Cognitive function is a significant predictor of daily functioning in the population, yet the extent to which common mental health symptoms account for this relationship remains unclear.

This study aimed to examine the relationship between cognition, mental health and functioning across two cohorts.

Participants were recruited from an online population cohort, HealthWise Wales (N = 3679), and a psychiatric cohort, the National Centre for Mental Health (NCMH, N = 1036), to complete a cognitive battery and the World Health Organization Disability Assessment Schedule (WHODAS). We assessed the associations between cognitive performance and the WHODAS, as well as two measures of life functioning: current employment and cohabitation with a partner. We examined the role of current mood, psychiatric and neurodevelopmental history and lifestyle factors using linear and logistic regression.

Higher cognitive performance was associated with fewer functional difficulties on the WHODAS (HealthWise Wales: B = −0.12, 95% CI (−0.15,−0.09), P < 0.001; NCMH: B = −0.1, 95% CI (−0.13,−0.08), P < 0.001), being in employment or education (HealthWise Wales: odds ratio 1.22, 95% CI (1.11,1.34), P < 0.001; NCMH: odds ratio 1.31, 95% CI (1.19,1.46), P < 0.001) and living with a partner (HealthWise Wales only: odds ratio 1.19, 95% CI (1.06,1.32), P = 0.003). Higher levels of depression and anxiety symptoms were consistently associated with reduced functioning across all analyses. The relationship between cognition and functioning remained significant but attenuated after accounting for these symptoms.

Cognitive function was associated with functioning in both clinical and population-derived samples. Current symptoms of depression and anxiety play a key role in this relationship. Both cognitive function and common mental health problems may be potential intervention targets to alleviate daily difficulties.

Access to depression care can be improved by overcoming a combination of supply-side barriers and demand-side factors.

To describe the systematic development of a community-based intervention to improve uptake of, and adherence to, a psychosocial treatment for depression delivered by trained primary healthcare staff in Goa, India.

This mixed-methods study included five steps: Step 1, Synthesis of existing evidence by conducting relevant systematic reviews and a review of public health programmes in India; Step 2, In-depth interviews with community stakeholders (n = 35); Step 3, Consultation workshops with community stakeholders (n = 19) and primary healthcare staff (n = 34); Step 4, Triangulation of findings from the preceding steps; and Step 5, Content development for the intervention (e-course for training and the community intervention toolkit for delivery).

Overall, 20 strategies to enhance help-seeking and 5 strategies to improve adherence were identified to constitute the intervention. The community-based intervention is organised into four domains (Learn, Inform, Engage and Follow-up), with self-care integrated throughout the intervention. This intervention is designed to be delivered by a community volunteer who is motivated to cater to the communities’ needs. The community volunteer is trained to deliver the intervention via a blended approach, an e-course and in-person one-on-one learning support by a coach, who later acts as a facilitator during the intervention delivery phase.

The systematic method enabled the development of a comprehensive intervention with contextually appropriate delivery strategies. The effectiveness of the intervention is presently being tested as part of a Hybrid Type II Implementation-Effectiveness randomised controlled trial. If found effective, the intervention has the potential to be a low-cost and sustainable opportunity to improve demand and adherence to depression treatment while also providing essential social, emotional and logistical support during the recovery process.

Since the full-scale Russian invasion in 2022, health facilities and healthcare workers in Ukraine have been systematically targeted. Despite growing calls to prioritise their mental health, robust evidence on the magnitude of the problem and its determinants remains limited.

To estimate the prevalence of mental health problems among doctors and nurses in Ukraine, and examine their association with key exposures.

We conducted a cross-sectional survey between May and September of 2025, in a non-probabilistic sample of doctors and nurses working in Ukraine. The survey included validated self-report instruments to assess depression (Patient Health Questionnaire-9), anxiety (Generalised Anxiety Disorder-7) and suicidal thoughts, as well as workplace risk factors (bullying, sexual harassment, violent threats, physical violence) and protective factors (social support, purpose and meaning at work). Associations were examined using multilevel regression models with extensive sensitivity analyses, including Bayesian models and survey raking weights.

Among 23 805 respondents, 1 in 3 doctors and 1 in 4 nurses reported symptoms compatible with probable depression, 1 in 4 doctors and 1 in 6 nurses reported symptoms compatible with probable anxiety, and about 1 in 10 doctors and nurses reported suicidal thoughts. Workplace violence – particularly bullying – was strongly associated with depression and anxiety, whereas physical violence showed the strongest association with suicidal thoughts. Purpose and meaning at work were consistently associated with better mental health. Associations were overall high and similar across regions with different levels of active conflicts. Estimates were robust across analytic approaches.

Elevated prevalences and strong associations with workplace factors support a zero-tolerance approach to violence and the implementation of scalable mental health strategies that also strengthen protective factors.

