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.

Contemporary data relating to antipsychotic prescribing in UK primary care for patients diagnosed with severe mental illness (SMI) are lacking.

To describe contemporary patterns of antipsychotic prescribing in UK primary care for patients diagnosed with SMI.

Cohort study of patients with an SMI diagnosis (i.e. schizophrenia, bipolar disorder, other non-organic psychoses) first recorded in primary care between 2000 and 2017 derived from Clinical Practice Research Datalink. Patients were considered exposed to antipsychotics if prescribed at least one antipsychotic in primary care between 2000 and 2019. We compared characteristics of patients prescribed and not prescribed antipsychotics; calculated annual prevalence rates for antipsychotic prescribing; and computed average daily antipsychotic doses stratified by patient characteristics.

Of 309 378 patients first diagnosed with an SMI in primary care between 2000 and 2017, 212,618 (68.7%) were prescribed an antipsychotic between 2000 and 2019. Antipsychotic prescribing prevalence was 426 (95% CI, 420–433) per 1000 patients in the year 2000, reaching a peak of 550 (547–553) in 2016, decreasing to 470 (468–473) in 2019. The proportion prescribed antipsychotics was higher among patients diagnosed with schizophrenia (81.0%) than with bipolar disorder (64.6%) and other non-organic psychoses (65.7%). Olanzapine, quetiapine, risperidone and aripiprazole accounted for 78.8% of all antipsychotic prescriptions. Higher mean olanzapine equivalent total daily doses were prescribed to patients with the following characteristics: schizophrenia diagnosis, ethnic minority status, male gender, younger age and greater relative deprivation.

Antipsychotic prescribing is dominated by olanzapine, quetiapine, risperidone and aripiprazole. We identified potential disparities in both the receipt and prescribed doses of antipsychotics across subgroups. To inform efforts to optimise prescribing and ensure equity of care, further research is needed to understand why certain groups are prescribed higher doses and are more likely to be treated with long-acting injectable antipsychotics compared with others.

Studies in cognitively normal individuals on associations between psychiatric symptomatology and incident dementia have not reliably differentiated psychiatric syndromes from neuropsychiatric symptoms (NPS) that represent neurodegeneration. Conventional modelling often overlooks symptom natural history. Mild behavioural impairment (MBI) is a syndrome that leverages later-life emergent and persistent NPS to identify a high-risk group for incident dementia.

We aimed to explore associations of MBI, and conventionally-measured NPS (NPS-not-MBI), with incident dementia in cognitively normal individuals and the cognitively normal subset with subjective cognitive decline (SCD).

Using National Alzheimer's Coordinating Center data, MBI was operationalised by the absence of past psychiatric disorders (symptom emergence) and the presence of symptoms at >2/3 of pre-dementia visits (symptom persistence). Kaplan–Meier survival curves and Cox proportional hazards regressions modelled dementia incidence across NPS groups and MBI domains, adjusted for age, gender, education, race, APOE-ε4, and cognitive status.

The sample comprised 1408 MBI (age 75.2 ± 9.5; 54.3% female), 5625 NPS-not-MBI (age 71.6 ± 8.8; 65.5% female) and 5078 No-NPS (age 71.2 ± 8.9; 67.6% female) participants. Compared with No-NPS, MBI participants had lower dementia-free survival (P < 0.0001) and 2.76-fold greater adjusted dementia incidence rate (95% CI: 2.27–3.35, P < 0.001); incidence rate in NPS-not-MBI did not differ from No-NPS (hazard ratio 0.97, 95% CI: 0.82–1.14, P = 0.687). Of those with MBI who progressed to dementia, 76.0% developed Alzheimer's disease. Similarly, in the SCD subsample (n = 3485), persons with MBI had 1.99-fold greater dementia incidence versus No-NPS (95% CI: 1.46–2.71, P < 0.001) while NPS-not-MBI did not differ from No-NPS (hazard ratio 0.92, 95% CI: 0.70–1.19, P = 0.511).

Incorporating natural history into assessment of psychiatric symptoms in accordance with MBI criteria enhances dementia prognostication and modelling.

