Polypharmacy and Antidepressant Acceptability in Comorbid Depression and Type 2 Diabetes

BACKGROUND: Polypharmacy may increase the risk of drug interactions, side-effects and poor adherence. However, the impact of polypharmacy on antidepressant acceptability in individuals with type 2 diabetes (T2DM) is unknown. AIM: In adults with T2DM, to investigate the association between the number of prescribed medications and: i) early antidepressant discontinuation (<32 weeks); ii) switching antidepressant agents. DESIGN: Cohort study using UK primary care data from the years 2000-2018. METHODS: We used cox regression with penalised B-splines to describe the association between the number of concurrently prescribed medications at the time of starting antidepressant treatment, and each of our outcomes. RESULTS: We identified 73,808 individuals with comorbid depression and T2DM starting antidepressant treatment for the first time. The median number of concurrent medications prescribed was 7. Within 32 weeks, 44.26% of participants discontinued antidepressant treatment altogether, and 11.75% of participants switched antidepressant agents. We found an inverse relationship between the number of concurrent medications and discontinuing antidepressant treatment altogether. The median number of 7 concurrent medications was associated with a 65.06% decrease early antidepressant discontinuation HR 0.45, 95% CIs 0.37-0.55). We found no evidence of an association, in our main analysis, between the number of concurrent medications and switching antidepressant agents. CONCLUSIONS: Early discontinuation of antidepressants is common in adults with T2DM. However, individuals with higher levels of concurrent polypharmacy may be more adherent to treatment. These are likely to represent individuals with worse physical/mental health. Individuals with lower levels of concurrent polypharmacy may benefit from adherence support

Association between polypharmacy and depression relapse in individuals with comorbid depression and type 2 diabetes: a UK electronic health record study

BACKGROUND: Individuals with physical comorbidities and polypharmacy may be at higher risk of depression relapse, however, they are not included in the 'high risk of relapse' group for whom longer antidepressant treatment durations are recommended. AIMS: In individuals with comorbid depression and type 2 diabetes (T2DM), we aimed to investigate the association and interaction between depression relapse and (a) polypharmacy, (b) previous duration of antidepressant treatment. METHOD: This was a cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) from years 2000 to 2018. We used Cox regression models with penalised B-splines to describe the association between restarting antidepressants and our two exposures. RESULTS: We identified 48 001 individuals with comorbid depression and T2DM, who started and discontinued antidepressant treatment during follow-up. Within 1 year of antidepressant discontinuation, 35% of participants restarted treatment indicating depression relapse. As polypharmacy increased, the rate of restarting antidepressants increased until a maximum of 18 concurrent medications, where individuals were more than twice as likely to restart antidepressants (hazard ratio (HR) = 2.15, 95% CI 1.32-3.51). As the duration of previous antidepressant treatment increased, the rate of restarting antidepressants increased - individuals with a previous duration of ≥25 months were more than twice as likely to restart antidepressants than those who previously discontinued in <7 months (HR = 2.36, 95% CI 2.25-2.48). We found no interaction between polypharmacy and previous antidepressant duration. CONCLUSIONS: Polypharmacy and longer durations of previous antidepressant treatment may be associated with depression relapse following the discontinuation of antidepressant treatment

Crotalus atrox venom preconditioning increases plasma fibrinogen and reduces perioperative hemorrhage in a rat model of surgical brain injury.

Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries

Genomic selection in commercial perennial crops: applicability and improvement in oil palm (Elaeis guineensis Jacq.)

Genomic selection (GS) uses genome-wide markers to select individuals with the desired overall combination of breeding traits. A total of 1,218 individuals from a commercial population of Ulu Remis x AVROS (UR x AVROS) were genotyped using the OP200K array. The traits of interest included: shellto- fruit ratio (S/F, %), mesocarp-to-fruit ratio (M/F, %), kernel-to-fruit ratio (K/F, %), fruit per bunch (F/B, %), oil per bunch (O/B, %) and oil per palm (O/P, kg/palm/year). Genomic heritabilities of these traits were estimated to be in the range of 0.40 to 0.80. GS methods assessed were RR-BLUP, Bayes A (BA), Cπ (BC), Lasso (BL) and Ridge Regression (BRR). All methods resulted in almost equal prediction accuracy. The accuracy achieved ranged from 0.40 to 0.70, correlating with the heritability of traits. By selecting the most important markers, RR-BLUP B has the potential to outperform other methods. The marker density for certain traits can be further reduced based on the linkage disequilibrium (LD). Together with in silico breeding, GS is now being used in oil palm breeding programs to hasten parental palm selection

Association between the mood stabilizing treatment of bipolar disorder and risk of suicide attempts: A self-controlled case series study

