analysis for relapse and adverse events were created and compared between clozapine and other antipsychotics.

In adults, clozapine was associated with a 14% lower relapse rate versus other drugs (adjusted hazard ratio: 0.86, 95% CI: 0.83–0.90) over the 10-year follow-up. In the first 21 months, the relapse rate was higher for clozapine but then reversed. Over 1000 person-months, clozapine-treated adults could be expected to have 38 relapse hospitalisations compared with 45 for other drugs. In children/youth, clozapine had a 38% lower relapse rate compared with other antipsychotic medications (adjusted hazard ratio: 0.62, 95% CI: 0.49–0.78) over the follow-up period. This equates to 29 hospitalisations for clozapine and 48 for other drugs over 1000 person-months. In adults, clozapine had a higher risk for adverse events (hazard ratio: 1.34, 95% CI: 1.18–1.54) over the entire follow-up compared with other antipsychotics. This equates to 1.77 and 1.30 hospitalisations over 1000 person-months for clozapine and other drugs, respectively.

Clozapine was associated with lower relapse overall, but this was accompanied by higher adverse events for adults. For children/youth, clozapine was associated with lower relapse all throughout and had no difference in adverse events compared with other antipsychotics.

Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA).

To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD).

We analysed data of all patients registered on the UK Clozaril® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 109/L and/or white blood cell count < 3.0 × 109/L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored.

Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%.

Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals.

It remains unknown whether severe mental disorders contribute to fatally harmful effects of physical illness.

To investigate the risk of all-cause death and loss of life-years following the onset of a wide range of physical health conditions in people with severe mental disorders compared with matched counterparts who had only these physical health conditions, and to assess whether these associations can be fully explained by this patient group having more clinically recorded physical illness.

Using Czech national in-patient register data, we identified individuals with 28 physical health conditions recorded between 1999 and 2017, separately for each condition. In these people, we identified individuals who had severe mental disorders recorded before the physical health condition and exactly matched them with up to five counterparts who had no recorded prior severe mental disorders. We estimated the risk of all-cause death and lost life-years following each of the physical health conditions in people with pre-existing severe mental disorders compared with matched counterparts without severe mental disorders.

People with severe mental disorders had an elevated risk of all-cause death following the onset of 7 out of 9 broadly defined and 14 out of 19 specific physical health conditions. People with severe mental disorders lost additional life-years following the onset of 8 out 9 broadly defined and 13 out of 19 specific physical health conditions. The vast majority of results remained robust after considering the potentially confounding role of somatic multimorbidity and other clinical and sociodemographic factors.

A wide range of physical illnesses are more likely to result in all-cause death in people with pre-existing severe mental disorders. This premature mortality cannot be fully explained by having more clinically recorded physical illness, suggesting that physical disorders are more likely to be fatally harmful in this patient group.

Patients prescribed clozapine are increasingly living into old age. However, there is a lack of studies to guide prescribing in this age group. We sought to identify all clozapine patients in Hertfordshire Partnership NHS Foundation Trust over a 5-year period and review side-effect burden and co-prescribing in all patients aged over 65 years.

We identified 69 patients. The majority (61%) were stable in terms of mental state; 94% of cases had experienced a side-effect within the past year, with constipation occurring most commonly (65% of cases).

Our findings reveal a significant side-effect burden, particularly in relation to constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can be fatal; however, increasing age has not been a recognised risk factor for constipation in clozapine patients to date. This raises questions about increasing risk to physical health as patients age and adds to concerns about the lack of monitoring for CIGH.

Schizophreniform disorders tend to have an early onset. Early intervention in psychosis (EIP) services aim to provide early treatment, reduce long-term morbidity and improve social functioning. In 2016, changes to mental health policy in England mandated that the primarily youth-focused model should be extended to an ageless one, to prevent ageism; however, this was without strong research evidence.

An inner-city London EIP service compared sociodemographic and clinical factors between the under-35 years and over-35 years caseload cohorts utilising the EIP package following the implementation of the ageless policy.

Both groups received similar care, despite the younger group having significantly more clinical morbidity and needs.

Our results may indicate that service provisions are being driven by policy rather than clinical needs, potentially diverting resources from younger patients. These findings have important implications for future provision of EIP services and would benefit from further exploration.

Sexually transmitted infections (STIs), along with sexual health and behaviour, have received little attention in schizophrenia patients.

To systematically review and meta-analytically characterise the prevalence of STIs and sexual risk behaviours among schizophrenia patients.

Web of Science, PubMed, BIOSIS, KCI-Korean Journal Database, MEDLINE, Russian Science Citation Index, SciELO and Cochrane Central Register were systematically searched from inception to 6 July 2023. Studies reporting on the prevalence or odds ratio of any STI or any outcome related to sexual risk behaviours among schizophrenia samples were included. PRISMA/MOOSE-compliant (CRD42023443602) random-effects meta-analyses were used for the selected outcomes. Q-statistics, I2 index, sensitivity analyses and meta-regressions were used. Study quality and publication bias were assessed.

Forty-eight studies (N = 2 459 456) reporting on STI prevalence (including 15 allowing for calculation of an odds ratio) and 33 studies (N = 4255) reporting on sexual risk behaviours were included. Schizophrenia samples showed a high prevalence of STIs and higher risks of HIV (odds ratio = 2.11; 95% CI 1.23–3.63), hepatitis C virus (HCV, odds ratio = 4.54; 95% CI 2.15–961) and hepatitis B virus (HBV; odds ratio = 2.42; 95% CI 1.95–3.01) infections than healthy controls. HIV prevalence was higher in Africa compared with other continents and in in-patient (rather than out-patient) settings. Finally, 37.7% (95% CI 31.5–44.4%) of patients were sexually active; 35.0% (95% CI 6.6–59.3%) reported consistent condom use, and 55.3% (95% CI 25.0–82.4%) maintained unprotected sexual relationships.

Schizophrenia patients have high prevalence of STIs, with several-fold increased risks of HIV, HBV and HCV infection compared with the general population. Sexual health must be considered as an integral component of care.