Antipsychotics are first-line treatments for schizophrenia, yet many patients show inadequate response. Clozapine, the gold standard for treatment-resistant schizophrenia, remains underutilised due to safety and monitoring concerns.

To evaluate the adverse effects of clozapine in schizophrenia through a meta-analysis of randomised controlled trials (RCTs).

We systematically searched MEDLINE, CENTRAL, Embase, PsycINFO, ClinicalTrials.gov and WHO ICTRP up to 10 October 2024 for RCTs comparing clozapine (as either monotherapy or combination therapy) with other antipsychotics. We assessed 37 distinct adverse outcomes. Risk ratios were calculated for dichotomous outcomes and standardised mean differences for continuous outcomes, with confidence intervals.

A total of 116 RCTs (n = 8431) were included. In 69 monotherapy RCTs (n = 6281), clozapine showed no difference in either mortality (risk ratio 1.01, 95% CI: 0.50, 2.01, prevalence 0.1%) or discontinuation due to adverse effects (risk ratio 1.18, 95% CI: 0.91, 1.53, prevalence 7.2%). Agranulocytosis risk was nearly tripled (risk ratio 2.81, 95% CI: 0.97, 8.12, prevalence 0.7%), although with wide confidence intervals. Clozapine increased the risk of seizures (risk ratio 3.61, 95% CI: 1.80, 7.95, prevalence 3.1%) and orthostatic hypotension/bradycardia/syncope (risk ratio 1.66, 95% CI: 1.00, 2.77, prevalence 11%). No difference was found for myocarditis/cardiomyopathy (risk ratio 0.33, 95% CI: 0.01, 8.13). Clozapine increased the risk of leukopenia, hypersalivation, sedation, tachycardia, hypertension, constipation, nausea/vomiting, fever, flu-like syndrome and headache. In 47 combination RCTs (n = 2150), clozapine combinations were not associated with increased risk of severe adverse effects; no cases of agranulocytosis (21 RCTs, n = 894) or seizures (8 RCTs, n = 313) were reported in trials that explicitly assessed these outcomes.

Life-threatening adverse events remain rare with clozapine. With appropriate monitoring, its safety profile supports broader and potentially earlier use. Future studies should refine monitoring protocols and explore additional indications.

Schizophrenia is a severe psychiatric disorder characterised by positive symptoms, such as hallucinations and delusions, which are linked to dysregulated striatal connectivity. Although traditional models highlight the limbic striatum’s role in salience processing, emerging evidence suggests that the associative striatum, critical for cognitive control and habit formation, also plays a significant role. However, the structural connectivity underlying striatal subregions and its relationship to symptom severity and treatment response remains poorly understood.

This study aimed to investigate the structural connectivity of striatal subregions in first-episode schizophrenia (FE-SCZ) patients and to evaluate its association with positive symptoms and changes following antipsychotic treatment.

We recruited 80 FE-SCZ patients and 80 healthy controls who underwent diffusion tensor imaging probabilistic tractography to assess white matter tract strength between the striatum and ten cortical targets. Longitudinal analysis was conducted in patients at baseline (within 2 weeks of initial antipsychotic exposure) and after ongoing treatment to evaluate changes in connectivity and their relationship to symptom improvement.

FE-SCZ patients exhibited reduced connectivity between the dorsolateral prefrontal cortex (dlPFC) and associative striatum and increased connectivity between the anterior cingulate cortex (ACC) and associative striatum compared to controls. Longitudinal analysis revealed that antipsychotic treatment increased dlPFC–associative striatum connectivity and decreased ACC–associative striatum connectivity, which correlated with reductions in positive symptom severity.

These findings highlight the critical role of striatal subregions in the pathophysiology of schizophrenia, emphasising the associative striatum’s involvement in cognitive control and salience attribution. Changes in striatal connectivity after continued antipsychotic therapy may serve as a biomarker for symptom improvement, advancing our understanding of schizophrenia and guiding future therapeutic strategies.

