Duloxetine

Duloxetine

Clinical data
License data	EU EMA: by INN US FDA: duloxetine
Pregnancy category	C (USA)
Routes of administration	Oral
ATC code	N06AX21 (WHO)
Legal status
Legal status	US: WARNING Prescription only (USA)
Pharmacokinetic data
Protein binding	>90%
Metabolism	Liver, two P450 isozymes, CYP2D6 and CYP1A2.
Elimination half-life	8-17 hours
Excretion	70% in urine, 20% in feces
Identifiers
IUPAC name (+)-(S)-N-methyl-3-(1-naphthyloxy)- 3-(thiophen-2-yl)-propan-1-amine
CAS Number	136434-34-9
PubChem CID	60835
DrugBank	APRD00060
CompTox Dashboard (EPA)	DTXSID6048385
ECHA InfoCard	100.116.825
Chemical and physical data
Formula	C18H19NOS
Molar mass	297.416 g/mol

Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar) is a medically used drug that primarily targets major depressive disorders (MDD), pain related to diabetic peripheral neuropathy and stress urinary incontinence (SUI). It is manufactured and marketed by Eli Lilly and Company.

Duloxetine is labeled an SNRI for serotonin norepinephrine reuptake inhibitor.

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. Its behavior contrasts to most other dual-reuptake inhibitors in that Ki values are nearly 1:1.

Duloxetine may or may not lack affinity for monoamine receptors within the central nervous system. More study is needed.

While there is limited data available regarding the pharmacokinetic profile of duloxetine in humans, its half-life is reported to be 10 to 15 hours. Administration with food may delay the maximum concentration (Cmax) by approximately 4 hours (from 6 to 10 hours), and it may also decrease the extent of absorption (AUC) by 10%.

Trials

Among 2418 duloxetine-treated patients for major depressive disorder, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 duloxetine-treated patients were exposed for at least 180 days and 445 duloxetine-treated patients were exposed for at least 1 year.

Among 1074 duloxetine-treated patients for diabetic peripheral neuropathy, 568 patients participated in two 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to duloxetine for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to duloxetine, and 220 had 12 months of exposure.

In one trial nearly a fifth of the volunteers testing duloxetine, dropped out after a 19-year old student committed suicide at a company laboratory. The student, Traci Johnson, was one of 25 healthy patients at an Eli Lilly clinic who were being given larger than therapeutic doses of duloxetine. Four days before her death, Ms. Johnson was taken off duloxetine and given a placebo.

Four other patients who were given the drug during earlier trials also committed suicide, the company said.

Ms. Johnson's death came less than a week after a federal advisory panel concluded that the Food and Drug Administration should issue stronger warnings to doctors that this class of antidepressants may be linked to suicide and violent behavior in children and teenagers.

Duloxetine as Cymbalta now comes with a suicide risk warning for children and adolescents.

Dosing and administration

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 daily. Although doses up to 120 mg/day have been utilized, no clinical superiority has been demonstrated when compared to 60 mg/day and an increase of adverse events were noted at higher doses.

How it works

When serotonin and noradrenaline 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 noradrenaline released from nerve cells in the brain.

Duloxetine works by preventing serotonin and noradrenaline from being reabsorbed back into the nerve cells in the brain, specifically on the 5-HT receptor. This helps prolong the "mood lightening" effect of any released serotonin and noradrenaline. In this way, duloxetine is thought to help relieve depression.

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 sytem that naturally inhibit pain.

Duloxetine is also used to treat urinary incontinence.

Efficacy of Duloxetine (Cymbalta) versus Venlafaxine (Effexor)

In a study by Bymaster and colleagues it was found that duloxetine inhibited binding to the human NE and 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.

The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively.

Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Side effects

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.

-Dry mouth

-Headache

-Insomnia

-Sleepiness

-Dizziness

-Fatigue

-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

-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

-Myoclonus

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.

Brain shivers, also known as "the electric brain thing", "battery head", "brain zaps", "Blips", "Effexor shocks" or "brain spasms", are a rare but notorious withdrawal symptom of certain antidepressants. Paresthesia and "electric shock sensations" are clinical terms used to describe this symptom. Many medical professionals are still unaware of the possible occurrence.