Polygenic scores (PGS) have been used to quantify genetic liability for psychiatric disorders, but it remains unclear how these scores are associated with age- and gender-specific risk of diagnosis.

To examine associations between disorder-specific PGS and age- and gender-specific risk of psychiatric diagnoses across major psychiatric disorders.

We conducted a population-based case–cohort study using the Danish iPSYCH2015 sample, including individuals born in Denmark between 1981 and 2008 and followed for psychiatric diagnoses from 1994 to 2015. Cases comprised individuals diagnosed with major depressive disorder (MDD; N = 30 905), schizophrenia spectrum disorders (SCZ; N = 12 703), bipolar disorder (N = 3169), attention-deficit hyperactivity disorder (N = 25 167) or autism spectrum disorder (ASD; N = 15 677), alongside a randomly sampled subcohort (N = 52 765). Disorder-specific PGS were the exposures. Gender- and age-specific hazard ratios for first hospital-based diagnoses were estimated using Cox proportional hazards models.

All PGS were associated with risk of all disorders regardless of age. For MDD, the highest association per 1 s.d. increase in PGS was observed at ages 17–19 (males: hazard ratio 1.56; 95% CI 1.45–1.69; females: hazard ratio 1.48; 95% CI 1.40–1.57). SCZ-PGS showed marked gender differences, with the strongest association with SCZ diagnosis at ages 20–22 years for males (hazard ratio 1.71; 95% CI 1.54–1.90) and 17–19 years for females (hazard ratio 1.29; 95% CI 1.16–1.44). ASD–PGS associations were strongest in males at ages 4–6 (hazard ratio 1.51; 95% CI 1.44–1.61) and 7–9 years (hazard ratio 1.55; 95% CI 1.47–1.65), and in females at ages 13–15 years (hazard ratio 1.60; 95% CI 1.41–1.82). Gender differences were evident across disorders. The PGS–schizophrenia association was stronger in males, whereas for childhood-onset disorders, associations were stronger in females but emerged at older ages.

Polygenic burden for psychiatric disorders tends to be more strongly associated with risk of diagnosis at younger ages, with gender-specific patterns. Future genetic research should consider both age at diagnosis and potential gender differences.

Placebos have historically been used as comparative tools in randomised controlled trials (RCTs), but their therapeutic effect, particularly in psychiatric conditions, warrant a more detailed exploration to improve research design and clinical practice.

This systematic review and meta-analysis examines the factors influencing placebo treatment effects across major psychiatric disorders, including depression, anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).

This PROSPERO registered systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify RCTs with at least one placebo and one medication arm (citalopram or escitalopram), across four major groups of psychiatric conditions. Data extraction focused on study characteristics, methodology, target condition, participant demographics and outcome measurements. Cohen’s d effect sizes for placebo and medication groups were calculated, with random-effects model meta-analyses performed to assess heterogeneity and their correlates.

The review included 80 studies with 312 outcome measures, involving 19 776 participants (7 to 91 years old). A large placebo response was observed (effect size: 1.01; 95% CI: 0.93–1.10) with significant heterogeneity (I2: 99.61%). Significant differences in placebo responses were noted across clinical conditions, independent of the medication type. PTSD and depressive disorders exhibited the highest placebo effect size (1.14 and 1.02, respectively), whereas OCD showed the lowest (effect size: 0.62, P < 0.01). Anxiety disorders displayed a moderately large placebo effect size (0.86), with significant variability among anxiety disorder subclasses, specifically noting the lowest placebo effect size in specific phobia (0.23, P < 0.01). The medication effect size (1.43) also demonstrated considerable heterogeneity (I2: 99.76%) but was not significantly different across psychiatric conditions (P = 0.61). Placebo response magnitude was larger in studies with more study arms (b: 0.181, P < 0.01) and younger mean age of the participant (b: −0.010, P < 0.01). Moreover, clinician-rated outcomes versus patient self-reports (effect size: 1.07 v. 0.76, P < 0.01), multicentre studies (p < 0.01) and using intention-to-treat data (effect size: 1.08 v. 0.86, P = 0.01) were associated with larger placebo effect size.

This study used a unique approach to examine placebo responses from the same interventions across multiple major psychiatric disorders. We found substantial placebo responses across psychiatric conditions and significant heterogeneity, influenced by a range of study-related and demographic factors. The findings underscore the complexity of placebo responses and highlight the importance of considering these variances in both research design and clinical translation.

Most antidepressants do not independently treat impaired cognition associated with major depressive disorder (MDD). Elevated brain cortisol levels are associated with both MDD and cognitive impairment. Emestedastat is a brain-penetrant, intracellular cortisol synthesis inhibitor.

The XanaCIDD trial aimed to determine whether emestedastat 10 mg could improve both cognitive impairment and depression in a population with persistent MDD and cognitive impairment.

Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks’ blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery–Åsberg Depression Rating Scale (MADRS) and Patient Global Impression of Severity (PGI-S). Analyses used a mixed model for repeated measures (cognitive impairment and MADRS one-sided tests, others two-sided) and Cohen’s d effect size. No adjustments were made for multiple comparisons.

A total of 165 participants were enrolled and treated: 134 (81%) were on background antidepressants, 62% were female, mean prior number of MDD episodes was 10 and mean coding z-score was −1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 0.02). The trend towards benefit on the prespecified secondary depression end-point, MADRS, began at week 6 and was maximal at week 10 (2.7 points, Cohen’s d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild–moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group.

There was no benefit of emestedastat on the primary end-point of cognitive impairment and a large placebo effect, without correlation of cognitive impairment to depression changes or baseline characteristics. Trends towards potential antidepressant activity suggest that emestedastat may be a novel antidepressant worthy of further investigation.

The primary effect parameter in depression trials is usually a measure of depressive symptoms, e.g. the Hamilton Depression Rating Scale (HDRS). Such measures have been criticised for not covering patient-relevant domains, such as quality of life, and hence not accurately reflecting patient-experienced efficacy.

To investigate the relation between clinician-rated depressive symptoms and patient-reported quality of life measured by the Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF).

We included data from six acute-phase trials (n = 918) comparing mirtazapine to another antidepressant (amitriptyline, fluoxetine, paroxetine or venlafaxine) where both HDRS and Q-LES-Q-SF had been administered. No study included a placebo arm. Correlations between instruments (scales, subscales and items) were assessed after six weeks. Q-LES-Q-SF outcomes for participants who were in HDRS-defined remission were contrasted to those from participants with more severe depressive symptoms.

Q-LES-Q-SF ratings correlated strongly with HDRS-17 (r = −0.73, p < 0.0001) and HDRS-6 (r = −0.72, p < 0.0001), but somewhat weaker to HDRS-11 (r = −0.64, p < 0.0001). Depressed mood (r = −0.66, p < 0.0001) and work and activities (r = −0.65, p < 0.0001) showed the strongest item-level correlations to Q-LES-Q-SF. Participants in HDRS-remission had average Q-LES-Q-SF scores on the lower end of those reported by healthy controls, whereas patients with mild depressive symptoms (or worse) had average life-quality scores corresponding to severe impairment.

HDRS and Q-LES-Q-SF showed considerable agreement in depressed study participants treated with antidepressants, suggesting that HDRS meaningfully reflects patient-reported improvement.

Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant proportion of patients, slow onset, minimal cognitive benefit and side-effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) agonists may produce faster antidepressant effects via distinct mechanisms; however, there has been no experimental research in clinical populations to date.

To test whether the novel 5-HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD).

In a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg) or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and functional magnetic resonance imaging (fMRI) of implicit emotional face processing (days 6–9). Observer- and self-reported symptoms of depression were also measured at baseline and study end.

As anticipated, citalopram reduced relative accuracy and increased relative reaction time to identify negative faces, with corresponding changes in neural activity (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments demonstrated an early treatment response with reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety and negative affect.

PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects.

NCT03516604.

Postpartum depressive symptoms can vary substantially and probably reflect distinct subtypes. Understanding specific symptom patterns may help identify those at risk for later psychiatric care.

We aimed to identify subtypes of postpartum depressive symptoms and examine their associations with subsequent psychiatric care.

We conducted a cohort study using Danish nationwide health registers linked to population-based Edinburgh Postnatal Depression Scale (EPDS) scores from 2015 to 2021. Latent class analysis of EPDS responses identified subtypes among women with clinically relevant symptoms (EPDS ≥11), using a maternal background population as a reference group (EPDS <11). The outcome was psychiatric hospital contacts or redeemed psychotropic prescriptions within 1 year postpartum. We estimated standardised cumulative incidence rates and risk ratios using spline-based, time-to-event models.

Among 162 079 women, 11 847 (7.3%) had clinically relevant symptoms (EPDS ≥11). Five subtypes were identified: Mild-depressive (23%), Moderate-anxious (17%), Moderate-depressive (18%), Moderate-overwhelmed (31%) and Severe-depressive (11%). At 1 year, the standardised cumulative incidence of psychiatric care was 69.6 (95% CI, 61.4–79.0) per 1000 persons in the Mild-depressive subtype. Compared with this group, the adjusted risk ratio was 0.33 (95% CI, 0.28–0.38) in the background maternal population, between 1.11 (95% CI, 0.93–1.32) and 1.25 (95% CI, 1.06–1.48) across moderate subtypes and 2.37 (95% CI, 1.99–2.82) for the Severe-depressive subtype.

Distinct subtypes of postpartum depressive symptoms were associated with varying risks of subsequent psychiatric care, depending on both symptom severity and symptom type. These findings underscore the importance of systematic screening and tailored follow-up, even for women with mild to moderate symptoms.