Accumulating data show that probiotics may be beneficial for reducing depressive, anxiety, and stress symptoms. However, the best combinations and species of probiotics have not been identified. The objective of our study was to assess the most effective combinations and components of different probiotics through network meta-analysis.

A systematic search of four databases, PubMed, Web of Science, Cochrane, and Embase, was conducted from inception to 11 January 2024. The GRADE framework was used to assess the quality of evidence contributing to each network estimate.

We deemed 45 trials eligible, these included 4053 participants and 10 types of interventions. The quality of evidence was rated as high or moderate. The NMA revealed that Bifidobacterium exhibited a greater probability of being the optimal probiotic species for improving anxiety symptoms (SMD = −0.80; 95% CI −1.49 to −0.11), followed by Lactobacillus (SMD = −0.49; 95% CI −0.85 to −0.12). In addition, for multiple strains, compared with the other interventions, Lactobacillus + Bifidobacterium (SMD = −0.41; 95% CI −0.73 to −0.10) had a positive effect on depression.

The NMA revealed that Lactobacillus and Bifidobacterium had prominent efficacy in the treatment of individuals with anxiety, depression, and combination of Lactobacillus + Bifidobacterium had a similar effect. With few direct comparisons available between probiotic species, this NMA may be instrumental in shaping the guidelines for probiotic treatment of psychological disorders.

There is a clear demand for innovative therapeutics for bipolar disorder (BD).

We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation.

Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD.

Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

Suicide is a major concern among active-duty military personnel. Aggression represents a salient risk factor for suicide among civilians, yet is relatively understudied among military populations. Although several theories posit a relation between aggression and suicide with putative underlying mechanisms of social isolation, access to firearms, and alcohol use, researchers have yet to test these potential mediators. This study uses rich, longitudinal data from the Army Study to Assess Risk and Resilience (STARRS) Pre/Post Deployment Study (PPDS) to examine whether aggression longitudinally predicts suicide attempts and to identify mediators of this association.

Army soldiers (N = 8483) completed assessments 1 month prior to deployment and 1, 2–3, and 9–12 months post-deployment. Participants reported on their physical and verbal aggression, suicide attempts, social network size, firearm ownership, and frequency of alcohol use.

As expected, pre-deployment aggression was significantly associated with suicide attempts at 12-months post-deployment even after controlling for lifetime suicide attempts. Social network size and alcohol use frequency mediated this association, but firearm ownership did not.

Findings further implicate aggression as an important suicide risk factor among military personnel and suggest that social isolation and alcohol use may partially account for this association.

Mood and anxiety disorders are heterogeneous conditions with variable course. Knowledge on latent classes and transitions between these classes over time based on longitudinal disorder status information provides insight into clustering of meaningful groups with different disease prognosis.

Data of all four waves of the Netherlands Mental Health Survey and Incidence Study-2 were used, a representative population-based study of adults (mean duration between two successive waves = 3 years; N at T0 = 6646; T1 = 5303; T2 = 4618; T3 = 4007; this results in a total number of data points: 20 574). Presence of eight mood and anxiety DSM-IV disorders was assessed with the Composite International Diagnostic Interview. Latent class analysis and latent Markov modelling were used.

The best fitting model identified four classes: a healthy class (prevalence: 94.1%), depressed-worried class (3.6%; moderate-to-high proportions of mood disorders and generalized anxiety disorder (GAD)), fear class (1.8%; moderate-to-high proportions of panic and phobia disorders) and high comorbidity class (0.6%). In longitudinal analyses over a three-year period, the minority of those in the depressed-worried and high comorbidity class persisted in their class over time (36.5% and 38.4%, respectively), whereas the majority in the fear class did (67.3%). Suggestive of recovery is switching to the healthy class, this was 39.7% in the depressed-worried class, 12.5% in the fear class and 7.0% in the high comorbidity class.

People with panic or phobia disorders have a considerably more persistent and chronic disease course than those with depressive disorders including GAD. Consequently, they could especially benefit from longer-term monitoring and disease management.

Depression is a common mental health disorder that often starts during adolescence, with potentially important future consequences including ‘Not in Education, Employment or Training’ (NEET) status.

