Clomipramine, CYP2C19, and CYP2D6

Clomipramine (generic for Anafranil™) belongs to a class of drugs called tricyclic antidepressants (TCA). TCAs increase the levels of the neurotransmitters serotonin and norepinephrine in the brain. In individuals who are depressed, increased levels of serotonin and norepinephrine that occur after taking clomipramine can have a positive effect on mood. Clompiramine is a more potent TCA compared to others in the class such as nortriptyline and desipramine. This medication is typically used to treat obsessive-compulsive disorder (OCD) and disorders with an obsessive-compulsive component, such as depression, schizophrenia, or Tourette’s disorder. Important things to remember while taking this medication are to avoid alcohol, grapefruit, and grapefruit juice.

The CYP2C19 gene is a member of the cytochrome P450 gene family. The CYP2C19 enzyme is involved in the formation and breakdown of a variety of molecules and chemicals within cells. This ultimately affects the metabolism of a large number of drugs and drug classes including antidepressants, benzodiazepines, mephenytoin, proton pump inhibitors, and the antiplatelet drug clopidogrel. Variation in CYP2C19 is inherited and genetic testing is available to determine a specific individual’s metabolism of commonly prescribed drugs and how to choose the best treatment that will have the best outcomes.

Similarly to the CYP2C19 gene, the CYP2D6 gene is a member of the cytochrome P450 gene family. Genetic variation in CYP2D6 is thought to affect the metabolism of up to 25% commonly used drugs including antidepressants, antipsychotics, antiarrhythmics, opioid analgesics, and anticancer agents. Variation in CYP2D6 varies in different parts of the world: ultrarapid metabolizers are mainly concentrated in North Africa and Oceania, intermediate metabolizers are mainly concentrated in Asia, and poor metabolizers are mainly concentrated in Europe.

Clomipramine should be avoided in patients who are considered ultrarapid, rapid, or poor metabolizers of CYP2C19 because of the potential for suboptimal response. Ultrarapid or rapid metabolizers may achieve too low drug amounts in the body. Poor metabolizers, on the other hand, might end up having too much of the drug in the body. A different drug that is not metabolized by CYP2C19 should be considered for these individuals. Nortriptyline or desipramine are good alternatives because they do not undergo major metabolism by CYP2C19. If the decision is to continue treatment with clomipramine, the starting dose of poor metabolizers should be reduced by 50%. Patients who are normal metabolizers of CYP2C19 may begin treatment at the recommended starting dose. In all situations mentioned above, pharmacists should monitor therapeutic outcomes and adjust doses as necessary.

Clomipramine should be avoided in patients who are considered ultrarapid or poor metabolizers of CYP2D6 due to lack of efficacy. A different drug that is not metabolized by CYP2D6 should be considered for these individuals. If the decision is to continue treatment with clomipramine, the dose for ultrarapid metabolizers should be titrated to a higher target dose compared to normal metabolizers. The starting dose of poor metabolizers should be reduced by 50% due to increased likelihood of side effects. Intermediate metabolizers of CYP2D6 should have their starting dose reduced by 25% due to higher probability of side effects. Patients who are normal metabolizers of CYP2D6 may begin treatment at the recommended starting dose. In all situations mentioned above, pharmacists should monitor therapeutic outcomes and adjust doses as necessary.

40-year-old Caucasian male, Jonathan, has been prescribed clomipramine therapy for his depression and OCD. While visiting the clinic, his doctor mentioned pharmacogenomic testing to see if the patient may have a variation in CYP2C19 and/or CYP2D6 that might require a therapy adjustment. Jonathan denies the test, stating that he’s not in the mood to get tested and will take the medication “as is.” Jonathan comes back to the clinic appearing drowsy and a bit dizzy. He states he has been having major headaches for past week and is unable to sleep. His doctor decides to order genetic testing for CYP2D6 and CYP2C19. According to the test, Jonathan was found to be poor metabolizer of the drug. This could contribute to the side effects that Jonathan had been experiencing. As a result, his doctor reduces the clomipramine dose by 50%. No severe side effects were further observed while Jonathan is on this therapy.

Margaret, a 35 year old patient, has been having trouble managing her depression and OCD. She comes into the clinic asking for a prescription that will help with her conditions. The doctor prescribes her clomipramine and suggests that she have pharmacogenetic testing to ensure that this drug and specific dose will work for her. He states that there is evidence that if a patient is a CYP2D6 or CYP2C19 rapid or poor metabolizer, then she might have to change therapies. Margaret wants to ensure that clomipramine will work for her and goes forward with the testing. Testing showed that she is an intermediate metabolizer of the drug, with one decreased and one no function allele. As a result, her doctor reduces Clomipramine dose by 25%. Margaret has since improved and is satisfied with her therapy.

CYP2C19 and CYP2D6 genetic testing does not completely rule out the risks of taking clomipramine, 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 clomipramine. The links are to external websites and will be checked regularly for consistency.

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

Anafranil [package insert on the Internet]. Bethesda (MD): U.S. National Library of Medicine; [updated 25 May 2017; cited 2018 Jan 28]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4074b555-7635-41a9-809d-fae3b3610059.

Clinical Pharmacology [Internet]. Elsevier Inc. c2018. Clomipramine; [updated 17 Sept 2017; cited 2018 Jan 28]; [about 78 screens]. Available from: https://www-clinicalkey-com/pharmacology/monograph/137?sec=monindi.

Genetics Home Reference [Internet]. Bethesda (MD): U.S. National Library of Medicine; c2017. CYP2C19 gene; 2017 Jan 31 [cited 2017 Feb 1]; [about 3 screens]. Available from: https://ghr.nlm.nih.gov/gene/CYP2C19.

Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2016 Dec 20;102(1):37-44.

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information Inc. c.1978-2016. Clomipramine; [cited 2017 Feb 1]; [about 21 screens]. Available from: http://online.lexi.com /lco/action/doc/retrieve/docid/patch_f/6641.

Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clinical Pharmacology and Therapeutics. 2012;92(4):414-17.