Skip to main content
NCBI home page
CNS Drug Reviews logoLink to CNS Drug Reviews
. 2006 Jun 7;8(4):361–376. doi: 10.1111/j.1527-3458.2002.tb00234.x

Duloxetine Pharmacology: Profile of a Dual Monoamine Modulator

Kelly D Karpa 1, Jane E Cavanaugh 2, Joan M Lakoski 1,✉
PMCID: PMC6741700  PMID: 12481192

ABSTRACT

Dysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5‐HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use.

In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants.

In a six‐week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight‐week multicenter, double‐blind, placebo‐controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half‐life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5‐HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.

Keywords: Antidepressants, Depression, Duloxetine, Monoamines, Norepinephrine, Serotonin, Transporter, Urinary incontinence

Full Text

The Full Text of this article is available as a PDF (107.4 KB).

References

  • 1. Bata‐Garcia JL, Heredia‐Lopez FJ, Alvarez‐Cervera FJ, Arankowsky‐Sandoval G, Gongora‐Alfaro JL. Circling behavior induced by microinjection of serotonin reuptake inhibitors in the substantia nigra. Pharmacol Biochem Behav 2002;71 (1–2): 353–363. [DOI] [PubMed] [Google Scholar]
  • 2. Béïque J‐C, Lavoie N, de Montigny C, Debonnel G. Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol 1998;349:129–132. [DOI] [PubMed] [Google Scholar]
  • 3. Berk M, du Plessis AD, Birkett M Richardt D. An open‐label study of duloxetine hydrochloride, a mixed serotonin and noradrenaline reuptake inhibitor, in patients with DSM‐III‐R major depressive disorder. Int Clin Psychopharmacol 1997;12:137–140. [DOI] [PubMed] [Google Scholar]
  • 4. Bevan P, Cools AR, Archer T, Eds. Behavioural pharmacology of 5‐HT. Mahwah , New Jersey : Lawrence Erlbaum Associates, 1989. [Google Scholar]
  • 5. Bickford‐Wimer PC, Miller JA, Freedman R, et al. Age‐related reduction in responses of rat hippocampal neurons to locally applied monoamines. Neurobiol Aging 1988;9:173–179. [DOI] [PubMed] [Google Scholar]
  • 6. Blakely RD, Ramamoorthy S, Schroeter S, et al. Regulated phosphorylation and trafficking of antidepressant‐sensitive serotonin transporter proteins. Biol Psychiatry 1998;44:169–178. [DOI] [PubMed] [Google Scholar]
  • 7. Blier P, Bouchard C. Modulation of 5‐HT release in the guinea‐pig brain following long‐term administration of antidepressant drugs. Br J Pharmacol 1994;113:485–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Blier P, Chaput Y, de Montigny C. Long‐term 5‐HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5‐HT autoreceptors: An electrophysiological study in the rat brain. Naunyn Schmiedeberg's Arch Pharmacol 1988;337:246–254. [DOI] [PubMed] [Google Scholar]
  • 9. Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994;15:220–226. [DOI] [PubMed] [Google Scholar]
  • 10. Blier P, Glazin AM, Langer SZ. Interaction between serotonin uptake inhibitors and α2‐adrenergic heteroreceptors in the rat hypothalamus. J Pharmacol Exp Ther 1990;254:236–244. [PubMed] [Google Scholar]
  • 11. Bradley CC, Blakely RD. Alternative splicing of the human serotonin transporter gene. J Neurochem 1997;69:1356–1367. [DOI] [PubMed] [Google Scholar]
  • 12. Bymaster FP, Dreshfield‐Ahmad LJ, Threlkeld PG et al. 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 2001;6:871–880. [DOI] [PubMed] [Google Scholar]
  • 13. Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long‐term administration of antidepressant treatments: An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991;5:219–229. [PubMed] [Google Scholar]
