Report Questions FDA's Conclusions on Suicide Risk

The American College of Neuropsychopharmacology (ACNP) has determined that“ SSRIs and other new-generation antidepressant drugs, in aggregate, are associated with a small increase in the risk of [adverse event] reports (AEs) of suicidal thinking or suicide attempts in youth.” However, ACNP believes, increased reports of AEs are highly unlikely to accurately reflect real changes in incidence of actual suicidal events.

Moreover, ACNP said, its analysis of the AE reports upon which the Food and Drug Administration (FDA) based antidepressant black-box warnings shows the data are highly variable and inadequate to address the question of an actual causal association between the drugs and increased risk of suicidal thoughts or behaviors.

While AE reports appear to indicate an increased risk of suicidality with antidepressants compared with placebo, ACNP pointed out that clinical trials in which standardized questionnaires have been used to measure suicidal thoughts and behaviors have found no statistically significant difference in patients taking an active drug compared with those taking placebo.

More importantly, the report added, “Three other lines of evidence in youth: epidemiologic studies, autopsy studies, and recent cohort surveys, [also] do not support the hypothesis that SSRIs induce suicidal acts and suicide, instead indicating a possible beneficial effect.”

The report concluded that the benefits of treating youth who have depression with one antidepressant medication, in particular, outweigh the increase in risk of suicidal thoughts and nonfatal suicidal behavior found in an analysis of an FDA database of AE reports.

ACNP made six recommendations on how to approach the treatment of depression in youth and determine what association, if any, antidepressant drugs have with suicidality (Original article: see box).

“This is an excellent and well-referenced report,” said Darrel Regier, M.D., M.P.H., executive director of the American Psychiatric Institute for Research and Education and director of APA's Division of Research.“ It complements the Parentsmedguide.org summaries prepared by APA and the American Academy of Child and Adolescent Psychiatry earlier this year.” Regier is a member of ACNP.

The ACNP report details an exhaustive review by a task force made up of psychopharmacology specialists who reviewed the evidence both for and against an association between the drugs and suicidal thoughts and behaviors and, in particular, analyzed the same data used by the FDA to support requiring black-box warnings on all antidepressants marketed in the U.S.

The ACNP report appeared in the January Neuropsychopharmacology. While ACNP, a nonprofit professional society, does receive some of its revenue from pharmaceutical companies, no pharmaceutical industry funding was used to support the task force's work or fund the writing and publication of the report.

Efficacy Questions Addressed

The task force first reviewed the clinical trials submitted to regulatory agencies (including the FDA and the U.K. Medicines and Health Care Products Regulatory Agency) in applications for marketing approval to determine if individual antidepressants have shown significant efficacy in treating depression in youth.

The task force found that only fluoxetine (Prozac) had consistently demonstrated statistically significant efficacy in treating depression in children and adolescents in two placebo-controlled clinical trials (the minimum standard for FDA approval). Both citalopram (Celexa) and nefazodone (Serzone) have demonstrated significant efficacy in one clinical trial of youth with depression, but each drug was separately found to be no different from placebo in a second clinical trial.

Paroxetine (Paxil) and sertraline (Zoloft) each demonstrated significant efficacy compared with placebo in one trial; however, two other trials of each drug found no difference between drug and placebo. Venlafaxine (Effexor) and mirtazapine (Remeron) were no better than placebo in two clinical trials each.

Across the clinical trials that found some degree of efficacy for antidepressants in youth with depression, the degree of reported efficacy varied considerably, the ACNP task force noted. In looking at the individual positive trials, ACNP calculated the “number needed to treat” (NNT) and found a wide range from five to 51, with an average of 17.4.

The NNT signifies efficacy by determining that on average, 1 out of every 17.4 young patients treated with antidepressants would respond to the drug. Efficacy was as good as 1 out of every 5 patients (with fluoxetine) and as weak as 1 out of every 51 patients (citalopram).

When the task force looked at the AE reports in the FDA's database, it concluded that the case reports were so variable and questionable that any specific connection between AEs and a particular drug was negated.

It reviewed several meta-analyses of case reports detailing AEs, each of which came to differing conclusions. One meta-analysis found “no evidence of higher rates of suicide or suicide attempts, respectively,” for any antidepressant in children and adolescents.

Another published meta-analyses found that SSRIs “did not increase risk of suicide, and a protective effect could not be ruled out.” Still another large meta-analysis, which included more than 700 randomized clinical trials involving 87,650 patients, found more suicide attempts in the SSRI group compared with placebo, but no differences compared with other non-SSRI antidepressants.

In addition, the third meta-analysis found no difference in suicide rates between SSRIs, non-SSRIs, and placebo.

“By including so many trials,” the task force concluded,“ the study was limited by an absence of data on past suicidal behavior, heterogeneity of patient populations, short duration of most studies, and trials with small sample sizes. Thus, these meta-analyses [on the whole] provide no clear conclusion or consensus.”

Furthermore, the ACNP task force reviewed a large epidemiologic study of more than 159,000 general practice patients in the U.K. who took antidepressants between 1993 and 1999. This analysis found no difference in the incidence of suicidal thoughts and/or behaviors in those receiving an SSRI compared with a tricyclic antidepressant; however, this particular report did find that suicidal behavior was more common early in treatment.

Another recent epidemiological study, involving 65,103 patients who had more than 82,000 prescriptions for an antidepressant, examined risk of suicidality prior to starting the antidepressant as well as in the six months after starting medication. This study found the risk to be highest in the 30 days before medication was begun, not immediately after the start of medication.

In parallel with the task force's calculation of NNTs for the individual drugs, the panel also calculated the number needed to harm (NNH)—including suicidal thoughts, behaviors, and attempts—in the clinical trials database. Again the task force found a wide range of NNHs, from 24 up to 2,000 and an average of 402. This means 402 patients would have to be given antidepressant medications before one experienced an AE involving suicidal thoughts or behaviors.

So What's the Bottom Line?

“The NNH on average is 23 times that of the NNT average across the studies,” the task force concluded. “If one were to take an end point of suicide, since there have been none in these studies, the NNH value is unknown, but huge, implying a substantial risk-benefit ratio.”

Plainly put, ACNP strongly believes that antidepressant therapy, particularly with fluoxetine, can be highly beneficial while carrying some small risk.

As such, ACNP recommends continued use of fluoxetine, while calling for more studies to establish efficacy of other antidepressants. The task force also urges complete public disclosure of all data on the benefits and risks of SSRIs in children and adolescents (Original article: see box).

Ultimately, ACNP said, the challenge lies with researchers and clinicians to design better, systematic measures and assessments for evaluating suicidal behavior within the context of clinical trials. Improved monitoring of patients and more reliable reporting measures for AEs within clinical trials and after drugs are on the market are also needed.

The bottom line, the report concluded, is “more effective treatments are needed urgently.” Additional clinical trials must be conducted and should include high-risk patients, “such as those with a history of suicidal behavior.”

“Fears of unproven risks may lead to more untreated major depression in children and adolescents and more suicide. Prompt support for more definitive controlled clinical studies is urged to better guide clinical practice.”

Child and adolescent psychiatrist and APA Trustee David Fassler, M.D., commented, “As the authors note, there is no evidence that the use of SSRI antidepressants increases the risk of suicide in children and adolescents. The report is a useful contribution to the ongoing public and professional dialogue on this complex and controversial issue.”

The “ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth” is posted at<www.nature.com/npp/journal/vaop/ncurrent/full/1300958a.html>.▪