Trimipramine

The label describes trimipramine as an antidepressant with an anxiety-reducing, sedative component and says its mode of action is not known. It is indicated for the relief of symptoms of depression [1].

Outpatients usually start at 75 mg a day in divided doses and go up to 150 mg, with maintenance doses of 50 to 150 mg and no more than 200 mg a day; the whole daily dose can be taken at bedtime. Hospitalized patients start at 100 mg and may go up to 250 to 300 mg. Adolescents and older adults start at 50 mg and go up to about 100 mg. The label warns that antidepressants take ten days to four weeks to work, and that raising the dose does not shorten that lag but does increase side effects [1].

Like other tertiary-amine tricyclics, trimipramine is demethylated by CYP2C19 and hydroxylated by CYP2D6 [3]. In volunteers, its demethylated metabolite stayed below the limit of measurement in most people lacking CYP2C19 or CYP2C9 activity, which suggests both CYP2C enzymes contribute to that step, while CYP2D6 handles the further breakdown [2].

Two studies from the same Berlin group give unusually direct numbers. In the first, 42 healthy volunteers took a single 75 mg dose. The median oral clearance of trimipramine was 276 L/h in the reference group but 36 L/h in CYP2D6 poor metabolizers, partly because at least three times more of each dose escaped first-pass metabolism in poor metabolizers, and their exposure to the demethylated metabolite was 40 times higher [2]. In the second, which included people with a duplicated CYP2D6 gene, bioavailability was 44%, 16% and 12% with zero, two and three working copies, and total oral clearance was 27.3, 151 and 253 L/h in poor, normal and ultrarapid metabolizers. The authors concluded that poor metabolizers face very high exposure and a risk of side effects, while carriers of duplications may not reach effective levels [4].

These are short studies in small groups of healthy volunteers, and CPIC notes that fewer data support genotype-based dose changes for trimipramine than for amitriptyline or nortriptyline [3]. The amitriptyline page explains CYP2D6 activity scores and CYP2C19 alleles. In CPIC's frequency tables, about 6.5% of people of European ancestry are CYP2D6 poor metabolizers [5], and CYP2C19 poor metabolizers are about 2.4% of people of European ancestry and 13% of people of East Asian ancestry [6].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) considers it reasonable to extend its amitriptyline recommendations to trimipramine, with fewer supporting data [3]. Both genes 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 advice is written for the higher doses used in depression, and "starting dose" means the target steady-state dose [3].

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 trimipramine recommendation optional except a normal result for both genes [3][8]. CYP2D6 groups follow the activity score: poor 0, intermediate 0.25 to 1, normal 1.25 to 2.25, ultrarapid above 2.25 [9].

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 [10].

The FDA label gives no genotype-specific doses beyond the standard tricyclic CYP2D6 precautions, and FDA's Table of Pharmacogenetic Associations lists trimipramine and CYP2D6 in its section for effects on drug levels only [1][11].

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 [3]. Do not start, stop or change trimipramine because of a genetic result without talking to your prescriber.

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 trimipramine label's precautions say that a person stable on a tricyclic "may become abruptly toxic" when a CYP2D6 inhibitor is added, that all SSRIs inhibit CYP2D6 to some degree, and that at least 5 weeks may be needed between stopping fluoxetine and starting a tricyclic [1]. Age, liver disease and reduced kidney function may also call for lower tricyclic doses [3].

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 show the actual exposure, whatever the cause.

Why is the CPIC advice only optional if the studies show such large differences?

The studies measured drug levels over a few days in healthy volunteers. CPIC's grades reflect how much evidence exists for each drug, and for trimipramine most of it is extrapolated from amitriptyline and nortriptyline; see What the guidelines recommend.

Are there tricyclics that avoid CYP2C19?

CPIC names nortriptyline and desipramine as tricyclics without major CYP2C19 metabolism [3]. Both still depend on CYP2D6.

1. Trimipramine capsules (Breckenridge): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing and CYP2D6 precautions.
2. Kirchheiner J et al. Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol (2003). Trimipramine clearance by genotype.
3. 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.
4. Kirchheiner J et al. Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity. Pharmacogenetics (2003). Trimipramine in poor, normal and ultrarapid metabolizers.
5. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
6. CPIC. CYP2C19 frequency table (spreadsheet). Phenotype frequencies by biogeographic group.
7. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
8. CPIC guideline for CYP2D6, CYP2C19 and tricyclic antidepressants (ClinPGx guideline page). Current recommendation tables, including updates since publication.
9. 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.
10. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
11. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
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.