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Duloxetine chemical structure
| (+)-(S)-N-methyl-3-(1-naphthyloxy)- 3-(thiophen-2-yl)-propan-1-amine|
| CAS number |
| ATC code |
| PubChem |
| DrugBank |
|Molecular weight||297.416 g/mol|
|Metabolism||Liver, two P450 isozymes, CYP2D6 and CYP1A2.|
|Elimination half-life||8-17 hours|
|Excretion||70% in urine, 20% in feces|
|Pregnancy category||C (USA)|
|Legal status||Prescription only (USA)|
|Routes of administration||Oral|
Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar or Ariclaim) is a drug that primarily targets Major depressive disorder (MDD), Generalized Anxiety Disorder (GAD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). Duloxetine has not not been FDA approved for SUI or for fibromyalgia. It is manufactured and marketed by Eli Lilly and Company. Cymbalta for MDD was considered safe and well tolerated in a 52-week open-label study of 1,279 patients., although the manufacturer states that the effectiveness of Cymbalta in long-term use for MDD for more than 9 weeks has not been systematically evaluated in controlled trials.
Duloxetine is labeled an SNRI for serotonin norepinephrine reuptake inhibitor. Duloxetine is a systemic drug therapy that affects the body as a whole. Known also under the code name LY248686, it is a potent dual reuptake inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), possessing comparable affinities in binding to NE- and 5-HT transporter sites. It is a less potent inhibitor of dopamine reuptake.
Duloxetine was created by Lilly researchers and first publication of the discovery of the novel drug, then known as LY227942, was made in 1988 by David T. Wong and Frank P. Bymaster, two of the researchers behind Eli Lilly's fluoxetine (Prozac). Researchers reported "These findings suggest that LY227942 has the pharmacological profile of an antidepressant drug and is useful to study the pharmacological responses of concerted enhancement of serotonergic and norepinephrine neurotransmission."
Eli Lilly and Company had the formula for duloxetine hydrochloride patented in 1991. They began research on human subjects at 20mg by 1997. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant and the dose was increased to as high as 120mg in subsequent clinical trials done by Eli Lilly.
In November 2001, Lilly filed a New Drug Application (NDA) for duloxetine for depression with the Food and Drug Administration (FDA). The launch of duloxetine was planned for the second half of 2002. In April 2002, filing for stress urinary incontinence was anticipated for later in 2002. Analysts predicted in April 2002, that the drug would be launched in the first quarter of 2003.
On July 18, 2002, Eli Lilly made an agreement with Quintiles Transnational Corp. to jointly commercialize Cymbalta in the United States. Quintiels is a pharmaceutical research and marketing company. PharmaBio, the investment arm of Quintiles, invested $100 million to to help develop Cymbalta.
Lilly received an approvable letter from the FDA for Cymbalta (for depression) in September 2002. In October 2003, the U.S. Food and Drug Administration gave duloxetine a second approval letter saying it did not need to see any more test results before the drug got the final approval for depression. The federal agency said it would approve the drug once "manufacturing issues" had been sorted out, as Lilly had quality-control problems at two plants at the time.
Duloxetine as Cymbalta was finally approved by the FDA for Major Depressive Disorder in August of 2004, and Diabetic Neuropathy in September of 2004.
Eli Lilly and Company and Quintiles began co-promoting Lilly's new treatment for Cymbalta after it received regulatory approval in August 2004. Through its contract sales organization, Innovex, Quintiles has provided more than 500 sales representatives to help Lilly's substantial sales force promote Cymbalta in the United States for five years. In exchange, Quintiles stands to earn 8.5 percent of royalties from net sales of Cymbalta for depression and other neuroscience indications for eight years.
Cymbalta has not been approved for stress urinary incontinence (SUI) in the US but has been approved as Yentreve and Ariclaim for SUI in the European Union since August 2004. Yentreve and Ariclaim are produced by Boehringer Ingelheim and Eli Lilly and Company in a joint licensing agreement made in 2002.
In Japan, duloxetine has been jointly developed with the pharmaceutical company Shionogi Ltd. for depression since 1992, after signing a license agreement with Eli Lilly. As of January 2007, Shionogi had already received approval for the indication of depression, but is still conducting additional Phase III trials. For the treatment of pain related to diabetic peripheral neuropathy, Shionogi said it and Eli Lilly Japan K.K. will work together on the development as well as marketing. For this use, the drug is now going through Phase II clinical trials.
