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Out of the Pipeline


Duloxetine: Dual-action antidepressant

Targeting depression’s emotional and physical symptoms

Vol. 3, No. 9 / September 2004

Depression’s remission rates remain low,1 and its common somatic symptoms (aches and pains, headaches, backaches) often complicate diagnosis and treatment.2

Duloxetine, recently FDA-approved for treating major depression Table 1, has shown efficacy against depression’s emotional and somatic symptoms in clinical trials.

HOW IT WORKS

Duloxetine inhibits both serotonin and norepinephrine reuptake. Researchers suggest that antidepressants exhibiting this dual action may be more effective and act faster than single-action selective serotonin reuptake inhibitors.3,4 Newer dual-action antidepressants also are more tolerable than dual-action tricyclic antidepressants.

Table 1

Duloxetine: Fast facts

Drug brand name:
Cymbalta

Class
Serotonin and norepinephrine reuptake inhibitor

FDA-approved indication:
Treatment of major depressive episodes

Approval date:
August 3 2004

Manufacturer:
Eli Lilly and Co.

Dosing form:
20 mg, 30 mg, 60 mg capsules

Recommended dosage:
40 to 60 mg/d

Maximum dosage(studied in major depression):
120 mg/d

Researchers have seen synergism between serotonergic and noradrenergic pain modulation at the spinal cord,4,5 suggesting that dual-action antidepressants may ameliorate major depression’s somatic symptoms.

Table 2

Plasma levels of these agents may affect—or be affected by— duloxetine coadministration

CYP 2D6 substrates

Amitriptyline

Beta blockers Propranolol, metoprolol, timolol

Desipramine

Fluoxetine

Fluvoxamine

Haloperidol

Nortriptyline

Risperidone

Thioridazine

Type 1C antiarrhythmics Propafenone, flecainide

Venlafaxine

CYP 2D6 inhibitors

Cimetidine

Fluoxetine

Haloperidol

Paroxetine

Quinidine

CYP 1A2 inhibitors

Cimetidine

Ciprofloxacin

Enoxacin

Source: Reference 7

PHARMACOKINETICS

Despite its 12-hour plasma half-life, duloxetine has shown efficacy in clinical trials when given once daily. Mean plasma clearance is approximately 101 L/hr, with a mean volume of distribution of about 1640 L, meaning that duloxetine is distributed throughout the body.

The agent is more than 90% protein bound; thus, giving duloxetine concomitantly with another highly protein-bound agent could increase the side-effect risk of either drug.

Food does not alter duloxetine’s absorption but delays maximum concentration by about 4 hours Duloxetine may be taken before or after meals, though taking it after meals could reduce the risk of nausea—a common early side effect.

Duloxetine is metabolized by the 2D6 and 1A2 isoenzymes of the cytochrome P-450 system. It inhibits the CYP 2D6 isoenzyme but to a lesser extent than fluoxetine does.6 Co-administering duloxetine with a CYP 2D6 substrate or inhibitor or a CYP 1A2 inhibitor Table 27 could elevate plasma levels of duloxetine or the other agent, possibly increasing adverse effects.

EFFICACY

In an 8-week, placebo-controlled trial, Goldstein et al8 compared fluoxetine, 20 mg/d, and duloxetine, 40 mg/d titrated to 120 mg/d over 3 weeks, in 173 patients with major depressive disorder. Participants’ scores at baseline were 15 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and 4 on the Clinical Global Improvement-Severity scale. Estimated probability of remission was 56% with duloxetine, 30% with fluoxetine, and 32% with placebo, with remission defined as achieving a HAM-D-17 score 7.

In two prospective, double-blind, placebocontrolled trials of 512 patients with major depression,9,10 duloxetine, 60 mg/d, reduced body, back, and shoulder pain based on Visual Analog Scale (VAS) scores; pre- and posttreatment VAS scores were not listed in the published studies. Estimated probability of remission in these two studies was 44% and 43% among patients taking duloxetine vs 16% and 28% in the placebo groups. Remission again was defined as HAM-D-17 score 7.

TOLERABILITY

In the two double-blind studies just mentioned,9,10 Detke et al reported adverse event-related drop out rates of 12.5% and 13.8% for duloxetine, 60 mg/d, vs 4.3% and 2.3% for placebo. Nausea, insomnia, headaches, somnolence, dry mouth, and sweating were most frequently reported.

Dizziness. Mild dizziness was reported in 11.3% of patients who abruptly stopped duloxetine after 9 weeks.9

Headaches. In one comparator trial,8 fewer headaches (20%) were reported among patients taking duloxetine, 40 to 120 mg/d, vs those taking fluoxetine, 20 mg/d (33.3%), or placebo (31.4%).

Hypertension. Detke et al10 found no statistical separation in systolic and diastolic blood pressures between the duloxetine (60 mg/d) and placebo groups. Likewise, Goldstein et al8 found a similar incidence of hypertension among patients taking duloxetine, 40 to 120 mg/d, or placebo. In clinical trials,11 duloxetine increased blood pressure by a mean of 2.0 mm Hg (systolic) and 0.5 mm Hg (diastolic).

