Duloxetine (CYMBALTA) for Major Depressive Disorder - Nothing Special and Possible Liver Toxicity

Duloxetine (CYMBALTA) was approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in adults in August 2004. It has also been approved for a nerve condition seen in diabetics known as diabetic peripheral neuropathy. This article focuses on the use of duloxetine in depression.

Duloxetine is marketed by Eli Lilly and Company of Indianapolis.

MDD is a depressed mood accompanied by several of the following problems that have been present for at least several weeks. If a careful history, physical examination, and lab tests have ruled out specific causes of depression, then MDD is probably the diagnosis. The problems are sadness that impairs normal functioning, difficulty concentrating, low self-esteem, guilt, suicidal thoughts, extreme fatigue, low energy level or agitation, sleep disturbances (increased or decreased), or appetite disturbance (increased or decreased) with associated weight change.

Some drugs can also cause depression.

Duloxetine is classified as a serotonin and norepinephrine reuptake inhibitor (SNRI) or dual reuptake inhibitor. As one physician observer of drugs used to treat serious mental illness has noted, duloxetine has “dual the reuptake, triple the hype.” The other SNRI inhibitor on the market is venlafaxine (EFFEXOR).

Our major safety concern with duloxetine is the possibility of liver toxicity. The FDA medical officer that reviewed the drug found a small but statistically significant excess of discontinuations of treatment due to liver-related adverse events in patients treated with duloxetine compared to those given a placebo in clinical trials conducted before the drug was approved.

In his conclusions and recommendations regarding duloxetine’s liver toxicity, the medical officer wrote:

In the event that unconfounded cases of severe liver injury or acute liver failure related to duloxetine treatment are identified and submitted early in the postmarketing period, the division will use the threshold of three “clean” cases to initiate additional regulatory action that could range from a more prominent warning to the withdrawal of the drug product.

This is a remarkable statement. The FDA obviously has serious concerns about the safety of duloxetine, yet they still allowed it on the market. By approving duloxetine, the FDA has made the American public guinea pigs in a large uncontrolled safety experiment. Because duloxetine is nothing special and there are numerous options to treat major depressive disorder in adults, the proper course of action for the FDA should have been to require the manufacturer to conduct more studies to clarify the liver toxicity issue before approving the drug.

The FDA-approved professional product labeling, or package insert, for duloxetine does warn pharmacists and physicians about an increased risk of elevations in blood levels of liver enzymes. Elevations in liver enzyme levels are an early signal of possible liver toxicity. However, there is no requirement in the professional product labeling that physicians monitor liver enzymes. Physicians are cautioned not to prescribe duloxetine to patients who regularly use alcohol because of the possibility of liver toxicity.

Blood pressure elevation is another area of concern with duloxetine. The FDA medical officer recommended that:

Patients taking duloxetine should be monitored regularly for hypertension (high blood pressure). There is evidence for a dose dependent increase in the incidence of elevated blood pressure with duloxetine treatment. These increases do not appear to pose an acute risk; however, given that the treatment of Major Depressive Disorder (MDD) is chronic in nature, patients’ blood pressures could easily drift into ranges that are associated with increased risk of heart disease and stroke. 24% of patients taking duloxetine 120-mg/day (milligrams per day) experienced elevated blood pressures versus 9% of placebo patients.

The FDA-approved professional labeling for duloxetine advises that blood pressure be measured prior to starting treatment and periodically measured throughout treatment.

Duloxetine and all of the other antidepressants marketed in the U.S. now carry warnings in their professional product labeling about worsening of depression and an increased risk of suicide. Patients being treated with antidepressants should be observed closely for worsening of their depression and suicidal ideation and behavior, especially at the beginning of a course of drug therapy, or at the time of either increases or decreases in dose changes.

Duloxetine is not approved for use in children or adolescents with major depressive disorder. The drug’s professional product labeling contains the following uninformative statement about the use of duloxetine in children and adolescents “Safety and efficacy in pediatric patients have not been established.” This could mean that the drug failed in clinical trials in this age group but the manufacturer decided not to make the results public. The bottom line is that duloxetine has not been shown to be of therapeutic benefit in younger patients.

Abruptly stopping duloxetine treatment can result in a withdrawal syndrome that consists of the following symptoms: dizziness; nausea; headache; a sensation of pricking, tingling, or creeping on the skin (paresthesia); vomiting; irritability; and nightmare. Discontinuation of duloxetine should only be done under medical supervision.

Duloxetine was approved by the FDA on the basis that it was more effective than a placebo, in other words, better than nothing. One of the games that pharmaceutical manufacturers play when their new drug is only better than nothing is to create an image that the new drug has unique effects compared to other similar drugs in its family. In the case of duloxetine, Eli Lilly is trying to claim that the drug has special value in managing the painful symptoms of major depressive disorder.

At this time, any claim that duloxetine is useful for managing pain is groundless.

The Medical Letter on Drugs and Therapeutics, a source we frequently cite because of its independence from drug company influence, found that duloxetine was “nothing special” and concluded their October 11, 2004 report by saying:

Whether duloxetine offers any advantage over venlafaxine (EFFEXOR) or an SSRI [selective serotonin reuptake inhibitor] such as fluoxetine (PROZAC, and others) remains to be established. The manufacturer’s claim that duloxetine is the antidepressant for painful physical symptoms associated with depression is unsupported; no comparative trials are available.

What You Can Do

There is no medical reason why you should be taking duloxetine when safer antidepressants are available on the market.