C. Hendricks Brown, PhD

Suicide is the third leading cause of death in younger (10- to 14-year-old) adolescents in the United States and the leading cause of death in this age group in other countries, including China, Sweden, Ireland, Australia, and New Zealand.

 The enormous human cost of suicide in youth makes research and prevention a na-tional priority. Biological, psychological, social, and cultural factors all affect the risk of suicide; however, about 90% of youth suicides in the United States are associated with psychiatric illness,

In the general population, there is compelling evidence of lack of continuing treatment for depression. While most of those who complete suicide have sought professional help within one month of death,

 the majority are untreated at the time of death.

 Contrary to recent popular belief, very few children and adolescents who complete suicide are taking medication at the time.

Limited access to care and poor treatment compliance in young patients aggravates the problem. For example, in a study of 49 adolescents who completed suicide in Utah, antidepressants had been prescribed for 24%, but 

tested positive for SSRIs at the time of their death.

 In a postmortem study of 54 youths who completed suicide, only 4 had antidepressants detected on serum toxicological testing within 3 days of death.

Compared with completed suicide (12-month incidence, 8 of 100,000 youths aged 15 to 19 years),

 suicidal thinking and nonfatal attempts are much more common. Based on figures in the 2005 US Youth Risk Behavior Surveillance Report, 19% of teenagers aged 15 to 19 reported suicidal ideation, and 9% of teenagers reported making a suicide attempt during the past year.

 Depression annually occurs in 3% to 5% of youths and accounts for about 60% of suicides for all ages. Our best national estimates reveal that among youths receiving care for depression, 35% to 50% have made, or will make, a suicide attempt,

and 2% to 8% will commit suicide in a decade.

 Thus, treatment of youths who are depressed is an important strategy for preventing suicide.

Over the past few years, warnings have been made about antidepressants potentially causing suicide. In October 2003, the FDA issued a public health advisory for all antidepressants used in treating children and teenagers that cautioned about a potentially higher risk for suicide-attempted and completed. In December 2003, the British Medicines and Healthcare Products Regulatory Agency (MHRA) issued a letter to all doctors advising against the use of almost all antidepressants in anyone younger than 18 years. A similar warning was issued by the European Medicines Agency.

In February 2004, the FDA issued a public health advisory that further cautioned physicians, patients, and families about a possible link between suicide and antidepressants in children and adolescents. In October 2004, the FDA issued a black-box warning for increased suicidality in pediatric patients taking antidepressants, a step just short of banning use in this population. The FDA decision was based on randomized controlled trial (RCT) data suggesting an increase from 2% to 4% in suicidal ideation and behavior when antidepressants, including SSRIs, were prescribed for youths who had not been actively suicidal.

 In December 2006, the FDA convened another meeting of its scientific advisory committee, reviewed its RCT data for adults, and concluded that the black-box warning should be extended to young adults.

A major limitation of these studies is that no suicides were reported in the pediatric studies for either placebo or active medication, and only 8 completed suicides were reported in the adult studies, with no significant differences by condition (placebo, 2 of 36,049; test drug, 5 of 53,030; active control, 1 of 11,217). Also, the RCTs reviewed by the FDA excluded youths who had recently thought about or attempted suicide. As such, even the combination of the 372 studies and close to 100,000 patients provided little or no evidence about the effects of antidepressants on completed suicide.

Others have noted that the finding of increased suicidality in youths treated with antidepressants was limited to medical record data; there was no difference in suicidality obtained from standardized questionnaires.

In a recent reanalysis of the FDA data, augmented by additional studies that have become available since 2004, the difference between antidepressants and placebo in suicidal ideation (abstracted from medical records) was no longer statistically significant, whereas a pooled analysis of clinical response rates found a statistically significant beneficial effect for anxiety disorders and depression in children and adolescents that was not confined to any one antidepressant.

 The result of this study is that antidepressants do show evidence of an antidepressant effect in the pediatric population and that the risk of nonfatal suicidal acts or suicidal ideation is less than that estimated by the FDA in its earlier analyses, yielding a clearly positive benefit-to-risk ratio.

The FDA's findings for children appear to be inconsistent with psychological autopsy studies of completed suicide that suggest very few pediatric suicides were associated with SSRIs.

 They also are inconsistent with ecological studies on suicide completion

and attempts that indicate an overall protective effect of SSRIs in pediatric and young adult populations.

 found a significant inverse relationship between county-level SSRI prescription levels and adult suicide rates both within counties over time and between counties. This is consistent with a protective effect of SSRIs, both in the overall population and in a specific analysis of 5- to 14-year-olds in the United States.

 demonstrated an inverse association between SSRI prescription rates and SSRIs from 1980 to 1999 in 26 European countries; similar results have been found in the United States.

 confirmed a significant inverse association between SSRI sales and suicide rates from 1980 to 2004 in a county-level analysis in Norway. Isacsson

 hypothesized that an increase in antidepressant prescriptions in Sweden would be associated with a reduction in suicides. As a natural experiment, he found that a 3.5-fold increase in antidepressant prescriptions in Sweden over time was associated with a 19% decrease in suicides.