The brain shiver effect appears to be almost unique to those antidepressant chemicals that have an extremely short half-life in the body; that is, they are quick to disappear completely. This attribute of abruptness leaves the brain a relatively short time to adapt to a major neurochemical change when you stop taking the medication, and the symptoms may be caused by the brain's readjustment. There is no evidence that the shivers present any danger to the patient experiencing them.

Serious Adverse Effects

As duloxetine stays on the market longer many researchers worldwide are finding a variety of adverse effects.

As of Septmeber 27, 2005, journalist Jeanne Lenzer, writing for slate.com [1], uncovered 41 deaths and 13 suicides for patients taking duloxetine (cymbalta).

The French journal Prescrire International stated the opinion (2006 Oct;15(85):168-72) "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."

In the Journal of Annual Toxicology, (2006 Oct;30(8):576-480) the Los Angeles County Department of Coroner released a report of the first postmortem studies of duloxetine, which found cases of multiple drug reactions including duloxetine which was the cause death.

A case of hyponatremia induced by duloxetine was reported by doctors at Weil Medical College in New York (J Clin Psychopharmacol. 2006 Dec;26(6):675-6).

A case of dyskinesia during treatment with Duloxetine was reported in Germany (Pharmacopsychiatry. 2006 Nov;39(6):237-8).

Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjuction with other medications. (J Clin Psychopharmacol. 2006 Dec;26(6):681-683, Anesth Analg. 2006 Dec;103(6):1466-8).

Discontinuing Duloxetine

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.

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.

In another trial by Detke and colleagues, discontinuation rates were more frequent in duloxetine-treated patients and the most frequent adverse events were nausea, dry mouth, dizziness, and constipation.

Data obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder by Lilly Research found that patients with discontinuation-emergent adverse events (DEAEs) were reported by 44.3% of duloxetine patients, with an average of 2.4 DEAE's per patient. The report stated that abrupt discontinuation of duloxetine is associated with DEAE profiles similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. 35% of DEAE's lasted longer than one week. No follow up was published by Lilly stating the duration of DEAE's longer than one week ultimately persisted for.

Subsequently, Eli Lilly recommendeds that, "whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment." Tapering process may be moot for some patients, and they will still have discontinuation/withdrawal symptoms.

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.

Initial research on discontinuation/withdrawal syndrome attributes the syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor) and body (nerve growth factor) in the absence of duloxetine, as well as over-excited immune system. The latter due to duloxetine's immune suppressing effects.

Controversy

In the 1980s, Lilly waged a successful campaign to get fluoxetine, brand name Prozac, through the FDA even though not a single study submitted to the agency showed the drug to be effective for depression when taken alone. Once approved, Lilly marketed the drug as a revolutionary substance that selectively targeted the brain chemical serotonin: “This medicine works by bringing the level of serotonin in your brain back to normal.” Unlike the cheap generics on the market, the Prozac class of drugs does not affect norepinephrine, which was said to cause all the side effects of the older tricyclic antidepressants. Thus began a marketing campaign that made Prozac and the other SSRI antidepressants billions of dollars in profits.

When the patent expired on Prozac, in 2001, and annual sales for Lilly went down from billions to millions, Lilly brought out a new antidepressant, Cymbalta, again after heavily massaging the FDA and providing no peer reviewed data. With its approval came a new and highly innovative marketing message: Cymbalta is better than Prozac because it has a dual action in the brain. It not only targets serotonin, it also impacts another important neurochemical, norepinephrine. This flatly contradicts the ‘serotonin/good, norepinephrine/bad’ story that launched the SSRI revolution that Lilly started with fluoxetine.

At the time of its release in 2004, Cymbalta was by far the most promising medicine in Eli Lilly's pipeline. Like venlafaxine, brand name Effexor, a pill 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 in June 2008, Lilly is working on at least two new antidepressants.

References

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.

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.

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® package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.

FDC Reports Pharmaceutical Approvals Monthly 2004;9(11):33-4.

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.

External links

• Manufacturer website
• Duloxetine and Duloxetine (Systemic) - medlineplus.org
• Prescribing Guide
• FDA Alert for Healthcare Professionals
• FDA Patient Information Sheet
• Cymbalta Information - depression-guide.com
• Askapatient.com Cymbalta User Ratings