As with several other noradrenergic medications, FDA recommends that clinicians check blood pressures before starting duloxetine therapy and periodically thereafter.

Duloxetine has not been studied in persons with poorly controlled hypertension.

Nausea. Mild to moderate nausea was the most common adverse event in one study;9 the effect dissipated after a median of 7 days. One patient reported severe nausea, and 1 patient out of 123 stopped the medication because of nausea.

Sexual dysfunction. Using the Arizona Sexual Experiences Scale (ASEX), Goldstein et al8 prospectively assessed sexual function in 70 men and women taking duloxetine or placebo. No statistical difference was seen between the two groups from baseline to endpoint.

In another study,12 duloxetine showed worsening only in ASEX item 4 (“How easily can you reach an orgasm?”), indicating some adverse sexual effects in men. No such differences were found in women. Duloxetine’s effect on sexual function needs to be studied further.

Duloxetine is an FDA Use-in-Pregnancy category C medication, meaning that risk to the fetus has not been ruled out. The agent is contraindicated in patients taking monoamine oxidase inhibitors and in those with narrow-angle glaucoma. FDA recommends not using duloxetine in patients with hepatic insufficiency, endstage renal disease, and substantial alcohol use.

DOSING STRATEGIES

Duloxetine, 40 to 120 mg/d, appears to be safe and effective for most adults.8-10 FDA recommends starting at 40 mg/d (20 mg bid) to 60 mg/d (once-daily or 30 mg bid) with no regard to meals. Dosages >60 mg/d have not shown additional benefit. Age and tolerability should drive initial dosing and titration. Side-effect incidence has not been directly compared at 60, 90, and 120 mg/d.

CLINICAL IMPLICATIONS

In clinical trials, duloxetine has shown a high estimated probability of remission in major depression and has shown efficacy against depression’s physical and emotional symptoms. Based on efficacy and safety data, duloxetine appears to be a first-line treatment option for major depression.

Related resources

  • Gray GE. Concise guide to evidence-based psychiatry. Washington, DC: American Psychiatric Publishing, 2004.
  • Schatzberg AF, Nemeroff CB (eds). Textbook of psychopharmacology (3rd ed). Washington, DC: American Psychiatric Publishing, 2004.

Drug brand names

  • Amitriptyline • Elavil
  • Cimetidine • Tagamet
  • Ciprofloxacin • Cipro
  • Desipramine • Norpramin
  • Duloxetine • Cymbalta
  • Enoxacin • Penetrex
  • Fluoxetine • Prozac
  • Flecainide • Tambocor
  • Fluvoxamine • Luvox
  • Haloperidol • Haldol
  • Metoprolol • Toprol
  • Nortriptyline • Pamelor
  • Paroxetine • Paxil
  • Propafenone • Rythmol
  • Propranolol • Inderal
  • Risperidone • Risperdal
  • Thioridazine • Mellaril
  • Timolol • Blocadren, others
  • Venlafaxine • Effexor

Disclosure

Dr. Rakesh Jain receives research grants from Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Merck and Co., Organon, Pfizer Inc., and Sepracor. He is a consultant to and speaker for Eli Lilly and Co., and is a speaker for GlaxoSmithKline, Pfizer Inc., and Wyeth Pharmaceuticals.

Dr. Shailesh Jain reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of compefting products.

References

1. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or serotonin reuptake inhibitors. Br J Psychiatry 2001;178:234-41.

2. Fava M. The role of the serotonergic and noradrenergic neurotransmitter systems in the treatment of psychological and physical symptoms of depression. J Clin Psychiatry 2003;64(suppl 13):26-9.

3. Tran PV, Bymaster FP, McNamara RK, Potter WZ. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol 2003;23:78-86.

4. Ansari A. The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature. Harv Rev Psychiatry 2000;7:257-77.

5. Willis WD, Westlund KN. Neuroanatomy of the pain system and the pathways that modulate pain. J Clin Neurophysiol 1997;14:2-31.

6. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003;73:170-7.

7. Sadock BJ, Sadock VA. Kaplan and Sadock's pocket handbook of psychotropic drug treatment (3rd ed). Baltimore, MD: Lippincott Williams and Wilkins, 2001.

8. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack M. Duloxetine in the treatment of major depression disorder: a double-blind clinical trial. J Clin Psychiatry 2002;63:225-31.

9. Detke MJ, Lu Y, Goldstein DJ, et al. Duloxetine 60 mg once-daily for major depressive disorder: a randomized double-blind placebocontrolled trial. J Clin Psychiatry 2002;63:308-15.

10. Detke MJ, Lu Y, Goldstein DJ, et al. Duloxetine 60 mg once daily dosing versus placebo in the treatment of major depression. J Psychiatr Res 2002;36:383-90.

11. Cymbalta prescribing information Eli Lilly and Co 2004.

12. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 2004;24:389-99.

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