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Letters to the Editor |
Institute for Clinical Chemistry, and Pathobiochemistry, Munich University of Technology, Klinikum rechts der Isar, Munich, Germany
aAddress correspondence to this author at: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, D-81675 Munich, Germany. Fax 49-89-4140-4875; e-mail W.Steimer{at}gmx.de.
To the Editor:
Amitriptyline belongs to the class of tricyclic antidepressants (TCAs), which have been a cornerstone of antidepressive therapy for more than 4 decades. Despite being replaced by newer drugs in the United States, TCAs, and amitriptyline in particular, are still widely used in Europe and many parts of the world, where prescriptions for TCAs far outnumber those for newer, more expensive drugs.
Recently, we reported significant correlations between sequence variations in the genes that encode the metabolizing enzymes cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19), serum amitriptyline/nortriptyline concentrations, and adverse drug reactions in a population of 50 depressed inpatients (1)(2).
However, genetic variations in drug-metabolizing enzymes do not sufficiently explain the wide interindividual variations commonly observed in drug response and clinical outcome. Obviously, other genetic and environmental factors must be considered as well. The influence of sequence variations in the gene ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1) on the disposition and efficacy of P-glycoprotein (P-gp) substrates (e.g., TCAs) is currently being discussed (3).
As part of the blood–brain barrier, P-gp actively exports significant amounts of antidepressant from the brain. Recent studies showed that penetration of amitriptyline and its metabolites (including nortriptyline) into the brain is enhanced in mice lacking P-gp (4)(5). Therefore, dysfunctional sequence variants of the ABCB1 gene might lead to diminished P-gp activity and higher bioavailability of P-gp substrates in the central nervous system. The nonsynonymous G2677T/A sequence variation (Ala893Ser/Thr) in ABCB1 can be used to differentiate between the 2 most common haplotypes found in Caucasians. We investigated whether this sequence variation contributes to therapeutic response or adverse effects. This study was performed in a population treated with amitriptyline, in whom we had previously found a highly significant correlation between sequence variations in the CYP2D6 and CYP2C19 genes and side effects (1)(2). The study included 50 Caucasian psychiatric inpatients in 2 centers, with at least medium-grade depressive disorder, who received amitriptyline at a fixed dose of 75 mg twice a day over 3 weeks.
Blood samples for monitoring concentrations of amitriptyline and nortriptyline were taken weekly, along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect [Dosage Record and Treatment Emergent Symptoms Scale (DOTES)] scores.
Genotyping was performed by fluorescence resonance energy transfer using specific probes and the LightCyclerTM system (Roche Molecular Biochemicals). We validated the procedure by checking the results with a published method for restriction-fragment-length polymorphism analysis (6) and found complete concordance. Patients were classified as wild-type homozygous (GG genotype), variant homozygous/combined heterozygous (TT or TA genotype), or heterozygous (GT or GA genotype). The genotype distribution was similar to that obtained with other Caucasian samples(3): 15 GG homozygotes (30%), 11 TT homozygotes (22%), 22 GT heterozygotes (44%), 1 GA heterozygote (2%), and 1 TA heterozygote (2%).
We used regression analysis and ANOVA, performed with SPSS 13.0 (SPSS), to test for significant differences among the different genotypes. We analyzed 3 ABCB1 genotype groups (homozygous, heterozygous, and variant) and 4 CYP risk groups as factor variables. CYP side effect risk groups had been previously defined based on nortriptyline concentrations and genotype-dependent increased adverse effects (1). Clinical response and side effects scores were examined as dependent variables. No significant effect of the P-gp polymorphism on therapeutic response (Hamilton Depression Scale and Clinical Global Impression Scale scores on day 21) could be identified (data not shown).
The ANOVA results regarding side effects obtained for the ABCB1 genotype and the CYP risk groups, as well as for the combined factor variables, are given in Table 1
. Beyond the known associations for the CYP risk groups, no significant additional effect of the P-gp polymorphism on the DOTES side effects total sum score on day 21 could be identified. Analysis of the 5 adverse events clusters of the DOTES score separately yielded the same result for 4 of the 5 clusters (Table 1
). We found a significant difference for anticholinergic/gastrointestinal symptoms (P = 0.026) that was nullified by post hoc testing for multiple comparisons.
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To summarize, in contrast to sequence variations in CYP2D6 and CYP2C19, the ABCB1 G2677T/A sequence variation did not significantly influence side effects in a group of depressed inpatients treated with amitriptyline, nor was it associated with therapeutic response. P-gp is involved in the disposition and uptake of several antidepressants into the brain, including amitriptyline and its primary metabolite, nortriptyline. However, these effects appear to be of minor clinical significance compared with CYP2D6 and CYP2C19 sequence variations that alter drug metabolism in vivo.
References
The following articles in journals at HighWire Press have cited this article:
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  M. J. Ehret Pharmacogenomics of Antidepressant Medications Journal of Pharmacy Practice, December 1, 2006; 19(6): 342 - 352. [Abstract] [PDF]
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