Depot Haloperidol Treatment in Outpatients With Schizophrenia on Monotherapy: Impact of CYP2D6 Polymorphism on Pharmacokinetics and Treatment Outcome

Abstract

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

“…The relationship between CYP2D6 and drug metabolism was examined in five studies 95,98,[101][102][103] and that between CYP3A5 and drug metabolism in one. 103 Different drugs were studied by each (clozapine, 103 aripiprazole, 101 perphenazine or zuclopenthixol, 102 haloperidol 95 and haloperidol injections 98 ), and no study undertook a comprehensive pharmacokinetic assessment, making it difficult to generalize these findings.…”

“…103 Different drugs were studied by each (clozapine, 103 aripiprazole, 101 perphenazine or zuclopenthixol, 102 haloperidol 95 and haloperidol injections 98 ), and no study undertook a comprehensive pharmacokinetic assessment, making it difficult to generalize these findings.…”

“…Ten studies were interested in the relationship between efficacy and CYP2D6 [90][91][92][93][95][96][97][98][99] or CYP1A2. 94 A wide variety of outcomes were considered across the studies but no two studies measured outcomes in exactly the same way.…”

A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms

“…First, the sample size (n ¼ 270), though limited, was higher than the mean sample size used in pharmacogenetic studies of acute AP-induced EPS (n ¼ 150). [7][8][9][10]32,33,[35][36][37][38][39][40][41][42][43][44][45] In fact, to our knowledge, only one study of Caucasians had a larger sample (n ¼ 665). 36 Second, although Bonferroni correction seems the most appropriate way to correct for multiple testing, it may be overly conservative.…”

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

“…At standard doses of those antipsychotics metabolized by the particular enzyme, poor metabolizers may experience toxic effects, ultra-rapid metabolizers may not respond and extensive metabolizers are usually well managed. Plasma levels of antipsychotic metabolites have been shown to be influenced by the genetically determined CYP metabolizer status [153,154]. Several studies have related poor metabolizer CYP variants with the apparition of side effects, including weight gain and movement disorders, during antipsychotic treatment.…”