Does childhood trauma predict poorer metacognitive abilities in people with first-episode psychosis?

Research suggests that people with first-episode psychosis (FEP) report more childhood traumas and have lower metacognitive abilities than non-clinical controls. Childhood trauma negatively affects metacognitive development in population studies, while the association remains largely unexplored in FEP populations. Metacognition refers to the identification of thoughts and feelings and the formation of complex ideas about oneself and others. This study hypothesized that childhood trauma would be associated with lower metacognitive abilities in people with FEP. In a representative sample of 92 persons with non-affective FEP, we assessed childhood trauma, metacognitive abilities and symptoms of psychosis. We used the Childhood Trauma Questionnaire (CTQ) and the Metacognitive Assessment Scale––Abbreviated which includes Self-reflectivity, Awareness of the Mind of the Other, Decentration and Mastery. Hierarchical regression analyses were performed with metacognitive domains as outcome variables and childhood traumas as independent variables, while controlling for age, gender, first-degree psychiatric illness and negative symptoms. We found few significant associations between the different types of childhood trauma and metacognitive domains, and they suggested childhood trauma are associated with better metacognitive abilities. Study limitations included the cross-sectional design and use of self-report measures. Future studies could preferably be prospective and include different measures of psychopathology and neuropsychology

Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy

Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1

The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands

Psychological Flexibility as a Buffer against Caregiver Distress in Families with Psychosis

Background: Research has shown that caregivers of persons with psychosis play an invaluable role in recovery, but unfortunately, often report high levels of distress. While cognitive models of caregiver distress have been well-supported, there is still limited knowledge of the psychological factors involved. Recent advances in cognitive behavioral therapy seem to converge on the importance of acceptance- and mindfulness based processes.Aim: To examine the impact of psychological flexibility on caregiver distress in the early phases of psychosis, while controlling for known predictors of caregiver distress.Method: Within a cross-sectional design, 101 caregivers of 38 persons with first-episode psychosis in a clinical epidemiological sample completed a series of self-report measures.Results: A linear mixed model analysis found that, after controlling for caregiver socio-demographic factors, service user symptoms, drug use and global functioning, psychological flexibility was a significant predictor of caregiver distress.Conclusion: Greater level of psychological flexibility in caregivers, seems to be related to lower levels of caregiver distress. This finding corresponds to studies within a broad range of emotional disorders. There may be important clinical implications in terms of facilitating the process of acceptance through interventions from the ‘third-wave’ or contextual cognitive behavioral therapies

Investigating the relationship between specific negative symptoms and metacognitive functioning in psychosis: a systematic review

Background: Disrupted metacognition is implicated in development and maintenance of negative symptoms, but more fine-grained analyses would inform precise treatment targeting for individual negative symptoms. Aims: This systematic review identifies and examines datasets that test whether specific metacognitive capacities distinctly influence negative symptoms. Materials and Methods: PsycINFO, EMBASE, Medline and Cochrane Library databases plus hand searching of relevant articles, journals and grey literature identified quantitative research investigating negative symptoms and metacognition in adults aged 16+ with psychosis. Authors of included articles were contacted to identify unique datasets and missing information. Data were extracted for a risk of bias assessment using the Quality in Prognostic Studies tool. Results: 85 published reports met criteria and are estimated to reflect 32 distinct datasets and 1623 unique participants. The data indicated uncertainty about the relationship between summed scores of negative symptoms and domains of metacognition, with significant findings indicating correlation coefficients from 0.88 to −0.23. Only eight studies investigated the relationship between metacognition and individual negative symptoms, with mixed findings. Studies were mostly moderate-to-low risk of bias. Discussion: The relationship between negative symptoms and metacognition is rarely the focus of studies reviewed here, and negative symptom scores are often summed. This approach may obscure relationships between metacognitive domains and individual negative symptoms which may be important for understanding how negative symptoms are developed and maintained. Conclusion: Methodological challenges around overlapping participants, variation in aggregation of negative symptom items and types of analyses used, make a strong case for use of Individual Participant Data Meta-Analysis to further elucidate these relationships