The prenatal and early-life periods pose a crucial neurodevelopmental window whereby disruptions to the intestinal microbiota and the developing brain may have adverse impacts. As antibiotics affect the human intestinal microbiome, it follows that early-life antibiotic exposure may be associated with later-life psychiatric or neurocognitive outcomes.

To explore the association between early-life (in utero and early childhood (age 0–2 years)) antibiotic exposure and the subsequent risk of psychiatric and neurocognitive outcomes.

A search was conducted using Medline, PsychINFO and Excerpta Medica databases on 20 November 2023. Risk of bias was assessed using the Newcastle-Ottawa scale, and certainty was assessed using the grading of recommendations, assessment, development and evaluation (GRADE) certainty assessment.

Thirty studies were included (n = 7 047 853 participants). Associations were observed between in utero antibiotic exposure and later development of autism spectrum disorder (ASD) (odds ratio 1.09, 95% CI: 1.02–1.16) and attention-deficit hyperactivity disorder (ADHD) (odds ratio 1.19, 95% CI: 1.11–1.27) and early-childhood exposure and later development of ASD (odds ratio 1.19, 95% CI: 1.01–1.40), ADHD (odds ratio 1.33, 95% CI: 1.20–1.48) and major depressive disorder (MDD) (odds ratio 1.29, 95% CI: 1.04–1.60). However, studies that used sibling control groups showed no significant association between early-life exposure and ASD or ADHD. No studies in MDD used sibling controls. Using the GRADE certainty assessment, all meta-analyses but one were rated very low certainty, largely owing to methodological and statistical heterogeneity.

While there was weak evidence for associations between antibiotic use in early-life and later neurodevelopmental outcomes, these were attenuated in sibling-controlled subgroup analyses. Thus, associations may be explained by genetic and familial confounding, and studies failing to utilise sibling-control groups must be interpreted with caution. PROSPERO ID: CRD42022304128

Links between personality disorders and antisocial outcomes has not examined individual personality disorders, and the contribution of comorbidities remain uncertain. Previous systematic reviews are dated.

To synthesise evidence from observational studies on the risk of antisocial outcomes and recidivism associated with personality disorders.

We searched six bibliographic databases (up to March 2024) for observational studies examining the risk of antisocial behaviour, interpersonal violence and recidivism in individuals diagnosed with personality disorders, compared to controls. We explored sources of heterogeneity using subgroup analyses and meta-regression.

We identified 21 studies involving 83 418 individuals with personality disorders from 10 countries examining antisocial and violent outcomes (Aim 1), and 39 studies of 14 131 individuals from 13 countries with recidivism (or repeat offending) as the outcome (Aim 2). We found increased risks of violence among individuals with any personality disorder (odds ratio 4.5, 95% CI 3.0–6.7), particularly antisocial personality disorder (odds ratio 7.6, 95% CI 5.1–11.5) and borderline personality disorder (odds ratio 2.6, 95% CI 1.8–3.9). Individuals with any personality disorder (odds ratio 2.3, 95% CI 2.0–2.6) and antisocial personality disorder (odds ratio 2.8, 95% CI 1.6–4.9) also demonstrated an elevated risk of recidivism. Personality disorder types and comorbid substance use disorder were associated with between-study heterogeneity.

The assessment and management of personality disorders should be considered as part of violence prevention strategies. Improving identification and treatment of comorbid substance misuse may reduce adverse outcomes in individuals with personality disorders.

Clozapine therapy presents a risk of agranulocytosis, necessitating monitoring of white blood cell count. The detection of benign ethnic neutropenia (BEN), in which neutropenia can be present without an increased risk of infection, is particularly important in preventing unnecessary withdrawal of clozapine. BEN is strongly linked to the CC homozygote of the single nucleotide polymorphism rs2814778 in the atypical chemokine receptor-1 (ACKR1) gene.

We introduced voluntary genetic testing for BEN in one of our clozapine clinics, with the aim of assessing the prevalence of undiagnosed BEN in patients on clozapine.

We offered genetic testing for BEN to patients undergoing medium- and long-term clozapine treatment, and conducted a comparative analysis of neutrophil counts across three identified groups: those previously diagnosed with BEN, those with newly discovered BEN and those confirmed by genetic testing not to have BEN.

