Duloxetine
566616
226119494
2008-07-16T22:13:33Z
Dphildebrand
4809906
corrected the spelling of cymbalta
{{drugbox
| IUPAC_name = (+)-(''S'')-''N''-Methyl-3-(naphthalen-1-yloxy)-<BR/>3-(thiophen-2-yl)propan-1-amine
| image = Duloxetine_chemical_structure.png
| image2 =
| width = 150
| CAS_number = 116539-59-4
| CAS_supplemental = (free base). {{CAS|136434-34-9}} ([[hydrochloride]])
| ATC_prefix = N06
| ATC_suffix = AX21
| ATC_supplemental =
| PubChem = 60835
| DrugBank = APRD00060
| C=18 | H=19 | N=1 | O=1 | S=1
| molecular_weight = 297.41456 g/mol
| smiles = CNCC[C@@H](C1=CC=CS1)OC2=CC=CC3=CC=CC=C32
| bioavailability = ~ 50% (32% to 80%)
| protein_bound = ~ 95%
| metabolism = Liver, two P450 isozymes, [[CYP2D6]] and [[CYP1A2]].
| elimination_half-life = 12,1 hours
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_category=
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| excretion = 70% in urine, 20% in feces
| licence_EU =Ariclaim
| licence_US =duloxetine
}}
[[Image:Cymbalta60mg.png|thumb|Cymbalta 60mg]]
'''Duloxetine''' (brand names '''Cymbalta''', '''Yentreve''') is a [[serotonin-norepinephrine reuptake inhibitor]] (SNRI) used for [[major depressive disorder]] (MDD), [[general anxiety disorder|generalized anxiety disorder]] (GAD), pain related to [[diabetic neuropathy]] and in some countries for [[stress urinary incontinence]] (SUI). It is manufactured and marketed by [[Eli Lilly]]. Large number of side effects occurring during duloxetine treatment and lack of clear advantage over existing medications prompted critical reviews concluding that duloxetine "should not be used" for stress urinary incontinence<ref name="pmid16400743">{{cite journal |author= |title=Duloxetine: new drug. For stress urinary incontinence: too much risk, too little benefit |journal=Prescrire Int |volume=14 |issue=80 |pages=218–20 |year=2005 |month=December |pmid=16400743 |doi= |url=}}</ref> and "currently has no place in the treatment of depression or diabetic neuropathy" as well.<ref name="pmid17121211">{{cite journal |author= |title=Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects |journal=Prescrire Int |volume=15 |issue=85 |pages=168–72 |year=2006 |month=October |pmid=17121211 |doi= |url=}}</ref><ref name="pmid17451072">Drug and Therapeutics Bulletin concurs: "There is insufficient published evidence of its comparative efficacy to judge its duloxetine place in depression among many other longer-established antidepressant drugs, or how it compares with other therapy for diabetic peripheral neuropathic pain. Therefore we can see no place for it in either indication." {{cite journal |author= |title=Is there a place for duloxetine? |journal=Drug Ther Bull |volume=45 |issue=4 |pages=29–32 |year=2007 |month=April |pmid=17451072 |doi= |url=http://dtb.bmj.com/cgi/pmidlookup?view=long&pmid=17451072 |issn=}}</ref>
== History ==
Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of [[fluoxetine]] (Prozac), and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990.<ref name="United States Patent: 4956388">{{cite web |url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4956388.PN.&OS=PN/4956388&RS=PN/4956388 |title=United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines |author=Robertson DW, Wong DT, Krushinski JH |date=1990-09-11 |format=htm |work= |publisher=USPTO |accessdate=2008-05-17}}</ref> The first publication on the discovery of the [[racemic]] form of duloxetine known as LY227942, was made in 1988.<ref>{{cite journal |author=Wong DT, Robertson DW, Bymaster FP, Krushinski JH, Reid LR |title=LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug |journal=Life Sci. |volume=43 |issue=24 |pages=2049–57 |year=1988 |pmid=2850421 |doi=10.1016/0024-3205(88)90579-6}}</ref> The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes two times more potently than (-)-enantiomer. This molecule was subsequently named duloxetine.<ref name="pmid14643350">{{cite journal |author=Bymaster FP, Beedle EE, Findlay J, ''et al'' |title=Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake |journal=Bioorg. Med. Chem. Lett. |volume=13 |issue=24 |pages=4477–80 |year=2003 |month=December |pmid=14643350 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0960894X03010072}}</ref>
Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant<ref>{{cite journal |author=Turcotte JE, Debonnel G, de Montigny C, Hébert C, Blier P |title=Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects |journal=Neuropsychopharmacology |volume=24 |issue=5 |pages=511–21 |year=2001 |month=May |pmid=11282251 |doi=10.1016/S0893-133X(00)00220-7 |url=http://www.nature.com/npp/journal/v24/n5/abs/1395628a.html}}</ref> and the dose was increased to as high as 120 mg in subsequent clinical trials.<ref name="pmid11926722">For example, see: {{cite journal |author=Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA |title=Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial |journal=J Clin Psychiatry |volume=63 |issue=3 |pages=225–31 |year=2002 |month=March |pmid=11926722 |doi= |url=}}</ref>
