Dietary caffeine to assess CYP1A2 activity, tailor clozapine doses, and predict treatment response: genetic, epigenetic and clinical analyses
Year: 2025
Type: article
Study design: Observational Study
Abstract: Caffeine metabolic ratios (CMR) following monitored caffeine intake are the gold standard to probe cytochrome P450 (CYP) 1A2 activity, which metabolizes antipsychotics like clozapine and olanzapine. Given caffeine’s ubiquity, we tested whether random CMR from dietary caffeine were associated with (1) clinical, genetic, and epigenetic factors linked to CYP1A2 activity; (2) plasma concentrations of clozapine and olanzapine; and (3) psychotropic treatment response. First, we analyzed two population-based studies (CoLaus|PsyCoLaus, N = 4898; SKIPOGH, N = 2054) to investigate random CMR associations with clinical, genome-wide, and epigenome-wide factors associated with CYP1A2 activity. Second, in psychiatric cohorts, we tested CMR associations with dose-normalized plasma concentrations (C/D) of clozapine (N = 164) and olanzapine (N = 222) and with psychotropic treatment response, including hospital admission risk (N = 1019) and prolonged stays (N = 1349). CMR were positively associated with age, CYP1A2 inducers including smoking, and negatively with female sex. CMR were negatively associated with clozapine C/D, explaining up to 14.9% of the variance; over six-fold the variance explained by genetic factors. A one-unit increase in CMR was associated with a 26% increased likelihood of hospital admission (p = 0.002) and reduced short-stay chance by 11% (p < 10 −3 ). Random CMR provides a useful method to probe CYP1A2 activity, contributing, alongside other variables, to personalizing clozapine doses and identifying psychiatric patients at risk of hospital admission and lengthy stays. Incorporating routine measurement of random CMR before introduction of clozapine could be considered to allow early assessment of CYP1A2 activity, a key determinant of personalized clozapine dose titration.
Source: Molecular Psychiatry
Authors: Nermine Laaboub, Frederik Vandenberghe, Nicolas Ansermot, Marianna Piras, Setareh Ranjbar, Dusan Petrovic, Giorgio Pistis, Sophie Vandenberghe-Dürr, Marie-Pierre F. Strippoli, Pedro Marques-Vidal, Belen Ponte, Menno Pruijm, Bruno Vogt, Franziska Gamma, Armin von Gunten, Kerstin Jessica Plessen, Philippe Conus, Séverine Crettol, Peter Vollenweider, Martin Preisig, Murielle Bochud, Chin B. Eap
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Awards: Clinical and pharmacogenetic study on side effect induced by atypical antipsychotics, Metabolic syndrome in psychiatry: human microbiome transplantation in germ-free mice and brain imaging, telomeres, metabolomic and GWAS analysis in psychiatric patients, Cardiovascular diseases and psychiatric disorders in the general population: a prospective follow-up study, Pharmacogenetic study on side-effects induced by psychotropic drugs, Cardiovascular diseases and psychiatric disorders in the general population: a prospective follow-up study, G2335849392, Blood pressure and renal function genetics, G2601817178, Blood pressure and the kidney: interface between genes and environment, G2957143966, Family study of specific subthreshold and threshold mood, anxiety, substance use and schizophrenia spectrum syndromes in the general population, Psychiatric disorders in 35 to 65 year-old residents of the city of Lausanne and their association to cardiovasular risk factors: a population based survey, G4288653450, G4598500934, G5531419334, G5599442719, G5735209081, G6715704539, G6927407676, G7262634952, Cardiovascular diseases and psychiatric disorders in the general population: a prospective follow-up study, G7319365870, G7975901996, Metabolic syndrome in psychiatry: clinical, genetic and pharmacogenetic studies, G8253295407, G8499801373, G880118091
OpenAlex ID: W4414276540