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Imipramine response

MedGen UID:
808063
Concept ID:
CN221257
Sign or Symptom
Synonym: Tofranil response
Drug:
Imipramine
MedGen UID:
43829
Concept ID:
C0020934
Pharmacologic Substance
A synthetic tricyclic derivative, antidepressant Imipramine enhances monoamine neurotransmission in certain areas of the brain. It also induces sedation through histamine 1 receptor blockage; hypotension through beta-adrenergic blockage; and diverse parasympatholytic effects. Imipramine has less sedative effect than other members of its therapeutic family. It is used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. (NCI04) [from NCI]
 
Genes (locations): CYP2C19 (10q23.33); CYP2D6 (22q13.2)

Definition

Imipramine is a tricyclic antidepressant used in the treatment of several psychiatric disorders including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment in the management of panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, a1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, also a tricyclic antidepressant. Further metabolism is catalyzed by CYP2D6. Individuals who are "CYP2D6 ultrarapid metabolizers" carry more than two normal function alleles (i.e., multiple copies), whereas individuals who are "CYP2C19 ultrarapid metabolizers" carry two increased function alleles. Individuals who are CYP2D6 or CYP2C19 "poor metabolizers" carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for imipramine states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. Their recommendations include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6. In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes. Amitriptyline and nortriptyline were used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, it may be reasonable to apply the recommendations to other tricyclics, including imipramine. For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., imipramine) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. [from Medical Genetics Summaries]

Professional guidelines

PubMed

Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P
Lancet Psychiatry 2020 Jul;7(7):581-601. doi: 10.1016/S2215-0366(20)30137-1. PMID: 32563306Free PMC Article
Hayasaka Y, Purgato M, Magni LR, Ogawa Y, Takeshima N, Cipriani A, Barbui C, Leucht S, Furukawa TA
J Affect Disord 2015 Jul 15;180:179-84. Epub 2015 Mar 31 doi: 10.1016/j.jad.2015.03.021. PMID: 25911132
Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH
Psychopharmacol Bull 1995;31(1):167-75. PMID: 7675981

Suggested Reading

PubMed

Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC
Clin Pharmacol Ther 2017 Jul;102(1):37-44. Epub 2017 Feb 13 doi: 10.1002/cpt.597. PMID: 27997040Free PMC Article

Recent clinical studies

Etiology

Ramsey TA, Strand S, Stern S, Mendels J
Neuropsychobiology 1981;7(2):94-8. doi: 10.1159/000117836. PMID: 7453954
Donnelly EF, Murphy DL, Waldman IN, Goodwin FK
Neuropsychobiology 1979;5(2):94-101. doi: 10.1159/000117669. PMID: 431801

Diagnosis

McGrath PJ, Stewart JW, Harrison WM, Ocepek-Welikson K, Rabkin JG, Nunes EN, Wager SG, Tricamo E, Quitkin FM, Klein DF
J Clin Psychopharmacol 1992 Jun;12(3):197-202. PMID: 1629387
Donnelly EF, Murphy DL, Waldman IN, Goodwin FK
Neuropsychobiology 1979;5(2):94-101. doi: 10.1159/000117669. PMID: 431801

Therapy

McGrath PJ, Stewart JW, Harrison WM, Ocepek-Welikson K, Rabkin JG, Nunes EN, Wager SG, Tricamo E, Quitkin FM, Klein DF
J Clin Psychopharmacol 1992 Jun;12(3):197-202. PMID: 1629387
Garvey M, DeRubeis RJ, Hollon SD, Evans MD, Tuason VB
J Affect Disord 1990 Nov;20(3):181-4. doi: 10.1016/0165-0327(90)90142-u. PMID: 2148338
Gibbons RD, Clark DC, Davis JM
Psychopharmacology (Berl) 1982;78(2):185-9. doi: 10.1007/BF00432260. PMID: 6817376
Ramsey TA, Strand S, Stern S, Mendels J
Neuropsychobiology 1981;7(2):94-8. doi: 10.1159/000117836. PMID: 7453954
Quitkin F, Rifkin A, Klein DF
Am J Psychiatry 1978 Jul;135(7):806-11. doi: 10.1176/ajp.135.7.806. PMID: 352160

Prognosis

McGrath PJ, Stewart JW, Harrison WM, Ocepek-Welikson K, Rabkin JG, Nunes EN, Wager SG, Tricamo E, Quitkin FM, Klein DF
J Clin Psychopharmacol 1992 Jun;12(3):197-202. PMID: 1629387
Garvey M, DeRubeis RJ, Hollon SD, Evans MD, Tuason VB
J Affect Disord 1990 Nov;20(3):181-4. doi: 10.1016/0165-0327(90)90142-u. PMID: 2148338
Ramsey TA, Strand S, Stern S, Mendels J
Neuropsychobiology 1981;7(2):94-8. doi: 10.1159/000117836. PMID: 7453954
Donnelly EF, Murphy DL, Waldman IN, Goodwin FK
Neuropsychobiology 1979;5(2):94-101. doi: 10.1159/000117669. PMID: 431801

