Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review.

BACKGROUND: Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained. METHODS: We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association. RESULTS: Of 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4, and hyponatremia, while adrenergic α 1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (adj. odds ratio = 1.21; 95% CI = 1.09-1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68-0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47. CONCLUSIONS: Antipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.

Association between the glyco-metabolic adverse effects of antipsychotic drugs and their chemical and pharmacological profile: a network meta-analysis and regression.

BACKGROUND: Glyco-metabolic deteriorations are the most limiting adverse reactions to antipsychotics in the long term. They have been incompletely investigated and the properties of antipsychotics that determine their magnitude are not clarified.To rank antipsychotics by the magnitude of glyco-metabolic alterations and to associate it to their pharmacological and chemical properties, we conducted a network meta-analysis. METHODS: We searched PubMed, Embase, and Psycinfo on 10 September 2020. We selected studies containing the endpoint-baseline difference or the distinct values of at least one outcome among glucose, HbA1c, insulin, HOMA-IR, triglycerides, total/HDL/LDL cholesterols. Of 2094 articles, 46 were included in network meta-analysis. Study quality was assessed by the RoB 2 and ROBINS-I tools. Mean differences (MD) were obtained by random-effects network meta-analysis; relations between MD and antipsychotic properties were analyzed by linear regressions. Antipsychotic properties investigated were acidic and basic pKa, polar surface area, polarizability, and occupancies of D2, H1, M1, M3, α1A, α2A, 5-HT1A, 5-HT2A, 5-HT2C receptors. RESULTS: We meta-analyzed 46 studies (11 464 patients); on average, studies lasted 15.47 weeks, patients had between 17.68 and 61.06 years of mean age and 61.64% were males. Olanzapine and clozapine associated with greater deteriorations, aripiprazole and ziprasidone with smaller deteriorations. Higher polarizability and 5-HT1A receptor occupancy were associated with smaller deteriorations, H1, M1, and M3 receptor occupancies with larger deteriorations. CONCLUSIONS: Drug rankings may guide antipsychotic switching toward metabolically safer drugs. Mechanistic insights may suggest improvements for combination therapies and drug development. More data are required regarding newer antipsychotics.

Beta-blocker-associated hypoglycaemia: New insights from a real-world pharmacovigilance study.

AIMS: To investigate the statistical association between hypoglycaemia and ß-blocker use and to define what patient and drug characteristics could potentially increase the risk for its occurrence. METHODS: We investigated the relationship between pharmacological parameters of ß-blockers and the occurrence of hypoglycaemia by conducting a case/non case analysis using the Food and Drug Administration Adverse Event Reporting System database. Pharmacological properties that could represent a predictive factor for hypoglycaemia were analysed through a multilinear binary logistic regression (null hypothesis rejected for values of P < .05). We also performed a systematic review of clinical studies on this association. RESULTS: Of 83 954 selected reports, 1465 cases (1.75%) of hypoglycaemia were identified. The association was found statistically significant for nadolol (reporting odds ratio [95% confidence interval]: 6.98 [5.40-9.03]), celiprolol (2.35 [1.35-4.10]), propranolol (2.14 [1.87-2.46]) and bisoprolol (1.42 [1.25-1.61]). Paediatric cases (n = 310) showed a positive association with hypoglycaemia for long half-life drugs (odds ratio [95% confidence interval]: 2.232 [1.398-3.563]) and a negative association for ß1-selectivity (0.644 [0.414-0.999]). Seven papers were included in the systematic review. Because of great heterogeneity in study design and demographics, hypoglycaemia incidence rates varied greatly among studies, occurring in 1.73% of the cases for propranolol treatment (n total participants = 575), 6.6% for atenolol (n = 30) and 10% for carvedilol (n = 20). CONCLUSION: Nadolol appears to be the ß-blocker significantly most associated with hypoglycaemia and children represent the most susceptible sample. Furthermore, long half-life and nonselective ß-blockers seem to increase the risk for its occurrence.

Primary and secondary negative symptoms severity and the use of psychiatric care resources in schizophrenia spectrum disorders: A 3-year follow-up longitudinal retrospective study.

Negative symptoms represent one of the core features of schizophrenia spectrum disorders (SSD), strongly correlated with low remission rates, poor real-world functioning, and worse quality of life. Despite the body of evidence attesting the role of negative symptoms in determining worse outcomes in SSD, few studies have directly investigated their impact on the use of psychiatric services and even fewer research have examined the differential impact between primary versus secondary negative symptoms. The present study aims to investigate whether SSD subjects with high levels of primary and of secondary negative symptoms at an index hospitalization show a different use of psychiatric services in the subsequent 3 years. A total of 429 subjects were included in the study. Results show that SSD patients with high levels of negative symptoms are characterized by an overall greater use of high-cost resources, with more admissions in the hospital acute care psychiatric ward and in high intensity residential inpatient services. Moreover, while primary negative symptoms appear to play a role in determining a greater use of psychiatric services, high levels of secondary negative symptoms are associated with an increased use of most psychiatric resources, especially of high-cost ones. In conclusion, negative symptoms have a relevant impact on the pattern of psychiatric resources utilization in SSD patients. While scientific research continues to look for effective treatments for primary negative symptoms, clinicians should pay particular attention to secondary negative symptoms, as these also have important consequences but may benefit from appropriate treatment.

Assessment and correlates of autistic symptoms in Schizophrenia Spectrum Disorders measured with the PANSS Autism Severity Score: A systematic review.