  • 14. Charney DS. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 1998;12 (Suppl 14): 11–14. [PubMed] [Google Scholar]
  • 15. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan‐depletion challenge in depressed patients treated with desipramine or fluoxetine: Implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 1999;46 (2): 212–20. [DOI] [PubMed] [Google Scholar]
  • 16. de Montigny C, Wang RY, Reader TA, Aghajanian GK. Monoaminergic denervation of the rat hippocampus: Microiontophoretic studies on pre‐ and post‐synaptic supersensitivity to norepinephrine and serotonin. Brain Res 1980;200:363–376. [DOI] [PubMed] [Google Scholar]
  • 17. Dugar A, Lakoski JM. Serotonergic function of aging hippocampal CA3 pyramidal neurons: Electrophysiological assessment following administration of 5,7‐dihydroxytryptamine in the fimbria‐fornix and cingulum bundle. J Neurosci Res 1997;47:58–67. [PubMed] [Google Scholar]
  • 18. Duman RS. The neurochemistry of mood disorders: preclinical studies In: Charney DS, Nestler EJ, Bunney BS, Eds. Neurobiology of mental illness. New York : Oxford University Press, 1999:333–364. [Google Scholar]
  • 19. Edwards AV. Aspects of autonomic and neuroendocrine function. Equine Vet J 1997;June(24, Suppl): 109–117. [DOI] [PubMed] [Google Scholar]
  • 20. Eison AS, Eison MS, Torrente JR, Wright RN, Yocca FD. Nefazodone: Preclinical pharmacology of a new antidepressant. Psychopharmacol Bull 1990;26:311–315. [PubMed] [Google Scholar]
  • 21. Engleman EA, Perry KW, Mayle DA, Wong DT. Simultaneous increases of extracellular monoamines in microdialysates from hypothalamus of conscious rats by duloxetine, a dual serotonin and norepinephrine uptake inhibitor. Neuropsychopharmacology 1995;12:287–295. [DOI] [PubMed] [Google Scholar]
  • 22. Engleman EA, Robertson DW, Thompson DC, Perry KW, Wong DT. Antagonism of serotonin 5‐HT1A receptors potentiates increases in extracellular monoamines induced by duloxetine in rat hypothalamus. J Neurochem 1996;66:599–603. [DOI] [PubMed] [Google Scholar]
  • 23. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the treatment of major depressive disorder: a double‐blind clinical trial. J Clin Psychiatry 2002;63 (3): 225–231. [DOI] [PubMed] [Google Scholar]
  • 24. Frazer A. Pharmacology of antidepressants. J Clin Psychopharmacol 1997;17(Suppl 1): 2S–18S. [DOI] [PubMed] [Google Scholar]
  • 25. Fuller RW, Hemrick‐Luecke SK, Snoddy HD. Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice. J Pharmacol Exp Ther 1994;269:132–136. [PubMed] [Google Scholar]
  • 26. Gobert A, Rivet J‐M, Cistarelli L, Melon C, Millan MJ. α2‐Adrenergic receptor blockade markedly potentiates duloxetine‐ and fluoxetine‐induced increases in noradrenaline, dopamine, and serotonin levels in the frontal cortex of freely moving rats. J Neurochem 1997;69:2616–2619. [DOI] [PubMed] [Google Scholar]
  • 27. Goodwin FK, Bunney WE. Depressions following reserpine: A reevaluation. Sem Psychiatry 1971;435–448. [PubMed] [Google Scholar]
  • 28. Gravel P, de Montigny C. Noradrenergic denervation prevents sensitization of rat forebrain neurons to tricyclic antidepressant treatment. Synapse 1987;1:133–139. [DOI] [PubMed] [Google Scholar]
  • 29. Haller J, Makara GB, Kruk MR. Catecholaminergic involvement in the control of aggression: Hormones, the peripheral sympathetic, and central noradrenegic systems. Neurosci Biobehav Rev 1998;22:85–97. [DOI] [PubMed] [Google Scholar]
