Working memory deficit, a key feature of schizophrenia, is a heritable trait shared with unaffected siblings. It can be attributed to dysregulation in transitions from one brain state to another.

Using network control theory, we evaluate if defective brain state transitions underlie working memory deficits in schizophrenia.

We examined average and modal controllability of the brain's functional connectome in 161 patients with schizophrenia, 37 unaffected siblings and 96 healthy controls during a two-back task. We use one-way analysis of variance to detect the regions with group differences, and correlated aberrant controllability to task performance and clinical characteristics. Regions affected in both unaffected siblings and patients were selected for gene and functional annotation analysis.

Both average and modal controllability during the two-back task are reduced in patients compared to healthy controls and siblings, indicating a disruption in both proximal and distal state transitions. Among patients, reduced average controllability was prominent in auditory, visual and sensorimotor networks. Reduced modal controllability was prominent in default mode, frontoparietal and salience networks. Lower modal controllability in the affected networks correlated with worse task performance and higher antipsychotic dose in schizophrenia (uncorrected). Both siblings and patients had reduced average controllability in the paracentral lobule and Rolandic operculum. Subsequent out-of-sample gene analysis revealed that these two regions had preferential expression of genes relevant to bioenergetic pathways (calmodulin binding and insulin secretion).

Aberrant control of brain state transitions during task execution marks working memory deficits in patients and their siblings.

Women with schizophrenia frequently discontinue antipsychotic medications during pregnancy. However, evidence on the risk of postpartum relapse associated with antipsychotic use during pregnancy is lacking.

To investigate the within-individual association between antipsychotic continuation during pregnancy and postpartum relapse in women with schizophrenia.

This retrospective cohort study used data of women with schizophrenia who gave live birth between 2007 and 2018 identified from the National Health Information Database of South Korea. Women were classified according to antipsychotic use patterns during the 12 months before delivery as non-users, discontinuers and continuers. Relapse was defined as admission for psychosis (ICD-10, F20–29). The incidence rate ratio (IRR) for admission for psychosis in the 6-month postpartum period was estimated using conditional Poisson regression, with the reference period set between 2 and 1 years before delivery. Additionally, we calculated the relative risk ratios (RRRs) for the IRRs of different antipsychotic use patterns.

Among the 3026 women included in the analysis (median age 34 years, interquartile range 31–37), the within-individual risk of admission for psychosis in the 6-month postpartum period was 0.56 times (RRR, 95% CI 0.36–0.87) lower in continuers (IRR = 1.31, 95% CI 0.89–1.72) than in discontinuers (IRR = 2.34, 95% CI 1.87–2.91). Among discontinuers, the IRRs of admission for psychosis in the 6-month postpartum period did not change significantly with the timing of discontinuation (trend P = 0.946).

Antipsychotic continuation during pregnancy was associated with a reduced risk of postpartum relapse in women with schizophrenia. Continuing antipsychotics during pregnancy would be recommended after a risk–benefit assessment.

Antidepressants are effective for depression, but most evidence excludes individuals with comorbid physical conditions.

To assess antidepressants’ efficacy and tolerability in individuals with depression and comorbid physical conditions.

Systematic review and network meta-analysis of randomised controlled trials (RCTs). Co-primary outcomes were efficacy on depressive symptoms and tolerability (participants dropping out because of adverse events). Bias was assessed with the Cochrane Risk-of-Bias 2 tool and certainty of estimates with the Confidence in Network Meta-Analysis approach. A study protocol was registered in advance (https://osf.io/9cjhe/).

Of the 115 included RCTs, 104 contributed to efficacy (7714 participants) and 82 to tolerability (6083 participants). The mean age was 55.7 years and 51.9% of participants were female. Neurological and cardiocirculatory conditions were the most represented (26.1% and 18.3% of RCTs, respectively). The following antidepressants were more effective than placebo: imipramine, nortriptyline, amitriptyline, desipramine, sertraline, paroxetine, citalopram, fluoxetine, escitalopram, mianserin, mirtazapine and agomelatine, with standardised mean differences ranging from −1.01 (imipramine) to −0.34 (escitalopram). Sertraline and paroxetine were effective for the largest number of ICD-11 disease subgroups (four out of seven). In terms of tolerability, sertraline, imipramine and nortriptyline were less tolerated than placebo, with relative risks ranging from 1.47 (sertraline) to 3.41 (nortriptyline). For both outcomes, certainty of evidence was ‘low’ or ‘very low’ for most comparisons.

Antidepressants are effective in individuals with comorbid physical conditions, although tolerability is a relevant concern. Selective serotonin reuptake inhibitors (SSRIs) have the best benefit–risk profile, making them suitable as first-line treatments, while tricyclics are highly effective but less tolerated than SSRIs and placebo.

There are 117.3 million people forcibly displaced because of war, conflict and natural disasters: 40% are children. With growing numbers, many high-income countries have adopted or are considering increasingly restrictive policies of immigration detention. Research on the impact of detention on mental health has focused on adults, although recent studies report on children.

To synthesise data on the impact of immigration detention on children’s mental health.

