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A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C)

  • Charlotte Brasch-Andersen
  • Malik U. Møller
  • Lene Christiansen
  • Mikael Thinggaard
  • Marit Otto
  • Kim Brøsen
  • Søren H. Sindrup
Pharmacogenetics

Abstract

Purpose

Previous studies have shown that a small fraction of patients with peripheral neuropathic pain experiences >50% pain relief during treatment with selective serotonin reuptake inhibitors (SSRIs), whereas most patients have no or only slight relief. The aim of this study was to investigate the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain.

Methods

We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin receptor 2A (HTR2A) gene, the serotonin receptor 2C (HTR2C) gene, the ABCB1 gene encoding for the P-glycoprotein, the CYP2C19 gene, and the serotonin transporter gene (SLC6A4).

Results

The SNP rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men (p = 0.047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram.

Conclusion

This study indicates that variation in the HTR2C gene is associated to the pain-relieving effect of escitalopram in patients with painful polyneuropathy.

Keywords

Pharmacogenetics Neuropathic pain SSRI treatment Treatment response 

Notes

Acknowledgement

The authors thank research nurses M. Sørensen and R. Mitzi Henriksen for collecting blood samples, and lab technician P. Jordan for skillful technical work. We declare no conflict of interest.

References

  1. 1.
    Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581PubMedCrossRefGoogle Scholar
  2. 2.
    Sindrup SH, Otto M, Finnerup NB, Jensen TS (2005) Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 96:399–409PubMedCrossRefGoogle Scholar
  3. 3.
    Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF (1990) The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42:135–144PubMedCrossRefGoogle Scholar
  4. 4.
    Sindrup SH, Bjerre U, Dejgaard A, Brosen K, Aaes-Jorgensen T, Gram LF (1992) The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther 52:547–552PubMedCrossRefGoogle Scholar
  5. 5.
    Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R (1992) Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250–1256PubMedCrossRefGoogle Scholar
  6. 6.
    Otto M, Bach FW, Jensen TS, Brosen K, Sindrup SH (2008) Escitalopram in painful polyneuropathy: a randomized, placebo-controlled, cross-over trial. Pain 139:275–283PubMedCrossRefGoogle Scholar
  7. 7.
    Suzuki R, Rygh LJ, Dickenson AH (2004) Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 25:613–617PubMedCrossRefGoogle Scholar
  8. 8.
    Lopez-Garcia JA (2006) Serotonergic modulation of spinal sensory circuits. Curr Top Med Chem 6:1987–1996PubMedCrossRefGoogle Scholar
  9. 9.
    Christiansen L, Tan Q, Iachina M, Bathum L, Kruse TA, McGue M et al (2007) Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population. Biol Psychiatry 61:223–230PubMedCrossRefGoogle Scholar
  10. 10.
    Rodriguez S, Gaunt TR, Day IN (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169:505–514PubMedCrossRefGoogle Scholar
  11. 11.
    Tan GM, Wu E, Lam YY, Yan BP (2010) Role of warfarin pharmacogenetic testing in clinical practice. Pharmacogenomics 11:439–448PubMedCrossRefGoogle Scholar
  12. 12.
    Hughes AR, Brothers CH, Mosteller M, Spreen WR, Burns DK (2009) Genetic association studies to detect adverse drug reactions: abacavir hypersensitivity as an example. Pharmacogenomics 10:225–233PubMedCrossRefGoogle Scholar
  13. 13.
    Hirschhorn JN, Lettre G (2009) Progress in genome-wide association studies of human height. Horm Res 71(Suppl 2):5–13PubMedCrossRefGoogle Scholar
  14. 14.
    Drago A, De RD, Serretti A (2009) Pharmacogenetics of antidepressant response: an update. Hum Genomics 3:257–274PubMedGoogle Scholar
  15. 15.
    Kato M, Zanardi R, Rossini D, De RD, Okugawa G, Kinoshita T et al (2009) 5-HT2A gene variants influence specific and different aspects of antidepressant response in Japanese and Italian mood disorder patients. Psychiatry Res 167:97–105PubMedCrossRefGoogle Scholar
  16. 16.
    Okada M, Northup JK, Ozaki N, Russell JT, Linnoila M, Goldman D (2004) Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution. Mol Psychiatry 9:55–64PubMedCrossRefGoogle Scholar
  17. 17.
    Fentress HM, Grinde E, Mazurkiewicz JE, Backstrom JR, Herrick-Davis K, Sanders-Bush E (2005) Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms. Pharmacogenomics J 5:244–254PubMedCrossRefGoogle Scholar
  18. 18.
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  19. 19.
    Eichhammer P, Langguth B, Wiegand R, Kharraz A, Frick U, Hajak G (2003) Allelic variation in the serotonin transporter promoter affects neuromodulatory effects of a selective serotonin transporter reuptake inhibitor (SSRI). Psychopharmacol (Berl) 166:294–297Google Scholar
  20. 20.
    Potvin S, Larouche A, Normand E, de Souza JB, Gaumond I, Marchand S et al (2010) No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls. Eur J Pain 14:742–746PubMedCrossRefGoogle Scholar
  21. 21.
    Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199PubMedCrossRefGoogle Scholar
  22. 22.
    Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33PubMedCrossRefGoogle Scholar
  23. 23.
    Kato M, Fukuda T, Serretti A, Wakeno M, Okugawa G, Ikenaga Y et al (2008) ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 32:398–404PubMedCrossRefGoogle Scholar
  24. 24.
    Noehr-Jensen L, Zwisler ST, Larsen F, Sindrup SH, Damkier P, Nielsen F et al (2009) Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker. Eur J Clin Pharmacol 65:887–894PubMedCrossRefGoogle Scholar
  25. 25.
    Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L et al (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Charlotte Brasch-Andersen
    • 1
    • 2
  • Malik U. Møller
    • 1
  • Lene Christiansen
    • 2
    • 3
  • Mikael Thinggaard
    • 3
  • Marit Otto
    • 4
    • 5
  • Kim Brøsen
    • 1
    • 6
  • Søren H. Sindrup
    • 4
  1. 1.Department of Clinical Biochemistry & PharmacologyOdense University HospitalOdenseDenmark
  2. 2.Department of Clinical GeneticsOdense University HospitalOdenseDenmark
  3. 3.Epidemiology, Institute of Public HealthUniversity of Southern DenmarkOdenseDenmark
  4. 4.Department of NeurologyOdense University HospitalOdenseDenmark
  5. 5.Department of NeurophysiologyAarhus University HospitalAarhusDenmark
  6. 6.Clinical Pharmacology, Institute of Public HealthUniversity of Southern DenmarkOdenseDenmark

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