Desipramine

The label describes the leading theory for tricyclics: they restore neurotransmitter levels by blocking reuptake in the brain. Secondary amines such as desipramine act more on norepinephrine reuptake, while tertiary amines such as amitriptyline act more on serotonin [1]. The label covers the treatment of depression and does not recommend desipramine for children.

The usual adult dose is 100 to 200 mg a day. In more severely ill patients it can be raised gradually to 300 mg a day, which should generally be started in hospital with frequent electrocardiograms (ECGs); doses above 300 mg are not recommended. Adolescents and older adults usually take 25 to 100 mg a day, with 150 mg as the upper limit. At very high doses, the label calls lengthening of the QRS or QT interval on the ECG the best available evidence of impending toxicity [1].

Desipramine is metabolized in the liver and about 70% is excreted in the urine. The ratio of its metabolite 2-hydroxydesipramine to desipramine may rise in older adults, most likely because the kidneys clear it more slowly [1]. CPIC notes that hydroxylation can become saturated at higher concentrations for some tricyclics, including desipramine, which means levels can rise more than expected as the dose goes up [2]. FDA lists desipramine among its examples of sensitive CYP2D6 substrates [3].

A CYP2D6 result is an activity score built from the two copies of the gene. A score of 0 means poor metabolizer, 0.25 to 1 intermediate, 1.25 to 2.25 normal and above 2.25 ultrarapid, which requires extra copies of the gene [4][5]. The amitriptyline page explains the scoring and the main alleles.

The Norpramin label says the rate at which tricyclics are metabolized "varies widely from individual to individual, chiefly on a genetically determined basis," with up to a 36-fold difference in desipramine levels at the same dose [1]. For tricyclics in general, it adds that CYP2D6 poor metabolizers have higher than expected levels, and the rise can be as large as an 8-fold increase in total exposure (AUC) [1]. CPIC expects more side effects in poor metabolizers and a higher chance of no benefit in ultrarapid metabolizers, whose levels stay low [2].

In CPIC's frequency tables, about 6.5% of people of European ancestry are poor metabolizers, compared with 2% to 3% in most other groups and under 1% of people of East Asian ancestry. Intermediate metabolizers make up roughly 23% to 39% of most groups [6].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) built its 2016 tricyclic guideline on studies of amitriptyline and nortriptyline. Because tricyclics have similar pharmacokinetics, it considers it reasonable to apply the same advice to desipramine, with the caveat that fewer data support dose changes for it [2]. Desipramine and CYP2D6 are CPIC level B: 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 [7]. The recommendations are written for the higher doses used in depression, and the "starting dose" means the target steady-state dose [2].

The FDA label gives no genotype-specific doses; its precautions explain the effect of CYP2D6 poor metabolism and of drugs that block the enzyme [1]. FDA's Table of Pharmacogenetic Associations lists desipramine and CYP2D6 in its section for effects on drug levels only [8].

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, before the dose has been adjusted to response, side effects or blood levels [2]. Do not start, stop or change desipramine because of a genetic result without talking to your prescriber.

Medicines that change the picture

Because desipramine depends so heavily on CYP2D6, drugs that block the enzyme matter as much as genes do. This is called phenoconversion. FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [3]. The fluoxetine label reports that previously stable levels of imipramine and desipramine rose more than 2- to 10-fold when fluoxetine was added, and that the effect can last 3 weeks or more after fluoxetine is stopped [9]. The Norpramin label adds that cimetidine, stimulants and phenothiazines can raise tricyclic levels, while barbiturates, alcohol and tobacco smoke can lower them [1].

Other factors

The label advises caution in people with heart disease, a family history of sudden death or heart rhythm problems, thyroid disease, seizures, glaucoma or urinary retention. Desipramine is substantially excreted by the kidney, so reduced kidney function can raise the risk of toxic reactions, and older adults may be more prone to falls and confusion [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 help less here than for nortriptyline: the label says an optimal therapeutic range for desipramine has not been established [1].

I take imipramine. Why does desipramine matter?

CYP2C19 converts imipramine into desipramine, and CYP2D6 clears both [2]. The imipramine page covers the two-gene interpretation.

Is desipramine an option if my CYP2C19 result is unusual?

CPIC names nortriptyline and desipramine as tricyclics without major CYP2C19 metabolism, so it suggests them when a tertiary-amine tricyclic is a poor fit for a CYP2C19 result [2]. Desipramine still depends on CYP2D6, so the table above applies.

1. Norpramin (desipramine hydrochloride) tablets (Validus): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, metabolism, CYP2D6 precautions and cardiac cautions.
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. 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.
5. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
6. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
7. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
8. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
9. Prozac (fluoxetine) capsules (Dista Products Company): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing, CYP2D6 inhibition, contraindications and pharmacokinetics.