  • 30. Hyttel J. Pharmacologic characterization of selective serotonin reuptake inhibitors (SSRIs). J Clin Psychopharmacol 1994;9:19–26. [DOI] [PubMed] [Google Scholar]
  • 31. Kasamo K, Blier P, de Montigny C. Blockade of the serotonin and norepinephrine uptake processes by duloxetine: In vitro and in vivo studies in the rat brain. J Pharmacol Exp Ther 1996;277:278–286. [PubMed] [Google Scholar]
  • 32. Kayama Y, Koyama Y. Brainstem neural mechanisms of sleep and wakefulness. Eur Urol 1998;33 (Suppl 3): 12–15. [DOI] [PubMed] [Google Scholar]
  • 33. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12‐month prevalence of DSM‐III‐R psychiatric disorders in the United States. Results for the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8–19. [DOI] [PubMed] [Google Scholar]
  • 34. Kihara T, Ikeda M. Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex. J Pharmacol Exp Ther 1995;272:177–183. [PubMed] [Google Scholar]
  • 35. Kilic F, Rudnick G. Oligomerization of serotonin transporter and its functional consequences. Proc Natl Acad Sci USA 2000;97:2106–3111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Kitayama S, Ikeda T, Mitsuhata C, Sato T, Morita K, Dohi T. Dominant negative isoform of rat norepinephrine transporter produced by alternative RNA splicing. J Biol Chem 1999;274:10731–10736. [DOI] [PubMed] [Google Scholar]
  • 37. Katoh A, Eigyo M, Ishibashi C, et al. Behavioral and electroencephalographic properties of duloxetine (LY248686), a reuptake inhibitor of norepinephrine and serotonin, in mice and rats. J Pharmacol Exp Ther 1995;272:1067–1075. [PubMed] [Google Scholar]
  • 38. Leonard BE. New approaches to the treatment of depression. J Clin Psychiatry 1996;57 (Suppl 4): 26–33. [PubMed] [Google Scholar]
  • 39. Millan MJ, Brocco M, Veiga S, Cistarelli L, Melon C, Gobert A. WAY 100,635 enhances both the 'anti‐depressant' actions of duloxetine and its influence on dialysate levels of serotonin in frontal cortex. Eur J Pharmacol 1998;341:165–167. [DOI] [PubMed] [Google Scholar]
  • 40. Mongeau R, de Montigny C, Blier P. Electrophysiologic evidence for desensitization of α2‐adrenoreceptors on serotonin terminals following long‐term treatment with drugs increasing norepinephrine synaptic concentration. Neuropsychopharmacology 1994;10:41–51. [DOI] [PubMed] [Google Scholar]
  • 41. Moore RY. The anatomy of central serotonin neuron systems in the rat brain In: Jacobs BL, Gelperine A, Eds. Serotonin neurotransmission and behavior. Cambridge , MA : The MIT Press, 1981;35–71. [Google Scholar]
  • 42. Muth EA, Haskins JT, Moyer JA, Husbands GEM, Nielson ST, Sigg EB. Antidepressant biochemical profile of the novel bicyclic compound Wy‐45,233, an ethyl cyclohexanol derivative. Biochem Pharmacol 1986;35:4493–4497. [DOI] [PubMed] [Google Scholar]
  • 43. Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. Biochemical, neurological, and behavioral effects of Wy‐45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev Res 1991;23:191–199. [Google Scholar]
  • 44. Nelson JC, Mazure CM, Bowers MB, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991;48:303–307. [DOI] [PubMed] [Google Scholar]
  • 45. Nierenberg AA, Feighner JP, Rudoloph R, Cole JO, Sullivan J. Venlafaxine for treatment‐resistant unipolar depression. J Clin Psychopharmacol 1994;14:419–423. [PubMed] [Google Scholar]
  • 46. Owens MJ, Morgan NW, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 1997;283:1305–1322. [PubMed] [Google Scholar]
