the level of evidence supporting this recommendation is not as strong as that for PM status. It should be recognized that TCAs are categorized based on their chemical structure into two categories: secondary and tertiary amines. Differences in their chemical structure dictate affinity to neurotransmitters. Tertiary amines (e.g., amitriptyline) have more pronounced serotonergic activity whereas secondary amines (e.g., nortriptyline) have more pronounced noradrenergic activity.26 Chemical structure also influences which enzymes are preferentially involved in metabolism and influences the overall ratio of tertiary to secondary amine plasma concentration ratio, clearance, and adverse-effect profile. The guidelines note that recommendations available for amitriptyline and nortriptyline may be applied to other tricyclic antidepressants, using the rationale that TCAs as a class have very similar pharmacokinetic profiles, and amitriptyline and nortriptyline are model drugs for each of their respective amine categories.24 However, the relationships between pharmacogenomic markers and serum concentrations or treatment outcomes have not been extensively studied with the other tricylic agents.