We took a structured life course modeling approach to examine how depressive symptoms during adolescence might be associated with later NEET status, using a high-quality longitudinal data resource. We considered four plausible life course models: (1) an early adolescent sensitive period model where depressive symptoms in early adolescence are more associated with later NEET status relative to exposure at other stages; (2) a mid adolescent sensitive period model where depressive symptoms during the transition from compulsory education to adult life might be more deleterious regarding NEET status; (3) a late adolescent sensitive period model, meaning that depressive symptoms around the time when most adults have completed their education and started their careers are the most strongly associated with NEET status; and (4) an accumulation of risk model which highlights the importance of chronicity of symptoms.

Our analysis sample included participants with full information on NEET status (N = 3951), and the results supported the accumulation of risk model, showing that the odds of NEET increase by 1.015 (95% CI 1.012–1.019) for an increase of 1 unit in depression at any age between 11 and 24 years.

Given the adverse implications of NEET status, our results emphasize the importance of supporting mental health during adolescence and early adulthood, as well as considering specific needs of young people with re-occurring depressed mood.

ADHD symptoms are associated with emotional problems such as depressive and anxiety symptoms from early childhood to adulthood, with the association increasing with age. A shared aetiology and/or a causal relationship could explain their correlation. In the current study, we explore these explanations for the association between ADHD symptoms and emotional problems from childhood to adulthood.

Data were drawn from the Twins Early Development Study (TEDS), including 3675 identical and 7063 non-identical twin pairs. ADHD symptoms and emotional symptoms were reported by parents from childhood to adulthood. Self-report scales were included from early adolescence. Five direction of causation (DoC) twin models were fitted to distinguish whether associations were better explained by shared aetiology and/or causal relationships in early childhood, mid-childhood, early adolescence, late adolescence, and early adulthood. Follow-up analyses explored associations for the two subdomains of ADHD symptoms, hyperactivity-impulsivity and inattention, separately.

The association between ADHD symptoms and emotional problems increased in magnitude from early childhood to adulthood. In the best-fitting models, positive genetic overlap played an important role in this association at all stages. A negative causal effect running from ADHD symptoms to emotional problems was also detected in early childhood and mid-childhood. When distinguishing ADHD subdomains, the apparent protective effect of ADHD symptoms on emotional problems in childhood was mostly driven by hyperactivity-impulsivity.

Genetic overlap plays an important role in the association between ADHD symptoms and emotional problems. Hyperactivity-impulsivity may protect children from emotional problems in childhood, but this protective effect diminishes after adolescence.

More knowledge about positive outcomes for people with first-episode psychosis (FEP) is needed. An FEP 10-year follow-up study investigated the rate of personal recovery, emotional wellbeing, and clinical recovery in the total sample and between psychotic bipolar spectrum disorders (BD) and schizophrenia spectrum disorders (SZ); and how these positive outcomes overlap.

FEP participants (n = 128) were re-assessed with structured clinical interviews at 10-year follow-up. Personal recovery was self-rated with the Questionnaire about the Process of Recovery-15-item scale (total score ⩾45). Emotional wellbeing was self-rated with the Life Satisfaction Scale (score ⩾5) and the Temporal Experience of Pleasure Scale (total score ⩾72). Clinical recovery was clinician-rated symptom-remission and adequate functioning (duration minimum 1 year).

In FEP, rates of personal recovery (50.8%), life satisfaction (60.9%), and pleasure (57.5%) were higher than clinical recovery (33.6%). Despite lower rates of clinical recovery in SZ compared to BD, they had equal rates of personal recovery and emotional wellbeing. Personal recovery overlapped more with emotional wellbeing than with clinical recovery (χ2). Each participant was assigned to one of eight possible outcome groups depending on the combination of positive outcomes fulfilled. The eight groups collapsed into three equal-sized main outcome groups: 33.6% clinical recovery with personal recovery and/or emotional wellbeing; 34.4% personal recovery and/or emotional wellbeing only; and 32.0% none.

