June 2025

Background: Peripartum depression (PPD) is a prevalent mental health disorder in the peripartum period. However, a recent systematic review of clinical guidelines relating to PPD has revealed a significant inconsistency in recommendations. Aims: This study aimed to collect up-to-date evidence on the effectiveness of interventions and provide recommendations for prevention, screening and treating PPD. Method: A series of umbrella reviews on the effectiveness of PPD prevention, screening and treatment interventions was conducted. A search was performed in five databases from 2010 until 2023. The guidelines were developed according to the GRADE framework and AGREE II Checklist recommendations. Public stakeholder review was included. Results: One hundred and forty-five systematic reviews were included in the final analysis and used to form the guidelines. Forty-four recommendations were developed, including recommendations for prevention, screening and treatment. Psychological and psychosocial interventions are strongly recommended for preventing PPD in women with no symptoms and women at risk. Screening programmes for depression are strongly recommended during pregnancy and postpartum. Cognitive-behavioural therapy is strongly recommended for PPD treatment for mild to severe depression. Antidepressant medication is strongly recommended for treating severe depression in pregnancy. Electroconvulsive therapy is strongly recommended for therapy-resistant and life-threatening severe depression during pregnancy. Other recommendations are offered to healthcare professionals, stakeholders and researchers in managing PPD in different contexts. Conclusion: Treatment recommendations should be implemented after carefully considering clinical severity, previous history, risk-benefit for mother and foetus/infant and women's values and preferences. Implementation of evidence-based clinical practice guidelines within country-specific contexts should be facilitated.

Background: While biomarkers are widely used in other medical fields, psychiatry has yet to introduce reliable biological diagnostic tools. Female reproductive transitions provide a unique window of opportunity for investigating psychiatric biomarkers. Hormonal changes across menstruation, pregnancy, parturition and perimenopause can have dramatic effects on mental health in vulnerable individuals, enabling the identification of unique biomarkers associated with these fluctuations. Aims: This review integrates current evidence concerning potential biomarkers, with focus on recent human studies in perinatal depression, anxiety and obsessive-compulsive disorder, postpartum psychosis, premenstrual dysphoric disorder and perimenopausal depression. Method: We identified potential articles to be included in this narrative review by using PubMed to obtain articles in English since 2010 on the six conditions listed above, with the additional keywords of 'biomarker', 'epigenetics', 'neuroactive steroid', 'immune', 'inflammatory' and 'neuroimaging'. Results: There is substantial published evidence regarding potential biomarkers of reproductive psychiatric disorders in the areas of epigenetics, neuroactive steroids, immune function and neuroimaging. This body of research holds significant potential to advance biomarker development, uncover disease mechanisms and improve diagnostic and therapeutic strategies, but there is as yet no clinically useful biomarker in commercial development for any reproductive psychiatric disorder. Conclusion: There is an urgent need for longitudinal, large-scale and multi-modal studies to examine potential biomarkers and better understand their functions across various stages of reproduction.

Health care workers (HCWs) faced more stressors during the COVID-19 pandemic, potentially increasing depression, anxiety and post-traumatic stress disorder (PTSD). Insight into mental health dynamics and determinants in HCWs during the pandemic could help to maintain and improve mental health and resilience in future pandemics. In this longitudinal cohort study, HCWs received five surveys from November 2020 to March 2023 assessing self-reported symptoms of depression (PHQ-9), anxiety (GAD-7), PTSD (PCL-5), stress (PSS), burn-out (UBOS-EE), insomnia (ISI), resilience (RS) and work engagement (UWES). In addition to the longitudinal analysis, mental health symptoms were assessed in relation to possible predictors, e.g. patient care roles or prior SARS-CoV-2 infection. A total of 384 HCWs (95% of HCWs given consent) completed at least one survey, 326 (81%) completed two or more. Mental health significantly declined in December 2021 compared to November 2020, with mean increases of 1.16 (95% CI 0.73 to 1.58, d = 0.48), 0.79 (95% CI 0.41 to 1.17, d = 0.37) and 1.96 (95% CI 0.95 to 2.97, d = 0.35) on the PHQ-9 (range 0–27), GAD-7 (range 0–21) and PCL-5 (range 0–80), respectively, with similar results in multivariable analysis. Symptoms returned to November 2020 levels in March 2023. No differences were found regarding patient care roles, prior SARS-CoV-2 infection, years of work experience, or hospital workdays per week. Mental health significantly declined during the COVID-19 pandemic, after which mental health symptoms returned to baseline as the burden of COVID-19 patients decreased and public measures were lifted. This demonstrates this population’s ability to successfully adapt to challenging experiences and emphasizes the need for support strategies tailored to the critical phases of any future healthcare crises.

Importance: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. Objective: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. Data sources: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. Study selection: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. Data extraction and synthesis: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. Main outcomes and measures: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. Results: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). Conclusions and relevance: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.

