Duloxetine (Cymbalta): Unimpressive

Duloxetine became available for Lilly Pharmaceutical in the U.S. in the summer of 2004.  It has been approved by the FDA.  It is a dual-action norepinepherine and serotonin medication, but the research has been unimpressive.  It is fairly expensive.  Nortriptyline is probably a better dual action anti-depressant and much less costly.  Also, fluoxetine, trazodone, 5-HTP, or imipramine are probably better initial choices both because of much lower costs and greater experience.  I would also consider trying bupropion (Wellbutrin), sertraline (Zoloft), citalopram (Celexa), St. John's wort, venlafaxine (Effexor) and lithium before duloxetine.  Adding 5-HTP or thyroid medication to a partially effective anti-depressant is another a good option before trying duloxetine.

Five people in clinical trials out of 9,000 have committed suicide while on duloxetine (NY Times 2/12/04).  One, a 19 year old college female without depression, hung herself in the Eli Lilly research dorm in Indianapolis four days after stopping duloxetine which was being researched for stress urinary incontinence.  Duloxetine has a short half-life, but there were no reported signs of drug withdrawal.  Duloxetine appears to be inferior for stress incontinence compared to much less expensive traditional treatments like oxybutynin and imipramine.

Almost all of the published research has been done by psychiatrists paid by the manufacturer.  Based on past experience, these studies should not be fully trusted.  Lilly is actually better than other manufacturers in that they are the first to make all of their studies available via an internet website.  Industry funding has had and continues to have a serious corrupting effect on such universities as Harvard, Duke, Stanford, Pittsburgh, and many others, both in the U.S. and in Europe, as well as Israel and Canada.

Side-Effects: Duloxetine Safe: In a review of safety data from eight industry-sponsored DB PC studies in which patients were randomized to duloxetine (40-120 mg/d; n = 1139) or placebo (n = 777) for up to 9 weeks with two studies including continuation phases in which acute treatment responders received duloxetine or placebo for an additional 26 weeks, the rates of serious side-effects for duloxetine- and placebo-treated patients were 0.3% and 0.6%, respectively (p = 0.282). Adverse events led to discontinuation in 9.7% of duloxetine-treated patients, compared with 4.2% of patients receiving placebo (p < 0.001). Side-effects with an incidence for duloxetine >/= 5.0% greater than placebo were nausea, dry mouth, constipation, insomnia, dizziness, fatigue, somnolence, increased sweating and decreased appetite. Duloxetine caused no weight gain. Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials. Hudson JI, Wohlreich MM, et al. Harvard-McLean. Hum Psychopharmacol. 2005 May 24

Duloxetine (Cymbalta) Withdrawal Side-Effect: In a pooled analysis of 6 short-term treatment studies, in which treatment was stopped abruptly, reported problems were 44.3% and 22.9% of duloxetine- and placebo-treated patients (p<0.05). The abrupt discontinuation of duloxetine compared with placebo caused dizziness (12.4%), nausea (5.9%), headache (5.3%), paresthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2.0%). The majority of these (65.0%) resolved within 7 days. More occurred with high dose 120 mg/day. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of DEAEs. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. Perahia DG, et al. Lilly Co. Gordon Hospital London, UK. J Affect Disord. 2005 Oct 30. Ed: These withdrawal effects may not be more than average for anti-depressants, which should be gradually withdrawn over a couple weeks at least.

Side-Effects: In a one-year open study of over 1200 patients (560 lasted the whole year), adverse events led to discontinuation in 218 patients (17.0%). This is about average for an anti-depressant.  The most frequent specific events leading to discontinuation were nausea (1.5%), somnolence (1.4%), vomiting (0.9%), hypomania (0.8%), pregnancy (0.8%), dizziness (0.6%), insomnia (0.6%), and hypertension (0.5%). Treatment-emergent adverse events that were reported by over 10% of patients included nausea, insomnia, headache, somnolence, dry mouth, dizziness, constipation, sweating increase, anxiety, diarrhea, and fatigue. Eli Lilly. J Clin Psychiatry. 2003 Oct;64(10):1237-44.  While Eli Lilly calls it "well tolerated," obviously many patients didn't tolerate it very well at all. This rate of side-effects may be no worse than other anti-depressants, but it's not anything to brag about.

