Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study.

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case-controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.

The Gut Microbiome in Depression and Potential Benefit of Prebiotics, Probiotics and Synbiotics: A Systematic Review of Clinical Trials and Observational Studies.

An emerging body of literature demonstrates differences in the gut microbiome (GMB) of patients with major depressive disorder (MDD) compared to healthy controls (HC), as well as the potential benefits of prebiotic, probiotic, and synbiotic treatment. We conducted a systematic review of 24 observational studies (n = 2817), and 19 interventional trials (n = 1119). We assessed alpha diversity, beta diversity, and taxa abundance changes in patients with MDD relative to HC, as well as the effect of prebiotics, probiotics, and synbiotics on depressive symptoms in individuals with clinical or subclinical depression. We observed no significant differences in alpha diversity but a significant difference in beta diversity between patients with MDD and HC. There were fluctuations in the abundance of specific taxa in patients with MDD relative to HC. Probiotic and synbiotic, but not prebiotic, treatment showed a modest benefit in reducing depressive symptoms in patients with MDD over four to nine weeks. The GMB profiles of patients with MDD differ significantly from HC, but further studies are needed to elucidate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and over longer follow-up before these therapies are implemented into clinical practice.

Reviewing pharmacogenetics to advance precision medicine for opioids.

BACKGROUND: Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed. OBJECTIVE: The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids. METHODS: For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing. RESULTS: Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited. CONCLUSION: There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.

The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment.

The gut microbiome (GMB) plays an important role in developmental processes and has been implicated in the etiology of psychiatric disorders. However, the relationship between GMB and schizophrenia remains unclear. In this article, we review the existing evidence surrounding the gut microbiome in schizophrenia and the potential for antipsychotics to cause adverse metabolic events by altering the gut microbiome. We also evaluate the current evidence for the clinical use of probiotic and prebiotic treatment in schizophrenia. The current data on microbiome alteration in schizophrenia remain conflicting. Longitudinal and larger studies will help elucidate the confounding effect on the microbiome. Current studies help lay the groundwork for further investigations into the role of the GMB in the development, presentation, progression and potential treatment of schizophrenia.

Pharmacogenetic/Pharmacogenomic Tests for Treatment Prediction in Depression.

Genetic factors play a significant but complex role in antidepressant (AD) response and tolerability. During recent years, there is growing enthusiasm in the promise of pharmacogenetic/pharmacogenomic (PGx) tools for optimizing and personalizing treatment outcomes for patients with major depressive disorder (MDD). The influence of pharmacokinetic and pharmacodynamic genes on response and tolerability has been investigated, including those encoding the cytochrome P450 superfamily, P-glycoprotein, monoaminergic transporters and receptors, intracellular signal transduction pathways, and the stress hormone system. Genome-wide association studies are also identifying new genetic variants associated with AD response phenotypes, which, combined with methods such as polygenic risk scores (PRS), is opening up new avenues for novel personalized treatment approaches for MDD. This chapter describes the basic concepts in PGx of AD response, reviews the major pharmacokinetic and pharmacodynamic genes involved in AD outcome, discusses PRS as a promising approach for predicting AD efficacy and tolerability, and addresses key challenges to the development and application of PGx tests.

Investigation of the Gut Microbiome in Patients with Schizophrenia and Clozapine-Induced Weight Gain: Protocol and Clinical Characteristics of First Patient Cohorts.

BACKGROUND: Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans. PURPOSE: Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics. METHODS: Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans.

BACKGROUND: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. METHODS: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. RESULTS: When examining Europeans (n = 147), we noticed an association between rs62097526 (ß = 0.39, p = 3.59 × 10-6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (ß = 0.411, p = 3.15 × 10-9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (ß = 0.271, p = 0.002) and African Americans (ß = 0.579, p = 5.73 × 10-5) with the same risk allele. Our top genes (p < 5 × 10-5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. CONCLUSIONS: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

Genetic validation study of protein tyrosine phosphatase receptor type D (PTPRD) gene variants and risk for antipsychotic-induced weight gain.