Background: Medication non-adherence and insufficiently managed disease worsen outcomes in people with schizophrenia. We aimed to compare the bioavailability of a long-acting oral weekly formulation of risperidone, LYN-005, with daily oral risperidone at steady state. Methods: In this open-label, non-randomised, phase 3 trial, clinically stable participants with schizophrenia or schizoaffective disorder were enrolled from five sites across the USA while residing in an inpatient facility for 5 weeks (with the exception of days 9-13). After a 7-day run-in period with immediate-release risperidone (2 mg or 6 mg), participants received five doses of long-acting oral weekly LYN-005 (15 mg or 45 mg, respectively), with a supplemental half dose of daily immediate-release risperidone during week 1. Primary endpoints compared pharmacokinetic parameters of LYN-005 (minimum concentration [Cmin] at weeks 1 and 5, and maximum concentration [Cmax] and average concentration [Cavg] at week 5) with those of immediate-release risperidone on the last day of the run-in period. Prespecified primary endpoint criteria were geometric mean ratios for Cmin at week 1 and week 5 (90% CI ≥0·8), Cmax at week 5 (90% CI ≤1·25), and Cavg at week 5 (0·8 ≤90% CI ≤1·4). No people with lived experience were involved in the study design. This study was registered with ClinicalTrials.gov, NCT05779241, and has been completed. Findings: Between April 13, 2023 and Dec 1, 2023, 83 participants were enrolled in the study (62 [75%] male and 21 [25%] female; 67 [81%] Black or African American, mean age 49·3 years [SD 11·5]), of whom 47 participants completed the 5-week study. In the pharmacokinetic analysis (n=44), sustained release of the active moiety was observed across all doses of LYN-005. Geometric mean ratios of LYN-005 versus immediate-release risperidone were 1·02 (90% CI 0·93-1·12) for Cmin at week 1, and 1·04 (90% CI 0·87-1·23), 0·84 (0·77-0·92), and 1·03 (0·93-1·13) for Cmin, Cmax, and Cavg, respectively, at week 5 and met predetermined criteria. In individuals taking LYN-005 (n=67), gastrointestinal treatment-emergent adverse events were most common (44 [66%] participants), with one serious treatment-emergent adverse event reported. Interpretation: Weekly LYN-005 provided sustained release of risperidone at therapeutic concentrations with similar bioavailability to immediate-release risperidone. Patients remained clinically stable and no unexpected safety signals emerged. This offers a novel long-acting oral drug delivery technology for schizophrenia and schizoaffective disorder.

Background: Early parenting interventions are the gold standard treatment for reducing antisocial behaviour (ASB) in children with conduct problems (CP), but the neurocognitive mechanisms underpinning treatment response are unknown. Methods: We assessed fMRI and performance data from a reward learning task in boys with CP (aged 5-10 years old) before and after gold-standard group parenting intervention. Matched controls were assessed concurrently at two equally spaced time points. The CP group was subdivided into those whose ASB improved or persisted over the course of treatment. Longitudinal group (Control, Improving CP, Persistent CP]) by time (Pre, Post) analyses were then conducted on task-based fMRI and reinforcement learning data. Results: Following intervention, a comparison of the Improving CP group with persistent CP and control groups showed: a) increased neural activity, in the direction of typically developing children, within the ventromedial prefrontal cortex (VMPFC), insula, posterior cingulate cortex and hippocampus in Improving CP, but not in the Persistent CP group; and, b) distinct changes in learning rate, action bias and reward/punishment sensitivity. Further, changes in insula activity and punishment/reward sensitivity correlated with changes in parenting behaviour. Conclusions: Improved ASB after early intervention is associated with changes in reward processing regions and specific reinforcement learning parameters. These changes are not observed in those with persistent CP and correlate with changes in parenting behaviour. These findings highlight the importance of early interventions for CP and reveal potential mechanisms underpinning successful treatment.

Background: Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest. Aims: To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI. Method: Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11. Results: Alternative second-line strategies led to higher response (28.2% v. 14.3%, odds ratio = 2.36 [95% CI 1.0-5.6], p = 0.05) and remission (16.9% v. 12.2%, odds ratio = 1.46, [95% CI 0.57-3.71], p = 0.27) rates, with greater HDRS-17 score reductions (-2.6 [95% CI -4.9 to -0.4], p = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94-6.80], p = 0.067; HDRS-17 difference: -2.7 [95% CI -5.5 to 0.0], p = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], p = 0.074; HDRS-17 difference: -3.1 [95% CI -5.8 to -0.3], p = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% v. 75%; p < 0.01), largely mild. Conclusions: Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.

