13 In addition to the genes listed in Table II, Horstmann and Binder also identified the following genes, for which there are only single, positive association reports: 5HT3A (serotonin receptor 3A, study N=100),26 SLC6A3 (dopamine transporter, study N=190),27 HSPA1A, HSPA1L (heat shock 70 kDa protein 1A and I
L, study N=142),28 p75 (p75 neutrophin receptor, study N=228),29 MAO-B (monoamine oxidade B, study N = 76),30 CRHR2 (corticotropin-releasing hormone 2, study N=159),31 GSK3B (glycogen synthase kinase-3 beta, study N=168),32 KCNK2 (TREK1) (potassium channel, subfamily K, member 2, study N=751),33 SERPINE1 (plasminogen activator inhibitor Inhibitors,research,lifescience,medical type 1, study N=140),34 ADRA2A (alpha 2 A-adr energic receptor, study N=93),35 CNR1 (cannabinoid receptor 1, study N=141),36 and PSMB4, TBX21, STAT3 (inflammation-related genes).37 In summary, in
the pharmacodynamic domain, variations in four genes have been shown in research studies totaling at least 1500 people each to be associated with antidepressant Inhibitors,research,lifescience,medical treatment response. They are the serotonin transporter gene promoter polymorphism (5-HTTLPR), FK506 binding protein 5 (FKBP5), glutamate receptor, ionotropic, kainate 4 (GRIK4), and serotonin receptor 2 A (HTR2A). However, as can be seen in Table II, there are enough conflicting results Inhibitors,research,lifescience,medical that make these findings not yet ready for universal acceptance. A key question that is emerging is the following: are we ready to Inhibitors,research,lifescience,medical translate existing findings to the clinic, or is further investigative work still required to clarify the role of these genes in antidepressant Vismodegib supplier response before translation can occur? Genetics of drug absorption and disposition: pharmacokinetics It makes intuitive and scientific sense for us to assume that the genetics underlying drug disposition (pharmaco kinetics) will contribute to biovailability at the site of the action, where pharmacodynamic Inhibitors,research,lifescience,medical effects occur. Two types of enzyme families are most important in this realm to affect antidepressant bioavailability: (i) the cytochrome P450 (CYP450) superfamily that regulates the degradation of antidepressants: and (ii) the superfamily of ATP binding
cassette (ABC) transporter enzymes that regulate entry of certain antidepressants from the bloodstream into brain parenchyma, across the blood-brain Thalidomide barrier (BBB). The major P-glycoprotein, a 170-KDa glycoprotein encoded by the ABCB1 (also known as MDR1 – multi drug resistance 1) gene, has a role in the pharmacogenomics of antidepressants through its effects on the entry of antidepressant substrates (such as the tricyclics, citalopram, venlafaxine, and paroxetine) into the brain3839; however the findings in this area have been contradictory40 In contrast, the data on the effects of CYP450 enzymes on the bioavailability of antidepressant drugs are very well established. The pharmacogenetic effects of CYP450 have been reviewed elsewhere.