Search

Aims While dopamine antagonists are an effective treatment for positive psychotic symptoms, they are rarely effective when it comes to treating the cognitive (memory, learning, planning, etc.) and negative (avolition and social withdrawal) symptoms of the disorder. Furthermore, for a sizeable proportion, standard dopamine antagonists are not effective for positive symptoms either. As such, refractory symptoms are a major burden for patients, carers, and clinical services. Methods To address this, The TUNE-UP (Treating Unmet Needs in Psychiatry) clinic in Oxford was established in September 2023 as an innovative solution aiming to: (A) Undertake an in-depth assessment of cognitive, negative, and positive symptoms; (B) Identify potentially modifiable causative factors contributing to refractory symptoms (e.g., cholinergic burden, sleep disturbances, physical comorbidities, affective symptoms); and (C) Implement management plans including community clozapine initiation where appropriate. We have analysed data from the clinic's initial five months of operation to establish a baseline understanding of our patient population and identify trends in symptoms. Results In the first five months of operations, 21 referrals were accepted comprising 80.9% males (mean age 43.3 years, SD 13.7). 3 were referred for cognitive symptoms, 1 for negative and cognitive symptoms, 11 for positive symptoms, 3 for medication optimisation, and 3 for clozapine re-titration. Of those fully assessed (N = 17), mean total symptom scores measured using the Positive and Negative Syndrome Scale (PANSS) were of mild/moderate severity (70.5, SD 18.4). Objective cognitive testing via the Screen for Cognitive Impairment in Psychiatry (SCIP) demonstrated a total mean score of 54.1 (SD 12.1), markedly below what would be expected in a matched control population (76.3). Cognitive scores were lower in those of older age (r = −0.62, p = 0.01). Subjective experience of cognitive impairment was measured using the Subjective Scale to Investigate Cognition in Schizophrenia, poor subjective cognition was associated with more severe negative symptoms (r = 0.57, p = 0.03), but not objective SCIP results (r = 0.12, p = 0.85). Conclusion Refractory positive symptoms remain a priority for clinicians, but cognitive and negative symptoms are highly prevalent reinforcing the need for a comprehensive approach. Routine structured assessment of all symptom domains is feasible in clinical practice. Future work should examine the longitudinal impact of various interventions on different symptom domains.

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community—including patients, carers, clinicians, researchers and funders—to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.

Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. Methods: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.

Abstract Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate striatal dopamine function, such as the hippocampus. This review draws together these recent data to discuss why the hippocampus may be especially vulnerable in the pathophysiology of psychosis. First, we describe the neurodevelopmental trajectory of the hippocampus and its susceptibility to dysfunction, exploring this region’s proneness to structural and functional imbalances, metabolic pressures, and oxidative stress. We then examine mechanisms of hippocampal dysfunction in psychosis and in individuals at high-risk for psychosis and discuss how and when hippocampal abnormalities may be targeted in these groups. We conclude with future directions for prospective studies to unlock the discovery of novel therapeutic strategies targeting hippocampal circuit imbalances to prevent or delay the onset of psychosis.

Abstract This study aims to meta-analytically characterize the presence and magnitude of within-group variability across neurocognitive functioning in young people at Clinical High-Risk for psychosis (CHR-P) and comparison groups. Multistep, PRISMA/MOOSE-compliant systematic review (PROSPERO-CRD42020192826) of the Web of Science database, Cochrane Central Register of Reviews and Ovid/PsycINFO and trial registries up to July 1, 2020. The risk of bias was assessed using a modified version of the NOS for cohort and cross-sectional studies. Original studies reporting neurocognitive functioning in individuals at CHR-P compared to healthy controls (HC) or first-episode psychosis (FEP) patients were included. The primary outcome was the random-effect meta-analytic variability ratios (VR). Secondary outcomes included the coefficient of variation ratios (CVR). Seventy-eight studies were included, relating to 5162 CHR-P individuals, 2865 HC and 486 FEP. The CHR-P group demonstrated higher variability compared to HC (in descending order of magnitude) in visual memory (VR: 1.41, 95% CI 1.02–1.94), executive functioning (VR: 1.31, 95% CI 1.18–1.45), verbal learning (VR: 1.29, 95% CI 1.15–1.45), premorbid IQ (VR: 1.27, 95% CI 1.09–1.49), processing speed (VR: 1.26, 95% CI 1.07–1.48), visual learning (VR: 1.20, 95% CI 1.07–1.34), and reasoning and problem solving (VR: 1.17, 95% CI 1.03–1.34). In the CVR analyses the variability in CHR-P population remains in the previous neurocognitive domains and emerged in attention/vigilance, working memory, social cognition, and visuospatial ability. The CHR-P group transitioning to psychosis showed greater VR in executive functioning compared to those not developing psychosis and compared to FEP groups. Clinical high risk for psychosis subjects shows increased variability in neurocognitive performance compared to HC. The main limitation of this study is the validity of the VR and CVR as an index of variability which has received debate. This finding should be explored by further individual-participant data research and support precision medicine approaches.

