Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Risk factors for PTSD symptoms following PICU admission for childhood septic shock.

ObjectivePaediatric intensive care unit (PICU) admission represents a traumatic event for many children. Follow-up studies have found post-traumatic stress disorder (PTSD) rates of 10-30%, with a particular prevalence following admission for sepsis. Dysregulated inflammatory responses are associated with PTSD. Sepsis involves a marked inflammatory response but the relationship between this and PTSD have not been clearly established. In this study we investigate associations between the inflammatory response, psychosocial risk factors, and PTS symptoms following PICU admission for septic shock.We investigate the outcomes for children aged > 3 years, discharged from one PICU following admission for septic shock between 2010 and 2017. The study was a retrospective analysis of PICU-specific PTS symptoms reported by parents at any time since discharge via the Trauma and Behavior Health screen. Demographics, pre-morbid health characteristics, and exposure to other traumatic events were assessed. Clinical characteristics and blood test results at admission and at 48 h were recorded from clinical records. Multiple linear regression was used to investigate relationships between PTS symptom scores and predictor variables.Data for 65 participants (48% male, median assessment age 8.0 years) was available. Median time since admission was 5.1 years. 30.8% children scored at risk of PTSD at any time since discharge Symptoms were significantly associated with acute CRP rise (p 0.03), other trauma exposures (p = 0.01), and female gender (p =0.04).PTS symptoms in children who have survived septic shock are prevalent. These findings support a possible contribution of acute inflammatory changes, cumulative traumatic exposure, and female gender in post-PICU PTSD development.

Psychosis as a disorder of muscarinic signalling: psychopathology and pharmacology.

Dopaminergic receptor antagonism is a crucial component of all licensed treatments for psychosis, and dopamine dysfunction has been central to pathophysiological models of psychotic symptoms. Some clinical trials, however, indicate that drugs that act through muscarinic receptor agonism can also be effective in treating psychosis, potentially implicating muscarinic abnormalities in the pathophysiology of psychosis. Here, we discuss understanding of the central muscarinic system, and we examine preclinical, behavioural, post-mortem, and neuroimaging evidence for its involvement in psychosis. We then consider how altered muscarinic signalling could contribute to the genesis and maintenance of psychotic symptoms, and we review the clinical evidence for muscarinic agents as treatments. Finally, we discuss future research that could clarify the relationship between the muscarinic system and psychotic symptoms.

Prevalence of multimorbidity in people with and without severe mental illness: a systematic review and meta-analysis.

BACKGROUND: People with severe mental illness, such as schizophrenia-spectrum disorder and bipolar disorder, face poorer health outcomes from multiple chronic illnesses. Physical multimorbidity, the coexistence of two or more chronic physical conditions, and psychiatric multimorbidity, the coexistence of three or more psychiatric disorders, are both emerging concepts useful in conceptualising disease burden. However, the prevalence of physical and psychiatric multimorbidity in this cohort is unknown. This study aimed to estimate the absolute prevalence of both physical and psychiatric multimorbidity in people with severe mental illness, and also compare the odds of physical multimorbidity prevalence against people without severe mental illness. METHODS: We searched CINAHL, EMBASE, PubMed, and PsycINFO from inception until Feb 15, 2024, for observational studies that measured multimorbidity prevalence. To be included, studies had to have an observational study design, be conducted in an adult population (mean age ≥18 years) diagnosed with either schizophrenia-spectrum disorder or bipolar disorder, and include a measurement of occurrence of either physical multimorbidity (≥2 physical health conditions) or psychiatric multimorbidity (≥3 psychiatric conditions total, including the severe mental illness). From control studies, a random-effects meta-analysis compared odds of physical multimorbidity between people with and without severe mental illness. Absolute prevalence of physical and psychiatric multimorbidity in people with severe mental illness was also calculated. Sensitivity and meta-regression analyses tested an array of demographic, diagnostic, and methodological variables. FINDINGS: From 11 144 citations we included 82 observational studies featuring 1 623 773 individuals with severe mental illness (specifically schizophrenia-spectrum disorder or bipolar disorder), of which 21 studies featured 13 235 882 control individuals without severe mental illness (descriptive data for the entire pooled cohorts were not available for numbers of males and females, age, and ethnicity). This study did not feature involvement of people with lived experience. The odds ratio (OR) of physical multimorbidity between people with and without severe mental illness was 2·40 (95% CI 1·57-3·65, k=11, p=0·0009). This ratio was higher in younger severe mental illness populations (mean age ≤40 years, OR 3·99, 95% CI 1·43-11·10) compared with older populations (mean age >40 years, OR 1·55, 95% CI 0·96-2·51; subgroup differences p=0·0013). For absolute prevalence, 25% of those with severe mental illness have physical multimorbidity (95% CI 0·19-0·32, k=29) and 14% have psychiatric multimorbidity (95% CI 0·08-0·23, k=21). INTERPRETATION: This is the first meta-analysis to estimate physical alongside psychiatric multimorbidity prevalence, showing that these are common in people with schizophrenia-spectrum disorder and bipolar disorder. The greater burden of physical multimorbidity in people with severe mental illness compared with those without is higher for younger cohorts, reflecting a need for earlier intervention. Our findings speak to the utility of multimorbidity for characterising the disease burden associated with severe mental illness, and the importance of facilitating integrated physical and mental health care. FUNDING: None.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. STUDY DESIGN: This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. STUDY RESULTS: 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089). CONCLUSIONS: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Corrigendum: The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: a 1H-MRS study in first-episode psychosis patients.