Clinical prediction guides

McGrath PJ, Stewart JW, Harrison WM, Ocepek-Welikson K, Rabkin JG, Nunes EN, Wager SG, Tricamo E, Quitkin FM, Klein DF
J Clin Psychopharmacol 1992 Jun;12(3):197-202. PMID: 1629387
Gibbons RD, Clark DC, Davis JM
Psychopharmacology (Berl) 1982;78(2):185-9. doi: 10.1007/BF00432260. PMID: 6817376
Ramsey TA, Strand S, Stern S, Mendels J
Neuropsychobiology 1981;7(2):94-8. doi: 10.1159/000117836. PMID: 7453954
Donnelly EF, Murphy DL, Waldman IN, Goodwin FK
Neuropsychobiology 1979;5(2):94-101. doi: 10.1159/000117669. PMID: 431801
Quitkin F, Rifkin A, Klein DF
Am J Psychiatry 1978 Jul;135(7):806-11. doi: 10.1176/ajp.135.7.806. PMID: 352160

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted 1 information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2016 Statement from the US Food and Drug Administration (FDA): The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.

Please review the complete therapeutic recommendations that are located here: (1).

2016 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC):

Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to other TCAs including clomipramine, desipramine, doxepin, imipramine, and trimipramine, with the acknowledgement that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline. […]

CYP2D6 dosing recommendations.

[…]. The recommended starting dose of amitriptyline or nortriptyline does not need adjustment for those with genotypes predictive of CYP2D6 normal metabolism. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers. The strength of this recommendation is classified as “moderate” because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or normal metabolizers in the literature, making these studies difficult to evaluate.

CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations. However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended. Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations; therefore, alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended.

CYP2C19 dosing recommendations.

[…]. The usual starting dose of amitriptyline may be used in CYP2C19 normal and intermediate metabolizers. Although CYP2C19 intermediate metabolizers would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 intermediate metabolizers should receive an alternate dose.

Patients taking amitriptyline who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations and an imbalance between parent drug and metabolites causing treatment failure and/or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events. For patients taking amitriptyline, extrapolated pharmacokinetic data suggest that CYP2C19 rapid or ultrarapid metabolizers may need a dose increase. Due to the need for further studies investigating the clinical importance of CYP2C19*17 regarding tricyclic metabolism and the possibility of altered concentrations, we recommend to consider an alternative tricyclic or other drug not affected by CYP2C19. This recommendation is classified as optional due to limited available data. If amitriptyline is administered to a CYP2C19 rapid or ultrarapid metabolizer, therapeutic drug monitoring is recommended.

CYP2C19 poor metabolizers are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations. The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Use an alternative agent not metabolized by CYP2C19 (e.g., nortriptyline and desipramine) or consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.

Please review the complete therapeutic recommendations that are located here: (2).

2011 Summary of recommendations from the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP):

For CYP2D6 poor metabolizers, defined as patients carrying two inactive alleles, reduce the dose of imipramine by 70% and monitor imipramine and desipramine plasma concentrations.

For CYP2D6 intermediate metabolizers, defined as patients carrying two decreased-activity alleles or one active/ decreased-activity allele and one inactive allele, reduce the dose of imipramine by 30% and monitor imipramine and desipramine plasma concentrations.

For CYP2D6 ultrarapid metabolizers, defined as patients carrying a gene duplication in the absence of inactive or decreased-activity alleles, select an alternative drug (e.g., citalopram, sertraline) or increase dose by 70% and monitor imipramine and desipramine plasma concentration (Table 5).

For CYP2C19 poor metabolizers, reduce the dose of imipramine by 30% and monitor plasma concentration of imipramine and desipramine or select an alternative drug (e.g., fluvoxamine, mirtazapine).

For CYP2C19 intermediate metabolizers, there is insufficient data to allow calculation of dose adjustment for imipramine, select an alternative drug (e.g., fluvoxamine, mirtazapine)

There are no data for dose recommendations for CYP2C19 ultrarapid metabolizers (Table 6).

Please review the complete therapeutic recommendations that are located here: (30, 31).

Table 5. CYP2D6 phenotypes and the therapeutic recommendations for imipramine therapy, from The Dutch Pharmacogenetics Working Group (2011)
The level of evidence for the therapeutic (dose) recommendations is 4/4 (“good quality”) for all metabolizer types. There are no data for ultrarapid metabolizers. The Table is adapted from Swen J.J., Nijenhuis M., de Boer A., Grandia L. et al. Pharmacogenetics: from bench to byte - an update of guidelines. Clinical pharmacology and therapeutics. 2011;89(5):662–73 (30).
PhenotypeRecommendations for imipramine therapy
Ultrarapid metabolizerSelect alternative drug (e.g., citalopram, sertraline) or increase dose by 70% and monitor imipramine and desipramine plasma concentration
Intermediate metabolizerReduce dose by 30% and monitor imipramine and desipramine plasma concentrations
Poor metabolizerReduce dose by 70% and monitor imipramine and desipramine plasma concentrations
Table 6. CYP2C19 phenotypes and the therapeutic recommendations for imipramine therapy, from The Dutch Pharmacogenetics Working Group (2011)
The level of evidence for the therapeutic (dose) recommendations is 4/4 (“good quality”) for all metabolizer types. The table is adapted from (31)
PhenotypeRecommendations for imipramine therapy
Ultrarapid metabolizerNo dose recommendations
Intermediate metabolizerNo dose recommendations
Poor metabolizerReduce dose by 70% and monitor plasma concentration of imipramine and desipramine or select alternative drug (e.g., fluvoxamine, mirtazapine)

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.

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