Duloxetine (Cymbalta®)

Duloxetine in Brief
  • Generic name : Duloxetine hydrochloride
  • Brand names: Cymbalta®, Xeristar®, Yentreve®
  • Therapeutic class: Antidepressant
  • Pharmacologic class: Serotonin-Norepinephrine Reuptake Inhibitor
  • FDA Approved: August 3, 2004
  • Patent expiration date: June, 2013
  • Chemical Formula: C18H19NOS-HCl
  • Pregnancy Category: C
  • Habit forming? No
  • Originally discovered: 1988, Eli Lilly & Company, USA USA

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD


The first publication of the discovery of the new potential antidepressant LY227942 was made in 1988 by Eli Lilly and Company researchers 30. LY248686 (Duloxetine hydrochloride, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine) was synthesized for research purposes. LY227942 was the starting point for the development of duloxetine.

Duloxetine has been shelved in the early 1990s, in part because low doses had no effect on depression. But Lilly scientists discovered that higher doses relieved depression at least as well as Prozac. Subsequent testing proved the drug also curbed stress-related urinary incontinence. Eli Lilly originally patented duloxetine formula on June 11, 1991 (US patent No 5023269 "3-aryloxy-3-substituted propanamines").


Duloxetine was originally approved by the US FDA in August 3, 2004 for the treatment of depression under the trade name Cymbalta. Shortly after the approval for depression, duloxetine became the first and only officially indicated drug in the U.S. for the treatment of pain from diabetic peripheral neuropathy. In February 2007, the FDA approved Cymbalta for the treatment of generalized anxiety disorder (GAD). Finally, on November 2010, Cymbalta was licensed for chronic musculoskeletal pain.

FDA approved indications

  • Depression (MDD)
  • Diabetic peripheral neuropathic pain
  • Generalized anxiety disorder
  • Fibromyalgia 3, 18
  • Chronic musculoskeletal pain

Duloxetine for Fibromyalgia

Fibromyalgia is a chronic and painful musculoskeletal disorder. It affects 2 to 4 percent of the U.S. population. It is characterized by widespread pain and fatigue, sometimes to a disabling degree.

In a good-quality placebo-controlled trial, duloxetine (60 mg twice daily for 12 weeks) was shown to be moderately efficacious, safe, and well tolerated in the off-label treatment of patients with fibromyalgia 18. In clinical trials 3, 18 duloxetine treatment was associated with:

  • moderate reductions in the total score on the Fibromyalgia Impact Questionnaire
  • reductions in Brief Pain Inventory average pain severity and interference scores, number of tender points, and FIQ stiffness score
  • significant improvements in mean tender point pain threshold and several quality-of-life measures

However, significant improvement with duloxetine occurred in females only, whereas a treatment benefit was not shown in men.

The study has shown that Cymbalta's effect on fibromyalgia symptoms is independent of any effect on mood. There was no significant difference in response rates between patients with and without major depression 18.

Off-label & Investigational uses

  • Stress urinary incontinence (officially approved in Europe) 12
  • Chronic pain
  • Chronic fatigue syndrome 19
  • Low back pain33

Duloxetine "pros" and "cons"

Cymbalta appears to be an attractive option for MDD patients presenting with painful physical symptoms. This antidepressant may offer important benefits for postmenopausal women who have depression and menopause-related symptoms 21. Cymbalta is effective treatment in generalized anxiety disorder with significant pain symptoms 22.


  • Reduces painful physical symptoms of depression 11
  • Low risk of weight gain with short-term treatment 24
  • Lower rate of sexual side effects that with SSRIs 4, 10
  • Antidepressant effects may be noticed after one week 13
  • Convenience of once-daily dosing
  • Low risk of duloxetine emergent hypomania, mania, or hypomanic-like symptoms 25
  • Specifically studied for pain
  • True "dual agent" -- increases levels of norepinephrine at lower doses than venlafaxine (Effexor) 27
  • Relatively low cardiovascular risks 23
  • Effective in elderly patients with recurrent major depressive disorder 7
  • Effective in the prevention of depression relapse 8