[This corrects the article DOI: 10.3389/fpsyt.2022.967941.].

Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

The magnitude and variability of neurocognitive performance in first-episode psychosis: a systematic review and meta-analysis of longitudinal studies.

Neurocognitive deficits are a core feature of psychotic disorders, but it is unclear whether they affect all individuals uniformly. The aim of this systematic review and meta-analysis was to synthesize the evidence on the magnitude, progression, and variability of neurocognitive functioning in individuals with first-episode psychosis (FEP). A multistep literature search was conducted in several databases up to November 1, 2022. Original studies reporting on neurocognitive functioning in FEP were included. The researchers extracted the data and clustered the neurocognitive tasks according to the seven Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) domains and six additional domains. Random-effect model meta-analyses, assessment of publication biases and study quality, and meta-regressions were conducted. The primary effect size reported was Hedges g of (1) neurocognitive functioning in individuals at FEP measuring differences with healthy control (HC) individuals or (2) evolution of neurocognitive impairment across study follow-up intervals. Of 30,384 studies screened, 54 were included, comprising 3,925 FEP individuals and 1,285 HC individuals. Variability analyses indicated greater variability in FEP compared to HC at baseline and follow-up. We found better neurocognitive performance in the HC group at baseline and follow-up but no differences in longitudinal neurocognitive changes between groups. Across the 13 domains, individuals with FEP showed improvement from baseline in all studied domains, except for visual memory. Metaregressions showed some differences in several of the studied domains. The findings suggest that individuals with FEP have marked cognitive impairment, but there is greater variability in cognitive functioning in patients than in HC. This suggests that subgroups of individuals suffer severe disease-related cognitive impairments, whereas others may be much less affected. While these impairments seem stable in the medium term, certain indicators may suggest potential further decline in the long term for a specific subgroup of individuals, although more research is needed to clarify this. Overall, this study highlights the need for tailored neurocognitive interventions for individuals with FEP based on their specific deficits and progression.

Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis.

BACKGROUND: The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions. METHODS: For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393). FINDINGS: Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone. INTERPRETATION: Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations. FUNDING: UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.

Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-Sensitive Magnetic Resonance Imaging and [18F]-DOPA Positron Emission Tomography Study.

BACKGROUND: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin (NM)-sensitive magnetic resonance imaging provides a marker of long-term dopamine function. We examined whether midbrain NM-sensitive magnetic resonance imaging contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia than in healthy control (HC) participants and whether this correlated with dopamine synthesis capacity. METHODS: One hundred fifty-four participants (schizophrenia group: n = 74, HC group: n = 80) underwent NM-sensitive magnetic resonance imaging of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n = 38) also received [18F]-DOPA positron emission tomography to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. RESULTS: SN-VTA NM-CNR was significantly higher in patients with schizophrenia than in HC participants (effect size = 0.38, p = .019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r = 0.44, p = .005) and striatal Kicer (r = 0.71, p < .001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r = 0.53, p = .005) and that this relationship seemed strongest between the ventral SN-VTA and associative striatum in schizophrenia. CONCLUSIONS: Our results suggest that NM levels are higher in patients with schizophrenia than in HC individuals, particularly in midbrain regions that project to parts of the striatum that receive innervation from the limbic and association cortices. The direct relationship between measures of NM and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and thus as potential therapeutic targets.

Do Cognitive Subtypes Exist in People at Clinical High Risk for Psychosis? Results From the EU-GEI Study.

BACKGROUND AND HYPOTHESIS: Cognition has been associated with socio-occupational functioning in individuals at Clinical High Risk for Psychosis (CHR-P). The present study hypothesized that clustering CHR-P participants based on cognitive data could reveal clinically meaningful subtypes. STUDY DESIGN: A cohort of 291 CHR-P subjects was recruited through the multicentre EU-GEI high-risk study. We explored whether an underlying cluster structure was present in the cognition data. Clustering of cognition data was performed using k-means clustering and density-based spatial clustering of applications with noise. Cognitive subtypes were validated by comparing differences in functioning, psychosis symptoms, transition outcome, and grey matter volume between clusters. Network analysis was used to further examine relationships between cognition scores and clinical symptoms. STUDY RESULTS: No underlying cluster structure was found in the cognitive data. K-means clustering produced "spared" and "impaired" cognition clusters similar to those reported in previous studies. However, these clusters were not associated with differences in functioning, symptomatology, outcome, or grey matter volume. Network analysis identified cognition and symptoms/functioning measures that formed separate subnetworks of associations. CONCLUSIONS: Stratifying patients according to cognitive performance has the potential to inform clinical care. However, we did not find evidence of cognitive clusters in this CHR-P sample. We suggest that care needs to be taken in inferring the existence of distinct cognitive subtypes from unsupervised learning studies. Future research in CHR-P samples could explore the existence of cognitive subtypes across a wider range of cognitive domains.

PsyCog: A computerised mini battery for assessing cognition in psychosis.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.