Psychopharmacology

, Volume 185, Issue 3, pp 395–399 | Cite as

A dose-finding study of duloxetine based on serotonin transporter occupancy

  • Akihiro Takano
  • Kazutoshi Suzuki
  • Jun Kosaka
  • Miho Ota
  • Shoko Nozaki
  • Yoko Ikoma
  • Shuji Tanada
  • Tetsuya Suhara
Original Investigation

Abstract

Rationale

Positron emission tomography (PET) has been utilized for determining the dosage of antipsychotic drugs. To evaluate the dosage of antidepressants such as selective serotonin reuptake inhibitors, serotonin transporter occupancy (5-HTT) is also a useful index.

Objectives

We investigated the degree of 5-HTT occupancy with different doses of the antidepressant duloxetine and the time-course of 5-HTT occupancy using PET.

Methods

PET scans with [11C]DASB were performed before and after a single administration of duloxetine (5–60 mg), and three consecutive scans were performed after a single dose or repeated doses of 60 mg of duloxetine.

Results

5-HTT occupancies by duloxetine were increased by 35.3 to 86.5% with dose and plasma concentration increments. The ED50 value of 5-HTT occupancy was 7.9 mg for dose and 3.7 ng/ml for plasma concentration. In the time-course of 5-HTT occupancy, mean occupancies were 81.8% at 6 h, 71.9% at 25 h, and 44.9% at 53 h after a single administration, and 84.3% at 6 h, 71.9% at 49 h, and 47.1% at 78 h after repeated administrations.

Conclusions

Based on 5-HTT occupancy, 40 mg and more of duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of 5-HTT occupancy with a once-a-day administration schedule.

Keywords

Duloxetine Occupancy 5-HTT PET DASB Time-course 

Notes

Acknowledgement

This research was conducted as LY248686 (duloxetine) phase I study in Japan, and was partially supported by Shionogi and Co., Ltd.

References

  1. Andree B, Hedman A, Thorberg SO, Nilsson D, Halldin C, Farde L (2003) Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain. Psychopharmacology (Berl) 167:37–45Google Scholar
  2. Brannan SK, Mallinckrodt CH, Detke MJ, Watkin JG, Tollefson GD (2005) Onset of action for duloxetine 60 mg once daily: double-blind, placebo-controlled studies. J Psychiatr Res 39:161–172CrossRefPubMedGoogle Scholar
  3. Brannan SK, Mallinckrodt CH, Brown EB, Wohlreich MM, Watkin JG, Schatzberg AF (2005) Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res 39:43–53CrossRefPubMedGoogle Scholar
  4. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT (2001) Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 25:871–880CrossRefPubMedGoogle Scholar
  5. Chalon SA, Granier LA, Vandenhende FR, Biek PR, Bymaster FP, Joliat MJ, Hirth C, Potter WZ (2003) Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. Neuropsychopharmacology 28:1685–1693CrossRefPubMedGoogle Scholar
  6. Detke MJ, Lu Y, Goldstein DJ, McNamara RK, Demitrack MA (2002) Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res 36:383–390CrossRefPubMedGoogle Scholar
  7. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA (2002) Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 63:308–315PubMedGoogle Scholar
  8. Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I (2004) Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol 14:457–470CrossRefPubMedGoogle Scholar
  9. Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76PubMedGoogle Scholar
  10. Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S (2001) Positron emission tomography quantification of [11C]-DASB binding to the human serotonin transporter: modeling strategies. J Cereb Blood Flow Metab 21:1342–1353PubMedGoogle Scholar
  11. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA (2002) Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry 63:225–231PubMedGoogle Scholar
  12. Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA (2000) Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB. Eur J Nucl Med 27:1719–1722CrossRefPubMedGoogle Scholar
  13. Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H, Suhara T, Suzuki K, Innis RB, Carson RE (2003) Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 23:1096–1112CrossRefPubMedGoogle Scholar
  14. Kish SJ, Furukawa Y, Chang LJ, Tong J, Ginovart N, Wilson A, Houle S, Meyer JH (2005) Regional distribution of serotonin transporter protein in postmortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol 32:123–128CrossRefPubMedGoogle Scholar
  15. Mamo D, Sedman E, Tillner J, Sellers EM, Romach MK, Kapur S (2004) EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study. Psychopharmacology (Berl) 175:382–388CrossRefGoogle Scholar
  16. Meyer JH, Wilson AA, Ginovart N, Goulding V, Hussey D, Hood K, Houle S (2001) Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [11C]DASB PET imaging study. Am J Psychiatry 158:1843–1849CrossRefPubMedGoogle Scholar
  17. Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835CrossRefPubMedGoogle Scholar
  18. Parsey RV, Kent JM, Oquendo MA, Richards MC, Pratap M, Cooper TB, Arango V, Mann JJ (2006) Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography. Biol Psychiatry(in press)Google Scholar
  19. Suhara T, Takano A, Sudo Y, Ichimiya T, Inoue M, Yasuno F, Ikoma Y, Okubo Y (2003) High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Arch Gen Psychiatry 60:386–391CrossRefPubMedGoogle Scholar
  20. Takano A, Suhara T (2005) The necessary parameters for estimating the time-course of receptor occupancy. Int J Neuropsychopharmacol 8:143–144CrossRefPubMedGoogle Scholar
  21. Takano A, Suhara T, Yasuno F, Suzuki K, Takahashi H, Morimoto T, Lee YJ, Kusuhara H, Sugiyama Y, Okubo Y (2006) The antipsychotic sultopride is overdosed—a PET study of drug-induced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol (in press)Google Scholar
  22. Tauscher J, Jones C, Remington G, Zipursky RB, Kapur S (2002) Significant dissociation of brain and plasma kinetics with antipsychotics. Mol Psychiatry 7:317–321CrossRefPubMedGoogle Scholar
  23. Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P (2001) Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology 24:511–521CrossRefPubMedGoogle Scholar
  24. Wilson AA, Garcia A, Jin L, Houle S (2000) Radiotracer synthesis from [11C]-iodomethane: a remarkably simple captive solvent method. Nucl Med Biol 27:529–532CrossRefPubMedGoogle Scholar
  25. Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S (2000) Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of 11C-labeled 2-(phenylthio)araalkylamines. J Med Chem 43:3103–3110CrossRefPubMedGoogle Scholar
  26. Wong DT (1998) Duloxetine (LY248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate. Expert Opin Investig Drugs 7:1691–1699CrossRefPubMedGoogle Scholar
  27. Yasuno F, Hasnine AH, Suhara T, Ichimiya T, Sudo Y, Inoue M, Takano A, Ou T, Ando T, Toyama H (2002) Template-based method for multiple volumes of interest of human brain PET images. Neuroimage 16:577–586CrossRefPubMedGoogle Scholar
  28. Yildiz A, Sachs GS (2001) Administration of antidepressants. Single versus split dosing: a meta-analysis. J Affect Disord 66:199–206CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Akihiro Takano
    • 1
  • Kazutoshi Suzuki
    • 1
  • Jun Kosaka
    • 1
  • Miho Ota
    • 1
  • Shoko Nozaki
    • 1
  • Yoko Ikoma
    • 1
  • Shuji Tanada
    • 2
  • Tetsuya Suhara
    • 1
  1. 1.Molecular Imaging CenterNational Institute of Radiological SciencesChibaJapan
  2. 2.Department of Medical ImagingNational Institute of Radiological SciencesChibaJapan

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