Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.
Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970-2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.
Kirchheiner
J
J
Institute of Clinical Pharmacology, Campus Charité Mitte, University Medicine Berlin, Berlin, Germany. julia.kirchheiner@gmx.de
Nickchen
K
K
Bauer
M
M
Wong
M-L
ML
Licinio
J
J
Roots
I
I
Brockmöller
J
J
D000483:Alleles; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003580:Cytochromes / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D004843:Epistasis, Genetic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D017981:Receptors, Neurotransmitter / Q000235:genetics; D012701:Serotonin / Q000378:metabolism
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D002352:Carrier Proteins; D003580:Cytochromes; D017981:Receptors, Neurotransmitter; D012701:Serotonin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D004298:Dopamine; D009638:Norepinephrine