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Duloxetine: Dual-action antidepressant

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Targeting depression’s emotional and physical symptoms


 

References

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.

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