Research indicates that treatment outcomes are poorer for people with long-term physical health conditions (LTCs) in Talking Therapies services (formerly known as Improving Access to Psychological Therapies). However, the impact of having an LTC on attendance at assessment and treatment appointments within Talking Therapies remains unclear. Internet-enabled therapies may be one way to overcome barriers to treatment engagement in Talking Therapies. However, their effect on engagement and the influence of LTC status on receipt of internet-enabled therapies is unknown.

To explore the association between LTC status and assessment attendance, treatment engagement and internet-enabled therapy receipt within Talking Therapies services, and whether receipt of internet-enabled treatment bolsters engagement.

We used anonymous patient-level data from two inner London Talking Therapies services during January to December 2022 (n = 17 095 referrals). Binary logistic regression models were constructed to compare differences between LTC and non-LTC groups on (a) assessment attendance, (b) engagement and (c) internet-enabled therapy receipt. In our regression models, we controlled for key clinical and demographic covariates.

There were no differences between patients with or without an LTC in assessment attendance or treatment engagement, after controlling for covariates. Across the whole sample, receiving internet-enabled treatment increased engagement. People with an LTC were less likely to receive an internet-enabled treatment.

Having an LTC does not negatively affect assessment attendance and engagement with talking therapies. However, receiving an internet-enabled treatment bolstered engagement in our regression models. People with an LTC were less likely to receive internet-enabled treatment.

An increasing number of observational studies have reported associations between frailty and mental disorders, but the causality remains ambiguous.

To assess the bidirectional causal relationship between frailty and nine mental disorders.

We conducted a bidirectional two-sample Mendelian randomisation on genome-wide association study summary data, to investigate causality between frailty and nine mental disorders. Causal effects were primarily estimated using inverse variance weighted method. Several secondary analyses were applied to verify the results. Cochran's Q-test and Mendelian randomisation Egger intercept were applied to evaluate heterogeneity and pleiotropy.

Genetically determined frailty was significantly associated with increased risk of major depressive disorder (MDD) (odds ratio 1.86, 95% CI 1.36–2.53, P = 8.1 × 10−5), anxiety (odds ratio 2.76, 95% CI 1.56–4.90, P = 5.0 × 10−4), post-traumatic stress disorder (PTSD) (odds ratio 2.56, 95% CI 1.69–3.87, P = 9.9 × 10−6), neuroticism (β = 0.25, 95% CI 0.11–0.38, P = 3.3 × 10−4) and insomnia (β = 0.50, 95% CI 0.25–0.75, P = 1.1 × 10−4). Conversely, genetic liability to MDD, neuroticism, insomnia and suicide attempt significantly increased risk of frailty (MDD: β = 0.071, 95% CI 0.033–0.110, P = 2.8 × 10−4; neuroticism: β = 0.269, 95% CI 0.173–0.365, P = 3.4 × 10−8; insomnia: β = 0.160, 95% CI 0.141–0.179, P = 3.2 × 10−61; suicide attempt: β = 0.056, 95% CI 0.029–0.084, P = 3.4 × 10−5). There was a suggestive detrimental association of frailty on suicide attempt and an inverse relationship of subjective well-being on frailty.

Our findings show bidirectional causal associations between frailty and MDD, insomnia and neuroticism. Additionally, higher frailty levels are associated with anxiety and PTSD, and suicide attempts are correlated with increased frailty. Understanding these associations is crucial for the effective management of frailty and improvement of mental disorders.

Physical activities are widely implemented for non-pharmacological intervention to alleviate depressive symptoms. However, there is little evidence supporting their genotype-specific effectiveness in reducing the risk of self-harm in patients with depression.

To assess the associations between physical activity and self-harm behaviour and determine the recommended level of physical activity across the genotypes.

We developed the bidirectional analytical model to investigate the genotype-specific effectiveness on UK Biobank. After the genetic stratification of the depression phenotype cohort using hierarchical clustering, multivariable logistic regression models and Cox proportional hazards models were built to investigate the associations between physical activity and the risk of self-harm behaviour.

A total of 28 923 subjects with depression phenotypes were included in the study. In retrospective cohort analysis, the moderate and highly active groups were at lower risk of self-harm behaviour. In the followed prospective cohort analysis, light-intensity physical activity was associated with a lower risk of hospitalisations due to self-harm behaviour in one genetic cluster (adjusted hazard ratio, 0.28 [95% CI, 0.08–0.96]), which was distinguished by three genetic variants: rs1432639, rs4543289 and rs11209948. Compliance with the guideline-level moderate-to-vigorous physical activities was not significantly related to the risk of self-harm behaviour.