Various key events characterise experiences in later life, such as retirement, bereavement, caregiving, developing long-term conditions and hospital admission. Given their potential to disrupt lives, such events may affect older people’s mental health, but research on the associations between such events and depression has produced inconsistent findings.

To investigate the impact of key events in later life on depression trajectories in a representative cohort of people aged 50–69 in England.

Our sample draws on 6890 respondents aged 50–69 in Wave 1 (2002/2003) of the English Longitudinal Study of Ageing, following them through to Wave 9 (2018/2019). We measured depression using the eight-item Center for Epidemiological Studies Depression scale. Later life events included retirement, spouse/partner death, becoming an unpaid caregiver, developing a limiting long-term illness and hospital admissions because of a fall or non-fall causes. Piecewise mixed-effects logistic regression models tested for changes in the trajectories of depression before and after each event.

Statistically significant improvements in the trajectory of depression were observed following spousal bereavement, one’s own retirement and hospital admission because of causes other than falls, with reductions in the odds of depression of 48% (odds ratio: 0.52 (95% CI: 0.44–0.61)), 15% (0.85 (0.78–0.92)) and 4% (0.96 (0.94–0.99)), respectively. No changes were associated with developing a limiting long-term illness, becoming an unpaid caregiver or following spousal retirement or a hospital admission because of a fall.

The findings highlight the relative resilience among older adults in England in terms of depression following key later life events. There is still a role to play in delivering mental health support for older people following such events, particularly by improving the identification of those at risk of certain events as part of a broader strategy of prevention. Findings also underscore the importance of partner/spousal circumstances on individual mental health.

The association between geriatric depression and out-of-hospital cardiac arrest (OHCA) has not been fully clarified.

This study aimed to develop and validate a predictive model for OHCA in older patients through a longitudinal, population-based approach.

This study analysed data from the National Health Insurance Research Database for the period 2011–2020, focusing on older patients both diagnosed with depression and treated with antidepressant medications. A multivariate logistic regression model was used to identify potential predictors of OHCA. Considering the effect of COVID-19, data-sets from 2019 and 2020 were used as external validation. The model’s performance was evaluated using receiver operating characteristic (ROC) curves and confusion matrix metrics.

Out of 104 022 geriatric patients with depression, 2479 (2.4%) experienced OHCA. Significant predictors of OHCA included age, male gender, previous utilisation of medical resources, renal failure with haemodialysis, existing comorbidities, medication changes and recent psychotherapy. The ROC values for the predictive models ranged from 0.707 to 0.771 in the 2019 and 2020 external validations for 7-, 30- and 90-day OHCA. For 2019, the 7-day model demonstrated sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of 0.600, 0.718, 2.130, 0.560 and 3.840, respectively. For 2020, these metrics for the 7-day model were 0.775, 0.655, 2.250, 0.340 and 6.550, respectively.

This study developed and validated a predictive model for OHCA in older patients with depression. The model identified crucial predictors, providing valuable insights for psychiatrists and emergency clinicians to identify high-risk patients and implement early preventive measures.

Research suggests that there may be an association between prescribed opioid use and suicide-related behaviours.

This 15-year retrospective population-based cohort study examines the relationship between opioid use, self-harm and suicide.

The study was based on the POPPY II study, a population-based cohort of 3 268 282 adults who initiated a prescription opioid between 1 July 2003 and 31 December 2018, in Australia. Prescription dispensing data were linked to hospitalisation, death and other data collections. Opioid use was defined as current opioid exposure, cumulative duration of exposure and estimated daily dose. Outcomes were self-harm hospitalisation and suicide mortality, categorised as overall and according to the method (opioid poisoning, non-opioid substance poisoning and other methods). Time-varying generalised estimating equations were used to assess the relationship with self-harm hospitalisation, and Cox proportional hazard models were used to assess the relationship with suicide mortality, controlling for known suicide-related risk factors.

