Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects

Jill C. Chappell, Graeme Eisenhofer, Michael J. Owens, Harry Haber, D. Richard Lachno, Robert A. Dean, Mary Pat Knadler, Charles B. Nemeroff, Malcolm I. Mitchell, Michael J. Detke, Smriti Iyengar, Beth Pangallo, Evelyn D. Lobo

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalJournal of clinical psychopharmacology
Volume34
Issue number1
DOIs
StatePublished - Feb 1 2014

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Keywords

  • 5-HIAA
  • CSF
  • DHPG
  • Duloxetine
  • Norepinephrine
  • Serotonin

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Chappell, J. C., Eisenhofer, G., Owens, M. J., Haber, H., Lachno, D. R., Dean, R. A., Knadler, M. P., Nemeroff, C. B., Mitchell, M. I., Detke, M. J., Iyengar, S., Pangallo, B., & Lobo, E. D. (2014). Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects. Journal of clinical psychopharmacology, 34(1), 9-16. https://doi.org/10.1097/JCP.0000000000000061