Duloxetine (Cymbalta) Slightly Better than Placebo; Paroxetine was Not: In an industry-funded DB PC study of duloxetine 20 mg twice daily and 40 mg twice daily vs placebo and paroxetine 20 mg/d in depressed outpatients, duloxetine at 40 mg/d was slightly superior to placebo by 2.43 points (P = 0.034), while paroxetine was not (1.51 points; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). Duloxetine in the Treatment of Depression: A Double-Blind Placebo-Controlled Comparison With Paroxetine. Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA. PRN Consulting, Indianapolis. J Clin Psychopharmacol. 2004 Aug;24(4):389-99 Comparing the effects of 8-week treatment with fluoxetine and imipramine on fasting blood glucose of patients with major depressive disorder. Eli Lilly and other drug companies intentionally hide many studies in which their drugs don't work very well.  I am pretty sure that duloxetine was the drug that a drug company researcher explained was better than placebo in only one of eight Eli Lilly funded studies.  This forced the company to delay applying to the FDA to allow it to market the drug.  It needs two studies to get FDA approval. It is sad to see Harvard and Indiana University joining in this charade. 

Duloxetine 120 mg Better than Fluoxetine 20/d in Questionable Study: Eli Lilly study. Duloxetine dual NE and 5HT reuptake inhibitor. 173 patients (aged 18-65 years) with DSM-IV major depressive disorder were randomly allocated to receive placebo (N = 70), duloxetine (N = 70), or fluoxetine, 20 mg q.d. (N = 33). Duloxetine dose was titrated in the first 3 weeks in a forced-titration regimen from 40 mg (20 mg b.i.d.) to 120 mg/day (60 mg b.i.d.). Estimated probabilities of response and remission were 64% and 56%, respectively, for duloxetine, compared with 52% and 30% for fluoxetine and 48% and 32% for placebo. Side-effects insomnia and asthenia. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. J Clin Psychiatry 2002 Mar;63(3):225-31. [Editor: This study found fluoxetine no better than placebo, a finding probably due to chance alone. Perhaps if more patients had been randomized to fluoxetine, this chance finding would not have occurred.]

Duloxetine 60mg QD Better than Placebo: Eli Lilly manufacturer’s study. In a 297-patient 9-week DB PC study of major depressive disorder, the response and remission rates with duloxetine were 65% and 43% vs. 42% and 28% for placebo. 12.5% stopped the medicine vs. 4% stopping the placebo with the leading reasons being nausea, dry mouth, dizziness, and constipation. Detke MJ, Lu Y, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315

Duloxetine Balanced Dual Action: Duloxetine has low nanomolar affinity at both the NET and SERT and is among the most potent inhibitors of in vitro binding at both transporters. Duloxetine is also the most balanced among the currently available reuptake inhibitors, with less than a 10-fold difference in affinity to the NE and 5-HT transporters. Venlafaxine, another SNRI, is nearly 30 times more selective at the 5-HT binding site than at the NE binding site. In contrast, milnacipram, available in Europe, is a more potent NE reuptake inhibitor than a 5-HT reuptake inhibitor. By comparison, citalopram is nearly 3400-fold more selective at the SERT than at the NET

Duloxetine Called Fast Acting: Another study demonstrated significant improvement in HAMD-17 total score after only a 2-week treatment with duloxetine (60 mg/day). 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. [see comments.]. J Clin Psychiatry. 2002;63:308-315.

Duloxetine Said to Help Depression and Pain: In two 9-week DB PC studies totalling 90 patients with Major Depressive Disorder, those given duloxetine (60 mg/day) had a higher probability of remission for duloxetine-treated patients (44.1%) was also significantly higher than that for placebo (16.1%). The drug company researchers lumped together the results of six studies of pain to report improved pain symptoms with duloxetine. The rate of discontinuation due to adverse events was significantly higher for duloxetine-treated patients (21.0%) than placebo (6.7%). Duloxetine for the treatment of major depressive disorder in older patients. Nelson JC, Wohlreich MM, et al. Eli Lilly and Co. Am J Geriatr Psychiatry. 2005 Mar;13(3):227-35. Ed: This is certainly an odd industry report, lumping together two studies for depression and six studies for pain. Amitriptyline and nortriptyline both achieve the same benefits at a much lower cost and no higher rate of side-effects.

Duloxetine Might Help Pain: A significant reduction in overall pain severity in depression was also claimed, and a rapid and sustained relief of back pain. 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.

Duloxetine Low Weight Gain: The rate of nausea among patients treated with duloxetine compares favorably with the SSRIs and venlafaxine, and it appears to have no clinically significant effect on weight gain or blood pressure. Pitsikas N. Duloxetine Eli Lilly & Co. Curr Opin Invest Drugs. 2000;1:116-121.

