68 In summary, the above clinical variables predict poor antidepressant outcomes in LLD. However, there is insufficient understanding of how they contribute to poorer outcomes, and so their clinical utility is limited. This lack of understanding is part of the gap between personalized medicine (matching treatment, to patients based upon patient characteristics) and the current trialand-error approach to LLD management. The relationship of genetic and drug exposure variability to TRLLD Functional genetic polymorphisms change the pharmacodynamics of antidepressant medications; therefore, Inhibitors,research,lifescience,medical it is posited that antidepressant outcomes in LLD can be predicted by genetic

variation in their homologous receptor targets.69 In other words, functional genetic variation of the 5-HTT is expected to affect. SSRI response, while variation in the norepinephrine transporter (NET) is expected to affect. SNRI response. One example is the serotonin transporter linked polymorphic region (5-HTTLPR) in the promoter Inhibitors,research,lifescience,medical of the gene that encodes for the serotonin transporter (5-HTF), the primary Inhibitors,research,lifescience,medical target of SSRIs. A deletion

polymorphism in 5-HTTLPR, the s allele (s=“short” vs l=“long”), appears to be functional: it reduces expression of 5-HTT so that individuals with the s allele have fewer 5-HTTs than those with 1/1 genotype. The association of the s allele with poorer SSRI outcomes has been demonstrated in LLD,70 including a study from

our group that, was the first to report this association in LLD.20 The association appears specific to SSRIs and was not found with mirtazapine71 or nortriptyline.70 In addition, Inhibitors,research,lifescience,medical we think that measures of drug exposure are needed to Inhibitors,research,lifescience,medical interpret clinical and genetic findings.72 Specifically, we think that, pharmacokinetic modeling is important in pharmacogenetic analyses. Supporting this contention, Lotrich et al73 found that the LY2835219 purchase 5-HTTLPR s allele predicted poorer treatment outcome at lower concentrations of paroxetine but not at. higher concentrations. Following up on this observation, Lotrich examined depressed elderly subjects who were treated in an openlabel paroxetine study and who were genotyped (n=110). Again, there was an interaction between paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5)=1.8; P<0.05): paroxetine concentrations were correlated with change in the Hamilton Sodium butyrate Depression Rating Scale (HAM-D) in subjects with the s allele, but not. in subjects homozygous for the 1 allele. In other words, the s allele moderated the impact of the drug. ‘ITtiesc data demonstrate the importance of pharmacokinetic data for conducting meaningful pharmacogenetic analyses. This issue is particularly relevant to geriatrics, as age-related changes in drug elimination amplify drug concentration differences for a given dose.