Dosing and administration
Each capsule of duloxetine contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.
The recommended oral dose for initiation of therapy in MDD is 40 mg/day (administered as 20 mg twice daily) to 60 mg/day (administered either as once daily or as 30 mg twice daily). The recommended dose for diabetic peripheral neuropathic pain is 60 mg once daily. Clinically, doses up to 120 mg/day have been utilized; a 2004 double-blind study by Goldstein, et al, showed slight clinical superiority for 80 mg/day when compared to 60 mg/day.
Mechanism of Action
When serotonin and norepinephrine are released from nerve cells in the brain they act to "lighten mood". When they are reabsorbed into the nerve cells, they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and norepinephrine released from nerve cells in the brain.
Duloxetine works by preventing serotonin, norepinephrine, and to a lesser extent dopamine, from being reabsorbed back into the nerve cells in the brain, specifically on the 5-HT and NE and D2 receptors respectively. This helps prolong the "mood lightening" effect of any released serotonin and norepinephrine. In this way, duloxetine is thought to help relieve depression.
Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core depression symptoms and help regulate the perception of pain. Disturbances of serotonin and/or norepinephrine may explain the presence of both the emotional and physical symptoms, including painful physical symptoms, of depression. Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine. While the mechanism of action of duloxetine is not fully known, scientists believe its effect on both emotional symptoms and pain perception is due to increasing the activity of serotonin and norepinephrine in the central nervous system.
It may take between two to four weeks for the benefits of this medicine to appear, so the manufacturer suggests it is very important that you keep taking it, even if it doesn't seem to make much difference at first. They go on to state that if the patient feels that the depression has gotten worse, has any of the listed side effects, or any distressing thoughts or feelings in these first few weeks, then they should talk to their prescribing doctor.
Duloxetine is also used to treat nerve pain in the feet, legs or hands that is due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous system that naturally inhibit pain. Duloxetine is not effective for the numbness or tingling, nor is it effective for the other complications of diabetes. It does not treat the underlying nerve damage, but can help reduce the pain.
Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
- Monoamine Oxidase Inhibitors
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.
- Uncontrolled Narrow-Angle Glaucoma
In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
- CNS Acting Drugs
Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
- Cymbalta and thioridazine should not be co-administered.
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.
Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients.
In a trial for mild major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group
- Dry mouth
- Sleepiness or somnolence
- Dizziness or Orthostatic hypotension
- Increased sweating
- Decreased appetite and weight loss
- Rapid weight gain
- Blurred vision
- Paresthesia (relates to "brain shivers or brain zaps")
- Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
- Anxiety, nervousness, agitation
- Decreased sex drive or difficulty achieving orgasm
- Impotence or delayed ejaculation
- Hot flashes
- Taste disturbances
- Difficulty passing urine
- Increase in blood pressure or heart rate
- Cold hands or feet
- Inflammation of the liver or hepatitis
Duloxetine and other SSRIs have been shown to cause sexual side effects in some patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years or possibly indefinitely even after the drug has been completely withdrawn. This disorder is known as Post SSRI Sexual Dysfunction.
Antidepressants may cause the amount of sodium in the blood to drop - a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching or convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with liver cirrhosis and those who are dehydrated or taking diuretic medicines. You should consult your doctor if you develop any of these symptoms while taking this medicine so that your blood sodium level can be checked if necessary.
Duloxetine as Cymbalta comes with suicide risk warning for children and adolescents under 18.
Serious Adverse Effects
Since duloxetine is a newer drug (FDA-approval 2004), not many peer-reviewed articles have been published on its adverse effects and effect of long term use is still unknown. More than 40 different types of adverse effects have been reported, including completed suicide attempts and severe hepatic disorders.
- Journalists Jeanne Lenzer and Nicholas Pyke, writing for The Independent newspaper, uncovered 41 deaths and 13 suicides for patients taking duloxetine as of June 19, 2005.
- The French journal Prescrire International stated the opinion "In practice, duloxetine currently has no place in the treatment of depression or diabetic neuropathy. Its efficacy has not yet been demonstrated to be even equivalent to that of other available drugs, and it has too many adverse effects, given this degree of uncertainty."
- The Los Angeles County Department of Coroner released a report of the first postmortem studies of duloxetine, which found 12 cases involving duloxetine which was the ultimate cause of death. 5 cases were determined multiple drug intoxication and 2 were determined suicide
- A case of hyponatremia induced by duloxetine was reported by doctors at Weil Medical College in New York.
- Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.
- A case of fulminant hepatic failure involving duloxetine which resulted in death was reported by the Department of Internal Medicine, Ohio State University, Columbus, Ohio.
Postmarketing Spontaneous Reports
Adverse events reported since market introduction that were temporally related to Cymbalta therapy include rash reported rarely and the following adverse events reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens-Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.
- Further information: SSRI discontinuation syndrome
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt. Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome.
The manufacturer of Cymbalta, Eli Lilly, warns that one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction.
"During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate."
Tapering process may be moot for some patients, and they will still have discontinuation/withdrawal symptoms.
Discontinuation symptoms systematically evaluated in patients taking duloxetine following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare.
Many patients on the drug longer than the Lilly test trials on discontinuation (which only studied patients after 9 weeks of exposure to Cymbalta), report anecdotal evidence of major withdrawals from Cymbalta lasting from weeks to many months.
Clinical Worsening and Suicide Risk
All adult and pediatric patients being treated with duloxetine for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when decreasing the dose.
Efficacy of Duloxetine (Cymbalta) versus Venlafaxine (Effexor)
In a study by Bymaster and colleagues it was found that duloxetine inhibited binding to the human norephinepherine (NE) and serotonin (5-HT) transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively.
Thus, duloxetine more potently blocks serotonin and norephinepherine transporters in vitro and in vivo than venlafaxine, arguably making it the most potent of all commercially available SNRIs. Duloxetine and venlafaxine have not been measured against milnacipran. Milnacipran is not yet available in the United States.
Some suggest that one of Eli Lilly's primary motivations for developing Cymbalta was the expiration of the antidepressant Prozac's patent in 2001. With cheaper generic versions available, the company's Prozac profits fell drastically. However, Cymbalta's profile as a drug is significantly different from Prozac's, and it may be useful for other types of diseases, so claims that Cymbalta is simply a way to divert money away from generic Prozac sales are highly dubious.
The drug scored a second FDA approval a month after it was approved for depression, when it also became the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy on September 7, 2004. The approval was based on two clinical trials done by Eli Lilly between June 2001 to August 2003. At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymblata showed modest improvement for diabetic pain over baseline, with 51 percent of patients treated with Cymbalta reporting at least a 30 percent sustained reduction in pain. In comparison, 31 percent of patients treated with placebo reported this magnitude of sustained pain reduction. At 60mg per day 89.5% of patients had treatment adverse effects in one trial, and 87% in the other trial.
Stress Urinary Incontinence and Suicidality
Duloxetine as Yentreve and Ariclaim was approved for use of stress urinary incontinence (SUI) in the EU on August 13, 2004. In November 2002, Eli Lilly and Company and Boehringer Ingelheim, a German pharmaceutical company, signed a long-term agreement to jointly develop and commercialize duloxetine hydrochloride.
Although the FDA approved Cymbalta for MDD and diabetic neuropathy, and Yentreve was approved for use of SUI in the European Union, Eli Lilly rescinded their request for FDA approval for SUI use in the United States. In a 9,400-person trial of duloxetine for the treatment of SUI in women, eleven suicide attempts and three cases of suicidal ideation were reported. Withdrawal of an application from FDA approval process is usually the result of the manufacturer's failure to demonstrate in clinical trials that the drug's risk-benefit ratio is positive.
The trials including 19 year old Traci Johnson and four other patients who committed suicide during Lilly trials for duloxetine were cleared by the FDA, stating that underlying depression - not the drug - causes sufferers to become suicidal. Ms. Johnson was in a Lilly trial testing duloxetine as Yentreve, a urinary stress incontinence medication, and not in an anti-depressant trial. In light of suicide risks, some critics claim that the FDA approval of duloxetine for MDD and diabetic neuropathy is irresponsible. On the other hand, the number of participants in the SUI studies was large, and trials of duloxetine for MDD and diabetic neuropathy showed no increase in suicidality.
At the time of its release in 2004, duloxetine was by far the most promising medicine in Eli Lilly's pipeline. Though it had been sitting on the shelf since 1991, in the wake of losing its monopoly on Prozac, combined with the commercial popularity of Wyeth's Effexor, Eli Lilly went into full scale production of Cymbalta, making it a top priority. Like venlafaxine, brand name Effexor, a SNRI that affects both serotonin and norepinephrine sold by Wyeth that had $2 billion in sales annually since 2003, analysts say that Cymbalta may outperform even Effexor. Sales for Cymbalta could reach $2.6 billion to $3.1 billion in 2009, according to Merrill Lynch.