Elderly: Duloxetine Better than Placebo; Side-Effects Common: In an industry DB PC 9-week study of 90 adults over age 54, duloxetine 60 mg/d had a 44% rate of remission vs. 16% with placebo. Side-effects requiring discontinuation occurred in 21% with duloxetine vs. 7% with placebo. Pain symptoms also decreased. Duloxetine for the treatment of major depressive disorder in older patients. Nelson JC, Wohlreich MM, et al. Eli Lilly Co. Am J Geriatr Psychiatry. 2005 Mar;13(3):227-35.

Stress Incontinence

Duloxetine Helps Stress Incontinence Modestly: In a 12-week DB PC study funded by the manufacturer Lilly Drugs, 494 women with stress incontinence were given duloxetine 40 mg twice a day or placebo. Incontinent episodes decreased 50% on duloxetine vs. 29% on placebo. Discontinuation due to side-effects was much higher with duloxetine at 22% (mostly nausea) vs. 5%. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. Van Kerrebroeck P, Abrams P, Lange R, Slack M, Wyndaele JJ, Yalcin I, Bump RC; For the Duloxetine UI Study Group. BJOG. 2004 Mar;111(3):249-257

Duloxetine Helps Stress Incontinence: 683 women aged 22 to 84 years with prominent symptoms of stress urgency incontinence and at least seven episodes of incontinence per week for at least three months entered a DB PC study of 40 mg duloxetine twice daily for 12 weeks vs. placebo. Duloxetine incontinence decreased (50% vs. 27%; P < .001), increase in voiding interval (20 vs. 2 minutes; P < .001), and improvements quality-of-life survey (P < .001). Global Impression of Improvement 62% vs. 40%. Withdrawal from the study due to side-effects was 4% for placebo vs. 24% for duloxetine (P < .001). Nausea most common, tended to be mild to moderate and to resolve within one to four weeks. J Urol 10/02. Funded by Lilly Drugs.

Duloxetine Helps Stress Incontinence Slightly: In a Lilly funded 486-patient DB PC European-Australian-S. African-Argentine study, 54% of the duloxetine vs. 40% of the placebo group showed improvement. 17% of the duloxetine patients vs 1.7% of the placebo patients dropped out due to complaints of side-effects. Duloxetine vs. placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC; For the Duloxetine UI Study Group. BJU Int. 2004 Feb;93(3):311-318

Imipramine Helps Stress Incontinence: Anti-cholinergic medications are often used for stress incontinence. Imipramine has anti-cholinergic effects. A prospective but not DB study of imipramine 75 mg/day found that 35% of patients were cured of their incontinence, 25% had greater than a 50% improvement, and the other 40% were considered to have failed due to improving less than 50% while on imipramine. Br J Obstet Gynaecol. 1999 Oct;106(10):1089-92. Ed: This level of improvement, while not in a DB study, seems to be at least as good as the results reported with duloxetine.  Imipramine is much less expensive and has been used for 40 years without a significant level of serious problems. Oxybutynin (Ditropan) is an antispasmodic anticholinergic medication also used for stress incontinence. A long-acting Ditropan can be taken once a day but costs considerably more with no better results. DB studies with oxybutynin show an average decrease in incontinent episodes of over 70%, i.e., much better than duloxetine.  Oxybutynin costs $12/month wholesale. Duloxetine will likely be over $100/month.

Fibromyalgia

Duloxetine (Cymbalta) Some Benefit for Fibromyalgia: In a 12-week DB PC study of 207 fibromyalgia sufferers, duloxetine 60 mg twice a day improved slightly more (P = 0.027) on the total fibromyalgia score, but not for pain (P = 0.130). Duloxetine-treated subjects had greater reductions in Brief Pain Inventory average pain severity score (P = 0.008), Brief Pain Inventory average interference from pain score (P = 0.004), number of tender points (P = 0.002), and FIQ stiffness score (P = 0.048), and had significantly greater improvement in mean tender point pain threshold (P = 0.002), CGI-Severity (P = 0.048), PGI-Improvement (P = 0.033), and several quality-of-life measures. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, Goldstein DJ. University of Cincinnati. Arthritis Rheum. 2004 Sep;50(9):2974-84. Ed: This apparently industry funded study’s abstract doesn’t give any actual figures of improvement. With large studies, small benefits can be statistically significant but less significant clinically. It is very likely that other much less expensive and better tested anti-depressants like amitriptyline and nortriptyline do as well or better.