Systematic searches were conducted in PsycINFO, MEDLINE and Embase databases and grey literature and studies assessed using PRISMA guidelines (PROSPERO registration CRD42023369680). Included studies were quantitative, assessed children younger than 18 years who had been in immigration detention and reported mental health symptoms or diagnoses. Methodological quality was assessed using the Appraisal Tool for Cross-Sectional Studies. Meta-analyses estimated prevalence for major depression and post-traumatic stress disorder (PTSD).

Twenty-one studies reported data on 9620 children. Most studies were cross-sectional, had small sample sizes and used convenience sampling. A profoundly detrimental impact on children’s mental health across a variety of countries and detention settings was demonstrated. Meta-analysis found pooled prevalence of 42.2% for depression [95% CI 22.9, 64.3] and 32.0% for PTSD [95% CI 19.4, 48.0]. Severity of mental health impact increased with exposure to indefinite or protracted held detention.

Immigration detention harms children. No period of detention can be deemed safe, as all immigration detention is associated with adverse impacts on mental health. Our review highlights the urgency of alternative immigration policies that end the practice of detaining children and families.

The methodology and impact of independent inquiries of homicides by people in care of mental health services have been questioned.

To analyse characteristics of patients who committed homicide, their victims and inquiries published in England between 2010 and 2023.

Documentary and thematic analysis of 162 mental health homicide inquiries. We compared characteristics of perpetrators with those from the National Confidential Inquiry into Suicide and Safety (2018), and characteristics of victims with those in the general population of England and Wales. We examined methodology used by inquiries and thematically analysed root causes, contributory factors, recommendations, action plans, predictability and preventability.

Fifty-two per cent of perpetrators had a diagnosis of schizophrenia and 52% had a history of non-adherence to medication and follow-up; 71% of victims in mental health homicides were family, friends or partners compared with 44% in the general population; 77% of inquiries used no clear methodology. The most frequent root causes and contributory factors related to deficits in assessment, treatment, follow-up or discharge, and risk assessment. There was no direct link between putative causes and resulting recommendations. The most frequent recommendations related to changing policy, improving clinical governance and training. Only 4% of inquiries deemed the homcide to be predictable and preventable.

There is considerable variation in the methodology of mental health homicide inquiries, with little use of human factors and systems theory. Inquiries repeatedly identify the same themes, and most mental health homicides are found to be neither predictable nor preventable. We make recommendations for improving consistency and usefulness.

Despite the high prevalence of social and performance anxiety, current treatments do not meet the full needs of patients. Development of novel anxiolytics with rapid onset of action for on-demand treatment of social and performance anxiety is an active area of clinical research.

To examine the anxiolytic effect of VQW-765, an α7-nAChR agonist, in subjects with performance anxiety.

We conducted a randomised, double-blind, placebo-controlled trial of 230 adults with a history of public speaking anxiety. Participants were randomly assigned to receive a single oral dose of 10 mg VQW-765 (n = 116) or placebo (n = 114), followed by a Trier Social Stress Test (TSST). Anxiety levels were assessed by the Subjective Units of Distress Scale (SUDS). Heart rate was monitored during the TSST. Plasma concentration of VQW-765 was measured after the TSST.

Subjects receiving VQW-765 showed a trend of improvement in intensity of anxiety, as measured by the SUDS, during the performance phase of a TSST compared with placebo (P = 0.1443). Females showed a larger magnitude and significant response to VQW-765 (P = 0.034). The pharmacokinetic/pharmacodynamic analysis observed an inverted U-shaped exposure–response relationship. Subjects in the middle 50% quantiles of VQW-765 plasma concentration showed significant improvement in the SUDS rating compared with placebo (P = 0.033); however, subgroup analysis revealed this was true only for females (P = 0.005). VQW-765 was safe and well tolerated.

This is the first study showing anxiolytic effect of an α7-nAChR agonist in humans. VQW-765 is a promising candidate to be developed for on-demand treatment of social anxiety disorder.

The duration of undiagnosed or untreated bipolar disorder (DUBD) has become a focus of research interest. However, its relationship with clinical characteristics and outcomes remains poorly understood.

The objective of this systematic review and meta-analysis was to examine DUBD and explore its relationships with clinical characteristics and outcomes in bipolar disorder.

We conducted a systematic search of the literature to identify studies reporting on DUBD and its relationships with clinical characteristics and outcomes including frequency of relapse into mood episodes, severity and persistence of mood symptoms, functional and cognitive measures, suicidality, hospital admission rate, and comorbidities such as substance use disorders.

Thirty articles met inclusion criteria for the systematic review, and 23 studies were included in the three different sets of meta-analyses. The pooled mean DUBD across all studies was 9.10 years. Early onset, depression as the polarity of the first mood episode, lifetime suicide attempts, comorbid anxiety and alcohol use disorders, and family history of bipolar disorder were associated with significantly longer DUBD, whereas diagnosis of bipolar I disorder and lifetime psychotic symptoms were associated with shorter DUBD. Studies that investigated outcomes subsequent to the diagnosis of bipolar disorder yielded conflicting results.