There were 49 215 self-harm hospitalisations at a crude rate of 262 per 100 000 person-years and 3087 suicide deaths at a crude rate of 16.5 per 100 000 person-years. Intentional opioid poisoning was the least common method for both self-harm hospitalisation and suicide. Following multivariable adjustment, current opioid exposure, longer cumulative duration and higher doses were significantly associated with a greater risk of opioid-related self-harm or suicide. In adjusted models, associations for other methods of self-harm and suicide were not as strong or consistent.

Opioid poisoning was the least common method of self-harm and suicide. Despite this, for the minority of people prescribed high doses and/or a long duration of prescription opioids, there is an increased risk for opioid-related self-harm and suicide after controlling for known covariates. Suicide-related behaviours should be screened and monitored in people prescribed opioids, particularly among those on long-term and/or high-dose opioids.

Postnatal depression (PND) affects up to one in four mothers. However, they may experience barriers to access to conventional treatments, indicating a need for alternatives such as arts-based interventions. A previous trial showed that a 10-week singing intervention could alleviate symptoms of PND.

To evaluate, in a larger sample and across a longer timeframe than previously, the clinical effectiveness, implementation effectiveness and cost-effectiveness of the Melodies for Mums (M4M) singing intervention for symptoms of PND.

One-hundred and ninety-nine mothers experiencing symptoms of PND (Edinburgh Postnatal Depression Scale score ≥10) and their babies were randomised to 10 weeks of in-person singing sessions (M4M, n = 133) or an active control (existing community-based mother–baby activities, n = 66). Mothers were re-assessed at weeks 6, 10, 20 and 36 for depression, healthcare use for themselves and their babies, and health-related quality of life according to the EQ5D-3. The perceived acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure) and feasibility (Feasibility of Intervention Measure) of the activity were also assessed at week 6. Trial registration number: NCT04834622.

Mothers in both groups experienced attenuation of depressive symptoms by week 10; however, those in the singing group maintained lower EPDS scores than those in the control group at week 20 (10.7 v. 12.2 (mean difference 95% CI [−2.96, −0.22]), P = 0.023) and week 36 (9.85 v. 11.4 [−2.93, −0.19], P = 0.026). Mothers in the singing group were also more likely to remain in the study (77 v. 57%, χ2(1) = 12.92, P < 0.001) and found their programme more acceptable (4.75 v. 4.0 [0.25, 0.83], U = 2436.5, P < 0.001), appropriate (4.25 v. 3.88 [0.12, 0.62], U = 2241.5, P < 0.001) and feasible (4.75 v. 4.0 [0.41, 0.91], U = 2568.0, P < 0.001). Finally, M4M was associated with 15 extra days of health and was found to be cost-effective (£126–539 per dyad).

M4M had a long-lasting effect on symptoms of PND and was perceived to be more suitable than existing activities; thus, M4M represents a worthwhile investment for healthcare systems as an intervention for mothers experiencing symptoms of PND.

Agitation and aggression occur in up to half of people living with dementia over the course of the disease. Although non-pharmacological interventions are used as first-line treatment strategies, antipsychotics may be indicated in severe cases. A major adverse effect of antipsychotics in dementia is stroke; the mechanism of action of atypical antipsychotic risperidone has been linked to cardiovascular disease (CVD) biological pathways in preclinical studies.

To evaluate the risk of stroke associated with risperidone across different patient subgroups defined by stroke and CVD history.

Anonymised primary care data from the UK-based Clinical Practice Research Datalink were used to identify individuals diagnosed with dementia after the age of 65 years between 2004 and 2023. Risk of stroke over 1 year was compared between individuals initiating risperidone and propensity-score-matched controls across subgroups with and without history of stroke and any CVD.