Schizophrenia Spectrum Disorders (SSD) and Autism Spectrum Disorders (ASD) are considered separate entities, but the two spectra share important similarities, and the study of these areas of overlap represents a field of growing scientific interest. The PANSS Autism Score (PAUSS) was recently developed specifically to assess autistic symptoms in people living with SSD reliably and quickly. The aims of the present systematic review were to provide a comprehensive assessment of the use of the PAUSS scale in available literature and to systematically analyze cognitive, functional and neurobiological correlates of autistic symptoms measured with this instrument in SSD. The systematic literature search included three electronic databases (PubMed, Scopus and PsycINFO) as well as a manual search in Google Scholar and in reference lists of included papers. Screening and extraction were conducted by at least two independent reviewers. Out of 213 identified records, 22 articles referring to 15 original studies were included in the systematic review. Studies were conducted in several different countries by independent groups, showing consistent scientific interest in the use of the scale; most works focused on cognitive and functional correlates of ASD symptoms, but some also considered neurobiological features. Results of included studies showed that autistic symptoms in people with SSD are consistently associated with worse cognitive performance, especially in the social cognition domain, and with worse psychosocial functioning. However, the presence of autistic symptoms appears to also have a protective role, particularly on functioning, in subjects with more severe psychotic symptoms. Further exploring the impact of autistic symptoms could be of significant scientific and clinical interest, allowing the development of tailored interventions to improve treatment for people living with SSDs.

Is there an association between inflammatory/anti-oxidant markers and the presence of psychotic symptoms or severity of illness in mood and psychotic disorders? A multi-centric study on a drug-free sample.

The immune and antioxidant systems are intimately connected and their role in the etiology of major psychiatric disorders is currently under study. The aim of this study was to evaluate the potential associations between inflammatory/antioxidant peripheral markers and presence of psychotic symptoms or severity of illness in patients affected by major psychiatric disorders. One hundred and twenty-six drug-free patients were included. A blood sample was collected to measure total/B/T lymphocytes and plasma levels of albumin, total bilirubin, uric acid, C-reactive protein, and vitamins A and E. Severity of illness was assessed using psychometric scales. Groups of patients divided according to diagnosis were compared in terms of measured markers using multivariate analyses of variance (MANOVAs). Linear and logistic regression analyses were performed to investigate the potential association between markers and severity of illness or presence/absence of psychotic symptoms. Albumin plasma levels were higher in patients with substance-induced psychotic disorder (SIPD) than subjects affected by schizophrenia (F â€‹= â€‹4.923; p â€‹= â€‹0.003). Lower vitamin E (OR â€‹= â€‹0.81; p â€‹= â€‹0.014) and T lymphocyte (OR â€‹= â€‹0.99; p â€‹= â€‹0.048) plasma levels were predictive of lifetime psychotic symptoms. Lower vitamin A levels were associated with higher Montgomery-Åsberg Depression Rating Scale scores (ߠ​= â€‹-24.26; p â€‹= â€‹0.029), independent of diagnosis. Patients with SIPD may be less vulnerable to oxidative stress. The severity of depressive symptoms, inversely associated with vitamin A plasma levels, is likely to be modulated by the degree of inflammation. Patients presenting with lifetime psychotic symptoms may be more vulnerable to oxidative stress and may have a higher activation of humoral immunity.

Changes in Anthropometric Parameters After Anti-TNFα Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Tumour necrosis factor (TNF)-α inhibitors have been widely used for the treatment of moderate-to-severe inflammatory bowel disease (IBD). TNFα also plays an important role in the regulation of weight homeostasis and metabolism and has been linked to variations in anthropometric responses. This relationship in patients with IBD has yet to be determined. OBJECTIVES: Our objective was to evaluate the effects of TNFα inhibitors on changes in anthropometric measures in both adults and children with IBD through a systematic review and meta-analysis. METHODS: Multiple database searches identified studies involving children and adults with IBD and treated with TNFα inhibitors and reporting at least one primary outcome measure. Where possible, data were combined for meta-analysis. The primary outcomes included weight, body mass index (BMI), waist circumference, height, height/velocity, and fat and lean mass. Secondary outcomes included surrogate markers of disease activity. A random-effects model was used to estimate the standardised mean difference (SMD). RESULTS: In total, 23 cohort studies (total 1167 participants) met the inclusion criteria. Meta-analysis was performed on 13 of these studies. In children, 6-29.3 months of anti-TNFα therapy had a small but statistically significant effect on weight (SMD 0.31; 95% confidence interval [CI] 0.12-0.49; P = 0.001) with a mean gain in z score of 0.30 (standard error [SE] 0.12). In adults, 2-22.4 months of treatment had a moderate effect on BMI (SMD 0.72; 95% CI 0.17-1.26; P = 0.010; mean gain 1.23 kg/m2; SE 0.21). A small but statistically significant increase in BMI z score was found in children (SMD 0.28; 95% CI 0.03-0.53; P = 0.026; mean change 0.31 ± standard deviation [SD] 0.14) after 12-29.3 months of therapy. A meta-analysis of four studies found a negligible but statistically significant increase in height (SMD 0.16; 95% CI 0.06-0.26; P = 0.002; mean change 0.17 z score [SE 0.05]). A negligible effect on fat mass (SMD 0.24; 95% CI -0.19-0.66; P = 0.272) was found in a meta-analysis of five studies. Of note, despite the high heterogeneity among the studies that addressed the issue, these results were also consistently supported by findings from studies not included in the meta-analysis and reviewed in the systematic review. Unfortunately, a lack of data meant we were unable to perform moderator analysis on observed heterogeneity. CONCLUSION: Anti-TNFα treatment appears to be associated with an increase in body weight, BMI, and other anthropometric parameters. Given the differing courses of IBD between children and adults, this association should be considered before initiating biologics for undernourished, overweight, and obese patients. Registration: PROSPERO registration number CRD42020163079.