We conducted genetic testing for BEN on 108 patients. Of these, 16 were already registered as having BEN and had the CC homozygote. A further 26 patients (24% of the cohort) who were previously not diagnosed with BEN by standard haematological monitoring were found to have the CC homozygote on genetic testing. Unadjusted mean neutrophil counts were lowest for those with previously diagnosed BEN (2.5 × 109/L, 95% CI 2.2–2.8; P < 0.001 v. other groups), but those with newly discovered BEN had mean counts that were significantly lower (4.1 × 109/L, 95% CI 3.6–4.7) than those with TT and CT genotypes (5.1 × 109/L, 95% CI 4.7–5.4; P = 0.006).

Undiagnosed BEN was common in our naturalistic cohort. The integration of genetic testing into standard monitoring would enhance the management of clozapine therapy, potentially allowing for the safe reintroduction or continuation of clozapine in patients with hitherto unrecognised BEN. All current and prospective clozapine patients should be genetically tested for BEN.

Using [18F]altanserin, a serotonin 2A receptor (5-HT2AR) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT2AR binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT2AR agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT2AR and neuroticism are both modulated by HPA axis function.

In this study, we examined whether the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT2AR agonist tracer [11C]Cimbi-36, and if their association is moderated by cortisol awakening response (CAR), an index of HPA axis function. If so, this could advance mechanistic insights into interventions that target the 5-HT2AR and reduce neuroticism.

Eighty healthy volunteers underwent [11C]Cimbi-36 PET scans and completed the NEO personality inventory (NEO-PI-R) for the assessment of neuroticism. Salivary samples were available for determination of CAR in 70 of the participants. Using linear latent variable models, we evaluated the association between 5-HT2AR binding and inward facets of neuroticism, namely depression, anxiety, self-consciousness and vulnerability to stress, and whether CAR moderated this association.

The study confirms the positive association between 5-HT2AR binding and the inward facets of neuroticism (β = 0.01, 95% CI = [0.0005: 0.02], P = 0.04), and this association is independent of CAR (P = 0.33).

The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT2AR and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.

Antidepressants’ effects are established in randomised controlled trials (RCTs), but not in the real world.

To investigate real-world comparative effects of antidepressants for depression and compare them with RCTs.

We performed a cohort study based on the QResearch database. We included people with a newly recorded diagnosis of depression, exposed to licensed antidepressants in the UK. We assessed all-cause dropouts (acceptability), dropouts for adverse events (tolerability), occurrence of at least one adverse event (safety), and response and remission on the Patient Health Questionnaire (PHQ)-9 (effectiveness) at 2 and 12 months. Logistic regressions were used to compute adjusted-odds ratio (aOR) with 99% CIs, assessing the associations between exposure to each antidepressant against fluoxetine (comparator) and outcomes of interest. We compared estimates from the real world with RCTs using ratio-of-odds ratio (ROR) with 95% CI.

A total of 673 177 depressed people were studied: females 57.1%, mean age 42.8 (s.d. 17.7) years, mean baseline PHQ-9 17.1 (s.d. 5.0) (moderately severe depression). At 2 months, antidepressant acceptability was 61.4%, tolerability 94.4%, safety 54.5%, PHQ-9 decreased to 12.3 (s.d. 6.5). At 12 months, acceptability was 12.3%, tolerability 87.5%, safety 28.8%, PHQ-9 12.9 (s.d. 6.8). In the short and long term, tricyclics, mirtazapine and trazodone were worse than fluoxetine for most outcomes; citalopram had better acceptability than fluoxetine (aOR 0.95; 99% CI 0.92, 0.97), sertraline had lower tolerability (aOR 1.12; 99% CI 1.06, 1.18), and both citalopram and sertraline had lower safety (aOR 1.17 and 1.25, respectively). In the long term, citalopram had better acceptability (aOR 0.78; 99% CI 0.76, 0.81) and effectiveness (aOR 1.12 for both response and remission), but worse tolerability (aOR 1.09; 99% CI 1.06, 1.13) and safety (aOR 1.12; 99% CI 1.08, 1.16). Observational and randomised data were similar for citalopram and sertraline, while there was some difference for drugs less prescribed in the real world.