With Cymbalta's patents set to expire on June 11, 2008, Lilly states it is working on at least two new antidepressants to bring to market to ensure its place in the SSRI antidepressant market. Eli Lilly originally patented duloxetine on June 11, 1991 and has asked the U.S. Patent and Trademark Office for an extension on the exclusivity of the chemical compound beyond 2008 (to June 11, 2013) with an official patent extension application on January 5, 2006.
As of Feb. 28, 2005, more than 1 million Cymbalta prescriptions have been dispensed since FDA approval in August 2004. For the year 2006, Cymbalta outperformed all branded antidepressants in the U.S. in terms of market growth as measured by both new prescriptions and total prescriptions. "Globally, the Cymbalta launch has been one of the most successful in both Lilly's history and that of the entire antidepressant market." Worldwide sales for Cymbalta grew at 91 percent in the third quarter compared with the same period last year. Eli Lilly is estimated to generate over $1 billion in annual sales in only its second full year with the drug on the market.
Generalized Anxiety Disorder
On May 11 2006, Eli Lilly and Company announced the recent submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Cymbalta for the treatment of generalized anxiety disorder (GAD). Approximately 6.8 million American adults, or about 3.1 percent of people age 18 and over, have GAD in a given year.
Eli Lilly said the US Food and Drug Administration has approved Cymbalta for the treatment of GAD in February 2007. Eli Lilly said that in clinical trials patients treated with Cymbalta for GAD experienced a 46 percent improvement in anxiety symptoms compared to 32 percent for those who took placebo, as measured by the Hamilton Anxiety Scale.
On October 19 2006, Eli Lilly issued a press release stating they had done trials which found Cymbalta, 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia (FM), with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology. Eli Lilly is in Phase III of its FM trials and is expected to submit a sNDA to the FDA for approval of Cymbalta for FM within the next 12 months.
Critics argue that randomized controlled trials of FM are difficult due to factors such as a lack of understanding of the pathophysiology and a heterogeneous FM patient population. Although there is a lack of understanding of what causes FM, it is estimated that approximately 5-7% of the U.S. population has FM, representing a large patient clientele. Eli Lilly hopes Cymbalta will be the first FDA approved medication for FM and had been promoting Cymbalta for FM since 2004.
In the study testing the efficacy of Cymbalta for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study. Researchers also tested the participants for depression.
Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11 percent of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study.
However, in one of the primary measures of pain there was no significant difference between the two groups at the end of the 12-week trial. Also, because the trial lasted only 12 weeks, it is impossible to tell how well the drug would control treatment for a longer period of time. Lastly, the primary researcher on the project has received more than $10,000 in consulting fees from Eli Lilly, the manufacturer of Cymbalta, all other researchers also had ties to the company, reflecting a conflict of interest.
Chronic Fatigue Syndrome
As of January 11 2007, Eli Lilly is currently enrolling patients for double blind Phase II and Phase III trials of Cymbalta for the use of Chronic Fatigue Syndrome (CFS) in conjunction with the University of Cincinnati. Chronic fatigue syndrome (CFS) is characterized by severe disabling fatigue of at least six months duration that cannot be fully explained by an identifiable medical condition. Eli Lilly has not publicly stated their hypothesis for use of Cymbalta for CFS.
- Selective Serotonin Reuptake Inhibitor
- Psychoactive drug
- ↑ Doctor's Guide - Eli Lilly Canada Press Release
- ↑ Wong DT, Robertosn DW, Bymaster FP, Krushinski JH, Reid LR. "LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug." Life Sci. 1988;43(24):2049-57.
- ↑ 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 May;24(5):511-21.
- ↑ Antilla S, Leinonen "Duloxetine Eli Lilly". Curr Opin Investig Drugs. 2002 Aug;3(8):1217-21
- ↑  NovaQuest Press Release 2002
- ↑  Triangle Business Journal February 20, 2004
- ↑ Goldstein, David J.; Lu, Yili; Detke, Michael J.; Wiltse, Curtis; Mallinckrodt, Craig; Demitrack, Mark A.(2004) Duloxetine in the Treatment of Depression: A Double-Blind Placebo-Controlled Comparison With Paroxetine. "Journal of Clinical Psychopharmacology." 24(4):389-399, August 2004.