Depressive disorders are among the most common psychiatric disorders worldwide and associated with half of all suicides. There is robust evidence indicating that both electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) effectively alleviate depressive symptoms in difficult-to-treat depression and enhance patient outcomes. However, there remains ongoing debate regarding their potential roles in preventing suicide and reducing all-cause mortality. Our study aims to investigate the impact of various neurostimulation techniques, including ECT, rTMS, and vagus nerve stimulation (VNS), on reducing suicidality, including suicidal ideation and completed suicides, as well as on overall mortality among individuals diagnosed with depression. In this systematic review and meta-analysis, we searched on MEDLINE via PubMed until January 9, 2024 for randomised controlled trials and controlled observational studies that investigated suicide and all-cause mortality outcomes after neurostimulation treatment for depression. Of the 1351 screened records we identified 26 studies eligible for inclusion in our systematic review. We included 11 studies on ECT (involving 17′890 subjects treated with ECT and 25′367 controls receiving treatment as usual), 5 studies on rTMS and 3 studies on VNS in our meta-analysis. In the cumulative cohort, 208 suicide deaths (1.70 %) were observed in the ECT group and 988 suicide deaths (5.02 %) were registered in the control group. Moreover, there were 511 deaths from all causes (3.13 %) in the ECT group, compared to 1325 deaths (6.64 %) in the control group. Thus, treatment with ECT demonstrated a significant 34 % decrease in the odds of suicide (OR 0.66, 95 % CI 0.50–0.88, p = 0.0047) and a 30 % reduction of death from all causes (OR 0.70, 95 % CI 0.62–0.79, p < 0.0001). The standardized mean difference (SMD) for suicidal ideation before and after ECT was −0.58 (95 % CI –0.10 to −1.07, p = 0.0177), suggesting a moderate effect size. We found no significant effect of rTMS on suicidal ideation with an SMD of −0.41 (95 % CI –1.01 – 0.19, p = 0.1795). In patients treated with VNS a 60 % reduction in the odds of death from all causes was observed (OR 0.40, 95 % CI 0.18–0.92, p = 0.0306). To conclude, there is consistent observational data supporting the protective effects of ECT against suicide and overall mortality.

Much is known about the use, benefits, and side-effects, of clozapine in treatment resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. This paper addresses this question. TRS patients show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven different to those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is much interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower D2 receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. This hypothesis, however, remains controversial. Clozapine's multi-receptor profile enables it to have beneficial actions on the non-psychotic symptoms common in TRS: its ability to bind to histamine H1, serotonin 5-HT1A and GABA-B receptors offers an explanation for its anxiolytic actions while effects on 5-HT1A, 5-HT2A and 5-HT7 receptors likely underly its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.

Schools are key for identifying challenges faced by young people who self-harm (SH). Understanding how school factors influence SH predictors is essential for developing effective school-based interventions. We aimed to conduct a secondary data analysis using the OxWell Student Survey to identify associations between young people's school experiences and SH. Using cross-sectional data from English secondary schools in the 2023 OxWell Student Survey, we conducted multi-level logistic regressions to analyse whether SH was associated with student age, gender, mental health (RCADS) and wellbeing (sWEMWBS). School experience measures included enjoyment, bullying, racism, extracurricular activities, school worry, and adults listening. Individual students' perception that the school did not deal well with bullying were associated with a 38% increase in SH (OR = 1.38; CI 1.20–1.59) and schools not dealing well with racism was associated with a 20% increase in the likelihood of SH (OR = 1.20; CI 1.04–1.38). Similarly, the likelihood of SH was 30% higher in schools with students feeling unfairly picked on by their teacher (OR = 1.30; CI 1.14–1.47). Greater SH was associated with being female (OR = 1.15; CI 0.99–1.32), gender diverse (OR = 3.49; CI 2.38–5.12), or preferring not to say (OR = 2.02; CI 1.44–2.83) compared to males. Lower wellbeing scores (OR = 0.93; CI 0.93–0.95) and higher RCADS scores (OR = 1.12; CI 1.11–1.13) were also linked to higher SH likelihood. Interventions that address bullying, racism, teacher-pupil relationships as well as providing specific support for more vulnerable groups such as females and gender diverse young people are important components of public mental health interventions that might reduce levels of SH. Future research should explore these relationships longitudinally.

Feeling and expressing love in daily life are interconnected and perhaps mutually influential experiences. In this study we examined the reciprocal dynamics of feeling and expressing love and its relation to well-being using an ecological momentary assessment design. Over a four-week period, we asked participants (N = 52; 67% Female; 80% White) to report their levels of feeling loved and expressing love six times a day. Using a continuous-time process model, we explored individual differences in inertia (i.e., persistence of a process over time) and cross-influences of felt and expressed love over time. We found that increases in expressing love led to increased feelings of being loved over time; however, increases in felt love did not lead to increases in expressing love. Notably, participants who experienced more persistent feelings of love (that is, greater inertia over time) indicated higher levels of flourishing. These results suggest new avenues for psychological well-being interventions which target increasing loving feelings through encouraging more expressions of love