  • High rates of nausea during treatment initiation 5
  • Higher rates of insomnia compared to SSRIs (may be a persistent side effect) 14, 16, 26
  • Making PTSD worse 28
  • Risk of weight gain with long-term treatment, the risk increases with higher doses 24
  • May cause severe withdrawal symptoms 2
  • Hepatic side effects. Duloxetine may cause aminotransferase increases. Patients with preexisting liver disease or excessive alcohol use are at a greater risk of duloxetine-induced liver injury 29.
  • Increases blood pressure 6
  • Potential for significant drug interactions between duloxetine and drugs that inhibit CYP1A2 enzymes or drugs that are metabolized by CYP2D6 enzymes.
  • May aggravate narrow-angle glaucoma.
  • Urinary retention
  • Rare cases of hyponatremia (low sodium level in the blood) have been reported31.
  • Very expensive.


Mechanism of action

Duloxetine is believed to exert its antidepressant effect through the potentiation of serotonergic and noradrenergic activity in the central nervous system.

Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. Duloxetine has no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors, and does not possess MAO-inhibitory activity.

Analgesic effect of duloxetine
While some effects of duloxetine on painful symptoms can be accounted for its antidepressant action, the data strongly suggests that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome 17.

Time to clear out of the system

The half-life of duloxetine is 10 to 15 hours. Steady-state is usually achieved after 3 days.

It may take 2 to 3 days for duloxetine to clear out of the system.

Onset of action

It usually takes 1-4 weeks to see improvements in symptoms and may take up to 4 to 7 weeks to achieve the remission. The symptoms showing improvements after 1-2 weeks of Cymbalta are depressed mood, guilt, suicidal ideation, work/activities, psychic anxiety, back pain and shoulder pain, retardation 13.

Efficacy rate: According to the studies that demonstrated efficacy of Cymbalta in the treatment of major depressive disorder the probabilities of remission range from 43% to 57% 15.

Weaning off Duloxetine

Most common duloxetine discontinuation symptoms include 9:

  • dizziness
  • nausea
  • headache
  • paresthesia
  • vomiting
  • irritability
  • nightmares

Duloxetine (Cymbalta) and weight gain

Short-term treatment is usually not associated with weight gain. Some persons may experience minor weight loss. However, there is a risk of weight gain with long-term treatment, and this risk increases with higher doses 24, 26.

Duloxetine (Cymbalta) and alcohol

The combination of duloxetine with alcohol can lead to liver injury. Duloxetine should be used with caution in patients with chronic liver disease, and substantial alcohol use 29.