In the overall cohort (28 403 risperidone users and 136 324 mtatched controls), risperidone was associated with increased risk of stroke (adjusted hazard ratio: 1.28; 95% CI: 1.20–1.37). In the risperidone user group, the incidence rate of stroke was substantially higher in those with a prior history of stroke (incidence rate: 222 per 1000 person-years) and CVD (incidence rate: 94.1 per 1000 person-years) than in the overall cohort (incidence rate: 53.3 per 1000 person-years). Relative risks related to risperidone were similar across all CVD and stroke subgroup comparisons (hazard ratios between 1.23 and 1.44).

People with dementia with a prior history of CVD are at a significant increased risk of stroke, and risperidone further exacerbates this risk. Moreover, risperidone increases risk of stroke in patients without a prior history of CVD. This quantification of stroke risk across subgroups with and without history of CVD may help with communication of risk and aid more judicious prescribing.

Clozapine remains underused despite its unparalleled efficacy in treatment-refractory schizophrenia. One of the reasons for its underuse is the fear of severe neutropenia and its consequences.

To scrutinise the association between severe neutropenia and clozapine in a cohort of patients clinically diagnosed with clozapine-induced severe neutropenia.

We used data from the South London and Maudsley National Health Service Foundation Trust’s anonymised case register, known as the Clinical Record Interactive Search. We extracted details of cases where clozapine use was associated with two consecutive neutrophil counts below 1.5 × 109/L. A panel of clinicians independently assessed each case. Agreement was reached on which cases clozapine was the likely or definite cause of the severe neutropenia, the risk to life and whether or not rechallenge with clozapine could be attempted.

There were 96 cases where two consecutive neutrophil counts below 1.5 × 109/L were registered. The panel judged that 9 (9.4%) were definitely caused by clozapine and a further 11 (11.5%) were probably caused by clozapine. Overall, 18 (18.8%) patients should be precluded from ever receiving clozapine again according to the panel (all from the 20 cases where clozapine was the definite or probable cause). Of the remaining 76 cases of severe neutropenia the cause could not be determined in 60 cases, but in 11 cases the cause was benign ethnic neutropenia, in 2 others the cause was cancer chemotherapy, in 2 it was infections and in 1 it was laboratory error. In almost 80% of cases, clozapine was not the clear cause of the neutropenia observed.

The large majority of severe neutropenia episodes mandating cessation of clozapine may not be caused by clozapine. Threshold-based monitoring systems cause unnecessary stopping of clozapine because they lack the necessary specificity for clozapine-related blood disorders.

Pulmonary embolism is said to be more common in clozapine-treated patients than either in patients treated with other antipsychotics or in the general population.

To explore clinical features and outcomes of clozapine-related pulmonary embolism in the UK.

We studied UK Yellow Card reports recorded as clozapine-related respiratory, thoracic and mediastinal disorders, 1990–2022.

Of 474 unique reports of people with clozapine-associated pulmonary embolism, 339 (59% male) remained after applying strict exclusion criteria. Of these, 164 patients (48%) died. The mean clozapine dose was 336.7 (range 25–1000) mg d−1 (N = 126). There was no difference in dose between the fatal and non-fatal outcomes. The median age at onset of pulmonary embolism was 45 years (range 21–82 years; N = 309). The median duration of clozapine treatment until onset was 2.9 years (range 2 days–22.7 years; N = 306). Sixty-five (39%) non-fatal and 36 (22%) fatal emboli occurred within 1 year of treatment. People who died were more likely to be obese (adjusted odds ratio 2.61; 95% CI 1.44–4.91) and to be noted as sedentary (adjusted odds ratio 6.07; 95% CI 1.58, 39.9). The 3 year moving average of cases was 0–5 per year, 1990–1999, 26 in 2010 and 16 in 2022. There was no change in the proportion of deaths by year of report (p = 0.41).

Clozapine-related pulmonary embolism is a significant concern with a high fatality rate. This risk necessitates a proactive approach to not only prevention, but also early recognition and management.

Schizophrenia is associated with a reduced average lifespan due to accelerated ageing. Early studies have predominantly focused on the global brain age gap, limiting our understanding of region-specific ageing. Moreover, the relationship between accelerated ageing and schizophrenia disease progression has not been directly examined.