Bipolar disorder (BPD) is associated with high rates of suicide attempts but the anti-suicidal effect of mood stabilizing agents remains unclear. This study aimed to examine the association between mood stabilizing agents (lithium, valproate, lamotrigine, carbamazepine or antipsychotics) and risk of suicide attempts in patients with BPD using self-controlled case series study design. Among 14,087 patients with BPD who received mood stabilizing agents from 2001 to 2020 in Hong Kong, 1316 patients had at least one suicide attempts during the observation period. An increased risk of suicide attempts was observed 14 days before treatment initiation compared to non-exposed period. Following treatment initiation, an increased risk with smaller magnitude was found with the use of mood stabilizing agents. A lower risk was observed with lithium and antiepileptics while the risk remained attenuated with decreasing magnitude with antipsychotics. During 30-day post-treatment period, the risk was elevated. Therefore, this study suggests that use of mood stabilizing agents is not causally associated with an increased risk of suicide attempts. Indeed, there are potential protective effects of lithium and antiepileptics against suicide attempts. Assiduous monitoring of symptoms relapse and warning signs of suicide should be part of the management plan and discussed between clinicians, caregivers and patients

Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia

IMPORTANCE: Evidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs. OBJECTIVE: To compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia. DESIGN, SETTINGS, AND PARTICIPANTS: In this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021. EXPOSURES: Use of LAIAs vs OAs. MAIN OUTCOMES AND MEASURES: Risk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression. RESULTS: Of the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events. CONCLUSIONS AND RELEVANCE: This self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness

Identifying mortality risks in patients with opioid use disorder using brief screening assessment: Secondary mental health clinical records analysis

BACKGROUND: Risk assessments are widely used, but their ability to predict outcomes in opioid use disorder (OUD) treatment remains unclear. Therefore, the aim was to investigate if addiction-specific brief risk screening is effective in identifying high mortality risk groups and if subsequent clinical actions following risk assessment impacts on mortality levels. METHODS: Opioid use disorder (OUD) patients were identified in the South London and Maudsley Case Register. Deaths were identified through database linkage to the national mortality dataset. Cox and competing-risk regression were used to model associations between brief risk assessment domains and all-cause and overdose mortality in 4488 OUD patients, with up-to 6-year follow-up time where 227 deaths were registered. Data were stratified by admission to general mental health services. RESULTS: All-cause mortality was significantly associated with unsafe injecting (HR 1.53, 95% CI 1.10-2.11) and clinically appraised likelihood of accidental overdose (HR 1.48, 95% CI 1.00-2.19). Overdose-mortality was significantly associated with unsafe injecting (SHR 2.52, 95% CI 1.11-5.70) and clinically appraised suicidality (SHR 2.89, 95% CI 1.38-6.03). Suicidality was associated with a twofold increase in mortality risk among OUD patients who were not admitted to mental health services within 2 months of their risk assessment (HR 2.03, 95% CI 1.67-3.24). CONCLUSIONS: Diagnosis-specific brief risk screening can identify OUD patient subgroups at increased risk of all-cause and overdose mortality. OUD patients, where suicidality is evident, who are not admitted into services are particularly vulnerable

A cost-effectiveness analysis of provider and community interventions to improve the treatment of uncomplicated malaria in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: There is mounting evidence of poor adherence by health service personnel to clinical guidelines for malaria following a symptomatic diagnosis. In response to this, the World Health Organization (WHO) recommends that in all settings clinical suspicion of malaria should be confirmed by parasitological diagnosis using microscopy or Rapid Diagnostic Test (RDT). The Government of Nigeria plans to introduce RDTs in public health facilities over the coming year. In this context, we will evaluate the effectiveness and cost-effectiveness of two interventions designed to support the roll-out of RDTs and improve the rational use of ACTs. It is feared that without supporting interventions, non-adherence will remain a serious impediment to implementing malaria treatment guidelines. METHODS/DESIGN: A three-arm stratified cluster randomized trial is used to compare the effectiveness and cost-effectiveness of: (1) provider malaria training intervention versus expected standard practice in malaria diagnosis and treatment; (2) provider malaria training intervention plus school-based intervention versus expected standard practice; and (3) the combined provider plus school-based intervention versus provider intervention alone. RDTs will be introduced in all arms of the trial. The primary outcome is the proportion of patients attending facilities that report a fever or suspected malaria and receive treatment according to malaria guidelines. This will be measured by surveying patients (or caregivers) as they exit primary health centers, pharmacies, and patent medicine dealers. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider and community knowledge. Costs will be estimated from both a societal and provider perspective using standard economic evaluation methodologies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01350752

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD