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The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study

Published online by Cambridge University Press:  23 July 2013

Barbara Breitenstein ,
Sandra Scheuer ,
Hildegard Pfister ,
Manfred Uhr ,
Susanne Lucae ,
Florian Holsboer ,
Marcus Ising  and
Tanja M. Brückl
Barbara Breitenstein
Affiliation:
HolsboerMaschmeyer NeuroChemie, Munich, Germany Max Planck Institute of Psychiatry, Munich, Germany
Sandra Scheuer
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
Hildegard Pfister
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
Manfred Uhr
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
Susanne Lucae
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
Florian Holsboer
Affiliation:
HolsboerMaschmeyer NeuroChemie, Munich, Germany Max Planck Institute of Psychiatry, Munich, Germany
Marcus Ising
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
Tanja M. Brückl*
Affiliation:
Max Planck Institute of Psychiatry, Munich, Germany
*
*Address for correspondence: Dr. Tanja Brückl, Max Planck Institute of Psychiatry, Kraepelinstr. 10, 80804 München, Germany. (Email [email protected])
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Abstract

Background

The gene product of the ABCB1 gene, the P-glycoprotein, functions as a custodian molecule in the blood–brain barrier and regulates the access of most antidepressants into the brain. Previous studies showed that ABCB1 polymorphisms predicted the response to antidepressants that are substrates of the P-gp, while the response to nonsubstrates was not influenced by ABCB1 polymorphisms. The aim of the present study was to evaluate the clinical application of ABCB1 genotyping in antidepressant pharmacotherapy.

Methods

Data came from 58 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project, whose ABCB1 gene test results were implemented into the clinical decision making process. Hamilton Depression Rating Scale (HAM-D) scores, remission rates, and duration of hospital stay were documented with dose and kind of antidepressant treatment.

Results

Patients who received ABCB1 genotyping had higher remission rates [χ2(1) = 6.596, p = 0.005, 1-sided] and lower Hamilton sores [t(111) = 2.091, p = 0.0195, 1-sided] at the time of discharge from hospital as compared to patients without ABCB1 testing. Among major allele homozygotes for ABCB1 single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015 (TT/GG genotype), an increase in dose was associated with a shorter duration of hospital stay [rho(28) = –0.441, p = 0.009, 1-sided], whereas other treatment strategies (eg, switching to a nonsubstrate) showed no significant associations with better treatment outcome.

Discussion

The implementation of ABCB1 genotyping as a diagnostic tool influenced clinical decisions and led to an improvement of treatment outcome. Patients carrying the TT/GG genotype seemed to benefit from an increase in P-gp substrate dose.

Conclusion

Results suggest that antidepressant treatment of depression can be optimized by the clinical application of ABCB1 genotyping.

Keywords

ABCB1antidepressant treatment outcomemajor depressionP-glycoproteinpharmacogenetic testing
Type
Original Research
Information
CNS Spectrums , Volume 19 , Issue 2 , April 2014 , pp. 165 - 175
Copyright
Copyright © Cambridge University Press 2013 

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Footnotes

Regardless of the order of the authors’ listed names, B. Breitenstein and S. Scheuer are joint first authors.

We thank Gertrud Ernst-Jansen, Karin Hofer, Elisabeth Kappelmann, Beate Siegel, Melanie Huber, Maik Ködel, and Susann Sauer for excellent technical assistance. Parts of the study were supported by a grant of the German Federal Ministry of Education and Research (BMBF), project no. 01KG0709.

