TCAs (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) undergo demethylation by CYP2C19 followed by hydroxylation by CYP2D6 (metabolites of the above medications with the addition of desipramine and nortriptyline).25 Polymorphisms in one or both genes may alter drug metabolism and therefore symptom response as well as dose-related adverse effects. Based on available data, the guidelines recommend a 50% dose reduction of amitriptyline and nortriptyline in persons who are CYP2D6 or CYP2C19 PMs.24 For CYP2D6 ultrarapid metabolizers (UMs), therapy with amitriptyline or nortriptyline should be avoided, or the initial target dose should be increased. For CYP2C19 UMs, alternative therapy should be considered, but the evidence supporting this recommendation was recognized as being not strong at this time. In situations when a patient is a CYP2D6 intermediate metabolizer (IM), the guidelines note that clinicians could reduce the initial dose by 25%, but 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