In 2001 Lilly filed a New Drug Application (NDA) for duloxetine for depression with the US [[Food and Drug Administration]] (FDA). However, in 2003 the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "Duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring" at the new highest recommended dose of 120 mg, "where 24% patients had one or more [blood pressure] readings of 140/90 vs. 9% of placebo patients."<ref name="reg history">{{cite web |url=http://www.fda.gov/cder/foi/nda/2004/021427_s000_Cymbalta_AdminCorres.pdf |title=Approval package for: application number NDA 721-427. Administrative/Correspondence #2 |author= |date=2003 |format=PDF |work= |publisher=The FDA Center for Drug Evaluation and Research |pages= |accessdate=2008-05-18}}</ref>
After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004.<ref>[http://www.fda.gov/bbs/topics/news/2004/NEW01113.html FDA news]</ref> In 2007 [[Health Canada]] approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.<ref>[http://cpe0013211b4c6d-cm0014e88ee7a4.cpe.net.cable.rogers.com/NocWeb/viewnoce.jsp?noc=kjmd Health Canada Notice of Compliance Database - duloxetine]. November 1, 2007, retrieved November 24, 2007.</ref>
Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004. In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the U.S., stating that discussions with the FDA indicated "the agency is not prepared at this time to grant approval ... based on the data package submitted." A year later Lilly abandoned the pursuit of this indication in the U.S. market.<ref name=Yentreve>{{cite web |url=http://www.thestreet.com/_googlen/stocks/pharmaceuticals/10268662.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA |title=Lilly Won't Pursue Yentreve for U.S.|author=Steyer R |date=2006-02-15 |format=htm|publisher=TheStreet.com |accessdate=2008-05-18}}</ref>
==Indications==
The main uses of duloxetine are in [[major depressive disorder]], [[general anxiety disorder]], [[stress urinary incontinence]] and painful [[peripheral neuropathy]]. In addition, it is being studied for various other indications.
===Major depressive disorder===
Duloxetine is efficacious for the treatment of major depression. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; other three trials were inconclusive.<ref name="FDA-1">{{cite web |url=http://www.fda.gov/cder/foi/nda/2004/021427_s000_Cymbalta_Medr_P1.pdf |title=Clinical review for NDA 21-427 Cymbalta (duloxetine). |author= Andreason PJ|date= |format=PDF |work=CDER approval package for application number 21-427. Medical review # 3. |publisher=FDA |page=12|accessdate=2008-05-22}}</ref> A meta-analysis of these trials indicated that the effect size of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied.<ref name="pmid18199864">{{cite journal |author=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R |title=Selective publication of antidepressant trials and its influence on apparent efficacy |journal=N. Engl. J. Med. |volume=358 |issue=3 |pages=252–60 |year=2008 |month=January |pmid=18199864 |doi=10.1056/NEJMsa065779 |url=}}</ref> The rationale behind the development of duloxetine was that inhibition of the reuptake of both serotonin and norepinephrine would make it work better than SSRIs, which inhibit only the reuptake of serotonin. However, in a comparative meta-analysis of clinical trials duloxetine appeared to be insignificantly less effective than SSRIs.<ref name="pmid17588546">{{cite journal |author=Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC |title=Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents |journal=Biol. Psychiatry |volume=62 |issue=11 |pages=1217–27 |year=2007 |month=December |pmid=17588546 |doi=10.1016/j.biopsych.2007.03.027 |url=}}</ref> A head-to-head comparison of duloxetine with an SSRI [[escitalopram]] found duloxetine to be both less tolerable and less effective.<ref name="pmid18545055">{{cite journal |author=Lam RW, Andersen HF, Wade AG |title=Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials |journal=Int Clin Psychopharmacol |volume=23 |issue=4 |pages=181–7 |year=2008 |month=July |pmid=18545055 |doi=10.1097/YIC.0b013e3282ffdedc |url=}}</ref>
===Stress urinary incontinence===
{{expand|date=May 2008}}
