Doxepin, CYP2C19, and CYP2D6

Doxepin belongs to a category of medications known as tricyclic antidepressants (TCAs). All TCAs possess chemical structures that include three groupings of atoms arranged in rings. This is why these drugs are called tricyclic. Doxepin is primarily used to treat mild depression and anxiety disorders, as well as insomnia if administered at low doses. It is important to take this medication as prescribed even if effects are slow to occur. Research about this drug puts forth the consensus that anti-anxiety activity occurs during the first week of therapy while antidepressant activity may take two to four weeks to transpire.

The way in which doxepin treats depression and anxiety is not fully understood. It is speculated that doxepin (and other tricyclic antidepressants) elevates the levels of norepinephrine and serotonin through preventing their removal from brain tissue (i.e. reuptake). These two molecules are connected to symptoms of depression if their levels are low in the brain, so increasing their concentrations within the brain is thought to help treat the disorder.

Before a drug can reach its target, it is usually metabolized through the liver by proteins known as cytochromes. These cytochromes process the drug, eliminate it from the blood, and can change the amount that actually reaches the target organ. Each specific protein in the body is made based on genetic information contained within a specific gene, and the genes that produce cytochromes may change from person to person. This changes the rate at which each person may metabolize certain drugs and alters how a specific person may respond to a specific medication.

Specifically, the metabolism of doxepin involves two separate cytochrome systems that are encoded by two separate genes: CYP2C19 (pronounced sip-2-see-19) and CYP2D6 (pronounced sip-2-dee-6). The first gene produces a protein whose label is “cytochrome P450 2C19” while the second produces “cytochrome P450 2D6.” Each of these cytochromes alters the processing of doxepin, and changing the amount of either may alter how effectively a person may respond to this drug.

A given individual will possess certain forms of specific cytochrome-producing genes that result in altered production of the cytochrome protein. Based on these changes, any given person may be characterized as a poor metabolizer, intermediate metabolizer, extensive metabolizer, rapid metabolizer or an ultrarapid metabolizer.

The effect of CYP2D6 on doxepin metabolism possesses the greatest amount of scientific data. CYP2D6 poor metabolizers may have a reduced efficiency eliminating doxepin, and several studies have indicated that these metabolizers have abnormally high levels of the drug in their blood after taking a dose. In fact, one study reported a doxepin-induced death that occurred as a result of poor CYP2D6 metabolism. On the other hand, ultrarapid CYP2D6 metabolizers have demonstrated increased clearance of doxepin and therefore displayed low blood concentrations of the drug after ingestion. Therefore, dose adjustments may need to occur in response to the specific form of the CYP2D6 gene that an individual possesses. More studies are needed to further solidify these findings.

Much less data is available that describes the effect of CYP2C19 gene changes on doxepin processing. In fact, only one small study was performed surrounding the topic. The study observed that the rate at which the body processed doxepin changed by a factor of two between poor and extensive CYP2C19 metabolizers. However, a product of doxepin processing was still observed in CYP2C19 poor metabolizers. This fact demonstrates that other mechanisms process the drug, even if CYP2C19 activity is low. Consequently, more studies are needed to fully document the effects of CYP2C19 differences on doxepin processing.

Caleb is a 28 year-old male dental student that recently visited his physician after complaining about feeling sad, unmotivated, and feeling very tired most of the time. He states that he had started experiencing these symptoms about 2 months ago, and is unable to focus on studying and feels less inclined to go out or spend time with friends. The physician diagnoses the condition as depression, and recommends that Caleb start taking doxepin, a tertiary amine tricyclic antidepressant, starting at a low dose of 25 mg once a day. Before initiating treatment, the physician offers to perform a genetic test on Caleb to determine whether or not doxepin will be optimal treatment; Caleb declines testing. Clinical laboratories can perform genetic tests that can predict the functionality of the CYP2D6 and CYP2C19 enzymes, which doxepin is primarily metabolized by. If the patient is shown to be a poor metabolizer of these enzymes, the patient will have increased concentrations of the drug and as a result, will have an increased chance of adverse effects, such as dizziness, sedation, tachycardia, and hypotension.

About a month later, the same physician sees another patient, a 33 year-old female named Laura who is an attorney. She complains of feeling lonely and lacks motivation after her husband passed away unexpectedly. She is unable to focus on her work, and finds herself sleeping more and finding it difficult to wake up in the morning. The physician diagnoses Laura with depression, and before making a recommendation, offers to perform genetic testing in order to provide an optimal treatment option. Laura agrees to undergo testing, and it is shown that she is a poor metabolizer of the CYP2D6 enzyme. The physician concludes that doxepin would not be an appropriate treatment option, and decides to prescribe citalopram, a serotonin-selective reuptake inhibitor, 20 mg taken by mouth once a day. A year later, Laura has shown significant improvements, and the doctor begins to titrate the dose down to slowly take her off the medication.

CYP2D6 and CYP2C19 genetic testing does not completely rule out the risks of taking Doxepin, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

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

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

Clinical Pharmacology [Internet]. Tampa (Fl): Elsevier Gold Standard. 2015 [updated 2015 Aug 14; cited 2015 Dec 4]. Available from: http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=210&sec=mondesc&t=0.

Doxepin [package insert on the Internet]. Bethesda (MD): U.S. National Library of Medicine; [updated 2014 Oct 27; cited 2015 Dec 22]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1bec1223-5239-4eb6-a9e8-62444106d2c0.

Hicks J, Swen J, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium guidline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013 May;93(5):402-8.

Kirchheiner J, Meineke I, Müller G, Roots I, Brockmöller J. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002;12:571–80.

Medscape [Internet]. New York: WebMD LLC; c1994-2017. Doxepin [cited 2015 Dec 22]. Available from: http://reference.medscape.com/drug/silenor-doxepin-342940#0

Micromedex [Internet]. Greenwood Village (CO): Truven Health Analytics LLC; c2017 [cited 2015 Dec 22]. Available from: http://www.micromedexsolutions.com

M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. Pharmacogenomics Knowledge for Personalized Medicine. Clinical Pharmacology & Therapeutics [Internet]. 2012 [cited 2015 Dec 4];92(4):414-417. Available from: https://www.pharmgkb.org/pathway/PA165981686