Further reading


  • 1. U.S. Food and Drug Administration. Duloxetine U.S. Prescribing Information.
  • 2. Petition to Cymbalta manufacturer, Eli Lilly and Company. [Not available]
  • 3. Arnold LM, Lu Y, Crofford LJ et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84 PubMed
  • 4. Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med. 2007 Jul;4(4 Pt 1):917-29. PubMed
  • 5. Greist J, McNamara RK, Mallinckrodt CH, Rayamajhi JN, Raskin J. Incidence and duration of antidepressant-induced nausea. Clin Ther. 2004 Sep;26(9):1446-55. PubMed
  • 6. Derby MA, Zhang L, Chappell JC, Gonzales CR, Callaghan JT, Leibowitz M, Ereshefsky L, Hoelscher D, Leese PT, Mitchell MI. The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate. J Cardiovasc Pharmacol. 2007 Jun;49(6):384-93. PubMed
  • 7. Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, Rotz BT, Mohs RC. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007 Jun;164(6):900-9. PubMed
  • 8. Perahia DG, Gilaberte I, Wang F, et al. Duloxetine in the prevention of relapse of major depressive disorder: double-blind placebo-controlled study. Br J Psychiatry. 2006 Apr;188:346-53. PubMed
  • 9. Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. J Affect Disord. 2005 Dec;89(1-3):207-12. Epub 2005 Nov 2. PubMed
  • 10. Delgado PL, Brannan SK, Mallinckrodt CH, Tran PV, McNamara RK, Wang F, Watkin JG, Detke MJ. Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder. J Clin Psychiatry. 2005 Jun;66(6):686-92. PubMed
  • 11. Brannan SK, Mallinckrodt CH, Brown EB, Wohlreich MM, Watkin JG, Schatzberg AF. Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res. 2005 Jan;39(1):43-53. PubMed
  • 12. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC; Duloxetine UI Study Group. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int. 2004 Feb;93(3):311-8. PubMed
  • 13. Hirschfeld RM, Mallinckrodt C, Lee TC, Detke MJ. Time course of depression-symptom improvement during treatment with duloxetine. Depress Anxiety. 2005;21(4):170-7. PubMed
  • 14. Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA. Duloxetine in the treatment of depression. J Clin Psychopharmacol. 2004 Aug;24(4):389-99. PubMed
  • 15. Mallinckrodt CH, Goldstein DJ, Detke MJ, Lu Y, Watkin JG, Tran PV. Duloxetine: A New Treatment for the Emotional and Physical Symptoms of Depression. Prim Care Companion J Clin Psychiatry. 2003 Feb;5(1):19-28. PubMed
  • 16. Wade A, Gembert K, Florea I. Curr Med Res Opin. 2007 Jul;23(7):1605-14.
  • 17. Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol. 2006 Nov;21(6):311-7. PubMed
  • 18. Arnold LM, Rosen A, Pritchett YL, D'Souza DN, Goldstein DJ, Iyengar S, Wernicke JF.A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005 Dec 15;119(1-3):5-15. PubMed
  • 19.Clinical Trial: Double Blind Trial of Duloxetine in Chronic Fatigue Syndrome ClinicalTrials.gov
  • 21. Joffe H, Soares CN, Petrillo LF, Viguera AC, Somley BL, Koch JK, Cohen LS. Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine. J Clin Psychiatry. 2007 Jun;68(6):943-50. PubMed
  • 22. Russell JM, Weisberg R, Fava M, Hartford JT, Erickson JS, D'Souza DN. Efficacy of duloxetine in the treatment of generalized anxiety disorder in patients with clinically significant pain symptoms. Depress Anxiety. 2007 Jun 22. PubMed
  • 23. Wernicke J, Lledo' A, Raskin J, Kajdasz DK, Wang F. An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies. Drug Saf. 2007;30(5):437-55. PubMed
  • 24. Wise TN, Perahia DG, Pangallo BA, Losin WG, Wiltse CG. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8(5):269-78. PubMed
  • 25. Dunner DL, D'Souza DN, Kajdasz DK, Detke MJ, Russell JM. Is treatment-associated hypomania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression. J Affect Disord. 2005 Jul;87(1):115-9. PubMed
  • 26. Wohlreich MM, Mallinckrodt CH, Prakash A, Watkin JG, Carter WP. Duloxetine for the treatment of major depressive disorder: safety and tolerability associated with dose escalation. Depress Anxiety. 2007;24(1):41-52. PubMed
  • 27. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT. Neuropsychopharmacology. 2001 Dec;25(6):871-80. PubMed
  • 28. Deneys ML, Ahearn EP. Exacerbation of PTSD symptoms with use of duloxetine. J Clin Psychiatry. 2006 Mar;67(3):496-7.
  • 29. Kang SG, Park YM, Lee HJ, Yoon B. Duloxetine-induced liver injury in patients with major depressive disorder. Psychiatry Investig. 2011 Sep;8(3):269-71. Full text
  • 30. Wong DT, Robertson DW, Bymaster FP, Krushinski JH, Reid LR. LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant. Life Sci. 1988;43(24):2049-57. PubMed
  • 31. Li RM, Wang C, Liu ZW, Zhao B. A case of severe hyponatremia induced by duloxetine and ziprasidone. Chin Med J. 2012 Oct;125(20):3750-1.
  • 32. Kale PP, Addepalli V. Augmentation of antidepressant effect of duloxetine by caffeine in mice. Pharmacol Biochem Behav. 2014 Sep;124:238-44. PubMed
  • 33. Schukro RP, Oehmke MJ, Geroldinger A, et al. Efficacy of Duloxetine in Chronic Low Back Pain with a Neuropathic Component: A Randomized, Double-blind, Placebo-controlled Crossover Trial. Anesthesiology. 2016 Jan;124(1):150-8. PubMed

Published: March 31, 2008
Last updated: December 03, 2017

Interesting facts

Duloxetine facts
  • Eli Lilly's patent on Cymbalta has been expired on June 11, 2013.
  • Caffeine may strengthen anxiolytic effect of duloxetine32.

More Facts
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