[[Stress urinary incontinence]] is involuntary loss of urine when the bladder comes under strain, e.g. from coughing, sneezing or other movements that increase the intraabdominal pressure. Duloxetine was first reported to improve outcomes in SUI in 1998.<ref>{{cite journal |author=Voelker R |title=International group seeks to dispel incontinence "taboo" |journal=JAMA |volume=280 |issue=11 |pages=951–3 |year=1998 |month=September |pmid=9749464 |doi= |url=http://jama.ama-assn.org/cgi/content/full/280/11/951}}</ref> Systematic reviews with meta-analysis, conducted in 2005 ([[Cochrane Collaboration|Cochrane]])<ref>{{cite journal |author=Mariappan P, Ballantyne Z, N'Dow JM, Alhasso AA |title=Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD004742 |year=2005 |pmid=16034945 |doi=10.1002/14651858.CD004742.pub2 |url=http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004742/frame.html}}</ref> and 2008 (University of Minnesota),<ref>{{cite journal |author=Shamliyan TA, Kane RL, Wyman J, Wilt TJ |title=Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women |journal=Ann. Intern. Med. |volume=148 |issue=6 |pages=459–73 |year=2008 |month=March |pmid=18268288}}</ref> each found ten controlled trials. Both systematic reviews concluded that duloxetine did not lead to cure of [[stress urinary incontinence]] in the vast majority of people, but that episodes of incontinence were reduced by about 50%. This was associated with an improvement in [[quality of life]] measurements. Mild side-effects were common, and about a fifth had to discontinue the medication because of poor tolerance.
===Painful peripheral neuropathy===
{{expand|date=May 2008}}
At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymbalta showed modest improvement for diabetic pain over baseline, with 51% of patients treated with Cymbalta reporting at least a 30% sustained reduction in pain. In comparison, 31% of patients treated with placebo reported this magnitude of sustained pain reduction. At 60mg per day 89.5% of patients had some marked treatment adverse effects in one trial, and 87% in the other trial.<ref>{{cite journal |author=Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S |title=Duloxetine vs. placebo in patients with painful diabetic neuropathy |journal=Pain |volume=116 |issue=1-2 |pages=109–18 |year=2005 |month=July |pmid=15927394 |doi=10.1016/j.pain.2005.03.029}}</ref><ref>{{cite journal |author=Raskin J, Pritchett YL, Wang F, ''et al'' |title=A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain |journal=Pain Med |volume=6 |issue=5 |pages=346–56 |year=2005 |pmid=16266355 |doi=10.1111/j.1526-4637.2005.00061.x |url=}}</ref>
Duloxetine is also used to treat [[nerve]] pain in the feet, legs, or hands due to nerve damage caused by poorly controlled [[diabetes]]. Duloxetine is thought to enhance the nerve signals within the central nervous system which 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.<ref>[http://www.esi-topics.com/fbp/2006/june06-MichaelJDetke.html Essential Science Indicators]</ref>
=== 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).
Eli Lilly said the FDA has approved Cymbalta for the treatment of GAD in February 2007.<ref>[http://www.news-medical.net/?id=22194] News-Medical.Net February 26, 2007</ref> Eli Lilly said that in clinical trials patients treated with Cymbalta for GAD experienced a 46% improvement in anxiety symptoms, compared to 32% for those who took placebo, as measured by the Hamilton Anxiety Scale.
=== Fibromyalgia ===
On [[October 19]], [[2006]], Eli Lilly issued a press release saying they had done trials which found that Cymbalta, at 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,<ref>[http://www.fmaware.org/fminfo/brochure.htm] National Fibromyalgia Association Brochure</ref> 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.<ref name=Arnold2004> {{cite journal |author=Arnold LM, Lu Y, Crofford LJ, ''et al'' |title=A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder |journal=Arthritis Rheum. |volume=50 |issue=9 |pages=2974–84 |year=2004 |month=September |pmid=15457467 |doi=10.1002/art.20485 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/109609649/HTMLSTART}}</ref>
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.<ref name=Arnold2004/>
Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11% 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.<ref name=Arnold2004/>
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.<ref name=Arnold2004/>
The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008. <ref>{{cite web |url=http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=316740 |title=FDA Approves Cymbalta® for the Management of Fibromyalgia |date=2008-06-16 |work=Eli Lilly Co. |accessdate=2008-06-17}}</ref>
=== 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]].<ref>[http://clinicaltrials.gov/ct/show/NCT00375973?order=1] Clinicaltrials.gov</ref> CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition. Eli Lilly has not publicly stated their hypothesis for use of Cymbalta for CFS.{{Fact|date=May 2007}}
== Contraindications ==
The following contraindications are listed by the manufacturer:{{fact|date=May 2008}}
* Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
* [[Monoamine oxidase inhibitor]]s - concomitant use in patients taking [[monoamine oxidase inhibitor]]s is contraindicated.
