About 5% to 8% and 1% to 7% of the Caucasian population are considered as poor metabolizers (PMs) or ultrarapid metabolizers (UMs), respectively (Table I).22,43,44 In Caucasians, there is a lower proportion (3% -5%) of PMs of CYP 2C19, which is frequently involved in Ndemethylation of tertiary amines (amitriptyline and citalopram). CYP 3A4/5 shows wide interindividual Inhibitors,research,lifescience,medical variability in its OSI-906 in vitro activity. CYP 3A5 is expressed
in only one-third of the Caucasian population.45 As regards CYP 1A2, only its inducibility (eg, by tobacco smoke) is genetically polymorphic.46,47 Clinically, a PM status may represent a higher risk for adverse effects in patients treated with antidepressants known to be substrates of the deficient enzyme, while UMs undergo a higher risk for nonresponse, due to subtherapeutic plasma concentrations.39,48-53 The clinical relevance of the genetic polymorphisms of UDP-glucuronosyltransf Inhibitors,research,lifescience,medical erases in pharmacopsychiatry is not clear.30,54 Genotyping, which represents a “trait marker,” is readily available and clinically recommended for CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, and CYP 3A4/5; phenotyping,
used as a “state-marker,” may be performed for the same enzymes. The result Inhibitors,research,lifescience,medical of genotyping is not influenced by environmental factors and has life-long validity Phenotyping requires the administration of drugs and is therefore a more invasive procedure. Therefore, indications
for phenotyping and genotyping may differ. As mentioned in Table I, transport proteins such as P-glycoprotein in the Inhibitors,research,lifescience,medical intestinal mucosa and in the blood–brain barrier may be implicated in the regulation of the availability of antidepressants for the brain, but there is still a lack of clinical data.55-57 Relationships Inhibitors,research,lifescience,medical between drug doses, plasma concentrations, and clinical variables TDM is based on the hypothesis assumption that there is a well-defined relationship between the drug plasma concentration and its clinical effects (therapeutic effect, adverse effects, and toxicity). However, while such a relationship is generally well admitted for lithium and for the tricyclic antidepressants nortriptyline, amitriptyline, desipramine, and imipramine, inconsistent results were obtained in studies on other tricyclic or similarly structured antidepressants, either SSRls, and other recently introduced antidepressants.20,58-62 Interestingly, systematic reviews and meta-analyses14,59 that were based on adequately designed studies yielded evidence of a relationship between clinical variables and plasma concentration for some tricyclic drugs. This suggests that numerous studies were poorly designed methodologically in order to demonstrate an evident relationship between concentration and effects or side effects.