Our aim was to investigate the cortical spatiotemporal patterns in ageing and disease progression in schizophrenia.

Using multi-site, resting-state functional magnetic resonance imaging data, we analysed intrinsic activity fluctuations in 2353 healthy controls and 546 subjects with schizophrenia. We assessed normative models of ageing trajectories in brain activities in healthy controls, and examined the developmental trajectory of deviations from normative reference ranges with disease progression in schizophrenia.

The ageing trajectories of both groups demonstrated spatiotemporal variability unfolding along the sensorimotor–association cortical axis, characterised by a rapid decline in transmodal association cortices at younger ages and followed by an accelerated decline in primary cortices at older ages. However, schizophrenia exhibited a more rapid rate of decline across the entire cerebral cortex, particularly during the short-duration stage. Further analysis revealed that the spatial variability of disease-induced ageing deviations persisted along the sensorimotor–association cortical axis throughout disease progression. The premature involvement of neurotransmitter systems, including dopamine and serotonin, may underlie accelerated ageing.

Our work uncovers regional ageing trajectories organised along the sensorimotor–association cortical axis, and provides new insights into the mechanisms of atypical ageing and disease progression in schizophrenia.

The Resilience Hub was established to support people in need of psychological/psychosocial support following the 2017 Manchester Arena terrorist attack.

To use mental health screening measures over 3 years following the Arena event to examine the variation in symptoms reported by adults registered with the Hub, and whether this was associated with treatment access characteristics.

Adults engaging with Hub services were separated into eight cohorts depending on when they registered post-incident. Participants completed screening measures for symptoms of trauma, depression, generalised anxiety and work/social functioning. Baseline and follow-up scores over 3 years were compared among the eight admission groups. All types of appointment were recorded in terms of the number of minutes of clinical ‘contact time’ involved, to explore associations with time taken to register.

Overall, baseline screening scores increased as time to register post-event increased. Over the 3 years of follow-up, a decrease in scores was observed for all 4 screening measures, indicating improvement in mental well-being. Those taking longer to register had higher follow-up scores. However, they showed a slightly stronger decrease in average change of score per follow-up month. Mean contact time per month was greater (apart from the 18-months admission group) in individuals delaying registration. Increased contact time was associated with decreased follow-up screening scores for depression and anxiety.

People who registered earlier were less symptomatic, suggesting there may be a potential beneficial impact of early engagement with support services following traumatic events. All who registered showed improvement in symptoms, including those delaying registration, with increased contact time being beneficial. This reinforces the benefits of encouraging early and sustained engagement with services as soon as possible post-incident.

Children in care who experience frequent placement changes face an increased risk of negative mental health outcomes. Emerging evidence suggests a bidirectional relationship, where placement instability can both predict and result from mental health difficulties. Understanding the strength and direction of this relationship is crucial for informing policy and practice, yet UK-based evidence remains unconsolidated.

To conduct the first systematic review and meta-analysis examining the relationship between placement instability and mental health in the UK care system.

This review was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024493617). We searched five databases (up to August 2024) for peer-reviewed UK studies that included a care-experienced sample, measured placement (in)stability, measured mental health, and quantitatively examined the relationship between placement instability and mental health. A random-effects meta-analysis was conducted, and study quality was assessed using the Newcastle–Ottawa Scale.

Fifteen studies (N = 6905) were included, with twelve studies (n = 5536) contributing to the meta-analysis. Children with unstable placements were more than twice as likely to experience mental health difficulties compared to those with stable placements (odds ratio 2.07, 95% CI 1.65–2.59). However, evidence on the causal direction of this relationship was limited.

Placement instability doubles the risk of mental health difficulties for care-experienced children, who already face elevated rates of mental disorders. Further research is urgently needed to clarify the bidirectional nature of this relationship and guide targeted intervention. Meanwhile, policymakers should prioritise collaborations between mental health services and local authorities to prevent the cycle of instability and mental health deterioration.