Abstract Introduction Q.Clear is a Bayesian penalised likelihood (BPL) reconstruction algorithm available on General Electric (GE) Positron Emission Tomography (PET)-Computed Tomography (CT) and PET-Magnetic Resonance (MR) scanners. This algorithm is regulated by a β value which acts as a noise penalisation factor and yields improvements in signal to noise ratio (SNR) in clinical scans, and in contrast recovery and spatial resolution in phantom studies. However, its performance in human brain imaging studies remains to be evaluated in depth. This pilot study aims to investigate the impact of Q.Clear reconstruction methods using different β value versus ordered subset expectation maximization (OSEM) on brain kinetic modelling analysis of low count brain images acquired in the PET-MR. Methods Six [11C]PHNO PET-MR brain datasets were reconstructed with Q.Clear with β100–1000 (in increments of 100) and OSEM. The binding potential relative to non-displaceable volume (BP ND ) were obtained for the Substantia Nigra (SN), Striatum (St), Globus Pallidus (GP), Thalamus (Th), Caudate (Cd) and Putamen (Pt), using the MIAKAT™ software. Intraclass correlation coefficients (ICC), repeatability coefficients (RC), coefficients of variation (CV) and bias from Bland–Altman plots were reported. Statistical analysis was conducted using a 2-way ANOVA model with correction for multiple comparisons. Results When comparing a standard OSEM reconstruction of 6 iterations/16 subsets and 5 mm filter with Q.Clear with different β values under low counts, the bias and RC were lower for Q.Clear with β100 for the SN (RC = 2.17), Th (RC = 0.08) and GP (RC = 0.22) and with β200 for the St (RC = 0.14), Cd (RC = 0.18)and Pt (RC = 0.10). The p-values in the 2-way ANOVA model corroborate these findings. ICC values obtained for Th, St, GP, Pt and Cd demonstrate good reliability (0.87, 0.99, 0.96, 0.99 and 0.96, respectively). For the SN, ICC values demonstrate poor reliability (0.43). Conclusion BP ND results obtained from quantitative low count brain PET studies using [11C]PHNO and reconstructed with Q.Clear with β

Objectives To assess the magnitude of mental health outcomes and associated factors among psychiatric professionals in mental health services during COVID-19 in China.Design, setting and participants This cross-sectional, survey-based, region-stratified study collected demographic data and mental health measurements from psychiatric professionals in 34 hospitals between 29 January and 7 February 2020, in China. Hospitals equipped with fever clinics or deployed on wards for patients with COVID-19 were eligible.Primary outcome and measures The severity of symptoms of depression, anxiety, insomnia and distress were assessed by the Chinese versions of 9-item Patient Health Questionnaire, 7-item Generalised Anxiety Disorder, 7-item Insomnia Severity Index and 22-item Impact of Event Scale-Revised, respectively. Multivariable logistic regression and structural equation modelling was performed to identify factors associated with mental health outcomes.Results A total of 610 psychiatric professionals were included. 29.8% were employed in Wuhan, and 22.5% were frontline workers. A considerable proportion of participants reported symptoms of depression (461 (75.6%)), anxiety (282 (46.2%)), insomnia (336 (55.1%)) and mental stress (481 (78.9%)). Psychiatric symptoms were associated with worrying about infection (eg, OR 2.36 (95% CI 1.27 to 4.39) for anxiety), risks of exposure to COVID-19 (eg, having inadequate personal protection equipment, OR 2.43 (1.32 to 4.47) for depression) and self-perceived physical health (eg, OR 3.22 (2.24 to 4.64) for mental stress). Information sources of COVID-19 were also found to be both positively (eg, information from relatives, OR 2.16 (1.46 to 3.21) for mental stress) and negatively (eg, information from TV, OR 0.52 (0.35 to 0.77) for mental stress) associated with mental stress. There is preliminary evidence that mental health might benefit from greater availability of mental healthcare services. The structural equation model analysis indicated that worrying about infection may be the primary mediator via which risk of exposure to COVID-19 pandemic affects the mental health of psychiatric professionals.Conclusions The current findings demonstrate several pathways via which the COVID-19 pandemic may have negatively affected the mental health of psychiatric professionals in China.