Do Not Use: Duloxetine (CYMBALTA)

After previously concluding that duloxetine (CYMBALTA) should not be used for major depressive disorder (MDD), Public Citizen’s Health Research Group has now classified the drug as “Do Not Use” for any form of depression as well as for all other uses for which it has been approved (for example, generalized anxiety or any form of pain, including fibromyalgia). For none of the approved indications is there evidence that the benefits outweigh the multiple serious risks discussed in this article.

In support of this “Do Not Use” determination for duloxetine, we cite the ongoing research debate over depression treatment involving serotonin (regarding its arguable connection to mental disorders) as well as a long list of serious adverse events — including suicidal thinking, drug interactions, increased bleeding and serotonin syndrome.

The conclusion that duloxetine should not be used for any purpose also was reached in February 2009 by Prescrire, the French journal of drug safety and efficacy, which stated, “Duloxetine: to be avoided in all circumstances.”

Duloxetine has been an unquestionable commercial success. In 2010, more than 14.5 million duloxetine prescriptions were written, with sales exceeding $2.6 billion. This success can be attributed not to solid evidence that duloxetine is a better drug than the other antidepressants, but to an aggressive advertising strategy promising that depression could be averted by simply adjusting the levels of chemical transmitters in the brain.

Questionable effectiveness of antidepressants

The way that duloxetine works is unknown, even though the Food and Drug Administration (FDA) classifies it as a serotonin and norepinephrine reuptake inhibitor (SNRI). The drug affects two naturally occurring chemical transmitters in the brain: serotonin and norepinephrine.The role of serotonin in the development of any mental disorder, including depression, is debatable. A 2005 Public Library of Science Medicine (PLoSM) editorial pointed out:

[T]here is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counter-evidence.

There are other important questions about the effectiveness of antidepressants. Dr. Irving Kirsch, in research published in 2002 with the provocative title The Emperor’s New Drugs, analyzed studies submitted to the FDA to support the approval of the six most widely prescribed antidepressants approved between 1987 and 1999. Approximately 80 percent of the subjects in the antidepressant and placebo groups responded. On the 17- and 21-item Hamilton Depression Scales (questionnaires used to assess the efficacy of antidepressants), subjects’ scores in the antidepressant and placebo groups differed by only two points. Improvement in the Hamilton scores of those taking the highest doses of antidepressants was no different than in those taking the lowest doses.

Furthermore, two statistical summaries of antidepressant clinical trials — in PLoSM and the Journal of the American Medical Association — found that the differences in behavior between subjects using antidepressants and those using placebos may be minimal or nonexistent.

Research is beginning to reveal that there may be effective alternatives to antidepressant drugs. Studies have concluded that exercise training may be considered an alternative to antidepressants for treatment of depression in older persons. In one study involving older people with varying degrees of depression, although antidepressants helped with a more rapid initial therapeutic response, after 16 weeks of treatment, exercise was equally effective as either medication or a combination of both in reducing depression. This was true both in patients who were more seriously depressed and those with lesser degrees of depression.

Duloxetine’s risks

The disputed serotonin theory of mental illness (including depression) and the dubious effectiveness of antidepressants in mild to moderate depression make a particularly strong case against using duloxetine, especially in view of the drug’s known risks.

The following are the major safety concerns associated with duloxetine use.

Suicidality. The FDA requires that duloxetine and all other antidepressants display a black box warning (see duloxetine’s warning) in their product labels regarding the increased risk of suicidal thinking and behavior in children, adolescents and young adults. This effect has been demonstrated in short-term studies of MDD and other psychiatric disorders.

A black box warning is the strongest type of safety alert the FDA can demand of drug manufacturers and can be required when there is evidence of serious injuries or death with a drug.

Drug-drug interactions. Duloxetine must not be used at the same time or around the same time that members of another family of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), are used. The MAOI family consists of four drugs: phenelzine (NARDIL), isocarboxazid (MARPLAN), tranylcypromine (PARNATE) and selegiline (ELDEPRYL).

The use of duloxetine with MAOIs can cause sometimes fatal drug interactions. These interactions may result in elevated temperature, muscle rigidity, muscle spasm, nervous system instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Serious reactions also may surface when using duloxetine with other drugs. In July 2006, the FDA issued a public health advisory about the possibility of life-threatening reactions that may be caused by the interaction of migraine headache drugs, called triptans (e.g., almotriptan [AXERT]), and certain anti-depressants.

Increased bleeding. Duloxetine use may increase the risk of bleeding, especially when taken with other drugs that affect blood clotting, such as nonsteroidal anti-inflammatory drugs and aspirin. 

Liver toxicity and liver failure. Liver toxicity and liver failure, sometimes fatal, have been reported in patients treated with duloxetine. Patients who develop jaundice (yellowing of the skin or eyes) or other evidence of of liver toxicity should stop taking duloxetine and should not restart it unless another cause of these symptoms can be established. 

Serotonin syndrome or Neuroleptic malignant syndrome (NMS). Serotonin is found in the brain, blood and gastrointestinal tract. Taking a combination of triptans, selective serotonin reuptake inhibitors and SNRIs (such as duloxetine) can increase serotonin to extremely high levels that could result in serotonin syndrome. Symptoms can include restlessness, hallucinations, loss of coordination, rapid heartbeat, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting and diarrhea. NMS also can occur when the body has too much serotonin.

In addition to the most serious adverse reactions discussed above, the most commonly observed adverse reactions in duloxetine-treated patients (incidence of at least 5 percent and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, drowsiness, fatigue, constipation, decreased appetite and hyperhidrosis (abnormally increased sweating).

What You Can Do

Do not discontinue any medication without consulting the prescribing physician. You should not stop duloxetine treatment abruptly. Gradual discontinuation under medical supervision is best.

Seek immediate treatment if you develop signs of liver toxicity, serotonin syndrome or NMS.

Consumers may report serious adverse events or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088