In August 2004, the Food and Drug Administration (FDA) approved Eli Lilly's duloxetine (Cymbalta) for the treatment of major depressive disorder. In September 2004, the FDA also granted approval of duloxetine for pain caused by diabetic peripheral neuropathy. Depression is a psychiatric disorder that affects an estimated 18 million U.S. citizens and is expected to be the second leading cause of disease or injury by 2020. 1,2
Indications
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Other examples include: mirtazapine (Remeron) and venlafaxine (Effexor).
Duloxetine may be used in patients in which selective serotonin reuptake inhibitors (SSRIs) have not been effective or as a first-line choice for the treatment of depression. The medication has a similar side effect profile to SSRIs, but has a faster onset of therapeutic action. 3
Four randomized, placebo-controlled studies have been conducted using duloxetine for the treatment of major depressive disorder. 4-6 Two of these studies used 60 mg daily doses, one used 120 mg daily doses, and one used 40 or 80 mg daily doses. More than 1,000 patients ranging from 18 to 83 years of age were involved in studies that continued for 8 to 9 weeks. Another 1,200 patients were followed for up to 1 year in an open-label study with flexible doses of 80 to 120 mg/day. 7
Mechanism of Action
The biochemical pathophysiology of depression is complex and poorly understood. The long-held mono-amine deficiency hypothesis of depression proposes that depression is a result of decreased activity in the monoaminergic pathways. 3 More specifically, alterations in the function of the neurotransmitters, receptors, and/or transporters of the serotonin precursor 5-hydroxy-tryptamine and norepinephrine are associated with depression. Antidepressant medications typically focus the mechanism of action on only one of these neurotransmitters-the re-uptake inhibition of 5-HT with SSRIs or norepinephrine with tricyclic antidepressants.
Duloxetine's mechanism of action is believed to be related to the potentiation of serotonin and norepinephrine through its inhibition of the reuptake of these neurotransmitters. The increase in these synaptic neurotransmitters is believed to improve the symptoms of depression. In vitro studies of duloxetine indicate it does not have a significant affinity for dopaminergic, adrenergic, cholinergic, or histaminergic receptors, nor does it inhibit monoamine oxidase. 7
Drug Metabolism
Duloxetine is well absorbed after oral administration. The enteric coating favors absorption beyond the stomach in the less acidic environment of the small intestine. Maximal plasma concentrations occur within 6 hours after ingestion. Concomitant ingestion of food may slightly delay the time of peak concentration and marginally decrease the extent of absorption. 7 The drug is highly bound (>90%) to plasma proteins, primarily albumin and glycoproteins.
Duloxetine undergoes extensive metabolism in the liver's CYP 2D6 and CYP 1A2 enzymatic subsystems. Although numerous metabolites are produced, these do not appear to result in any significant pharmacologic activity. The metabolites of duloxetine are excreted predominantly in the urine (70%) and feces (20%).
Duloxetine is primarily metabolized by the hepatic cytochrome P-450 enzymes, and drug interactions need to be considered. Drugs such as cimetidine (Tagamet), ciprofloxacin (Cipro), and enoxacin (Penetrex) that inhibit CYP 1A2 and quinidine (Quinaglute) that inhibit CYP 2D6, may cause increased duloxetine concentrations. 8
Duloxetine may inhibit the CYP 2D6 enzyme and other medications metabolized by this system. These drugs include: desipramine (Norpramin), nortriptyline (Aventyl), amitriptyline (Elavil), imipramine (Tofranil), phenothiazines and Type 1C antiarrhythmics (propafenone/ flecainide). Those with a narrow therapeutic range should be carefully monitored for elevated levels. The practitioner should also be aware that because duloxetine is highly protein-bound, the coadministration of other highly protein-bound drugs might cause alterations in the concentration of either drug.
Contraindications
Duloxetine is contraindicated in patients with a known sensitivity to this medication or with a patient on a monoamine oxidase inhibitor. Additionally, patients with narrow-angle glaucoma should avoid this drug. Duloxetine is not recommended for patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min).
Duloxetine is a Pregnancy Category C medication and has not been studied in pregnant women. The clinician should carefully evaluate the risks and benefits of using this medication in pregnancy. The medication is not recommended for use by nursing mothers. Increased patient age is not a specific contraindication to the use of duloxetine and the dose need not be adjusted for this factor alone.
Adverse Reactions
Adverse events leading to discontinuation in the studies were similar among the treatment groups. The most common (occurring in >5% of the drug-treated study population) included nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating. 7,8 Sexual dysfunction, a common side effect of many antidepressants, was significant only in males using duloxetine. Difficulty in reaching orgasm was the one item in the Arizona Sexual Experience Scale (ASEX) that was significantly different for the drug-group males versus the placebo-group males. No significant sexual dysfunction was reported in women. However, estimates of sexual dysfunction, especially in patients with psychiatric disorders, are likely to be underestimated due to patient and provider reluctance to report such experiences. 7
Dosage and Administration
Duloxetine is available in 20, 30, and 60 mg capsules and is distributed in bottles of 30, 60, 90, or 1000 capsules and in 100 unit-dose cartons. The typical dose is 40 mg given as 20 mg twice daily or 60 mg given either as 30 mg twice daily or 60 mg once daily. Duloxetine may be given without regard to meals.
Special Instructions
There is a critical need for identification of this disease. Simple depression screening tools are useful and reasonable resources to help identify a depressed patient (see Table: "Depression Screening Tool"). Careful monitoring for abrupt changes in behavior should always be part of the plan of care in the depressed patient.
The most common adverse effects are nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, increased sweating, and in males, sexual dysfunction. 7,8 The prescriber should gradually taper the dose if stopping the medication.
The practitioner should be cautious about the use of duloxetine in patients with elevated serum transaminase levels (i.e., those with chronic alcoholism or other hepatic disease). A slight increase in blood pressure (average 2 mm Hg systolic and 0.5 mm Hg diastolic) was noted in the clinical trials and therefore, blood pressure should be monitored frequently. 7 Patients with bipolar disorder may present with episodes of hypomania that could be mistaken for depression. Caution should be exercised in patients with a history of mania/hypomania when prescribing duloxetine. 8
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