Cyp2d6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants—a pilot study

Rau, Thomas; Wohlleben, Gerlinde; Wuttke, H; Thuerauf, Norbert; Lunkenheimer, Jens; Lanczik, M.; Eschenhagen, Thomas

doi:10.1016/j.clpt.2003.12.015

Cited by 180 publications

(110 citation statements)

References 30 publications

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“…It is, however, in line with previous findings. [6][7][8][9][18][19][20] Intermediate metabolizers treated with CYP2D6 medication suffered from somewhat more moderate/marked side effects than EMs (39 vs 22%, P ¼ 0.099; see Figure 2). When both groups were further subdivided into those receiving daily doses of CYP2D6 substrates above the population median and those below or equal, IMs treated with higher CYP2D6 doses displayed more side effects than EMs (9/13, 69% vs 4/23, 17%, P ¼ 0.003; see Figure 3).…”

Section: Cyp2d6 Gene Dose and Adverse Drug Effectsmentioning

confidence: 99%

“…The function of the CYP2D6 polymorphisms in drug interaction profiles, side effects and therapeutic outcome is well documented for UMs and PMs. [6][7][8][9][10] Genotyping before treatment has been postulated as a useful tool in preventing side effects and providing dose recommendations. 11,12 However, there are little data on the clinical impact of CYP2D6 polymorphisms on therapeutic drug treatment, response to therapy and side effects of IMs.…”

Section: Introductionmentioning

confidence: 99%

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Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

et al. 2009

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The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs. Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with abovemedian doses (9/13, 69% vs 4/23, 17%, P ¼ 0.003), than IMs with belowmedian doses (5/22, 23%, P ¼ 0.012) and IMs with other medication (24/84, 29%, P ¼ 0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P ¼ 0.017) probably due to increased side effects. Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping. This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.

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Section: Cyp2d6 Gene Dose and Adverse Drug Effectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

et al. 2009

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“…In a German study evaluating the effect of CYP2D6 genotype on treatment with CYP2D6-dependent antidepressants, PMs and UMs were significantly overrepresented as compared to the control population, respectively, in the group of patients suffering from adverse drug reactions (fourfold) and nonresponders (fivefold). 34 At the same time, Grasmader et al 35 did not find any influence of CYP2D6 and CYP2C19 genotype on antidepressant drug response, although the incidence of relevant side effects tended to be higher in PMs of CYP2D6. A high risk for cardiotoxic events and severe arrhythmia was reported in four patients treated with venlafaxine admitted to a cardiologic unit who all were CYP2D6 PMs.…”

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confidence: 96%

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

et al. 2007

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“…[11][12][13][14][15][16][17] Adverse drug effects are expected to occur more frequently in poor metabolizers, whereas the group of ultrarapid metabolizers may be prone to therapeutic failure. 6,[18][19][20] Until recently, genotyping tests did not allow an adequate prediction of the metabolic capacity of the large subgroups of patients with impaired yet residual CYP2D6 function (intermediate metabolizers; 5-15% of Caucasians). 13 Therefore, a clear-cut gene-dose effect could not be established so far.…”

Section: Introductionmentioning

confidence: 99%

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients

et al. 2007

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The inactivation and clearance of the tricyclic antidepressant imipramine is dependent on CYP2D6 activity. First, CYP2C19 converts imipramine into the active metabolite desipramine, which is then inactivated by CYP2D6. This retrospective single center study aimed to prove whether CYP2C19 and ample CYP2D6 genotyping (taking into consideration four null alleles and three decreased-activity alleles) could be used to predict imipramine and desipramine plasma concentrations in depressed patients, and whether genotype-based drug dose recommendations might assist in the early management of imipramine pharmacotherapy. In 181 subjects with major depressive disorder, drug doses were recorded, imipramine and desipramine plasma concentrations were monitored and CYP2C19 (*2) and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41 and gene duplication) were obtained, yielding graded allele-specific CYP2D6 patient groups. Desipramine and imipramine þ desipramine plasma concentration per drug dose unit, imipramine dose at steady state, and imipramine dose requirement significantly depended on CYP2D6 genotype (Kruskal-Wallis test, P < 0.0001). Mean (7s.d.) drug dose requirements were 131 (7109), 155 (770), 217 (795), 245 (7125), 326 (7213), and 509 (7292) mg imipramine/day in carriers of 0, 0.5, 1, 1.5, 2, and > 2 active CYP2D6 genes, respectively. Our protocol for CYP2D6 genotyping will thus importantly aid in the prediction of imipramine metabolism, allowing for the use of an adjusted starting dose and faster achievement of predefined imipramine þ desipramine plasma levels in all genetic patient subgroups. Therefore, therapeutic efficacy and efficiency may be improved, the number of adverse drug reactions decreased, and hospital stay reduced.

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Cyp2d6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants—a pilot study

Abstract: The results suggest that the CYP2D6 genotype is associated with the occurrence of adverse effects and clinical nonresponse in psychiatric patients treated with CYP2D6-dependent antidepressants.

Cited by 180 publications

References 30 publications

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients

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