In FEP, 68% had minimum one positive outcome after 10 years, suggesting a good life with psychosis. This knowledge must be shared to instill hope and underlines that subjective and objective positive outcomes must be assessed and targeted in treatment.

Studies investigating parenthood and how it affects long-term outcomes are lacking among individuals with schizophrenia spectrum disorders. This study aimed to examine the life of participants 20 years after their first diagnosis with a special focus on parenthood, clinical illness course, and family-related outcomes.

Among 578 individuals diagnosed with first-episode schizophrenia spectrum disorder between 1998 and 2000, a sample of 174 participants was reassessed at the 20-year follow-up. We compared symptom severity, remission, clinical recovery, and global functioning between 75 parents and 99 non-parents. Also, family functioning scored on the family assessment device, and the children's mental health was reported. We collected longitudinal data on psychiatric admission, supported housing, and work status via the Danish registers.

Participants with offspring had significantly lower psychotic (mean (s.d.) of 0.89 (1.46) v. 1.37 (1.44), p = 0.031) negative (mean [s.d.] of 1.13 [1.16] v. 1.91 [1.07], p < 0.001) and disorganized symptom scores (mean [s.d.] of 0.46 [0.80] v. 0.85 [0.95], p = 0.005) and more were in remission (59.5% v. 22.4%, p < 0.001) and in clinical recovery (29.7% v. 11.1%, p = 0.002) compared to non-parents. When investigating global functioning over 20 years, individuals becoming parents after their first diagnosis scored higher than individuals becoming parents before their first diagnosis and non-parents. Regarding family-related outcomes, 28.6% reported unhealthy family functioning, and 10% of the children experienced daily life difficulties.

Overall, parents have more favorable long-term outcomes than non-parents. Still, parents experience possible challenges regarding family functioning, and a minority of their children face difficulties in daily life.

To address if the long-standing association between maternal infection, depression/anxiety in pregnancy, and offspring neurodevelopmental disorder (NDD) is causal, we conducted two negative-control studies.

Four primary care cohorts of UK children (pregnancy, 1 and 2 years prior to pregnancy, and siblings) born between 1 January 1990 and 31 December 2017 were constructed. NDD included autism/autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. Maternal exposures included depression/anxiety and/or infection. Maternal (age, smoking status, comorbidities, body mass index, NDD); child (gender, ethnicity, birth year); and area-level (region and level of deprivation) confounders were captured. The NDD incidence rate among (1) children exposed during or outside of pregnancy and (2) siblings discordant for exposure in pregnancy was compared using Cox-regression models, unadjusted and adjusted for confounders.

The analysis included 410 461 children of 297 426 mothers and 2 793 018 person-years of follow-up with 8900 NDD cases (incidence rate = 3.2/1000 person years). After adjustments, depression and anxiety consistently associated with NDD (pregnancy-adjusted HR = 1.58, 95% CI 1.46–1.72; 1-year adj. HR = 1.49, 95% CI 1.39–1.60; 2-year adj. HR = 1.62, 95% CI 1.50–1.74); and to a lesser extent, of infection (pregnancy adj. HR = 1.16, 95% CI 1.10–1.22; 1-year adj. HR = 1.20, 95% CI 1.14–1.27; 2-year adj. HR = 1.19, 95% CI 1.12–1.25). NDD risk did not differ among siblings discordant for pregnancy exposure to mental illness HR = 0.97, 95% CI 0.77–1.21 or infection HR = 0.99, 95% CI 0.90–1.08.

Maternal risk appears to be unspecific to pregnancy: our study provided no evidence of a specific, and therefore causal, link between in-utero exposure to infection, common mental illness, and later development of NDD.

Cognitive impairment constitutes a prevailing issue in the schizophrenia spectrum, severely impacting patients' functional outcomes. A global cognitive score, sensitive to the stages of the spectrum, would benefit the exploration of potential factors involved in the cognitive decline.

