Paroxetine and CYP2D6

Paroxetine (Paxil® and generic products) is used for patients with a wide array of mental disorders including depression, generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic attacks, posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD) among others. All of these disorders are caused by a chemical imbalance of serotonin and other neurotransmitters in the brain, which paroxetine aims to correct.

Paroxetine is classified as a selective serotonin reuptake inhibitor (SSRI). Like most SSRIs, paroxetine works by gradually increasing the amount of serotonin available for your brain to use. In theory, this gradual increase of serotonin along with counseling and lifestyle modification can resolve most symptoms of the disorder and allow the patient to lead a normal life.

The gene of interest is CYP2D6 (“pronounced sip-two- dee-six”), which is a sequence of DNA that results in the formation of a specific chemical that breaks down paroxetine. This gene helps to eliminate paroxetine from your body.

Each person will break down paroxetine at a different pace depending on their specific type of CYP2D6 gene. People that have CYP2D6 versions that work slowly (known as “poor metabolizers” or “intermediate metabolizers”) have very minor or no additional side effects from taking paroxetine. However, individuals with a hyperactive CYP2D6 gene (known as “ultra-rapid metabolizers”) will break down paroxetine quickly which may prevent the drug from working. People who are known as “ultra- rapid metabolizers” are recommended to talk to their doctor about changing medications.

Lena, a 51 year old African-American female, was diagnosed by her psychiatrist with depression brought on by menopause. Her doctor decided to prescribe her 20mg of paroxetine once daily because he felt that it would help her with her hot flashes as well. Lena informed her doctor that her sister was also prescribed this medicine three years ago and had to switch medications because “it just didn’t work.” Lena’s doctor explained to her that her sister could have a genetic mutation that causes her to rapidly metabolize the paroxetine. This would cause it to be inactivated before it could take effect. Her doctor took this into consideration and decided to order a blood test to see if Lena is a CYP2D6 ultra-rapid metabolizer as he suspected her sister was. Her doctor received her lab results 2 weeks later and found that Lena possessed an ultra-rapid metabolizer version of the CYP2D6 gene. Upon hearing this news, Lena’s doctor decided that it was inappropriate to prescribe her paroxetine and switched her medication to citalopram.

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

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

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

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2015. Paroxetine Hydrochloride; [cited 2015 Nov 23]; [about 3 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=087ff0d3-1761- 47ea-a8c1- 7c4cb679af97/.

Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology and Therapeutics. 2015;98(2):127-134.

Paxil (paroxetine hydrochloride) tablets and oral suspension [package insert]. Research Triangle Park (NC): GlaxoSmithKline; 2003 Aug.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2015. Paroxetine; [cited 2015 May 3]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA450801/.

Saruwatari J, Nakashima H, Tsuchimine S, Nishimura M, Ogusu N, Yasui-Furukori N. Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders. Pharmgenomics Pers Med. 2014 May 28;7:121-7.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics Knowledge for Personalized Medicine. Clinical Pharmacology and Therapeutics. 2012;92(4):414-417.