A genotype-specific dose of light-intensity physical activity reduces the risk of self-harm by around a fourth in depressive patients.

Depressive disorders pose a significant global public health challenge, yet evidence on their burden remains insufficient.

To report the global, regional and national burden of depressive disorders and their attributable risk factors from 1990 to 2021.

Data from the Global Burden of Disease 2021 were analyzed for 204 countries and territories from 1990 to 2021. We explored the age-standardised incidence, prevalence and disability-adjusted life years (DALYs) of depressive disorders by age, gender and sociodemographic index.

In 2021, there were 357.44 million incident cases, 332.41 million prevalent cases and 56.33 million DALYs. Age-standardised rates for incidence, prevalence and DALYs were 4333.62, 4006.82 and 681.14 per 100 000 persons, with annual declines of 0.06%, 0.03% and 0.04%. Uganda, Greenland and Lesotho had the highest prevalence, while Spain, Mexico and Uruguay showed the largest increases. Greenland and Brunei Darussalam had the highest and lowest age-standardised DALYs rates, respectively. DALYs peaked in the 55–59 age group for men and 60–64 for women, with higher rates in women. Regionally, a U-shaped association was found between the sociodemographic index and DALYs rates. Population growth was the main driver for the increase in DALYs cases. Childhood maltreatment was the leading risk factor, with intimate partner violence affecting more females and childhood sexual abuse more males.

Despite decreasing trends in incidence, prevalence and DALYs rates, absolute case numbers and age-standardised rates continue to increase for depressive disorders. Tackling childhood abuse and improving depressive disorder management are crucial to reducing future burdens.

Estimating the risk of developing bipolar disorder (BD) in children and adolescents (C&A) with depressive disorders is important to optimize prevention and early intervention efforts. We aimed to quantitatively examine the risk of developing BD from depressive disorders and identify factors which moderate this development.

In this systematic review and meta-analysis (PROSPERO:CRD42023431301), PubMed and Web-of-Science databases were searched for longitudinal studies reporting the percentage of C&A with ICD/DSM-defined depressive disorders who developed BD during follow-up. Data extraction, random-effects meta-analysis, between-study heterogeneity analysis, quality assessment, sub-group analyses, and meta-regressions were conducted.

Thirty-nine studies were included, including 72,371 individuals (mean age=13.9 years, 57.1% females); 14.7% of C&A with a depressive disorder developed BD after 20.4–288 months: 9.5% developed BD-I (95% CI=4.7 to 18.1); 7.7% developed BD-II (95% CI=3.2% to 17.3%); 19.8% (95% CI=9.9% to 35.6%) of C&A admitted into the hospital with a depressive disorder developed BD. Studies using the DSM (21.6%, 95% CI=20.2% to 23.1%) and studies evaluating C&A with a major depressive disorder only (19.8%, 95% CI=16.8% to 23.1%) found higher rates of development of BD. Younger age at baseline, a history of hospitalization and recruitment from specialized clinics were associated with an increased risk of developing BD at follow-up. Quality of included studies was good in 76.9% of studies.

There is a substantial risk of developing BD in C&A with depressive disorders. This is particularly the case for C&A with MDD, DSM-diagnosed depressive disorders, and C&A admitted into the hospital. Research exploring additional predictors and preventive interventions is crucial.

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.

Western Australia's response to the COVID-19 pandemic was swift and effective in implementing public health protections and preventing the spread of the virus for the first 2 years. However, healthcare staff continued to be at increased risk of mental health concerns.

To investigate the longitudinal patterns of post-traumatic stress symptoms (PTSS), depression and anxiety among healthcare workers in Western Australia, and the risk and protective factors associated with changes in status during the first wave.

Participants comprised 183 healthcare staff working at tertiary hospitals and major clinics across Perth, for whom longitudinal data were available. Questionnaire data were collected before Western Australia's first major COVID-19 community wave in early 2022 and following the first wave in late 2022. Online surveys comprised validated measures assessing psychological symptoms, risk and protective factors, and original measures of workplace factors.

Overall rates of PTSS, depression and anxiety remained stable across the two assessment points. However, latent growth models revealed that those with lower PTSS, depression or anxiety symptoms at baseline reported a larger increase in symptoms over time, and those with higher symptoms at baseline had a smaller decline over time, indicating a ‘catch-up’ effect. Workplace stressors, sleep difficulties and trauma exposure were key risk factors for changes in psychological symptoms from baseline, and workplace and social supports played protective roles.

Improvements in systemic workplace factors are needed to support healthcare workers’ mental health during periods of acute stress, even in settings with high levels of emergency preparedness.

