Imipramine

The label hypothesizes that imipramine works by blocking the uptake of norepinephrine at nerve endings, and notes that its effect on bedwetting seems separate from its antidepressant effect. One to three weeks of treatment may be needed before the full antidepressant effect appears [1].

For depression, outpatients usually start at 75 mg a day and go up to 150 mg, with maintenance doses of 50 to 150 mg and no more than 200 mg a day. Hospitalized patients can start at 100 mg and, if needed, go to 250 to 300 mg. Adolescents and older adults start at 30 to 40 mg a day and rarely need more than 100 mg. For bedwetting, children start at 25 mg an hour before bedtime, up to 50 mg under age 12 or 75 mg over 12; the label says higher doses do not work better and cause more side effects. An ECG is advised before larger-than-usual doses [1].

CPIC describes the tertiary-amine tricyclics, imipramine among them, as mainly demethylated by CYP2C19. For imipramine the product is desipramine, which is pharmacologically active with clinical features distinct from the parent drug. CYP2D6 then hydroxylates both into less active metabolites, and at higher concentrations this hydroxylation can saturate for imipramine and desipramine [2]. FDA lists imipramine among its examples of moderately sensitive CYP2D6 substrates [3].

The two genes act at different steps, as on the amitriptyline page, which explains CYP2D6 activity scores and CYP2C19 alleles. A slow CYP2C19 enzyme shifts the balance toward imipramine; a slow CYP2D6 enzyme slows the clearance of both imipramine and desipramine. For tricyclics in general, the label says CYP2D6 poor metabolizers have higher than expected levels, with rises as large as an 8-fold increase in total exposure (AUC) [1]. CPIC acknowledges that fewer data support genotype-based dose changes for imipramine than for amitriptyline or nortriptyline [2].

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 [5].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) considers it reasonable to extend its amitriptyline recommendations to imipramine, with fewer supporting data [2]. Both genes are CPIC level B for imipramine: 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]. The advice is written for the higher doses used in depression; CPIC does not address bedwetting doses, though it finds no evidence that its tricyclic guidance cannot be extended to children [2].

When both genes have a result, a Gene2Rx report shows one combined CPIC recommendation. The advice in each cell matches the amitriptyline table, but CPIC rates every imipramine 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. A CYP2D6 ultrarapid result requires extra copies of the gene, because every increased-function CYP2D6 allele is a gene duplication [9].

The FDA label gives no genotype-specific doses beyond the standard tricyclic CYP2D6 precautions, and FDA's Table of Pharmacogenetic Associations lists imipramine 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: 30% of the normal imipramine dose for CYP2D6 poor metabolizers, 70% for intermediate metabolizers, 1.7 times for ultrarapid metabolizers, and a 70% dose reduction for CYP2C19 poor metabolizers [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 imipramine because of a genetic result without talking to your prescriber.

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 [3]. The fluoxetine label reports that previously stable imipramine and desipramine levels rose more than 2- to 10-fold when fluoxetine was added, an effect that can last 3 weeks or more after fluoxetine is stopped [12]. The imipramine label adds that methylphenidate may slow imipramine's metabolism, so a lower dose may be needed [1].

Other factors

Older adults and people with heart disease are at special risk of the heart rhythm effects of imipramine, and the label calls for heart monitoring at all doses in people with cardiovascular disease [1]. Age, liver disease and reduced kidney function may also call for lower tricyclic doses whatever the genotype [2].

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 imipramine and desipramine show the actual exposure, whatever the cause.

My child takes imipramine for bedwetting. Does the result apply?

CPIC's tables are written for depression doses, and the bedwetting dose is lower (25 to 75 mg) [2][1]. CPIC notes that CYP2D6 activity is mature by early childhood and that CYP2C19 activity may be higher in children than in adults [2]. A poor metabolizer result is still worth raising with the prescriber.

How is imipramine related to desipramine?

Desipramine is the active compound CYP2C19 makes from imipramine; see the desipramine page for its CYP2D6-only interpretation.

1. Imipramine hydrochloride tablets (Lupin): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing and CYP2D6 precautions.
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. 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.
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. Prozac (fluoxetine) capsules (Dista Products Company): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing, CYP2D6 inhibition, contraindications and pharmacokinetics.