Evaluation of risk factors for elevated tricyclic antidepressant plasma concentrations

Billups, Sarah J.; Delate, Thomas; Dugan, Daniel J.

doi:10.1002/pds.1697

Cited by 17 publications

(4 citation statements)

References 13 publications

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“…The evidence for the effects of CYP2D6 polymorphism on the PK of CNSactive CYP2D6 substrates is clearly given [14][15][16][17][18][19][20][21][24][25][26][27][28][29][30][31][32], and CYP2D6 genotyping can definitely help avoid serious adverse reactions. However, the ultimate proof for a clear link to the clinical outcome/endpoints is still lacking.…”

Section: Discussionmentioning

confidence: 99%

“…The risk is not limited to the direct use in children after tonsillectomy but also applies to breastfeeding mothers treated with codeine [15][16][17][18][19][20][21]. Other examples are tardive dyskinesia after metoclopramide in PMs [22,23]; cardiac and neurotoxic effects with tricyclic antidepressants in PMs [24][25][26], but also with some newer antidepressants such mirtazapine [27,28] in UMs and venlafaxine in PMs [29,30]; and the higher incidence of Parkinson-like symptoms in PMs treated with typical antipsychotics such as haloperidol [31]. While in the beginning, mostly CNS and cardiovascular drugs were in the focus [32], the efficacy of the antiestrogen tamoxifen has been shown to be linked to the CYP2D6 genotype [33].…”

Section: Introductionmentioning

confidence: 99%

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Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Haertter

2013

Drug Metabolism and Drug Interactions

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The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of >25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNS-active drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Haertter

2013

Drug Metabolism and Drug Interactions

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“…Also in the study of Billups et al [38] , concomitant SSRI intake could be determined as independent risk factor for elevated blood levels of TCAs. In this case-control study, female subjects (OR 1.78), patients on high doses of amitriptyline ( 1 150 mg/day, OR 4.08) and with concurrent intake of fluoxetine and paroxetine (OR 1.75) had the highest risk for toxic TCA concentrations in plasma.…”

Section: Cyp Enzyme Inhibition By Adsmentioning

confidence: 96%

Antidepressants: Clinically Relevant Drug Interactions to Be Considered

Schellander

Donnerer²

2010

Pharmacology

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Drug interactions in clinical practice are common and have developed into an increasing challenge for the medical profession. Specifically antidepressant drugs (ADs), which are among the 5 most frequently prescribed drugs, are predestined for adverse drug interactions because of their multiple mechanisms of action and/or their influence on drug-metabolizing cytochrome P450 (CYP) enzymes. Although selective serotonin reuptake inhibitors (SSRIs) and other new-generation ADs have an overall improved safety profile, their potential for drug interactions is to be considered. A review of the current literature has been performed, and selected examples of clinically relevant interactions with ADs have been chosen. With regard to pharmacodynamic interactions, the serotonin syndrome, the risk of bleeding under SSRI therapy, and the corrected Q–T interval prolongation are discussed in this review. The inhibitory effects of new-generation ADs on CYP enzymes show great variability and might be relevant for prescription recommendations in elderly patients and in patients with polypharmacy. The CYP-enzyme-inducing effect of St. John’s wort, a popular over-the-counter herbal drug, may lead to decreased plasma levels of CYP substrates. When comparing prescription data and observed adverse drug events, there is fortunately a safety gap between the number of potential drug-drug interactions and the number of clinically observed side effects due to drug-drug interactions.

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“…39 Female gender and higher drug doses increase the risk of side effects. 40 TCAs were shown to be comparable or more effective than SSRIs, but less well tolerated. 41 Their advantage may be efficacy in treatment-resistant depression.…”

Section: Tricyclic Antidepressantsmentioning

confidence: 99%

Getting the balance right: Established and emerging therapies for major depressive disorders

Perović

Jovanović²,

Miljković³

et al. 2010

NDT

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Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

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Evaluation of risk factors for elevated tricyclic antidepressant plasma concentrations

Abstract: Recognizing and monitoring predictors of elevated or toxic TCA Cps, including increasing TCA dose, female gender, and concurrent use of fluoxetine or paroxetine, may reduce serious adverse drug reactions and deaths in the TCA-receiving patient population.

Cited by 17 publications

References 13 publications

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Antidepressants: Clinically Relevant Drug Interactions to Be Considered

Getting the balance right: Established and emerging therapies for major depressive disorders

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