Antidepressants showed low acceptability, moderate-to-high tolerability and safety, and small-to-moderate effectiveness in the real world. Real-world and RCT estimates showed similar findings only when the analyses were carried out using large datasets; otherwise, the results diverged.

Discipline is a crucial aspect of parenting, shaping child development and behaviour. Time-out, a widely used disciplinary strategy with a strong evidence-base, has recently come under scrutiny with concerns about potential adverse effects on children's emotional development and attachment, particularly for those with a history of adversity.

To contribute critical empirical insights to the current controversy surrounding time-out by exploring the associations among time-out implementation, parent–child attachment and child mental health, and whether adversity exposure moderated these associations.

This cross-sectional study utilised a nationally representative sample of 474 primary caregivers in Australia, with children aged 6–8 years, who completed an online survey. Measures included the Implementation of Time-out Scale, Adverse Life Experiences Scale, Primary Attachment Style Questionnaire, Strengths and Difficulties Questionnaire and Spence Child Anxiety Scale.

Appropriately implemented time-out was associated with enhanced mental health and attachment, while inappropriate time-out correlated with adverse child outcomes. Exposure to adversity moderated the relationship between time-out implementation and child well-being, such that children exposed to adversity were most likely to experience attachment enhancement from appropriately implemented time-out.

Despite recent concerns of harm caused by time-out, particularly for children with a history of adversity, findings support the beneficial impact of time-out on child well-being and attachment when implemented in accordance with evidence-based parameters. Combatting misinformation and disseminating evidence-based time-out guidelines is crucial for promoting child well-being and attachment, especially for children who have experienced adversity.

Evidence is largely limited regarding the extent to which abnormal behavioural profiles, including physical inactivity, sedentary behaviour and inadequate sleep duration, impact long-term health conditions in individuals with pre-existing depression.

To investigate the associations between accelerometer-derived daily movement behaviours and mortality in individuals with pre-existing depression.

Between 2013 and 2015, a total of 10 914 individuals with pre-existing depression were identified from the UK Biobank through multiple sources including self-reported symptoms, records of antidepressant usage and diagnostic recording based on the 10th Revision of the International Classification of Diseases (ICD-10) codes F32–F33. These participants were subsequently followed up until 2021. Wrist-worn accelerometers were used for objective measurement of sleep duration, sedentary behaviour, moderate-to-vigorous physical activity (MVPA) and light physical activity (LPA) over a span of seven consecutive days.

During a median follow-up of 6.9 years, 434 deaths occurred among individuals with pre-existing depression. We observed a U-shaped association between sleep duration and mortality in individuals with pre-existing depression, with the lowest risk occurring at approximately 9 h/day. Both MVPA and LPA exhibited an L-shaped pattern in relation to mortality, indicating that engaging in higher levels of physical activity was associated with lower risk of mortality in individuals with pre-existing depression, but the beneficial effect reached a plateau after 50 min/day for MVPA and 350 min/day for LPA. We found a positive association between sedentary time and mortality, and the risk apparently increased above 8 h/day. Moreover, substituting 1 hour/day of sedentary time with LPA or MVPA was significantly associated with a 12% (hazard ratio: 0.88, 95% CI: 0.83–0.94) and 24% (hazard ratio: 0.76, 95% CI: 0.61–0.94) lower risk of mortality, respectively.

Our study found the beneficial effect of adequate sleep duration, high levels of physical activity and short sedentary time on risk of mortality among individuals with pre-existing depression.

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.

Abrupt cessation of heavy cannabis use can cause a withdrawal syndrome characterised by irritability, anxiety, insomnia, reduced appetite and restlessness. Recent reports have also described people in whom cannabis withdrawal immediately preceded the acute onset of psychosis.

To identify cases of psychosis associated with cannabis withdrawal.

We completed a systematic review of the literature, which comprised case reports, case series and other studies. We also searched a large electronic database of psychiatric healthcare records.

