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.

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.

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.

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.].

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.

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.

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

How to classify antipsychotics: time to ditch dichotomies?

The dichotomies of 'typical/atypical' or 'first/second generation' have been employed for several decades to classify antipsychotics, but justification for their use is not clear. In the current analysis we argue that this classification is flawed from both clinical and pharmacological perspectives. We then consider what approach should ideally be employed in both clinical and research settings.

Does Slow and Steady Win the Race? Rates of Antipsychotic Discontinuation, Antipsychotic Dose, and Risk of Psychotic Relapse.

BACKGROUND: Antipsychotics are recommended for prevention of relapse in schizophrenia. It is unclear whether increased risk of relapse following antipsychotic discontinuation is predominantly associated with an absolute magnitude of dose reduction or rate of antipsychotic reduction. Establishing the responsible mechanism is important because prolonged withdrawal schedules have been suggested to reduce risk of relapse. STUDY DESIGN: Individual patient data from antipsychotic discontinuation studies were obtained. We estimated the occupancy of receptors over time using half-lives and median effective dose ED50 values obtained from pharmacokinetic and receptor occupancy studies. Hazard ratios for relapse events were calculated using Cox proportional hazards models to assess the influence of formulation (oral, 1-monthly, and 3-monthly injections). The change in hazard ratio over time was estimated, and the effect of time-varying covariates was calculated, including rate of occupancy reduction and absolute receptor occupancy. STUDY RESULTS: Five studies including 1388 participants with schizophrenia were identified (k = 2: oral, k = 2: 1-monthly injection, k = 1: 3-monthly injection). Withdrawal of long-acting injectable medication did not lead to a lower hazard ratio compared with withdrawal of oral medication, and this included the period immediately following randomization. Hazard ratios were not associated with the rate of decline of receptor occupancy; however, they were associated with reduced absolute occupancy in trials of long-acting injections (P = .038). CONCLUSIONS: Antipsychotic discontinuation is associated with an increased risk of psychotic relapse, related to receptor occupancy. Although relapse does not appear to be related to the rate of discontinuation, gradual discontinuation strategies may allow for easier antipsychotic reinstatement in case of symptomatic worsening.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development.

BACKGROUND: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. METHODS: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). FINDINGS: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. INTERPRETATION: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. FUNDING: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

Variability of glucose, insulin, and lipid disturbances in first-episode psychosis: a meta-analysis.

BACKGROUND: First-episode psychosis (FEP) is associated with metabolic alterations. However, it is not known if there is heterogeneity in these alterations beyond what might be expected due to normal individual differences, indicative of subgroups of patients at greater vulnerability to metabolic dysregulation. METHODS: We employed meta-analysis of variance, indexed using the coefficient of variation ratio (CVR), to compare variability of the following metabolic parameters in antipsychotic naïve FEP and controls: fasting glucose, glucose post-oral glucose tolerance test (OGTT), fasting insulin, insulin resistance, haemoglobin A1c (HbA1c), total-cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. Standardised mean difference in metabolic parameters between groups was also calculated; meta-regression analyses examined physiological/demographic/psychopathological moderators of metabolic change. RESULTS: Twenty-eight studies were analysed (1716 patients, 1893 controls). Variability of fasting glucose [CVR = 1.32; 95% confidence interval (CI) 1.12-1.55; p = 0.001], glucose post-OGTT (CVR = 1.43; 95% CI 1.10-1.87; p = 0.008), fasting insulin (CVR = 1.31; 95% CI 1.09-1.58; p = 0.01), insulin resistance (CVR = 1.34; 95% CI 1.12-1.60; p = 0.001), HbA1c (CVR = 1.18; 95% CI 1.06-1.27; p < 0.0001), total-cholesterol (CVR = 1.15; 95% CI 1.01-1.31; p = 0.03), LDL-cholesterol (CVR = 1.28; 95% CI 1.09-1.50; p = 0.002), and HDL-cholesterol (CVR = 1.15; 95% CI 1.00-1.31; p < 0.05), but not triglycerides, was greater in patients than controls. Mean glucose, glucose post-OGTT, fasting insulin, insulin resistance, and triglycerides were greater in patients; mean total-cholesterol and HDL-cholesterol were reduced in patients. Increased symptom severity and female sex were associated with worse metabolic outcomes. CONCLUSIONS: Patients with FEP present with greater variability in metabolic parameters relative to controls, consistent with a subgroup of patients with more severe metabolic changes compared to others. Understanding determinants of metabolic variability could help identify patients at-risk of developing metabolic syndrome. Female sex and severe psychopathology are associated with poorer metabolic outcomes, with implications for metabolic monitoring in clinical practice.