First, we performed principal component analysis on cognitive scores from 768 individuals across the schizophrenia spectrum, including first-degree relatives of patients, individuals at ultra-high risk, who had a first-episode psychosis, and chronic schizophrenia patients, alongside 124 healthy controls. The analysis provided 10 g-factors as global cognitive scores, validated through correlations with intelligence quotient and assessed for their sensitivity to the stages on the spectrum using analyses of variance. Second, using the g-factors, we explored potential mechanisms underlying cognitive impairment in the schizophrenia spectrum using correlations with sociodemographic, clinical, and developmental data, and linear regressions with genotypic data, pooled through meta-analyses.

The g-factors were highly correlated with intelligence quotient and with each other, confirming their validity. They presented significant differences between subgroups along the schizophrenia spectrum. They were positively correlated with educational attainment and the polygenic risk score (PRS) for cognitive performance, and negatively correlated with general psychopathology of schizophrenia, neurodevelopmental load, and the PRS for schizophrenia.

The g-factors appeared as valid estimators of global cognition, enabling discerning cognitive states within the schizophrenia spectrum. Educational attainment and genetics related to cognitive performance may have a positive influence on cognitive functioning, while general psychopathology of schizophrenia, neurodevelopmental load, and genetic liability to schizophrenia may have an adverse impact.

The ways in which perceived harm due to substance use affects relationships between psychotic and suicidal experiences are poorly understood. The goal of the current study was to redress this gap by investigating the moderating effects of harm due to substance use on pathways involving positive psychotic symptoms, the perceived cognitive-emotional sequelae of those symptoms, and suicidal ideation.

The design was cross-sectional. Mediation and moderated mediation pathways were tested. The predictor was severity of positive psychotic symptoms. Cognitive interpretative and emotional characteristics of both auditory hallucinations and delusions were mediators. Suicidal ideation was the outcome variable. General symptoms associated with severe mental health problems were statistically controlled for.

There was evidence of an indirect pathway between positive psychotic symptom severity and suicidal ideation via cognitive interpretation and emotional characteristics of both auditory hallucinations and delusions. Harm due to drug use, but not alcohol use, moderated the indirect pathway involving delusions such that it was most prominent when harm due to drug use was at medium-to-high levels. The components of suicidal ideation that were most strongly affected by this moderated indirect pathway were active intent, passive desire, and lack of deterrents.

From both scientific and therapy development perspectives, it is important to understand the complex interplay between, not only the presence of auditory hallucinations and delusions, but the ensuing cognitive and emotional consequences of those experiences which, when combined with harm associated with substance use, in particular drug use, can escalate suicidal thoughts and acts.

Cognitive control (CC) involves a top–down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia.

This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity.

The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia.

These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC.

Although both pharmacotherapy and psychological treatments are considered to be efficacious in the treatment of major depressive disorder (MDD), one third of patients do not respond to treatment and many experience residual symptoms post-treatment. In this double-blind placebo-controlled randomized control trial (RCT), we assessed whether intranasal oxytocin (OT) augments the therapeutic efficacy of psychotherapy for MDD and improves the therapeutic alliance.

Twenty-three volunteers (12 female) with MDD underwent 16 sessions of interpersonal therapy. Prior to each session, volunteers self-administered 24 International Units of intranasal OT (n = 12; Syntocinon) or placebo (n = 11). Depressive symptoms were assessed with the Inventory of Depressive Symptomatology at pre- and post-treatment, and at a six month follow-up.

Multilevel modeling found a significant effect of OT on the negative slope of depressive symptoms over time (p < 0.05), with medium-large effect sizes at post-treatment (Cohen's d = 0.75) and follow-up (Cohen's d = 0.82). Drug intervention also predicted the intercept when examining the weekly ratings of the therapeutic alliance (p < 0.05), such that volunteers receiving OT, relative to placebo, reported improved therapeutic alliance at session 1. The agreement of goals between therapists and participants, a facet of the therapeutic alliance, mediated the relationship between drug intervention and clinical outcome.

In this pilot study, the administration of intranasal OT, relative to placebo, improved the therapeutic alliance at the beginning of therapy and therapeutic efficacy of psychotherapy in persons with MDD. Future RCTs should attempt to replicate these findings in larger samples with different therapeutic modalities (ClinicalTrials.gov: NCT02405715).