Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms.

We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls).

Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (−1019, −1007, −681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF.

Recent stress correlated positively with blood monocyte methylation at the −681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the −1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD.

These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Clinical guidelines recommend providing physical activity interventions (PAIs) to people with schizophrenia or bipolar disorder for weight management. However, the cost-effectiveness of PAIs is unknown.

To evaluate the availability and methodological quality of economic evaluations of PAIs for people with schizophrenia or bipolar disorder.

Four databases (MEDLINE, Embase, PsycInfo and Scopus) were searched on 5 July 2022. Based on the retrieved studies, forward and backward citation searches were conducted. Two reviewers independently selected studies for inclusion. Study quality was assessed using the Drummond checklist. Review results were presented using narrative synthesis.

Fourteen articles reporting nine studies were included. All included studies assessed PAIs within a multicomponent lifestyle intervention. Mixed findings were reported on the cost-effectiveness of multicomponent lifestyle intervention: three studies reported it as cost-effective; four studies reported it as not cost-effective; and two studies did not conclude whether it was cost-effective or not. Very limited evidence suggests that certain patient subgroups might be more likely to benefit from multicomponent lifestyle interventions with a PAI component: men; individuals with comorbid type 2 diabetes; and individuals who have been psychiatric hospital in-patients for ≥1 year. The quality of included studies ranged from moderate to high.

The current economic evidence suggests that not all modalities of multicomponent lifestyle intervention including a PAI component are cost-effective for people with schizophrenia or bipolar disorder; and not all people with schizophrenia or bipolar disorder would benefit equally from the intervention. Future research is urgently needed to identify the cost-effective modality of PAI for different patient subgroups.

The UK and USA currently report their highest number of drug-related deaths since records began, with higher rates among individuals experiencing homelessness.

Given that overdose prevention in homeless populations may require unique strategies, we evaluated whether substances implicated in death differed between (a) housed decedents and those experiencing homelessness and (b) between US and UK homeless populations.

We conducted an internationally comparative retrospective cohort study utilising multilevel multinomial regression modelling of coronial/medical examiner-verified drug-related deaths from 1 January 2012 to 31 December 2021. UK data were available for England, Wales and Northern Ireland; US data were collated from eight county jurisdictions. Data were available on decedent age, sex, ethnicity, housing status and substances implicated in death.

Homeless individuals accounted for 16.3% of US decedents versus 3.4% in the UK. Opioids were implicated in 66.3 and 50.4% of all studied drug-related deaths in the UK and the USA respectively. UK homeless decedents had a significantly increased risk of having only opioids implicated in death compared with only non-opioids implicated (relative risk ratio RRR = 1.87, 95% CI 1.76–1.98, P < 0.001); conversely, US homeless decedents had a significantly decreased risk (RRR = 0.37, 95% CI 0.29–0.48, P < 0.001). Methamphetamine was implicated in two-thirds (66.7%) of deaths among US homeless decedents compared with 0.4% in the UK.

Both the rate and type of drug-related deaths differ significantly between homeless and housed populations in the UK and USA. The two countries also differ in drugs implicated in death. Targeted programmes for country-specific implicated drug profiles appear warranted.

Common postpartum mental health (PMH) disorders such as depression and anxiety are preventable, but determining individual-level risk is difficult.

To create and internally validate a clinical risk index for common PMH disorders.

Using population-based health administrative data in Ontario, Canada, comprising sociodemographic, clinical and health service variables easily collectible from hospital birth records, we developed and internally validated a predictive model for common PMH disorders and converted the final model into a risk index. We developed the model in 75% of the cohort (n = 152 362), validating it in the remaining 25% (n = 75 772).

The 1-year prevalence of common PMH disorders was 6.0%. Independently associated variables (forming the mnemonic PMH CAREPLAN) that made up the risk index were: (P) prenatal care provider; (M) mental health diagnosis history and medications during pregnancy; (H) psychiatric hospital admissions or emergency department visits; (C) conception type and complications; (A) apprehension of newborn by child services (newborn taken into care); (R) region of maternal origin; (E) extremes of gestational age at birth; (P) primary maternal language; (L) lactation intention; (A) maternal age; (N) number of prenatal visits. In the index (scored 0–39), 1-year common PMH disorder risk ranged from 1.5 to 40.5%. Discrimination (C-statistic) was 0.69 in development and validation samples; the 95% confidence interval of expected risk encompassed observed risk for all scores in development and validation samples, indicating adequate risk index calibration.

Individual-level risk of developing a common postpartum mental health disorder can be estimated with data feasibly collectable from birth records. Next steps are external validation and evaluation of various cut-off scores for their utility in guiding postpartum individuals to interventions that reduce their risk of illness.

