Pharmacogenetics of Antipsychotics: Useful For the Clinician?

Abstract and Introduction

Abstract

Purpose of Review: The concept of individualized drug therapy on the basis of pharmacogenetics has become a central focus in psychopharmacology of schizophrenia. This article reviews recent advances in this field with respect to their importance for the clinician.
Recent Findings: First, there is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Secondly, prediction of response on the basis of variants in candidate genes is incipient and remains elusive. Thirdly, some advances have been made in understanding the pharmacogenetics of weight gain.
Summary: Despite much effort, only a few of the results are now ready for translation into clinical practice. Cytochrome P450 genotyping would be a big step forward towards a more individualized drug treatment based on molecular diagnostics and could improve treatment, reduce adverse effects and increase compliance of the patients. Another promising field may be that of predicting the antipsychotic-induced weight gain and it is hoped that commercially available DNA tests may be available within the next few years. Prediction of response is still hampered by many methodological and clinical problems and is not yet available to the clinician.

Introduction

There is substantial unexplained interindividual variability in treatment with antipsychotics, as a proportion of patients given a regular dose do not respond properly or experience limiting side effects. The nature of drug response is highly complex, involving genetic and nongenetic factors; the latter include age, gender, hepatic and renal status and, additionally, nutrition, smoking or alcohol intake. Within the last decade, the concept of individualized drug therapy on the basis of genetic investigations has become a major issue in psychopharmacology. After early results on an association between the serotonin-2A-receptor (5-HT2A) gene variants and the response to clozapine treatment,^[1,2] there was much enthusiasm about the identification of a genetic make-up for an optimally tailored drug treatment in schizophrenia.

Numerous association studies have since been carried out, with genes coding for either the pharmacokinetic (encompassing the processes that influence bioavailability) or pharmacodynamic (targets of drug action) pathways. Most pharmacodynamic studies concerned candidate genes that were proposed either by the aetiopathology of schizophrenia or by the putative pharmacological mechanisms of the drugs.^[3**] Despite some advances in various fields, however, the final goal of an optimally tailored therapy remains elusive. This review focuses primarily on recent studies and findings that are already relevant for the clinician, or that might become important in the near future.

Cite this: Pharmacogenetics of Antipsychotics: Useful For the Clinician? - Medscape - Jan 01, 2007.

Table 1. Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers
Enzyme	Substrate	Inhibitor	Inducer
CYP1A2	Clozapine, haloperidol olanzapine	Fluvoxamine, grapefruit juice, antibiotics	Carbamazepine, hyperforin, nicotine
CYP2C19	Diazepam, phenytoin	Fluoxetine, valproic acid, fluvoxamine	Carbamazepine, phenytoin
CYP2D6	Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol	Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics
CYP3A4	Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone	Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine	Carbamazepine, hyperforin, phenytoin

Table 1. Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers
Enzyme	Substrate	Inhibitor	Inducer
CYP1A2	Clozapine, haloperidol olanzapine	Fluvoxamine, grapefruit juice, antibiotics	Carbamazepine, hyperforin, nicotine
CYP2C19	Diazepam, phenytoin	Fluoxetine, valproic acid, fluvoxamine	Carbamazepine, phenytoin
CYP2D6	Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol	Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics
CYP3A4	Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone	Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine	Carbamazepine, hyperforin, phenytoin

Table 1. Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers
Enzyme	Substrate	Inhibitor	Inducer
CYP1A2	Clozapine, haloperidol olanzapine	Fluvoxamine, grapefruit juice, antibiotics	Carbamazepine, hyperforin, nicotine
CYP2C19	Diazepam, phenytoin	Fluoxetine, valproic acid, fluvoxamine	Carbamazepine, phenytoin
CYP2D6	Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol	Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics
CYP3A4	Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone	Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine	Carbamazepine, hyperforin, phenytoin

Table 1. Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers
Enzyme	Substrate	Inhibitor	Inducer
CYP1A2	Clozapine, haloperidol olanzapine	Fluvoxamine, grapefruit juice, antibiotics	Carbamazepine, hyperforin, nicotine
CYP2C19	Diazepam, phenytoin	Fluoxetine, valproic acid, fluvoxamine	Carbamazepine, phenytoin
CYP2D6	Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol	Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics
CYP3A4	Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone	Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine	Carbamazepine, hyperforin, phenytoin

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Pharmacogenetics of Antipsychotics: Useful For the Clinician?

Abstract and Introduction

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