The systematic review identified 44 individuals from 21 studies in whom cannabis withdrawal preceded the development of acute psychosis. In the health record study, we identified another 68 people, of whom 47 involved a first episode of psychosis and 21 represented further episodes of an existing psychotic disorder. Almost all people were daily cannabis users who had stopped using cannabis abruptly. Individuals who continued to use cannabis after the acute psychotic episode had a much higher risk of subsequent relapse than those who abstained (odds ratio 13.9 [95% CI: 4.1 to 56.9]; χ2 = 20.1, P < 0.00001).

Abrupt cannabis withdrawal may act as a trigger for the first episode of psychosis and a relapse of an existing psychosis. Acute psychotic symptoms can emerge after the cessation, as well as following the use, of cannabis.

In patients with treatment resistant depression (TRD), the ESCAPE-TRD study showed esketamine nasal spray was superior to quetiapine extended release.

To determine the robustness of the ESCAPE-TRD results and confirm the superiority of esketamine nasal spray over quetiapine extended release.

ESCAPE-TRD was a randomised, open-label, rater-blinded, active-controlled phase IIIb trial. Patients had TRD (i.e. non-response to two or more antidepressive treatments within a major depressive episode). Patients were randomised 1:1 to flexibly dosed esketamine nasal spray or quetiapine extended release, while continuing an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. The primary end-point was achieving a Montgomery–Åsberg Depression Rating Scale score of ≤10 at Week 8, while the key secondary end-point was remaining relapse free through Week 32 after achieving remission at Week 8. Sensitivity analyses were performed on these end-points by varying the definition of remission based on timepoint, threshold and scale.

Of 676 patients, 336 were randomised to esketamine nasal spray and 340 to quetiapine extended release. All sensitivity analyses on the primary and key secondary end-point favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.462 to 1.737 and from 1.417 to 1.838, respectively (all p < 0.05). Treatment with esketamine nasal spray shortened time to first and confirmed remission (hazard ratio: 1.711 [95% confidence interval 1.402, 2.087], p < 0.001; 1.658 [1.337, 2.055], p < 0.001).

Esketamine nasal spray consistently demonstrated significant superiority over quetiapine extended release using all pre-specified definitions for remission and relapse. Sensitivity analyses supported the conclusions of the primary ESCAPE-TRD analysis and demonstrated robustness of the results.

Early intervention in psychosis (EIP) services improve outcomes for young people, but approximately 30% disengage.

To test whether a new motivational engagement intervention would prolong engagement and whether it was cost-effective.

We conducted a multicentre, single-blind, parallel-group, cluster randomised controlled trial involving 20 EIP teams at five UK National Health Service (NHS) sites. Teams were randomised using permuted blocks stratified by NHS trust. Participants were all young people (aged 14–35 years) presenting with a first episode of psychosis between May 2019 and July 2020 (N = 1027). We compared the novel Early Youth Engagement (EYE-2) intervention plus standardised EIP (sEIP) with sEIP alone. The primary outcome was time to disengagement over 12–26 months. Economic outcomes were mental health costs, societal costs and socio-occupational outcomes over 12 months. Assessors were masked to treatment allocation for primary disengagement and cost-effectiveness outcomes. Analysis followed intention-to-treat principles. The trial was registered at ISRCTN51629746.

Disengagement was low at 15.9% overall in standardised stand-alone services. The adjusted hazard ratio for EYE-2 + sEIP (n = 652) versus sEIP alone (n = 375) was 1.07 (95% CI 0.76–1.49; P = 0.713). The health economic evaluation indicated lower mental healthcare costs linked to reductions in unplanned mental healthcare with no compromise of clinical outcomes, as well as some evidence for lower societal costs and more days in education, training, employment and stable accommodation in the EYE-2 group.

We found no evidence that EYE-2 increased time to disengagement, but there was some evidence for its cost-effectiveness. This is the largest study to date reporting positive engagement, health and cost outcomes in a total EIP population sample. Limitations included high loss to follow-up for secondary outcomes and low completion of societal and socio-occupational data. COVID-19 affected fidelity and implementation. Future engagement research should target engagement to those in greatest need, including in-patients and those with socio-occupational goals.