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http://www.familypracticenews.com/article/PIIS0300707305715152

Volume 35, Issue 16, Pages 1-13 (15 August 2005)

FDA Renews Alert On Antidepressants And Suicide Risk: Agency requests data from clinical trials.

ALICIA AULT (Contributing Writer)

The Food and Drug Administration is strongly advising health care providers and patients to be aware of a potential increased risk of suicidal behavior in adults who take antidepressants. The agency recommended a closer reading of current labeling—which warns of that potential—and improved monitoring of depressed patients on drug therapy.

The FDA has also asked manufacturers to submit all available clinical trial data on the drugs in an effort to determine whether any link exists between them and suicidal thoughts or acts.

The data request is similar to what had been asked of the manufacturers in 2004, when the agency sought to explore the link between antidepressants and suicidal ideation and attempts in children and adolescents. In March, the FDA asked 10 manufacturers to submit trial data on anticonvulsants because of the potential increased risk of suicidal behavior with those drugs.

According to an agency spokeswoman, the latest move was spurred by three papers published in February in the British Medical Journal. Two of those studies concluded that there was not necessarily a higher risk of suicidal behavior with selective serotonin reuptake inhibitors (SSRIs), but that it could not be ruled out. A third paper, a systematic review of published controlled trial data on SSRIs, found an association between the drugs and suicide attempts but said a more accurate estimate could only be gleaned by full reporting of events ("Data Mixed on SSRIs and Adult Risk of Suicide," March 15, 2005, p. 48).

The drugs covered by the FDA's latest request include citalopram (Celexa), duloxetine (Cymbalta), venlafaxine (Effexor), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine, mirtazapine (Remeron), nefazodone (Serzone), buproprion, and sertraline (Zoloft).

A separate alert was issued on duloxetine, after open-label extensions of controlled studies of the drug in stress urinary incontinence in adult women found a suicide attempt rate of 400/100,000 person-years, compared with 150–160/100,000 reported in the literature.

The FDA will sift through the data and categorize adverse events, including suicidal ideation, attempts, and completions, and other instances of self-harm, using the criteria developed by Columbia University to gauge risk in pediatric populations. The agency did not release other details, aside from saying that the "effort will involve hundreds of clinical trials and may take more than a year to complete."

Darrel Regier, M.D., director of the research division at the American Psychiatric Association, said he hopes the agency will not rely solely on spontaneous reports by investigators from the studies, which tend to be subjective, and may not reflect the entire picture. "I think they should give more emphasis to studies where they have Hamilton scales or where they have systematically evaluated the patients at the beginning for suicidal ideation and behavior," he told FAMILY PRACTICE NEWS.

A joint APA-American Academy of Family Practice pilot project could be the start of gathering more accurate data, he said. Twenty psychiatry practices and 20 primary care practices are participating in using the depression scale of the Patient Health Questionnaire-9 to identify depressed patients and monitor responses.

It's still unclear exactly how antidepressants affect mood, but there is some biologic plausibility to the idea that they could stimulate suicidal thoughts or acts, Dr. Regier said. There is some agreement that antidepressants put depressed patients at risk because they decrease psychomotor retardation before they have an elevating effect on mood. Medication or talk therapy can each have that "activation" effect. "The risky part of bringing somebody out of depression with any form of treatment is they have the energy to be able to effectively carry out a suicide attempt," he said.

Jeff Susman, M.D., chairman of the department of family medicine at the University of Cincinnati, agrees that antidepressants can have this activation effect. "Any treatment, whether with SSRIs or another form of pharmacotherapy, I think is likely to be associated with some risk of suicide association," he said, noting that the therapy might give patients the ability "to carry out an ideation they didn't have the wherewithal to act upon in the past."

But as clinicians become better at detecting and treating depression, they will see more patients at risk, and thus, report more attempts and completions, which could initially make the data hard to interpret. Plus, there's not much information on how the various medications differ. "We're really dealing with very incomplete data," said Dr. Sussman, who is on the speakers' bureaus or advisory boards of Forest Labs, Wyeth, Organon, and Pfizer in the areas of depression, anxiety, and mental health.

Antidepressant labels already have black box warnings on increased risk of suicidality in children and adolescents, and urge weekly face-to-face meetings between patients and clinicians during the first 4 weeks, followed by biweekly visits for the next month, and another visit at 12 weeks. The label also cautions that adults with major depressive disorder or comorbid depression "should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases."

Dr. Regier said some physicians fear that if they don't follow the FDA monitoring schedule that they may be exposed to liability for not following a standard of care. That may be dampening use of the medications, he said. Dr. Susman agreed that he's heard of reluctance to prescribe antidepressants.

"There is a palling effect, if you will, of the negative PR. The worst possible thing we could be doing is creating doubt in people's minds on whether depression should be treated with antidepressants," he said, noting that drug therapy is extremely effective.