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.

Childhood trauma is a major risk factor for chronic depression. It has been suggested that adults with chronic depression who have experienced childhood trauma may require long-term treatment owing to a breakdown of basic trust and related difficulties in developing a productive therapeutic relationship.

As empirical studies have been preliminary and scarce, we studied the effects of psychoanalytic therapy (PAT) versus cognitive–behavioural therapy (CBT) for chronic depression in adults with a history of childhood trauma. In this subgroup, we expected a greater symptom reduction in PAT compared with CBT.

In a large trial of long-term psychotherapies for chronic depression (LAC-Study; Clinical Trial Register ISRCTN91956346), 210 adults received open-ended CBT or PAT in an out-patient setting and were examined yearly over 5 years on the Beck Depression Inventory – II (BDI-II). Based on a linear mixed model approach, we tested participant-reported childhood trauma based on the Childhood Trauma Questionnaire (CTQ) as a predictor and moderator of treatment outcome. CTQ subscales were examined exploratively.

Depressive symptoms decreased over time (b = −4.55, s.e. = 0.90, 95% CI −6.32 to −2.81, T = −5.08; P < 0.001). A significant three-way interaction between childhood trauma, time and therapy group (b = −0.05, s.e. = 0.02, 95% CI −0.09 to −0.01, T = −2.42; P = 0.016) indicated that participants with childhood trauma profited especially well from PATs.

Our results indicate differential benefits from PAT compared with CBT among adults with chronic depression and a history of childhood trauma. The results have important implications for differential indication and policy.

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.

Physician-assisted suicide (PAS) is typically associated with serious physical illnesses that are prevalent in palliative care. However, individuals with mental illnesses may also experience such severity that life becomes intolerable. In February 2020, the previous German law prohibiting PAS was repealed. Patients with severe mental illnesses are increasingly likely to approach physicians with requests for PAS.

To explore the ethical and moral perspectives of medical students and physicians when making individual decisions regarding PAS.

An anonymised digital survey was conducted among medical students and physicians in Germany. Participants were presented with a case vignette of a chronically depressed patient requesting PAS. Participants decided on PAS provision and assessed theoretical arguments. We employed generalised ordinal regression and qualitative analysis for data interpretation.

A total of N = 1478 participants completed the survey. Of these, n = 470 (32%) stated that they would refuse the request, whereas n = 582 (39%) would probably refuse, n = 375 (25%) would probably agree and n = 57 (4%) would definitely agree. Patient-centred arguments such as the right to self-determination increased the likelihood of consent. Concerns that PAS for chronically depressed patients might erode trust in the medical profession resulted in a decreased willingness to provide PAS.

Participants displayed relatively low willingness to consider PAS in the case of a chronically depressed patient. This study highlights the substantial influence of theoretical medical-ethical arguments and the broader public discourse, underscoring the necessity of an ethical discussion on PAS for mental illnesses.

The serotonin 4 receptor (5-HT4R) is a promising target for the treatment of depression. Highly selective 5-HT4R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established.

To determine whether prucalopride (a 5-HT4R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system.

Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders.

Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76–0.99; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69–0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses.

These findings support preclinical data and suggest a role for 5-HT4R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.

Depressive disorders in adolescents affect all aspects of life and impose a very large burden of disease. Sleep is frequently affected by depression and is crucial for facing challenges during development. One of the postulated reasons for depression-induced sleep disruption is dysregulation of the physiological stress system.

To investigate the links of adolescent depressive disorders with subjective sleep quality, objective sleep quality, and the course of cortisol and alpha-amylase after awakening.

We compared subjective sleep quality (via daily questionnaires) and objective sleep quality (via actigraphy measurement) of 35 adolescents with depressive disorders and 29 healthy controls over 7 consecutive days. In addition, saliva samples were collected on 3 days to examine cortisol and alpha-amylase patterns after awakening.

No significant differences in cortisol or alpha-amylase awakening responses were observed between participants with depressive disorders and healthy controls. We found severe reductions in subjective sleep quality in the depression group (Z = −5.19, P < 0.001, d = 1.80) and a prolonged actigraphy-measured sleep onset latency (Z = −2.42, P = 0.015, d = 0.64) compared with controls. Reductions in subjective sleep quality were partially correlated with objective sleep measures (sleep onset latency: r = −0.270, P = 0.004, sleep efficiency: r = 0.215, P = 0.017).

Sleep onset latency seems to aggravate depressive symptoms and to have an important role in perception of sleep quality. Adolescents with depressive disorders should be supported regarding the establishment of good sleep hygiene and avoiding activities that may impede falling asleep.