Considering medication exposure in genomic association studies of cognition in psychotic disorders.

Cognitive dysfunction is a core feature of psychosis-spectrum illnesses, and the characterization of related genetic mechanisms may provide insights regarding the disease pathophysiology. Substantial efforts have been made to determine the genetic component of cognitive symptoms, without clear success. Illness-related moderators and environmental factors such as medications hinder the detection of genomic association with cognition. Polypharmacy is common in psychotic disorders, and the cumulative effects of medication regimens can confound gene-cognition associations. A review of the relative contributions of important pharmacological and genetic relationships identifies that the effects of medications on cognition in psychotic disorders may be at least, if not more, impactful than individual genes, thus underscoring the importance of accounting for medication exposure in gene-cognition association studies.

Association of CYP2B6 genetic polymorphisms with bupropion and hydroxybupropion exposure: A systematic review and meta-analysis.

INTRODUCTION: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified. OBJECTIVES: A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype-defined metabolizer phenotypes. METHODS: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotype-defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis. RESULTS: Eleven studies met the inclusion criteria for this systematic review, and 10 (including N = 413 participants) were included in the meta-analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared with the non-carriers (HB: RoM 0.77, 95% CI 0.71-0.83; active moiety: RoM 0.81, 95% CI 0.75-0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers. CONCLUSION: The CYP2B6*6 allele and genotype-determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6 genotype.

Methylation of FKBP5 and SLC6A4 in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder.

Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F (1, 19) = 7.492, p = 0.013] whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F (1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Decreases in FKBP5 methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.

Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials.

PURPOSE: This study aimed to investigate the neuroprotective effects of vitamin E for preventing chemotherapy-induced peripheral neuropathy (CIPN). METHODS: A comprehensive search from 1973 through July 2011 identified randomized controlled trials (RCTs) that reported the preventive effects of vitamin E on CIPN. The relative risk (RR) of CIPN with vitamin E supplementation, compared with placebo, was assessed with the Bayesian random effect model and expressed as RR with a 95 % credible-interval (CrI). Bayesian outcome probabilities were calculated as the probability (P) of RR < 1. RESULTS: Five RCTs, involving 319 patients, were identified. Upon pooling these RCTs, vitamin E supplementation (300 - 600 mg/day) had a significant effect on CIPN prevention (RR 0.43; 95 % CrI 0.10 - 1.00, P = 97.5 %). Subgroup analysis by chemotherapeutic agent type was only available for cisplatin and showed that vitamin E supplementation significantly reduced the incidence of CIPN (RR 0.26; 95 % CrI 0.06 - 0.89, P = 98.1 %). Furthermore, there were no adverse effects caused by vitamin E supplementation in any of the RCTs. CONCLUSION: Available data included in this meta-analysis show that vitamin E supplementation might significantly prevent CIPN. Currently, however, the data are insufficient to confidently conclude the true value. Large-scale, rigorously designed RCTs are needed to confirm the role of vitamin E supplementation in CIPN prevention.