References

1. Rush, AJ, Trivedi, MH, Wisniewski, SR, etal. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11): 1905–1917.Google Scholar
2. Narasimhan, S, Lohoff, FW. Pharmacogenetics of antidepressant drugs: current clinical practice and future directions. Pharmacogenomics. 2012; 13(4): 441–464.Google Scholar
3. Horstmann, S, Binder, EB. Pharmacogenomics of antidepressant drugs. Pharmacol Ther. 2009; 124(1): 57–73.CrossRefGoogle ScholarPubMed
4. Uhr, M, Grauer, MT, Holsboer, F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry. 2003; 54(8): 840–846.Google Scholar
5. Fukui, N, Suzuki, Y, Sawamura, K, etal. Dose-dependent effects of the 3435 C>T genotype of ABCB1 gene on the steady-state plasma concentration of fluvoxamine in psychiatric patients. Ther Drug Monit. 2007; 29(2): 185–189.Google Scholar
6. Uhr, M, Tontsch, A, Namendorf, C, etal. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008; 57(2): 203–209.Google Scholar
7. Gex-Fabry, M, Eap, CB, Oneda, B, etal. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008; 30: 474–482.Google Scholar
8. Kato, M, Fukuda, T, Serretti, A, etal. ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(2): 398–404.Google Scholar
9. Nikisch, G, Eap, CB, Baumann, P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Pharmacol Res. 2008; 58(5–6): 344–347.Google Scholar
10. Sarginson, JE, Lazzeroni, LC, Ryan, HS, etal. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenet Genomics. 2010; 20(8): 467–475.Google Scholar
11. Lin, K-M, Chiu, Y-F, Tsai, I-J, etal. ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment. Pharmacogenet Genomics. 2010; 21(4): 163–170.Google Scholar
12. Perroud, N, Bondolfi, G, Uher, R, etal. Clinical and genetic correlates of suicidal ideation during antidepressant treatment in a depressed outpatient sample. Pharmacogenomics. 2011; 12(3): 365–377.Google Scholar
13. De Klerk, OL, Nolte, IM, Bet, PM, etal. ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder. Pharmacogenomics J. 2012; 1–5.Google Scholar
14. Singh, AB, Bousman, CA, Ng, CH, Byron, K, Berk, M. ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression. Transl Psychiatry. In press. DOI: 10.1038/tp.2012.115.Google Scholar
15. Laika, B, Leucht, S, Steimer, W. ABCB1 (P-glycoprotein/MDR1) gene G2677T/a sequence variation (polymorphism): lack of association with side effects and therapeutic response in depressed inpatients treated with amitriptyline. Clin Chem. 2006; 52(5): 893–895.Google Scholar
16. Peters, EJ, Slager, SL, Kraft, JB, etal. Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample. Baune B, ed. PLoS One. 2008; 3(4): e1872.Google Scholar
17. Mihaljevic Peles, A, Bozina, N, Sagud, M, Rojnic Kuzman, M, Lovric, M. MDR1 gene polymorphism: therapeutic response to paroxetine among patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(6): 1439–1444.Google Scholar
18. Dong, C, Wong, M-L, Licinio, J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry. 2009; 14(12): 1105–1118.Google Scholar
19. Menu, P, Gressier, F, Verstuyft, C, etal. Antidepressants and ABCB1 gene C3435T functional polymorphism: a naturalistic study. Neuropsychobiology. 2010; 62(3): 193–197.Google Scholar
20. Perlis, RH, Fijal, B, Dharia, S, Heinloth, AN, Houston, JP. Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biol Psychiatry. 2010; 67(11): 1110–1113.CrossRefGoogle ScholarPubMed
21. Uher, R, Perroud, N, Ng, MYM, etal. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry. 2010; 167(5): 555–564.Google Scholar
22. Holsboer, F. How can we realize the promise of personalized antidepressant medicines? Nat Rev Neurosci. 2008; 9(8): 638–646.Google Scholar
23. Hennings, JM, Owashi, T, Binder, EB, etal. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients—findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res. 2009; 43(3): 215–229.Google Scholar
24. Ising, M, Lucae, S, Binder, EB, etal. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009; 66(9): 966–975.Google Scholar
25. Wigginton, JE, Cutler, DJ, Abecasis, GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005; 76(5): 887–893.Google Scholar
26. Barrett, JC, Fry, B, Maller, J, Daly, MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21(2): 263–265.Google Scholar
27. Uhr, M, Steckler, T, Yassouridis, A, Holsboer, F. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology. 2000; 22(4): 380–387.CrossRefGoogle Scholar
28. Uhr, M, Grauer, MT, Yassouridis, A, Ebinger, M. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res. 2007; 41(1–2): 179–188.Google Scholar
29. Uhr, M, Grauer, MT. abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res. 2003; 37(3): 179–185.Google Scholar
30. Wang, J-S, Zhu, H-J, Gibson, B-B, etal. Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biol Pharm Bull. 2008; 31(2): 231–234.Google Scholar
31. Chiu, H-W, Li, T-C. Rapid weight gain during mirtazapine treatment. J Neuropsychiatry Clin Neurosci. 2011; 23: E7.Google Scholar
32. Roose, SP. Tolerability and patient compliance. J Clin Psychiatry. 1999; 60(suppl 17): 14–17; discussion 46–48.Google Scholar
33. Gury, C, Cousin, F. Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability. Encephale. 1999; 25(5): 470–476.Google Scholar
34. Jürgens, G, Jacobsen, CB, Rasmussen, HB, etal. Utility and adoption of CYP2D6 and CYP2C19 genotyping and its translation into psychiatric clinical practice. Acta Psychiatr Scand. 2012; 125(3): 228–237.Google Scholar
35. O'Brien, FE, Clarke, G, Fitzgerald, P, etal. Inhibition of P-glycoprotein enhances transport of imipramine across the blood-brain barrier: microdialysis studies in conscious freely moving rats. Br J Pharmacol. 2012; 166(4): 1333–1343.Google Scholar
36. Zhu, HJ, Wang, JS, Markowitz, JS, etal. Risperidone and paliperidone inhibit p-glycoprotein activity in vitro. Neuropsychopharmacology. 2007; 32(4): 757–764.Google Scholar
37. Feng, B, Mills, JB, Davidson, RE, etal. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos. 2008; 36(2): 268–275.Google Scholar
38. Colabufo, NA, Berardi, F, Cantore, M, etal. Perspectives of P-glycoprotein modulating agents in oncology and neurodegenerative diseases: pharmaceutical, biological, and diagnostic potentials. J Med Chem. 2010; 53(5): 1883–1897.Google Scholar
39. Mrazek, DA, Biernacka, JM, O'Kane, DJ, etal. CYP2C19 variation and citalopram response. Pharmacogenet Genomics. 2011; 21(1): 1–9.Google Scholar
40. Horstmann, S, Lucae, S, Menke, A, etal. Association of GRIK4 and HTR2A genes with antidepressant treatment in the MARS cohort of depressed inpatients. Eur Neuropsychopharmacol. 2008; 18(suppl 4): 214–215.Google Scholar
41. Lucae, S, Ising, M, Horstmann, S, etal. HTR2A gene variation is involved in antidepressant treatment response. Eur Neuropsychopharmacol. 2010; 20(1): 65–68.Google Scholar
42. Porcelli, S, Fabbri, C, Serretti, A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol. 2012; 22(4): 239–258.Google Scholar
43. Paddock, S, Laje, G, Charney, D, etal. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007; 164(8): 1181–1188.Google Scholar
44. Binder, EB, Salyakina, D, Lichtner, P, etal. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004; 36(12): 1319–1325.Google Scholar