- ↑ Essential Science Indicators
- ↑ Cymbalta® package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.
- ↑ D. G. S. Perahia1, D. K. Kajdasz, D. J. Walker, J. Raskin, A. Tylee. "Duloxetine 60 mg once daily in the treatment of milder major depressive disorder". International Journal of Clinical Practice (Vol, 60 Issue 5 Pg 613 - May 2006)
- ↑ The Independent 19 June 2005
- ↑ "Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects." Prescrire International. (2006 Oct;15(85):168-72)
- ↑ Anderson D, Reed S, Lintemoot J, Kegler S, DeQuintana S, Sandberg M, Muto J. "A first look at duloxetine (Cymbalta) in a postmortem laboratory. Journal of Annual Toxicology. (2006 Oct;30(8):576-480)
- ↑ Safdieh JE, Rudominer R. "A case of hyponatremia induced by duloxetine". J Clin Psychopharmacol. 2006 Dec;26(6):675-6.
- ↑ Deuschle M, Mase E, Zink M. "Dyskinesia during treatment with duloxetine". Pharmacopsychiatry. 2006 Nov;39(6):237-8.
- ↑ J Clin Psychopharmacol. 2006 Dec;26(6):681-683, Anesth Analg. 2006 Dec;103(6):1466-8.
- ↑ Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. "Case report: fulminant hepatic failure involving duloxetine hydrochloride". Clin Gastroenterol Hepatol. 2006 Jul;4(7):912-7. Epub 2006 Jun 22.
- ↑ Loper T, Touchet B. Psychosomatics. 2007 Mar-Apr;48(2):179-80
- ↑  Cymbalta Side Effects, and Drug Interactions - RxList Monographs
- ↑ Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
- ↑ 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.
- ↑ Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
- ↑ Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT. "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 Dec;25(6):871-80
- ↑  FDA News
- ↑ Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. "Duloxetine vs. placebo in patients with painful diabetic neuropathy". Pain. 2005 Jul;116(1-2):109-18.
- ↑ Raskin J, Pritchett YL, Wang F, D'Souza DN, Waninger AL, Iyengar S, Wernicke JF. "A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain". Pain Med. 2005 Sep-Oct;6(5):346-56.
- ↑ FDA Historical Information on Duloxetine
- ↑  Alliance for Human Research Protection. "19 year old volunteer suicided in Eili Lilly laboratory". February 11, 2004.
- ↑ 2006E-0004: Patent Extension Application for CYMBALTA (duloxetine hydrochloride), U.S. Patent No. 5,023,269
- ↑ Cymblata Healthcare Professional Website
- ↑ CNNMoney.com December 07, 2006
- ↑  NIMH: The Numbers Count
- ↑  News-Medical.Net February 26, 2007
- ↑  National Fibromyalgia Association Brochure
- ↑  Duloxetine Effective in Fibromyalgia Arthritis Rheum. 2004;50:2974-2984
- ↑  Clinicaltrials.gov
- 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):225-31.
- Detke MJ, Lu Y, Goldstein DJ, McNamara RK, Demitrack MA. "Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression". J Psychiatr Res 2002;36:383-90.
- Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. "Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial". J Clin Psychiatry 2002;63(4):308-15.
- Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. "Duloxetine in the long-term treatment of major depressive disorder". J Clin Psychiatry 2003;64(10):1237-44.
- Bailey KP. Yale University School of Nursing, New Haven, Connecticut, USA. "Physical symptoms comorbid with depression and the new antidepressant duloxetine". J Psychosoc Nurs Ment Health Serv. 2003 Dec;41(12):13-8.
- Gutman DA, Owens MJ.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA. "Serotonin and norepinephrine transporter binding profile of SSRIs". Essent Psychopharmacol. 2006;7(1):35-41.
- Raskin J, Wang F, Pritchett YL, Goldstein DJ. "Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study". Pain Med. 2006 Sep-Oct;7(5):373-85.
- Manufacturer website
- Duloxetine - medlineplus.org
- Eli Lilly Cymbalta Prescribing Guide
- FDA Alert for Healthcare Professionals - Cymbalta Serotonin Syndrome
- FDA Patient Information Sheet on Cymbalta
- Cymbalta List of Side Effects - rxlist.com
- Cymbalta User Ratings - askapatient.com
- Eli Lilly Press Release for Cymbalta for GAD
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