Schizophrenia is a severe, debilitating disorder with a lifetime prevalence of 1% irrespective of gender or ethnicity and is typically treated with antipsychotic drugs. Antipsychotic-induced weight gain (AIWG) is a leading factor of patient non-compliance and has previously been shown to increase the risk of type 2 diabetes, metabolic syndrome, and cardiovascular events. The current study intends to replicate findings from a recent genome-wide association study in Han-Chinese patients implicating two gene variants (rs10977144 and rs10977154) of the protein tyrosine phosphatase receptor type D (PTPRD) in antipsychotic-induced weight gain (AIWG). We investigated a sample of European and African American ancestry (n = 201) and calculated percentage of weight change using linear regression corrected for type of antipsychotics, duration of treatment and principal components from ancestry checks. As secondary goal, we investigated additional gene variants of PTPRD previously not associated with AIWG. We found no association with rs10977144 and rs10977154. However, we found nominally significant results between PTPRD and AIWG with rs73398242 in Europeans (BETA = - 0.267, p = 0.002) and rs13294608 in African Americans (BETA = 0.423, p = 0.003). According to Haploreg, both SNPs are histone marks for enhancers and promoters across various brain regions including the cingulate gyrus and dorsolateral prefrontal cortex. In summary, our results tentatively suggest that PTPRD might be associated with AIWG although different SNPS might be involved in different ethnic groups.

Clinical implications of APOE genotyping for late-onset Alzheimer's disease (LOAD) risk estimation: a review of the literature.

Alzheimer's disease is a genetically complex neurodegenerative disorder representing the leading cause of dementia. Advances in personal genomics are increasing the public uptake of genetic susceptibility testing for complex diseases such as late-onset Alzheimer's disease (LOAD). For LOAD, the discovery of the major risk ε4 allele of the APOE gene has prompted a debate on the ethics and utility of presymptomatic (i.e., predictive) testing. Although the mechanistic contribution of APOE to disease onset remains uncertain, presymptomatic genetic testing provides a relative risk of developing LOAD. Presymptomatic testing for complex disorders, such as LOAD is much less conclusive than early-onset Alzheimer's disease (EOAD) which follows a Mendelian inheritance pattern. Given the lack of preventive strategies available for EOAD or LOAD, APOE genotyping offers limited clinical utility, thus, raising ethical and practical questions. We conducted a systematic search of five electronic databases or primary studies published during January 2008-January 2018 which investigated practical and ethical issues of presymptomatic APOE genotyping for LOAD risk estimation. We identified 31 articles which suggested that APOE genotyping for LOAD susceptibility provides potential benefits to at-risk patients and can guide changes in positive health-related behaviors. However, other individuals may experience test-related anxiety, depression and psychological distress. Future research should focus on developing an integrated risk assessment tool to enhance the utility of APOE genotyping. Furthermore, empirical research is required to understand actual psychological and social implications associated with testing.

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment.

Background: Antipsychotic-induced weight gain (AIWG) and other adverse metabolic effects represent serious side effects faced by many patients with psychosis that can lead to numerous comorbidities and which reduce the lifespan. While the pathophysiology of AIWG remains poorly understood, numerous studies have reported a positive association between AIWG and the therapeutic benefit of antipsychotic medications. Objectives: To review the literature to (1) determine if AIWG is consistently associated with therapeutic benefit and (2) investigate which variables may mediate such an association. Data Sources: MEDLINE, Google Scholar, Cochrane Database and PsycINFO databases were searched for articles containing all the following exploded MESH terms: schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles. Results: Our literature search uncovered 31 independent studies which investigated an AIWG-therapeutic benefit association with a total of 6063 enrolled individuals diagnosed with schizophrenia or another serious mental illness receiving antipsychotic medications. Twenty-two studies found a positive association while, 10 studies found no association and one study reported a negative association. Study variables including medication compliance, sex, ethnicity, or prior antipsychotic exposure did not appear to consistently affect the AIWG-therapeutic benefit relationship. In contrast, there was some evidence that controlling for baseline BMI/psychopathology, duration of treatment and specific agent studied [i.e., olanzapine (OLZ) or clozapine (CLZ)] strengthened the relationship between AIWG and therapeutic benefit. Limitations: There were limitations of the reviewed studies in that many had small sample sizes, and/or were retrospective. The heterogeneity of the studies also made comparisons difficult and publication bias was not controlled for. Conclusions: An AIWG-therapeutic benefit association may exist and is most likely to be observed in OLZ and CLZ-treated patients. The clinical meaningfulness of this association remains unclear and weight gain and other metabolic comorbidities should be identified and treated to the same targets as the general population. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG.