Pilot Study of the Cytochrome P450-2D6 Genotype in a Psychiatric State Hospital

León, José de; Barnhill, John W.; Rogers, Thea; Boyle, Jenni; Chou, Wen-Hwei; Wedlund, Peter J.

doi:10.1176/ajp.155.9.1278

Cited by 59 publications

(27 citation statements)

References 8 publications

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“…Our findings corroborate a recent report stating that psychiatric patients genotyped homozygous or heterozygous for CYP2C19 and CYP2D6 null alleles (CYP2C19*2, and CYP2D6*3, *4, *5 and *6) were hospitalized for a longer time during treatment with psychotropic medication, as compared with subjects without these alleles. 44 The allele frequencies and prevalence of 'abnormal' CYP2D6 genotypes (that is, without functional alleles or with an elevated number of functional alleles) that we found were in agreement with the figures previously reported for Western populations, 13,22,34,35,45,46 and depressed patients in specialized psychiatric hospitals, 47,48 respectively.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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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“…Activity of CYP enzymes is dependent on many factors such as inhibition or induction by other drugs and the allelic variants of a particular CYP enzyme expressed in an individual (Schmider et al 1999) The possibility of a link between CYP genotype and schizophrenia has been suggested by several investigators (Pirmohamed et al 1996;Dahl et al 1998;de Leon et al 1998;Jonsson et al 1998). All of them focused on CYP2D6 and the results were equivocal.…”

Section: Discussionmentioning

confidence: 99%

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

et al. 2000

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These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.

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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%

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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Pilot Study of the Cytochrome P450-2D6 Genotype in a Psychiatric State Hospital

Abstract: This study, limited by a small number of subjects, suggests that one-fifth of Caucasians admitted to a state hospital in Kentucky had genotypes associated with extremes in CYP2D6 activity that may have affected their response to CYP2D6 medications.

Cited by 59 publications

References 8 publications

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

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

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

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

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