Pharmacogenomics

The subject of pharmacogenomics has been of increasing interest to researchers and clinicians in all branches of contemporary medicine, including psychiatry. Inquiries into this field have been undertaken to gain a better understanding of the mechanisms by which variation between individuals occurs in clinical response to psychopharmacological treatment. Although pharmacogenetic principles are covered more thoroughly elsewhere in this text (see Chapter 3, "Genetics and Genomics"), here we will briefly focus on some of the recent work as applied to paroxetine. Specific attention will be paid to aspects of drug-gene interactions that affect tolerance and efficacy.

As previously described in this chapter, paroxetine's primary mode of action is likely mediated by its binding to the serotonin transporter (5-HTT). A well-known polymorphism (5-HT transporter gene-linked polymorphic region [5-HTTLPR]) has been located in the promoter region of the gene (SLC6A4) that encodes 5-HTT, resulting in two alleles referred to as "long" and "short." It has been proposed that this polymorphism might be a pharmacogenetic marker for antidepressant efficacy with some evidence that the short form, or S allele, results in reduced efficacy to SRI medications, including paroxetine (Zanardi et al. 2000). This finding was replicated in a study that included severity of drug-induced adverse events, dosing compliance indices, and discontinuations due to adverse events as main outcome measures in elderly depressed patients treated with paroxetine. The data revealed that subjects carrying the S allele experienced more severe adverse events, achieved lower final daily doses, and had more discontinuations during the course of the study. When, however, these subjects reached doses comparable with those of the homozygous L/L sample, efficacy measures were quite similar, albeit slower to exert maximal benefit, indicating that the main effect of the S allele was on the tolerability of paroxetine rather than its efficacy (G. M. Murphy et al. 2004). In the only known head-to-head comparison of paroxetine and another SRI, in regard to the 5-HTTLPR polymorphism, a sample of 81 depressed Japanese patients were treated with either paroxetine or fluvoxamine. The results showed that although both drugs had similar efficacy in L-carrying probands, S/S homozygotes responded significantly better to paroxetine (Kato et al. 2005).

Another intriguing locus that has been studied as a possible genetic marker for antidepressant efficacy is the 102 T/C single-nucleotide polymorphism (SNP) in the serotonin2A (5-HT2A) gene (5HTR2A). A second study, using the same patient sample and the same outcome measures as those of G. M. Murphy et al. (2004), was used to evaluate the role of the 102 T/C SNP in medication intolerance. Survival analysis showed a more or less linear relationship between the number of C alleles and the odds of patients discontinuing paroxetine therapy due to untoward effects (G. M. Murphy et al. 2003). Of note, when these investigators similarly studied the effect of genetic polymorphisms at the hepatic CYP2D6 gene, of which there are 40 known alleles, no signal could be detected with regard to tolerance or efficacy of paroxetine. The authors conclude that pharmacodynamic differences among patients, particularly at the 5HTR2A site, appear to have a greater impact on paroxetine tolerability than pharmacokinetic variables.

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