There is evidence that child maltreatment is associated with shorter telomere length in early life.

This study aims to examine if child maltreatment is associated with telomere length in middle- and older-age adults.

This was a retrospective cohort study of 141 748 UK Biobank participants aged 37–73 years at recruitment. Leukocyte telomere length was measured with quantitative polymerase chain reaction, and log-transformed and scaled to have unit standard deviation. Child maltreatment was recalled by participants. Linear regression was used to analyse the association.

After adjusting for sociodemographic characteristics, participants with three or more types of maltreatment presented with the shortest telomere lengths (β = −0.05, 95% CI −0.07 to −0.03; P < 0.0001), followed by those with two types of maltreatment (β = −0.02, 95% CI −0.04 to 0.00; P = 0.02), referent to those who had none. When adjusted for depression and post-traumatic stress disorder, the telomere lengths of participants with three or more types of maltreatment were still shorter (β = −0.04, 95% CI −0.07 to −0.02; P = 0.0008). The telomere lengths of those with one type of maltreatment were not significantly different from those who had none. When mutually adjusted, physical abuse (β = −0.05, 95% CI −0.07 to −0.03; P < 0.0001) and sexual abuse (β = −0.02, 95% CI −0.04 to 0.00; P = 0.02) were independently associated with shorter telomere length.

Our findings showed that child maltreatment is associated with shorter telomere length in middle- and older-aged adults, independent of sociodemographic and mental health factors.

It is well-known that childhood attention-deficit hyperactivity disorder (ADHD) is associated with later adverse mental health and social outcomes. Patient-based studies suggest that ADHD may be associated with later cardiovascular disease (CVD) but the focus of preventive interventions is unclear. It is unknown whether ADHD leads to established cardiovascular risk factors because so few cohort studies measure ADHD and also follow up to an age where CVD risk is evident.

To examine associations between childhood ADHD problems and directly measured CVD risk factors at ages 44/45 years in a UK population-based cohort study (National Child Development Study) of individuals born in 1958.

Childhood ADHD problems were defined by elevated ratings on both the parent Rutter A scale and a teacher-rated questionnaire at age 7 years. Outcomes were known cardiovascular risk factors (blood pressure, lipid measurements, body mass index and smoking) at the age 44/45 biomedical assessment.

Of the 8016 individuals assessed both during childhood and at the biomedical assessment 3.0% were categorised as having childhood ADHD problems. ADHD problems were associated with higher body mass index (B = 0.92 kg/m2, s.d. = 0.27–1.56), systolic (3.5 mmHg, s.d. = 1.4–5.6) and diastolic (2.2 mmHg, s.d. = 0.8–3.6) blood pressure, triglyceride levels (0.24 mol/l, s.d. = 0.02–0.46) and being a current smoker (odds ratio OR = 1.6, s.d. = 1.2–2.1) but not with LDL cholesterol.

Childhood ADHD problems predicted multiple cardiovascular risk factors by mid-life. These findings, when taken together with previously observed associations with cardiovascular disease in registries, suggest that individuals with ADHD could benefit from cardiovascular risk monitoring, given these risk factors are modifiable with timely intervention.

Early-onset psychosis (EOP) refers to the development of a first episode of psychosis before 18 years of age. Individuals at clinical high risk for psychosis (CHR-P) include adolescents and young adults, although most evidence has focused on adults. Negative symptoms are important prognostic indicators in psychosis. However, research focusing on children and adolescents is limited.

To provide meta-analytical evidence and a comprehensive review of the status and advances in the diagnosis, prognosis and treatment of negative symptoms in children and adolescents with EOP and at CHR-P.

PRISMA/MOOSE-compliant systematic review (PROSPERO: CRD42022360925) from inception to 18 August 2022, in any language, to identify individual studies conducted in EOP/CHR-P children and adolescents (mean age <18 years) providing findings on negative symptoms. Findings were systematically appraised. Random-effects meta-analyses were performed on the prevalence of negative symptoms, carrying out sensitivity analyses, heterogeneity analyses, publication bias assessment and quality assessment using the Newcastle–Ottawa Scale.

Of 3289 articles, 133 were included (n = 6776 EOP, mean age 15.3 years (s.d. = 1.6), males = 56.1%; n = 2138 CHR-P, mean age 16.1 years (s.d. = 1.0), males = 48.6%). There were negative symptoms in 60.8% (95% CI 46.4%–75.2%) of the children and adolescents with EOP and 79.6% (95% CI 66.3–92.9%) of those at CHR-P. Prevalence and severity of negative symptoms were associated with poor clinical, functional and intervention outcomes in both groups. Different interventions were piloted, with variable results requiring further replication.

