Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis

Abstract

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation‐dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI95 = 1.041–12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI95 = 1.473–42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ‐related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders

“…Plasma concentrations of clozapine and its main metabolite (N-desmethylclozapine) were determined as previously described. 27 We then calculated the metabolic ratio as: metabolic ratio = [clozapine levels]/[N-desmethyl-clozapine].…”

Clozapine Induced Extrapyramidal Symptoms Following Alcohol Consumption in Patient With Schizophrenia and Alcohol Dependence Syndrome: A Case Report of Sialorrhea, Acute Akathisia and Dystonia

“…For the cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4, CLZ serves as a substrate. CLZ also exhibits drug-food interaction with alcohol leading to an increase in the risk of seizures and extrapyramidal symptoms [8,9].…”

Personalized treatments in neuropsychiatric disorders

“…Several articles focused on the genetics of response to an adverse reactions of medications used to treat psychiatric disorders (Maes et al, 2020; Ortega‐Vázquez et al, 2020; Rybakowski, 2020; Vorspan et al, 2021). One article investigated biological markers of response to noninvasive brain stimulation in Autistic patients (Robinson‐Agramonte et al, 2021), while two articles focused on neurodegenerative disorders, specifically on Parkinson's disease (Cacabelos et al, 2021) and multiple sclerosis (Sánchez et al, 2021).…”

“…Ortega‐Vázquez et al (2020) explored if different genotypes on cytochromes (CYP) genes codifying for enzymes involved in clozapine metabolism were responsible for modulating the risk of clozapine‐induced side effect determined by concomitant alcohol intake in schizophrenia patients with refractory psychosis. Interestingly, patients homozygotes for the CYP1A2 *1C allele showed adverse reactions with a risk that was doubled in case of concomitant alcohol consumption.…”