* Uncontrolled narrow-angle [[glaucoma]] - in clinical trials, Cymbalta use was associated with an increased risk of [[mydriasis]] (dilation of the iris); therefore, its use should be avoided in patients with uncontrolled narrow-angle [[glaucoma]], in which mydriasis can cause sudden worsening.
* CNS acting drugs - given the primary central nervous system (CNS) effects of duloxetine, 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.
== Adverse effects ==
{{Prose|date=May 2008}}
[[Nausea]], [[somnolence]], [[insomnia]], and [[dizziness]] are the main side effects, reported by about 10% to 20% of patients.<ref>Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.</ref>
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:<ref>{{cite journal |author=Perahia DG, Kajdasz DK, Walker DJ, Raskin J, Tylee A |title=Duloxetine 60 mg once daily in the treatment of milder major depressive disorder |journal=Int. J. Clin. Pract. |volume=60 |issue=5 |pages=613–20 |year=2006 |month=May |pmid=16700869 |doi=10.1111/j.1368-5031.2006.00956.x |url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1368-5031.2006.00956.x?cookieSet=1}} {{PMC|1473178}}</ref>
Other side-effects include:
* [[Orthostatic hypotension]]
* [[Fatigue (physical)|Fatigue]]
* Vivid nightmares
* Increased sweating
* Decreased appetite and weight loss
* Blurred vision
* [[Paresthesia]]
* Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
* [[Tremor]]
* [[Anxiety]], [[nervousness]], [[agitation]]
* [[Palpitations]]
* 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
* [[Jaundice]]
* Inflammation of the liver or [[hepatitis]]
* [[Depersonalization]]
* [[Hypomania]]
* Weight gain or loss
Duloxetine and 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 longer, even after the drug has been completely withdrawn.{{Fact|date=September 2007}} This disorder is known as [[post-SSRI sexual dysfunction]].
=== Postmarketing spontaneous reports ===
Reported adverse events which were temporally correlated 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]].<ref>[http://www.rxlist.com/cgi/generic/cymbalta_ad.htm] Cymbalta Side Effects, and Drug Interactions - RxList Monographs</ref>
A number of more serious complications, in which duloxetine may have played a role, has been published in the form of case reports:
* The [[Los Angeles County, California|Los Angeles County]] Department of Coroner released a report of the first ''[[Post-mortem examination|post mortem]]'' studies of duloxetine; they identified twelve cases in which duloxetine was present on toxicologic analysis, but in no case was it deemed to be the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.<ref>{{cite journal |author=Anderson D, Reed S, Lintemoot J, ''et al'' |title=A first look at duloxetine (Cymbalta) in a postmortem laboratory |journal=J Anal Toxicol |volume=30 |issue=8 |pages=576–80 |year=2006 |month=October |pmid=17132255}}</ref>
* A case of [[hyponatremia]] induced by duloxetine was reported by doctors at [[Weill Cornell Medical College of Cornell University|Weill Cornell Medical College]] in New York. This is common to all SSRIs.<ref>{{cite journal |author=Safdieh JE, Rudominer R |title=A case of hyponatremia induced by duloxetine |journal=J Clin Psychopharmacol |volume=26 |issue=6 |pages=675–6 |year=2006 |month=December |pmid=17110834 |doi=10.1097/01.jcp.0000246207.73034.96}}</ref>
* A case of [[dyskinesia]] during treatment with duloxetine was reported in Germany.<ref>{{cite journal |author=Deuschle M, Mase E, Zink M |title=Dyskinesia during treatment with duloxetine |journal=Pharmacopsychiatry |volume=39 |issue=6 |pages=237–8 |year=2006 |month=November |pmid=17124651 |doi=10.1055/s-2006-951608}}</ref>
