Nortriptyline and CYP2D6

Nortriptyline (Aventyl®, others and generic products) is a drug used to treat the symptoms of depression. It belongs to a class known as tricyclic antidepressants (TCAs), whose mechanism of mood elevation is unknown. This medication has been found to work best at treating endogenous depressions as compared to other types.

The primary gene of interest is CYP2D6, which codes for the cytochrome P450 (CYP) enzyme 2D6 which is responsible for the metabolism for nortriptyline. Over or underexpression of the enzyme can therefore result in TCA efficacy and safety issues, respectively.

Most people with important changes in their CYP2D6 gene have one with reduced function or complete loss of function.

Between 7-21% of Caucasians carry alleles which cause them to be either an intermediate or poor metabolizer. These patients cannot break the drug down normally which leads to increased plasma concentrations of the active drug. Current guidelines for CYP2D6 poor metabolizers suggest avoiding the use of TCAs or considering a drug not metabolized by CYP2D6. However, if TCA use is warranted, the starting dose must be reduced to that of one half the normal starting dose.

A 30 year old Caucasian patient, Joseph, has been suffering from depression after being let go from his position at a law firm and has been unable to find work for two months now. He was going to be prescribed nortriptyline to treat his depression but was genotyped first by his psychiatrist. The results from the genetic test found that Joseph is a poor CYP2D6 metabolizer of nortriptyline, meaning if he was prescribed nortriptyline, the drug concentration in his body may rise to toxic levels and possibly causing an adverse event, thereby making treatment with nortriptyline unsafe.

Joseph is thus treated with a different agent that will increase his likelihood of being administered a successful first therapy treatment.

The links below provide access to important articles and information relative to nortriptyline. The links are to external websites and will be checked regularly for consistency.

• Nortriptyline Prescribing Information
• Nortriptyline Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Nortriptyline

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2014. Nortriptyline Hydrochloride; [cited 2014 Jul 25]; [about 5 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=aee2c1a1-d848- 4c3b-8c6d- 8a4f6ce94c28#nlm34089-3/.

Hicks JK, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clinical Pharmacology and Therapy. 2013 May;93(5):402-8.

Jornil J, Jensen KG, Larsen F, Linnet K. Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator. European Journal of Pharmaceutical Sciences. 2011 Oct;44(3):265-72.