Clomipramine

The label says clomipramine is presumed to act on obsessions and compulsions through its effects on serotonin, and that its ability to block serotonin reuptake is thought to be important, although the exact mechanism is unknown. Treatment starts at 25 mg a day and is raised to about 100 mg a day over the first 2 weeks, then gradually to a maximum of 250 mg a day for adults. Children and adolescents start at 25 mg, with a maximum of 3 mg/kg or 200 mg a day, whichever is smaller [1].

Clomipramine is extensively converted to desmethylclomipramine, an active metabolite whose levels exceed those of the parent drug with repeated dosing. The two have long half-lives (a mean of 32 hours for clomipramine and 69 hours for the metabolite after a 150 mg dose), and steady state takes 7 to 14 days. The pharmacokinetics are not proportional to dose, which suggests the metabolism can saturate; at doses near 200 to 250 mg a day both compounds may accumulate [1].

That matters because the label names seizures as the most significant risk of clomipramine. In premarketing trials at doses up to 300 mg a day, the cumulative seizure rate was 0.64% at 90 days and 1.45% at a year, and the label warns that accumulation may increase concentration-dependent side effects, seizures in particular [1].

The two genes act at different steps, as on the amitriptyline page, which explains CYP2D6 activity scores and the CYP2C19 alleles in detail. Slow CYP2C19 activity shifts the balance toward the parent drug; slow CYP2D6 activity slows the clearance of both the parent drug and its metabolite [2].

Direct evidence for clomipramine is limited. In a study of 678 hospitalized Dutch patients taking amitriptyline, citalopram or clomipramine, CYP2D6 genotype was associated with clomipramine metabolism, but no clear correlation was found between CYP2C19 genotype, including the increased-function *17 allele, and clomipramine metabolism [3]. CPIC acknowledges that fewer data support genotype-based dose changes for clomipramine than for amitriptyline or nortriptyline [2].

The results themselves are common. In CPIC's frequency tables, about 6.5% of people of European ancestry are CYP2D6 poor metabolizers and roughly 23% to 39% of most groups are CYP2D6 intermediate metabolizers [4]. CYP2C19 poor metabolizers are about 2.4% of people of European ancestry and 13% of people of East Asian ancestry, and about a third of people of European ancestry are rapid or ultrarapid metabolizers because they carry *17 [5].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) considers it reasonable to extend its amitriptyline recommendations to clomipramine because tricyclics have similar pharmacokinetics [2]. Both genes are CPIC level B for clomipramine: genetic information could be used to change prescribing, because alternative therapy or dosing is extremely likely to be as effective and safe as non-genetic dosing [6]. CPIC's advice is written for the higher doses used in conditions such as depression, and "starting dose" means the target steady-state dose [2].

When both genes have a result, a Gene2Rx report shows one combined recommendation from CPIC's table. The advice in each cell matches the amitriptyline table; the strengths differ, because CPIC rates every clomipramine recommendation optional except a normal result for both genes [2][7]. CYP2D6 groups follow the activity score: poor 0, intermediate 0.25 to 1, normal 1.25 to 2.25, ultrarapid above 2.25 [8].

If only one gene has a result, the single-gene advice matches the rows in which the other gene is normal.

The FDA label gives no genotype-specific doses. Its CYP2D6 precautions are the standard tricyclic text, and FDA's Table of Pharmacogenetic Associations lists clomipramine and CYP2D6 in its section for effects on drug levels only [1][10]. The Dutch Pharmacogenetics Working Group (DPWG) is more specific in its 2026 tricyclic guideline: 50% of the normal dose for CYP2D6 poor metabolizers treated for depression (or with side effects at the normal dose for other uses), 70% for intermediate metabolizers, 1.5 times for ultrarapid metabolizers, and an alternative drug for CYP2C19 ultrarapid metabolizers treated for anxiety or OCD [11]. Gene2Rx reports use the CPIC recommendations.

Bring the report to your prescriber or pharmacist with a list of everything you take. CPIC considers genotype-guided dosing most useful when a tricyclic is started [2]. Do not start, stop or change clomipramine because of a genetic result without talking to your prescriber; the label reports dizziness, nausea, headache and other withdrawal symptoms after abrupt discontinuation and recommends tapering [1].

Medicines that change the picture

Drugs that block these enzymes can make a person behave like a poor metabolizer, which is called phenoconversion. FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors, and fluconazole, fluoxetine, fluvoxamine and ticlopidine as strong CYP2C19 inhibitors [12]. The Anafranil label adds that haloperidol raises clomipramine levels, that enzyme inhibitors such as cimetidine and fluoxetine raise the levels of related tricyclics, and that clomipramine levels are lower in smokers [1].

Other factors

Age changes exposure on its own: in the label's studies, adults over 65 had higher steady-state levels than adults aged 18 to 40, and children under 15 had lower levels for a given dose than adults. Caution is advised for people with a history of seizures or other risk factors such as brain injury or alcoholism [1].

Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use. They read fixed positions and can miss rare variants. Array processing uses imputation to infer some variants that were not measured directly, but a variant at a position the data does not cover cannot be seen, so a normal result means none of the assessed variants was found among the positions your data covers. "Indeterminate" means the alleles found could not be assigned a function.

Blood levels of clomipramine and its metabolite show the actual exposure, whatever the cause.

Does CPIC's advice apply at the doses used for OCD?

CPIC's tables are written for higher doses rather than the low doses sometimes used for pain [2]. Clomipramine for OCD is usually raised to about 100 mg a day within two weeks and can go up to 250 mg a day [1].

Why is the evidence weaker than for amitriptyline?

Most tricyclic pharmacogenetic studies used amitriptyline or nortriptyline, and CPIC extends their results to clomipramine; see How CYP2C19 and CYP2D6 affect clomipramine.

1. Anafranil (clomipramine hydrochloride) capsules (SpecGx): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, pharmacokinetics, seizure risk and interactions.
2. Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther (2017). CPIC recommendations, tricyclic metabolism, dose scope and evidence summary.
3. de Vos A et al. Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J (2011). CYP2C19*17 and clomipramine metabolism.
4. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
5. CPIC. CYP2C19 frequency table (spreadsheet). Phenotype frequencies by biogeographic group.
6. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
7. CPIC guideline for CYP2D6, CYP2C19 and tricyclic antidepressants (ClinPGx guideline page). Current recommendation tables, including updates since publication.
8. Caudle KE et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci (2020). The CYP2D6 activity score ranges used since 2019.
9. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
10. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
11. Kleine Schaars K et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and CYP2C19 and tricyclic antidepressants. Eur J Hum Genet (2026). The Dutch tricyclic recommendations.
12. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.