DUBD may be associated with certain adverse outcomes. This association indicates the importance of adopting a more comprehensive approach to assessing mood disorders, with an emphasis on prioritising early screening for bipolar disorder. The significant heterogeneity among included studies suggests a need for improved methodological rigour in future research.

3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) has shown promising safety and efficacy in phase 3 studies of post-traumatic stress disorder, but has not been investigated for a primary diagnosis of major depressive disorder (MDD).

We aimed to explore the proof of principle and safety as a first study with MDMA-AT for MDD, and to provide preliminary efficacy data.

Twelve participants (7 women, 5 men) with moderate to severe MDD received MDMA in 2 open-label sessions 1 month apart, along with psychotherapy before, during and after the MDMA sessions, between January 2023 and May 2024. The primary outcome measure was mean change in Montgomery–Asberg Depression Rating Scale (MADRS), and the secondary outcome measure was mean change in functional impairment as measured with the Sheehan Disability Scale (SDS), both from baseline to 8 weeks following the second MDMA session. We used descriptive statistics and the two-tailed Wilcoxon signed-rank test to compare baseline and outcome scores. Repeated measures were analysed by a mixed-effects model.

Baseline MADRS was 29.6 (s.d. 4.9). Feasibility was demonstrated with sufficient recruitment and retention. MADRS scores were significantly reduced post treatment compared with baseline (mean difference –19.3, s.e. 2.4, CI –14.8 to –23.8, P < 0.001). SDS scores significantly decreased from baseline (mean difference –11.7, s.e. 2.2, CI –7.5 to –15.9, P = 0.001). There were no adverse events of special interest, and no unexpected or serious adverse events.

The study met the primary objectives of safety and feasibility, and provided indications of efficacy for MDMA-AT for MDD. Further studies with a randomised design are required to confirm these findings.

EudraCT no. 2021-000805-26.

Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.

Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.

We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (N = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10.

Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement (b = −1.6, t = −2.1, P = 0.033, 95% CI [−3.0, −0.1], where b is the coefficient of the relationship (i.e. effect size), and t is the t-statistic for that coefficient associated with the P-value). The effect was similar across all augmentation strategies. No other putative moderators were significant.

Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.

Researchers explore the biology of painful experiences not primarily felt in the body (‘non-physical pain’), sometimes referred to as mental, social or emotional pain. A critical challenge lies in how to operationalise this subjective experience for biological research, a crucial process for translating findings into clinical practice.

To map studies investigating biological features of non-physical pain, focusing on their conceptual features (i.e. terms and definitions of non-physical pain) and methodological characteristics (e.g. experimental paradigms and measures).

This methodological systematic review searched reports of primary research on the biological features of non-physical pain across Embase, MEDLINE and Web of Science. Using a meta-research approach, we synthetised results on terms, definitions, populations, experimental paradigms, confounders, measures of non-physical pain and investigation methods (e.g. functional magnetic resonance imaging).

We identified 92 human studies, involving 7778 participants. Overall, 59.1% of the studies did not report any definition of non-physical pain, and 82% of studies did not use a specific measure. Regarding the possibility of translating results to clinical settings, most of the human studies involved only healthy participants (71.7%) and the seven different experimental paradigms used to induce non-physical pain had unknown external validity. Confounders were not considered by 32.4% of the experimental studies. Animal studies were rare, with only four rodent studies.

Biomedical studies of non-physical pain use heterogeneous concepts with unclear overlaps and methods with unknown external validity. As has been done for physical pain, priority actions include establishing an agreed definition and measurement of non-physical pain and developing experimental paradigms with good external validity.

Links between personality disorders and antisocial outcomes has not examined individual personality disorders, and the contribution of comorbidities remain uncertain. Previous systematic reviews are dated.

To synthesise evidence from observational studies on the risk of antisocial outcomes and recidivism associated with personality disorders.

We searched six bibliographic databases (up to March 2024) for observational studies examining the risk of antisocial behaviour, interpersonal violence and recidivism in individuals diagnosed with personality disorders, compared to controls. We explored sources of heterogeneity using subgroup analyses and meta-regression.

We identified 21 studies involving 83 418 individuals with personality disorders from 10 countries examining antisocial and violent outcomes (Aim 1), and 39 studies of 14 131 individuals from 13 countries with recidivism (or repeat offending) as the outcome (Aim 2). We found increased risks of violence among individuals with any personality disorder (odds ratio 4.5, 95% CI 3.0–6.7), particularly antisocial personality disorder (odds ratio 7.6, 95% CI 5.1–11.5) and borderline personality disorder (odds ratio 2.6, 95% CI 1.8–3.9). Individuals with any personality disorder (odds ratio 2.3, 95% CI 2.0–2.6) and antisocial personality disorder (odds ratio 2.8, 95% CI 1.6–4.9) also demonstrated an elevated risk of recidivism. Personality disorder types and comorbid substance use disorder were associated with between-study heterogeneity.

The assessment and management of personality disorders should be considered as part of violence prevention strategies. Improving identification and treatment of comorbid substance misuse may reduce adverse outcomes in individuals with personality disorders.

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.

This study aimed to collect up-to-date evidence on the effectiveness of interventions and provide recommendations for prevention, screening and treating PPD.

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.

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.

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.