Negative symptoms are common in children and adolescents at early stages of psychosis, particularly in those at CHR-P, and are associated with poor outcomes. Future intervention research is required so that evidence-based treatments will become available.

The COVID-19 pandemic and associated lockdowns were predicted to have a major impact on suicidal behaviour, including self-harm. However, current studies have produced contradictory findings with limited trend data.

Nine years of linked individual-level administrative data were utilised to examine changes in hospital-presenting self-harm and ideation (thoughts of self-harm or suicide) before and during the pandemic.

National self-harm registry data were linked to demographic and socioeconomic indicators from healthcare registration records (n = 1 899 437). Monthly presentations of self-harm or ideation were split (pre-COVID-19 restrictions: April 2012 to February 2020; and during restrictions: March to September 2020). Auto-regressive integrated moving average (ARIMA) models were trained in R taking into consideration trends and seasonal effects. Forecast (‘expected’) monthly values were compared with ‘actual’ values, stratified by demographic factors and method of harm.

The number of individuals presenting with self-harm or ideation dropped significantly at the beginning of the pandemic (March–May 2020), before returning mostly to expected trends from June 2020. Stratified analysis showed similar presentation trends across most demographic subgroups except for those aged over 65 years, living alone or in affluent areas, where presentations remained unaffected, and those aged under 16 years, where numbers presenting with self-harm or ideation increased above expected levels.

Although population trends show an overall drop in presentations before a return to ‘normal’ from June 2020, the demographic profile of those presenting with self-harm or ideation varied significantly, with increases in children under the age of 16 years. This highlights important potential target groups who may have been most negatively affected by the pandemic.

To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.

To investigate the impact of this temporary policy change on clinical and safety outcomes.

All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.

Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02–28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection.

There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Cannabis has been associated with poorer mental health, but little is known of the effect of synthetic cannabinoids or cannabidiol (often referred to as CBD).

To investigate associations of cannabis, synthetic cannabinoids and cannabidiol with mental health in adolescence.

We conducted a cross-sectional analysis with 13- to 14-year-old adolescents across England and Wales in 2019–2020. Multilevel logistic regression was used to examine the association of lifetime use of cannabis, synthetic cannabinoids and cannabidiol with self-reported symptoms of probable depression, anxiety, conduct disorder and auditory hallucinations.

Of the 6672 adolescents who participated, 5.2% reported using of cannabis, 1.9% reported using cannabidiol and 0.6% reported using synthetic cannabinoids. After correction for multiple testing, adolescents who had used these substances were significantly more likely to report a probable depressive, anxiety or conduct disorder, as well as auditory hallucinations, than those who had not. Adjustment for socioeconomic disadvantage had little effect on associations, but weekly tobacco use resulted in marked attenuation of associations. The association of cannabis use with probable anxiety and depressive disorders was weaker in those who reported using cannabidiol than those who did not. There was little evidence of an interaction between synthetic cannabinoids and cannabidiol.

To our knowledge, this study provides the first general population evidence that synthetic cannabinoids and cannabidiol are associated with probable mental health disorders in adolescence. These associations require replication, ideally with prospective cohorts and stronger study designs.

Collaborative care (CC) and consultation liaison (CL) are two conceptual models aiming to improve mental healthcare in primary care. The effects of these models have not been compared in a Danish setting.

To examine the effects of CC versus CL for persons with anxiety and depression in Danish general practices (trial registration: NCT03113175 and NCT03113201).

Two randomised parallel superiority trials for anxiety disorders and depression were carried out in 2018–2019. In the CC-group, care managers collaborated with general practitioners (GPs) to provide evidence-based treatment according to structured treatment plans. They followed up and provided psychoeducation and/or cognitive–behavioural therapy. The GPs initiated pharmacological treatment if indicated, and a psychiatrist provided supervision. In the CL-group, the intervention consisted of the GP's usual treatment. However, the psychiatrist and care manager could be consulted. Primary outcomes were depression symptoms (Beck Depression Inventory-II, BDI-II) in the depression trial and anxiety symptoms (Beck Anxiety Inventory, BAI) in the anxiety trial at 6-month follow-up.

In total, 302 participants with anxiety disorders and 389 participants with depression were included. A significant difference in BDI-II score was found in the depression trial, with larger symptom reductions in the CC-group (CC: 12.7, 95% CI 11.4–14.0; CL: 17.5, 95% CI 16.2–18.9; Cohen's d = −0.50, P ≤ 0.001). There was a significant difference in BAI in the anxiety trial (CC: 14.9, 95% CI 13.5–16.3; CL: 17.9, 95% CI 16.5–19.3; Cohen's d = −0.34, P ≤ 0.001), with larger symptom reductions in the CC-group.

Collaborative care was an effective model to improve outcomes for persons with depression and anxiety disorders.

