FDA, NIMH Scrutinize Antidepressant-Linked Suicidality

March 1, 2007

In a meeting this past December, an FDA advisory committee recommended that the black-box warning of antidepressant-linked suicidality in children and adolescents should also warn of the risk in young adults. Meanwhile, the NIMH had announced in November its sponsorship of 5 new studies to elucidate this adverse drug effect, particularly focusing on the SSRI antidepressants.

In a meeting this past December, an FDA advisory committee recommended that the "black-box" warning of antidepressant-linked suicidality in children and adolescents should also warn of the risk in young adults. Meanwhile, the NIMH had announced in November its sponsorship of 5 new studies to elucidate this adverse drug effect, particularly focusing on the SSRI antidepressants.

"These new, multi-year projects will clarify the connection between SSRI use and suicidality," said NIMH Director Thomas Insel, MD. "They will help determine why and how SSRIs may trigger suicidal thinking and behavior in some people but not others, and may lead to new tools that will help us screen for those who are most vulnerable."

The Psychopharmacologic Drugs Advisory Committee recommended a warning covering a wider susceptible age range after reviewing a new meta-analysis of adult antidepressant trials. The committee made the recommendation despite hearing testimony that a broader warning could paradoxically increase suicide risk by further discouraging appropriate antidepressant treatment. Christopher Kratochvil, MD, representing the American Academy of Child and Adolescent Psychiatry, was one of several speakers to caution the committee about such an outcome.

There was a decline of about 20% in new pediatric antidepressant prescribing from 1 year before to 1 year after the current black-box warning was issued, according to Kratochvil. "This decline was due in part to physicians who stopped treating depressed patients, as well as referrals to specialists with excessive waiting periods due to a significant workforce shortage," he explained, "leaving many children and adolescents with depression with limited access to care."

Carolyn Robinowitz, MD, president-elect of the American Psychiatric Association, suggested that a "black-box panic" could result and further impede provision of needed care. Paula Clayton, MD, medical director of the American Foundation for Suicide Prevention stated, "not treating depression carries a far greater risk of suicide than any potential adverse effects of these medications."

These concerns notwithstanding, the committee found the FDA data of antidepressant-linked suicidality occurring through young adulthood compelling. "We want to extend the age in the black box and at the same time not discourage treatment," committee member Andrew Leon, MD, commented.

Analyzing trial data
In their meta-analysis of 372 antidepressant trials involving almost 100,000 subjects, FDA staffers Marc Stone, MD, and Lisa Jones, MD, MPH, found a suicidality adverse drug effect, manifested as ideation or behavior, more likely with the SSRI class (odds ratio, 1.23) than the tricyclic antidepressants (odds ratio, 0.8); other drugs fell between the two and were characterized by the analysts as "generally similar."

The suicidality risk for active drug relative to placebo was most prominent in adults younger than 25 years, while there was a negative association of suicidality with antidepressant treatment in older adults. "There appears to be a further distinction between a modest protective effect in subjects age 25 to 64 . . . and a stronger protective effect in subjects aged 65 and older," Stone and Jones observed.

Suicidality was found in 0.26% of subjects whose depression symptoms had responded to antidepressant treatment, according to the criteria of the respective trial, and in 1.18% of nonresponding subjects. Although there were too few patients manifesting suicidality for this distinction to be statistically significant, the analysts found it intriguing. "The results are consistent with the idea that an increased risk of suicidal behavior in young adults associated with antidepressant treatment may be limited to subjects who do not show a clinical response to treatment," they suggested.

The meta-analysis was characterized as "exploratory" by Thomas Laughren, MD, director of psychiatry products at the FDA, because suicidality had not been a primary effect for assessment in any of the trial designs. The new NIMH-sponsored studies, however, are expected to provide more detail on the risk of and emergence of antidepressant-linked suicidality.

The new studies
A study by Kelly Kelleher, MD, MPH, of Ohio State University and Joel Greenhouse, PhD, of Carnegie Mellon University will use much of the same data gathered by the FDA. However, Kelleher and Greenhouse have proposed innovative statistical approaches to integrate data from numerous other studies, and they anticipate revealing a "more complete picture of the relationship between antidepressant medication use and suicidal thoughts or actions," according to the NIMH announcement.

The NIMH grant to Marcia Valenstein, MD, of the University of Michigan, will enable analysis of the records of almost 1 million persons from the US Department of Veterans Affairs National Registry for Depression, Medicare records, and the National Drug Index to ascertain relationships between antidepressant use, suicide attempts and/or deaths, and use of concurrent medications or treatments. The NIMH indicated that the study will "help determine the relative effectiveness of different depression treatments in reducing suicidal thoughts and actions."

Wayne Goodman, MD, of the University of Florida, will study pediatric patients with obsessive-compulsive disorder to determine whether their SSRI treatment can induce an "activation syndrome" that may lead to suicidal thoughts or actions. "By focusing on patients with a disorder that is less likely to be associated with suicidality, he will be able to better assess whether SSRIs are related to an actual activation syndrome, and whether suicidality is a component of the syndrome," the NIMH announcement explains.

Several large datasets of SSRI users will be examined by Sebastian Schneeweiss, MD, ScD, of Brigham and Women's Hospital in Boston, to measure rates of suicidality and identify social and demographic factors that may be associated with SSRI use and suicidality. Schneeweiss will also examine the impact of the FDA warnings on the use of SSRIs. "The study aims to develop and better target prescribing and risk management strategies," the NIMH announced.

A fifth NIMH-funded study will be conducted by Prudence Fisher, PhD, of the New York State Psychiatric Institute. The investigator intends to construct a standardized computer tool for adolescents and parents that can be used to screen for antidepressant-linked suicidality. Fisher expects the study to yield "better and more reliable ways of monitoring for adverse reactions."

References:

Reference:1. Stone MB, Jones ML. Clinical review: relationship between antidepressant drugs and suicidality in adults. In meeting documents of the Psychopharmacologic Drugs Advisory Committee. Silver Spring, Md; 2006.