* Two episodes of [[serotonin syndrome]] have been documented in the use of duloxetine in conjunction with other medications.<ref>{{cite journal |author=Strouse TB, Kerrihard TN, Forscher CA, Zakowski P |title=Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine |journal=J Clin Psychopharmacol |volume=26 |issue=6 |pages=681–3 |year=2006 |month=December |pmid=17110838 |doi=10.1097/01.jcp.0000239793.29449.75}}</ref><ref>{{cite journal |author=Keegan MT, Brown DR, Rabinstein AA |title=Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs |journal=Anesth. Analg. |volume=103 |issue=6 |pages=1466–8 |year=2006 |month=December |pmid=17122225 |doi=10.1213/01.ane.0000247699.81580.eb |url=http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466}}</ref>
* 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]].<ref>{{cite journal |author=Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB |title=Case report: fulminant hepatic failure involving duloxetine hydrochloride |journal=Clin. Gastroenterol. Hepatol. |volume=4 |issue=7 |pages=912–7 |year=2006 |month=July |pmid=16797245 |doi=10.1016/j.cgh.2006.04.018}}</ref>
* An attack of acute [[porphyria]] in a patient with known [[variegate porphyria]] who had been commenced on duloxetine.<ref>{{cite journal |author=Loper T, Touchet B |title=An acute attack of porphyria in a patient taking duloxetine |journal=Psychosomatics |volume=48 |issue=2 |pages=179–80 |year=2007 |pmid=17329617 |doi=10.1176/appi.psy.48.2.179 |url=http://psy.psychiatryonline.org/cgi/content/full/48/2/179}}</ref>
=== Discontinuation syndrome ===
{{see |SSRI discontinuation syndrome}}
During marketing of other SSRIs and SNRIs, 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. This [[withdrawal]] phenomenon is known as the [[SSRI discontinuation syndrome]].
When discontinuing treatment with Cymbalta, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, 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."<ref>Cymbalta patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006</ref> This tapering process may be ineffective for some patients.{{fact|date=May 2008}}
In MDD placebo-controlled clinical trials of up to nine weeks' duration, systematically evaluating discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring 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.<ref>{{cite journal |author=Perahia DG, Kajdasz DK, Desaiah D, Haddad PM |title=Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder |journal=J Affect Disord |volume=89 |issue=1-3 |pages=207–12 |year=2005 |month=December |pmid=16266753 |doi=10.1016/j.jad.2005.09.003}}</ref>
=== Suicidality ===
The FDA requires all antidepressants, including duloxetine, to carry a [[black box warning]] stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.<ref name="FDA">{{cite web | author = Levenson M, Holland C| title =Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)|accessdate = 2007-05-13 | url = http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt}}</ref><ref name="FDA2">{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = CLINICAL REVIEW: RELATIONSHIP BETWEEN ANTIDEPRESSANT DRUGS AND SUICIDALITY IN ADULTS| accessdate = 2007-09-22 | author = Stone MB, Jones ML | authorlink = | coauthors = | date = 2006-11-17| format =PDF | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 11-74| language = | archiveurl = | archivedate = | quote = }}</ref><ref name="FDA3">{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | accessdate = 2007-09-22 | author = Levenson M, Holland C | authorlink = | coauthors = | date = 2006-11-17| format =PDF | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 75-140| language = | archiveurl = | archivedate = | quote = }}</ref>
To obtain [[statistically significant]] results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As [[suicidal ideation]] and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance. In line with the general results, duloxetine use in depressed adults insignificantly decreased the odds of suicidality by 12%<ref name="FDA2" /> or 20%<ref name="FDA3" /> depending of the statistical technique used. However, in the subgroup of young adults (18-24 years old) duloxetine increased the odds of suicidality 5-fold, close to statistical significance.<ref name="FDA2" /> There have been no trials of duloxetine in minors.