Longitudinal change in neurocognitive functioning in children and adolescents at clinical high risk for psychosis: a systematic review.

Clinical high risk of psychosis (CHR-P) population has become an attractive area of interest in preventing transitions to psychosis. The consequences of developing a psychotic disorder may be worse in cases of early onset. Thus, childhood and adolescence represent a critical developmental window, where opportunities to gain social and adaptive abilities depend on the individuals' neurocognitive performance. There have been previous syntheses of the evidence regarding neurocognitive functioning in CHR-P individuals and its longitudinal changes. However, there has been less focus on children and adolescents at CHR-P. A multistep literature search was performed from database inception until July 15th, 2022. PRIMSA/MOOSE compliant systematic review and PROSPERO protocol were used to identify studies reporting on longitudinal changes in neurocognitive functioning in children and adolescents (mean age of sample ≤ 18 years) at CHR-P and matched healthy control (HC) group. A systematic review of identified studies was then undertaken. Three articles were included, resulting in a total sample size of 151 CHR-P patients [mean (SD) age, 16.48 (2.41) years; 32.45% female] and 64 HC individuals [mean (SD) age, 16.79 (2.38) years; 42.18% female]. CHR-P individuals had worse outcomes in verbal learning, sustained attention and executive functioning domains compared to HC. Individuals taking antidepressants had better outcomes in verbal learning in contrast with those taking antipsychotics. In children and adolescents, neurocognition may be already impaired before the psychosis onset, and remains stable during the transition to psychosis. Further study should be performed to obtain more robust evidence.

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment.

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks' naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

Data-Driven Taxonomy for Antipsychotic Medication: A New Classification System.

BACKGROUND: Globally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous classification does not reflect the diversity of their pharmacological and clinical profiles. There is a need for a data-driven antipsychotic classification scheme suitable for clinicians and researchers that maps onto both pharmacological and clinical effects. Receptor affinity provides one starting point for such a scheme. METHODS: We analyzed affinities of 27 antipsychotics for 42 receptors from 3325 in vitro receptor binding studies. We used a clustering algorithm to group antipsychotics based on receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced clinical effects quantified according to an umbrella review of clinical trial and treatment guideline data. RESULTS: Clustering resulted in 4 groups of antipsychotics. The predominant receptor affinity and clinical effect "fingerprints" of these 4 groups were defined as follows: group 1, muscarinic (M2-M5) receptor antagonism (cholinergic and metabolic side effects); group 2, dopamine (D2) partial agonism and adrenergic antagonism (overall low side-effect burden); group 3, serotonergic and dopaminergic antagonism (overall moderate side-effect burden); and group 4, dopaminergic antagonism (extrapyramidal side effects and hyperprolactinemia). Groups 1 and 4 were more efficacious than groups 2 and 3. The classification was shown to predict out-of-sample clinical effects of individual drugs. CONCLUSIONS: A receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences. This approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.

Metastability as a candidate neuromechanistic biomarker of schizophrenia pathology.

The disconnection hypothesis of schizophrenia proposes that symptoms of the disorder arise as a result of aberrant functional integration between segregated areas of the brain. The concept of metastability characterizes the coexistence of competing tendencies for functional integration and functional segregation in the brain, and is therefore well suited for the study of schizophrenia. In this study, we investigate metastability as a candidate neuromechanistic biomarker of schizophrenia pathology, including a demonstration of reliability and face validity. Group-level discrimination, individual-level classification, pathophysiological relevance, and explanatory power were assessed using two independent case-control studies of schizophrenia, the Human Connectome Project Early Psychosis (HCPEP) study (controls n = 53, non-affective psychosis n = 82) and the Cobre study (controls n = 71, cases n = 59). In this work we extend Leading Eigenvector Dynamic Analysis (LEiDA) to capture specific features of dynamic functional connectivity and then implement a novel approach to estimate metastability. We used non-parametric testing to evaluate group-level differences and a naïve Bayes classifier to discriminate cases from controls. Our results show that our new approach is capable of discriminating cases from controls with elevated effect sizes relative to published literature, reflected in an up to 76% area under the curve (AUC) in out-of-sample classification analyses. Additionally, our new metric showed explanatory power of between 81-92% for measures of integration and segregation. Furthermore, our analyses demonstrated that patients with early psychosis exhibit intermittent disconnectivity of subcortical regions with frontal cortex and cerebellar regions, introducing new insights about the mechanistic bases of these conditions. Overall, these findings demonstrate reliability and face validity of metastability as a candidate neuromechanistic biomarker of schizophrenia pathology.