Neurocognitive deficits are a core feature of psychosis and depression. Despite commonalities in cognitive alterations, it remains unclear if and how the cognitive deficits in patients at clinical high risk for psychosis (CHR) and those with recent-onset psychosis (ROP) are distinct from those seen in recent-onset depression (ROD).

This study was carried out within the European project ‘Personalized Prognostic Tools for Early Psychosis Management’, and aimed to characterise the cognitive profiles of patients with psychosis or depression.

We examined cognitive profiles for patients with ROP (n = 105), patients with ROD (n = 123), patients at CHR (n = 116) and healthy controls (n = 372) across seven sites in five European countries. Confirmatory factor analysis identified four cognitive factors independent of gender, education and site: speed of processing, attention and working memory, verbal learning and spatial learning.

Patients with ROP performed worse than healthy controls in all four domains (P < 0.001), whereas performance of patients with ROD was not affected (P > 0.05). Patients at CHR performed worse than healthy controls in speed of processing (P = 0.001) and spatial learning (P = 0.003), but better than patients with ROP across all cognitive domains (all P ≤ 0.01). CHR and ROD groups did not significantly differ in any cognitive domain. These findings were independent of comorbid depressive symptoms, substance consumption and illness duration.

These results show that neurocognitive abilities are affected in CHR and ROP, whereas ROD seems spared. Although our findings may support the notion that those at CHR have a specific vulnerability to psychosis, future studies investigating broader transdiagnostic risk cohorts in longitudinal designs are needed.

Guided self-help (GSH) for anxiety is widely implemented in primary care services because of service efficiency gains, but there is also evidence of poor acceptability, low effectiveness and relapse.

The aim was to compare preferences for, acceptability and efficacy of cognitive–behavioural guided self-help (CBT-GSH) versus cognitive–analytic guided self-help (CAT-GSH).

This was a pragmatic, randomised, patient preference trial (Clinical trials identifier: NCT03730532). The Beck Anxiety Inventory (BAI) was the primary outcome at 8- and 24-week follow-up. Interventions were delivered competently on the telephone via structured workbooks over 6–8 (30–35 min) sessions by trained practitioners.

A total of 271 eligible participants were included, of whom 19 (7%) accepted being randomised and 252 (93%) chose their treatment. In the preference cohort, 181 (72%) chose CAT-GSH and 71 (28%) preferred CBT-GSH. BAI outcomes in the preference and randomised cohorts did not differ at 8 weeks (−0.80, 95% confidence interval (CI) −4.52 to 2.92) or 24 weeks (0.85, 95% CI −2.87 to 4.57). After controlling for allocation method and baseline covariates, there were no differences between CAT-GSH and CBT-GSH at 8 weeks (F(1, 263) = 0.22, P = 0.639) or at 24 weeks (F(1, 263) = 0.22, P = 0.639). Mean BAI change from baseline was a reduction of 9.28 for CAT-GSH and 9.78 for CBT-GSH at 8 weeks and 12.90 for CAT-GSH and 12.43 for CBT-GSH at 24 weeks.

Patients accessing routine primary care talking treatments prefer to choose the intervention they receive. CAT-GSH expands the treatment offer in primary care for patients with anxiety seeking a brief but analytically informed GSH solution.

The association of COVID-19 with death in people with severe mental illness (SMI), and associations with multimorbidity and ethnicity, are unclear.

To determine all-cause mortality in people with SMI following COVID-19 infection, and assess whether excess mortality is affected by multimorbidity or ethnicity.

This was a retrospective cohort study using primary care data from the Clinical Practice Research Database, from February 2020 to April 2021. Cox proportional hazards regression was used to estimate the effect of SMI on all-cause mortality during the first two waves of the COVID-19 pandemic.

Among 7146 people with SMI (56% female), there was a higher prevalence of multimorbidity compared with the non-SMI control group (n = 653 024, 55% female). Following COVID-19 infection, the SMI group experienced a greater risk of death compared with controls (adjusted hazard ratio (aHR) 1.53, 95% CI 1.39–1.68). Black Caribbean/Black African people were more likely to die from COVID-19 compared with White people (aHR = 1.22, 95% CI 1.12–1.34), with similar associations in the SMI group and non-SMI group (P for interaction = 0.73). Following infection with COVID-19, for every additional multimorbidity condition, the aHR for death was 1.06 (95% CI 1.01–1.10) in the SMI stratum and 1.16 (95% CI 1.15–1.17) in the non-SMI stratum (P for interaction = 0.001).

Following COVID-19 infection, patients with SMI were at an elevated risk of death, further magnified by multimorbidity. Black Caribbean/Black African people had a higher risk of death from COVID-19 than White people, and this inequity was similar for the SMI group and the control group.