Several commentators noted that the data FDA used in their analysis of duloxetine-associated suicidality may have been incomplete. According to Arif Khan, the Summary Basis of Approval used by the FDA to approve duloxetine for depression contained only the mention of two completed suicides out of 3490 patients, and the rest of the data was not sufficient to "conduct any meaningful analysis."<ref name="pmid17453659">{{cite journal |author=Khan A, Schwartz K |title=Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports |journal=Ann Clin Psychiatry |volume=19 |issue=1 |pages=31–6 |year=2007 |pmid=17453659 |doi=10.1080/10401230601163550}}</ref> Jeanne Lenzer wrote in [[The Independent]] and [[Slate (magazine)|Slate Magazine]], and this fact was also confirmed by a Lilly spokesman, that another two completed suicides, which occurred in the depression studies ran by the Lilly's Japanese partner Shionogi, have not been reported to the FDA.<ref name="Slate">{{cite web |url=http://www.slate.com/id/2126918/ |title=What the FDA isn't telling.|accessdate=2008-01-20 |author=Jeanne Lenzer |authorlink= |coauthors= |date=2005-09-27 |format=html |work= |publisher=Slate Magazine |pages= |language= |archiveurl= |archivedate= |quote=}}</ref><ref name="independent">{{cite web |url=http://news.independent.co.uk/health/article226432.ece |title=Was Traci Johnson driven to suicide by anti-depressants? That's a trade secret, say US officials|accessdate=2008-01-20 |author=Jeanne Lenzer and Nicholas Pyke |authorlink= |coauthors= |date=2005-06-05 |format=html|work= |publisher=Independent Online Edition |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> According to Lenzer, four completed suicides also occurred in the trials of duloxetine for stress urinary incontinence (SUI). As these trials failed, the FDA initially insisted that any information about them is a commercial secret and cannot be released.<ref name="independent" /> Later, in a short statement the FDA acknowledged that in SUI trials eleven suicide attempts occurred in persons taking duloxetine vs none in the placebo group.<ref>{{cite web |url=http://www.fda.gov/cder/drug/infopage/duloxetine/historical.htm |title=Historical Information on Duloxetine hydrochloride (marketed as Cymbalta) |accessdate=2008-01-20 |author= |authorlink= |coauthors= |date=2005-06 |format=html |work= |publisher= FDA|pages= |language= |archiveurl= |archivedate= |quote=}}</ref>
A series of four cases of duloxetine-associated suicidality has been reported. In all four cases depressed patients began having suicidal thoughts after starting on duloxetine or increasing its dose. These thoughts stopped, and the patients returned to normal after duloxetine was discontinued, and they were switched to another antidepressant.<ref>{{cite journal |author=Parikh AR; Thatcher BT; Tamano EA; Liskow BI |title=Suicidal Ideation Associated With Duloxetine Use: A Case Series |journal=J Clin Psychopharmacolgy |volume=28 |issue=1 |pages=102 |year=2008}}</ref>
A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine clinical pharmacology study, was highly publicized. For about a month she had been given high doses of duloxetine, and then she was switched to placebo. Four days after the switch, she hanged herself with her scarf from a shower rod in the bathroom of Lilly Laboratory for Clinical Research.<ref>{{cite web |url=http://www.philly.com/mld/inquirer/news/local/7932602.htm |title=Drug test altered in wake of suicide|accessdate=2008-01-20 |author=Walter F. Naedele |authorlink= |coauthors= |date=2004-02-12 |format=html |work= |publisher= Philadelphia Inquirer|pages= |language= |archiveurl= |archivedate= |quote=}}</ref><ref name="NYT">{{cite web |url=http://query.nytimes.com/gst/fullpage.html?res=9C03E5D8133AF931A25751C0A9629C8B63 |title=Student, 19, in Trial of New Antidepressant Commits Suicide|accessdate=2008-01-20 |author=Gardiner Harris |authorlink= |coauthors= |date=2004-02-12 |format=html |work= |publisher=New York Times |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> The [[New York Times]] article mentioned a withdrawal syndrome as a possible reason for this suicide.<ref name="NYT" />
== Pharmacology ==
A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norepinephrine (NE) and serotonin (5-HT) transporters. <ref>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</ref>
== See also ==
* [[Serotonin-norepinephrine reuptake inhibitor]] (SNRI)
* [[Neuropsychopharmacology]]
* [[Neuropharmacology]]
* [[Pharmacology]]
* [[Psychoactive drug]]
== References ==
{{reflist|2}}
== External links ==
* [http://www.cymbalta.com/ Manufacturer website]
* [http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500549.html Duloxetine] - medlineplus.org
* [http://pi.lilly.com/us/cymbalta-pi.pdf Eli Lilly Cymbalta Prescribing Guide]
* [http://www.fda.gov/cder/drug/InfoSheets/HCP/duloxetineHCP.htm FDA Alert for Healthcare Professionals - Cymbalta Serotonin Syndrome]
* [http://www.fda.gov/cder/drug/infosheets/patient/duloxetinePIS.pdf FDA Patient Information Sheet on Cymbalta]
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