The FDA has recently extended the black-box warning to young adults aged 18 to 24 years based on a meta-analysis of RCTs

 that showed increased rates of suicidal ideation in young adults under 25 years, but either no effects or protective effects in adults older than 25. However, Gibbons and colleagues

 showed that in a comparison of 18- to 25-year-olds who were treated with an SSRI alone versus those who had no antidepressant therapy, there was one third the risk of a serious suicide attempt in the treated group (odds ratio, 0.35; confidence interval, 0.14 to 0.85; 

 < .021). In this age group, treatment with an SSRI alone produced a 57% decrease in suicide attempts relative to the same young adult age group before antidepressant treatment was initiated.

Similar protective effects of antidepressant treatment were found for adults who were older than 25 years. The findings revealed that when active treatment was compared with no treatment rather than a placebo control condition, and the patients were not excluded on the basis of having preexisting suicidal behavior, antidepressants had a protective effect on suicidal behavior in both younger and older adult populations. Simon and Savarino

 have also shown that both antidepressant therapy and psychotherapy significantly reduce the risk of attempted suicide in the general population as well as in young adults aged 18 to 24 years.

Taken as a whole, these ecological data on suicide rates suggest that decreases in newer antidepressant prescriptions (SSRIs and serotonin-norepinephrine reuptake inhibitors [SNRIs]), in response to the FDA warnings, will lead to increases in the suicide rate. Unfortunately, just such a natural experiment has taken place. Between 2003 and 2005, SSRI prescription rates decreased by approximately 20% in children in the United States in response to public health advisories from the FDA and the MHRA in the United Kingdom as well as the 2004 FDA black-box warning (

 Smaller decreases have also been observed in SSRI prescription rates in adults younger than 60 years.	

Suicide rate data published by the CDC have recently been released for 2004.

 In youths (aged 5 to 19 years), there was a 14% increase in suicide rates from 2003 to 2004 (2.83 of 100,000 vs 3.23 of 100,000, 

 < .0001). Except for minor fluctuations in 1994 (1% increase) and in 2000 (3% increase), there had been a consistent reduction in youth suicide rates from 4.4 of 100,000 in 1988 to 2.83 of 100,000 in 2003 (

). If SSRIs were causing suicides in the general population, we would expect the reverse. In contrast to these results for youth, it was noted that at the same time prescription rates continued to rise for adults older than 60 years and their suicide rates continued to fall.

 In Europe, similar findings have been reported for SSRI prescription and suicide rates in youths.

Furthermore, the treatment as well as the diagnosis of childhood depression also decreased since the black-box warning took effect.

 Based on predictions from preadvisory data, SSRI prescriptions are 58% lower than predicted (had the warnings not taken place) and the rate of diagnosis of major depressive disorder by both pediatricians and primary care physicians is 32% lower.

 These reductions in antidepressant treatment and diagnosis of depression have "spilled over" to the adult population where significant decreases in the percentage of adults with new depressive episodes have been observed since the black-box warning was released.

In addition, the investigators found that there was a significant increase in the percentage of depressed adult patients who did not receive antidepressant treatment (from 20% before the black-box warning to 30% after the black-box warning).

 These findings fill in an intermediate step related to the observed decrease in antidepressant prescriptions, namely a decreased rate of diagnosis of new episodes of depression in both pediatric and adult populations.

The findings of this natural experiment support the hypothesis that the effect of the black-box warning has been to lower antidepressant prescription rates, which in turn has resulted in more untreated depression and a corresponding increase in suicide rates for children and adolescents.

 The FDA sought to improve treatment of depression, but an overall decline in diagnosis and treatment of depression implies that the black-box warning did not achieve this goal, and the decline is consistent with the possibility that the black-box warning has had the opposite effect.

Although unintended, the FDA's black-box warning has led to a decrease in the pharmacological treatment of pediatric depression and a decrease in the diagnosis of pediatric depression. At the same time, we have seen the largest increase in child, adolescent, and teen suicide since the CDC began recording these data in 1979. In the event that these results are further confirmed by 2005 suicide rate data, it becomes clear that the black-box warning should be reconsidered and replaced by an effort to improve diagnosis of major depression, improved access to treatment, and more careful monitoring of treatment with antidepressants where indicated.

A black-box warning has only been rescinded once in history, for the drug omeprazole in 2003, but given the mortality of youth suicide and the need to reverse these alarming trends and loss of life, such a step may prove necessary for antidepressant labeling in children and young adults.

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C. Hendricks Brown, PhD

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