  • 47. Piñeyro G, Blier P, Dennis T, de Montigny C. Desensitization of the neural 5‐HT carrier following its long‐term blockade. J Neurosci 1994;14:3036–3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Pitsikas N. Duloxetine. Curr Opin Investig Drugs 2000;1:511–521. [PubMed] [Google Scholar]
  • 49. Prange AJ, Wilson IC, Lynn CW, et al. L‐tryptophan in mania: Contribution to a Permissive Hypothesis of Affective Disorders. Arch Gen Psychiatry 1974;30:56–62. [DOI] [PubMed] [Google Scholar]
  • 50. Rénéric J‐P, Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology 1998;136:190–197. [DOI] [PubMed] [Google Scholar]
  • 51. Rueter LE, de Montigny C, Blier P. Electrophysiological characterization of the effect of long‐term duloxetine administration on the rat serotonergic and noradrenergic systems. J Pharmacol Exp Ther 1998;285:404–412. [PubMed] [Google Scholar]
  • 52. Rueter LE, Kasamo K, de Montigny C, Blier P. Effect of long‐term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain. Naunyn Schmiedeberg's Arch Pharmacol 1998;357:600–610. [DOI] [PubMed] [Google Scholar]
  • 53. Sánchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999;19:467–489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Sarkissian CF, Wurtman RJ, Morse AN, Gleason R. Effects of fluoxetine or D‐fenfluramine on serotonin release from, and levels in, rat femoral cortex. Brain Res 1990;529:294–301. [DOI] [PubMed] [Google Scholar]
  • 55. Seth R, Jennings, AL , Bindmand J, Phillips J, Bergmann K. Combination treatment with noradrenaline and serotonin reuptake inhibitors in resistant depression. Br J Psychiatry 1992;161:562–565. [DOI] [PubMed] [Google Scholar]
  • 56. Sharma A, Goldberg MJ, Cerimele BJ. Pharmacokinetics and safety of duloxetine, a dual serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000;40:161–167. [DOI] [PubMed] [Google Scholar]
  • 57. Shopsin B. Tryptophan and allopurinol in the treatment of depression. Lancet 1976;1:1189. [DOI] [PubMed] [Google Scholar]
  • 58. Sleight AJ, Smith RJ, Marsden CA, Palfreyman MG. The effects of chronic treatment with amitriptyline and MDL 72394 on the control of 5‐HT release in vivo. Neuropharmacology 1989;28:477–480. [DOI] [PubMed] [Google Scholar]
  • 59. Slotkin TA, Whitmore WL, Barnes GA, et al. Reduced inhibitory effect of imipramine on radiolabeled serotonin uptake into platelets in geriatric depression. Biol Psychiatry 1989;25:687–691. [DOI] [PubMed] [Google Scholar]
  • 60. Smith JE, Lakoski JM. Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus. Eur J Pharmacol 1997;323:69–73. [DOI] [PubMed] [Google Scholar]
  • 61. Smith JE, Lakoski JM. Electrophysiological study of the effects of the reuptake inhibitor duloxetine on serotonergic responses in the aging hippocampus. Pharmacology 1997;55:66–77. [DOI] [PubMed] [Google Scholar]
  • 62. Smith JE, Lakoski JM. Cellular electrophysiological effects of chronic fluoxetine and duloxetine administration on serotonergic responses in the aging hippocampus. Synapse 1998;30:318–328. [DOI] [PubMed] [Google Scholar]
  • 63. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose‐anesthetized female cat. J Pharmacol Exp Ther 1995;274:1014–1024. [PubMed] [Google Scholar]
  • 64. Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P. Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology 2001;5:511–521. [DOI] [PubMed] [Google Scholar]
  • 65. Wong DT, Bymaster FP, Mayle DA, Reid LR, Krushinski JH, Robertson DW. LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 1993;8:23–33. [DOI] [PubMed] [Google Scholar]

Articles from CNS Drug Reviews are provided here courtesy of Wiley

RESOURCES