Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

OBJECTIVE: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. METHODS: A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. RESULTS: Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CONCLUSION: CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

The effect of bariatric surgery on psychiatric course among patients with bipolar disorder.

OBJECTIVE: Bariatric surgery is the most effective therapy for severe obesity. People with bipolar disorder have increased risk of obesity, yet are sometimes considered ineligible for bariatric surgery due to their bipolar disorder diagnosis. This study aimed to determine if bariatric surgery alters psychiatric course among stable patients with bipolar disorder. METHODS: A matched cohort study (2006-2009) with mean follow-up of 2.17 years was conducted within Kaiser Permanente Northern California, a group practice integrated health services delivery organization that provides medical and psychiatric care to 3.3 million people. Participants were 144 severely obese patients with bipolar disorder who underwent bariatric surgery, and 1,440 control patients with bipolar disorder, matched for gender, medical center, and contemporaneous health plan membership. Controls met referral criteria for bariatric surgery. Hazard ratio for psychiatric hospitalization, and change in rate of outpatient psychiatric utilization from baseline to Years 1 and 2, were compared between groups. RESULTS: A total of 13 bariatric surgery patients (9.0%) and 153 unexposed to surgery (10.6%) had psychiatric hospitalization during follow-up. In multivariate Cox models adjusting for potential confounding factors, the hazard ratio of psychiatric hospitalization associated with bariatric surgery was 1.03 [95% confidence interval (CI): 0.83-1.23]. In fully saturated multivariate general linear models, change in outpatient psychiatric utilization was not significantly different for surgery patients versus controls, from baseline to Year 1 (-0.4 visits/year, 95% CI: -0.5 to 0.4) or baseline to Year 2 (0.4 visits/year, 95% CI: -0.1 to 1.0). CONCLUSIONS: Bariatric surgery did not affect psychiatric course among stable patients with bipolar disorder. The results of this study suggest that patients with bipolar disorder who have been evaluated as stable can be considered for bariatric surgery.

Elevated prenatal homocysteine levels as a risk factor for schizophrenia.

CONTEXT: Elevated prenatal homocysteine level is a plausible risk factor for schizophrenia because of its partial antagonism of N-methyl-D-aspartate receptors under physiologic glycine concentrations and its association with abnormal placental function and pregnancy complications. OBJECTIVE: We examined whether elevated maternal levels of homocysteine during the third trimester were associated with adult schizophrenia risk. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1967 and followed up for schizophrenia from 1981 through 1997. SETTING: Population-based birth cohort and health plan. PARTICIPANTS: Cases (n = 63) were diagnosed with schizophrenia and other spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls (n = 122) belonged to the birth cohort; had not been diagnosed with a schizophrenia spectrum or major affective disorder; and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum samples. MAIN MEASURES: Archived maternal serum samples were assayed for homocysteine levels during pregnancies of cases and matched controls. RESULTS: In a model that tested for a threshold effect of third-trimester homocysteine levels, an elevated homocysteine level was associated with a greater than 2-fold statistically significant increase in schizophrenia risk (odds ratio, 2.39; 95% confidence interval, 1.18-4.81; P = .02). CONCLUSIONS: These findings indicate that elevated third-trimester homocysteine levels may be a risk factor for schizophrenia. Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus. If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring.