Citalopram and CYP2C19

Citalopram (Celexa ®) is an antidepressant that belongs to a class of drugs called selective serotonin reuptake inhibitors (SSRIs). These drugs work by increasing levels of a neurotransmitter called serotonin in the brain, which is believed to be low in patients suffering from depression or anxiety. SSRIs do this by inactivating a certain “pump” located on the membranes of neurons. These pumps are responsible for moving serotonin from the space between neurons, back into the cell. By inhibiting these pumps, levels and consequently activity of serotonin in the brain is increased.

Citalopram (Celexa ®) is FDA approved for the treatment of depression. It is also used as an off-label treatment for alcoholism, obsessive-compulsive disorder, panic disorder, anxiety, and premenstrual dysphoric disorder.

The main gene of interest in citalopram metabolism, or elimination from the body, is the CYP2C19 gene. This gene has many different variants that lead to various levels of activity.

We can classify patients into four classes when it comes to their CYP2C19 gene. Ultra-rapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. 

In general, ultra-rapid metabolizers should be placed on a different medication. Extensive or intermediate metabolizers can use normal dosages, and poor metabolizers should either be given a reduced dosage or a different medication should be chosen that is not metabolized by the CYP2C19 enzyme. Selecting the right medication based on your genes will result in increased effectiveness as well as decreased side effects.

Cathy, a 60-year-old Asian female, was diagnosed with depression two months ago. She has been prescribed sertraline and has been compliant with her medication. Her physician notes that her symptoms have improved but the improvement could be better so he decides to switch her to citalopram 40mg. Her physician asks if she would like to get genotyping done before starting her new treatment but she refuses. Two weeks later during a busy work week, Cathy finds herself in the ER after fainting and falling down the stairs at work. In the ER, Cathy’s ECG shows that she has a marked QT prolongation. After ruling out all other causes and noting her recent change in medication, her citalopram was switched to another antidepressant and her side effects soon improved. A CYP2C19 genetic test was done and Cathy was found to be a slow metabolizer of citalopram.

A couple months later, a similar patient, 56-year-old Emily did opt to get CYP2C19 genetic testing done before starting her citalopram therapy. Emily was found to be a carrier of the CYP2C19 *2/*2 diplotype alleles, which meant Emily was a slow metabolizer and has an increased chance of adverse effects with a higher blood concentration of the drug. With this information in hand, Emily’s physician has two options: to reduce her initial dose of citalopram by 50%, with a maximum dose of 20mg/day or choose a medication that is not metabolized by the CYP2C19 pathway.

CYP2C19 genetic testing does not completely rule out the risks of acute toxicities related to citalopram, nor does it guarantee the medications will work. 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 citalopram. The links are to external websites and will be checked regularly for consistency.

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

Citalopram [package insert on the Internet]. Silver Spring (MD): US Food and Drug Administration; 2011 Aug 10 [cited 2017 Apr 15]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020822s038s040,021046s016s017lbl.pdf

Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Citalopram; [updated 2017 Feb 6; cited 2017 Apr 15]; [about 3 screens]. Available from: http://www.clinicalpharmacology-ip.com.lp.hscl.ufl.edu/Forms/drugoptions.aspx?cpnum=690&n=Citalopram&t=0

DRUGDEX ® [Internet]. Greenwood Village (CO): Thomson Reuters Inc.; c1974-2015 [cited 2015 Dec 2]. Available from: http://www.micromedexsolutions.com/micromedex2/librarian

Genelex [Internet]. Seattle (WA): Genelex Corporation; c1995-2014. CYP2C19 genotyping; [cited 2017 Apr 15]; [about 2 screens]. Available from: http://genelex.com/pharmacogenetic-tests/cyp2c19/

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. Clin Pharmacol Ther. 2015 Aug;98(2):127-34.

PharmGKB [Internet]. PharmGKB; c2001-2017. Citalopram; [updated 2017 Mar 15; cited 2017 Apr 15]; [about 3 screens]. Available from: https://www.pharmgkb.org/chemical/PA449015#tabview=tab0&subtab=31