Tricyclic Antidepressant Plasma Levels after Fluoxetine Addition

Vandel, S; Bertschy, Gilles; Bonin, Bruno; Nezelof, Sylvie; François, T.; Vandel, B; Sechter, D.; Bizouard, P.

doi:10.1159/000118838

Cited by 56 publications

(19 citation statements)

References 12 publications

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“…The data are also in agreement with those of drug interaction studies between these antidepressants. A tenfold increase in tricyclic plasma concentrations was seen when fluoxetine was coadministered (Bergström et al, 1992;Vandel et al, 1992) showing that tricyclic antidepressants possess a lower CYP2D6 affinity than fluoxetine.…”

Section: Difference In the Antidepressant Effect On Phenotypes?mentioning

confidence: 99%

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Vandel

Haffen

Nezelof

et al. 2004

Human Psychopharmacology

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Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic polymorphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and serotonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dextromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipramine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients.

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Section: Difference In the Antidepressant Effect On Phenotypes?mentioning

confidence: 99%

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Vandel

Haffen

Nezelof

et al. 2004

Human Psychopharmacology

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“…In terms of drug interactions, plasma concentrations of imipramine are increased by fluoxetine, [34) cimetidine,f35) methylphenidate,f36) oral contracep- Desipramine, the secondary amine metabolite of imipramine, has been used as an antidepressant since the mid 1960s. Strongly noradrenergic, it has a somewhat delayed tmax compared with its parent compound, i.e.…”

Section: Imipraminementioning

confidence: 99%

Pharmacokinetic Optimisation of Therapy with Newer Antidepressants

Goodnick

1994

Clinical Pharmacokinetics

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Since the early 1950s, when imipramine was first introduced, a whole series of antidepressants with differences in structures, neurochemical effects and pharmacokinetics have been developed. Structurally or functionally, they have been classified as tricyclic antidepressants (TCAs), tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). In addition, there is a series of antidepressants with unique structures. Many of the newer TCAs appear to have shorter half-lives than the standard TCAs (e.g. imipramine), allowing for the possibility of a more rapid response, but requiring the drugs to be given in multiple daily doses, which may reduce patient compliance. The short time to peak plasma concentration (tmax) can also lead to rapid onset of adverse effects. The tetracyclic antidepressants have longer elimination half-lives (t1/2) than the TCAs, but there is only very minimal evidence for a relationship between drug concentrations in the blood and clinical response. The triazolopyridines, like the newer TCAs, show pharmacokinetic evidence for rapid onset of adverse effects and the need for multiple daily doses due to short tmax and t1/2. The newer MAOIs are a significant addition to therapy, as the rapid binding action of these medications increases their safety margin with regard to tyramine interactions. Further information in this area is required. In addition, moclobemide has pharmacokinetic features that are clinically beneficial (e.g. aging and renal dysfunction have little effect on the elimination of the drug), but also features that are not beneficial (e.g. nonlinear pharmacokinetics). Among the SSRIs, there are a range of t1/2 values for the parent drugs, from relatively short t1/2 values of less than 24 hours (paroxetine, fluvoxamine) to among the longest found (e.g. 2 days for fluoxetine). Only 2 of the agents (sertraline and citalopram) have linear pharmacokinetics, and 1 drug has nonlinear pharmacokinetics within the usual therapeutic range (fluvoxamine). Once a therapeutic blood concentration is established, linearity is helpful in avoiding the small dose changes and repeated rechecking of concentrations of medications that would be required for those agents with nonlinear pharmacokinetics. Sertraline stands out as having the best effects on behaviour among all antidepressants. However, fluoxetine and fluvoxamine are least likely to penetrate into breast milk. All 3 of the structurally unique newer antidepressants [amfebutamone (bupropion), viloxazine venlafaxine] have relatively short tmax values (1 to 2 hours), which may relate to the early onset of adverse effects. Amfebutamone has the benefits of linear pharmacokinetics with potential for defined therapeutic blood concentrations, lack of effect of liver enzymes on metabolism of the drug, and lack of significant effects of either aging or hepatic dysfunction on elimination of the drug. Thus, the antidepressants best suited for pharmacokinetic optimisation of ...

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“…The interaction between fluoxetine and tricyclic antidepressants has since been confirmed in numerous cases (reviewed in [32]). Desipramine and nortriptyline are eliminated by hydroxylation catalyzed by CYP2D6 [4], and this led to the suspicion that fluoxetine and/or norfluoxetine are potent inhibitors of this isozyme.…”

Section: Fluoxetinementioning

confidence: 94%

The pharmacogenetics of the selective serotonin reuptake inhibitors

Brøsen

1993

Clin Investig

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Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious interactions with drugs metabolized by this isozyme, notably tricyclic antidepressants, some neuroleptics, and some antiarrhythmics. Citalopram, fluvoxamine and sertraline do not share this property. Fluvoxamine is the only SSRI that is a potent inhibitor of cytochrome P4501A2 and hence causes serious pharmacokinetic interactions with amitriptyline, clomipramine, imipramine, theophylline, and presumably caffeine and other drugs which are metabolized by the isozyme. Citalopram and fluoxetine are administered as racemates, but practically nothing is known about the stereoselective metabolism of the two drugs. Citalopram is partially metabolized via the mephenytoin oxidation polymorphism, and paroxetine is partially metabolized via the sparteine/debrisoquine oxidation polymorphism. The pharmacogenetic differences in the oxidation of the SSRIs themselves are probably of no clinical relevance.

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Tricyclic Antidepressant Plasma Levels after Fluoxetine Addition

Cited by 56 publications

References 12 publications

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients

Pharmacokinetic Optimisation of Therapy with Newer Antidepressants

The pharmacogenetics of the selective serotonin reuptake inhibitors

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