Antidepressant use by children and adolescents dramatically increased in recent decades (1
), with up to 8 million prescriptions written annually in the United States (3
). However, the use of antidepressant drug treatment has been fraught with controversy because of questions regarding both efficacy and safety. Efficacy results from pediatric trials are mixed and difficult to interpret, largely because of methodological limitations and regulatory idiosyncrasies in determining what is an “effective” study (4
). Furthermore, regulatory agencies in the United States and the United Kingdom raised concerns in 2003 about the emergence of suicidal thoughts or behaviors during antidepressant treatment in pediatric populations, which may have led to a recent decline in prescription rates (7
), rendering risk-benefit analyses even more challenging.
To evaluate the potential association between suicidality and antidepressants, the Food and Drug Administration (FDA) decided to undertake a meta-analysis to examine suicidal events from 24 randomized placebo-controlled pediatric trials of selective serotonin reuptake inhibitors (SSRIs) and other newer generation antidepressants. However, inconsistent labeling of potentially suicidal events was identified as a significant threat to accurate risk-assessment analyses. This concern first arose during an FDA review of one pediatric SSRI study, in which events suggestive of suicidality were labeled “emotional lability.” Subsequent examination of suicidality data from the other eight pediatric antidepressant studies underscored the problem, with a notable example being a subject who slapped herself in the face and was deemed as having made a suicide attempt (). The FDA determined that conclusions based on these data would be unreliable and might produce either a false signal that would result in unwarranted restriction of useful medications or an underestimation of risk and subsequent danger to the general public.
Examples of Difficulties in Adverse Event Labelinga
The problem of inconsistent nomenclature of suicidal ideation and behavior (suicidality) encountered in this data set is not unique. Indeed, the ongoing debate concerning nomenclature has perpetuated the use of multiple terms to refer to the same behavior, frequently with pejorative connotations (e.g., threat, gesture) and descriptors (e.g., “manipulative,” “hostile,” “nonserious”) (9
). Such variability in terminology has consequences that extend beyond imprecise communication, limiting comparison of epidemiological prevalence rates and hampering prevention efforts (13
). Additionally, it undermines the validity of risk-benefit analyses.
To enhance interpretability of pediatric antidepressant trial data to be used in their risk analysis, the FDA commissioned a study by Columbia University/New York State Psychiatric Institute investigators to classify all events that could represent suicidality. The investigators developed a systematic approach to the categorization of potential suicidal adverse events covering the full spectrum of suicidality, rooted in consensus recommendations and empirical findings regarding suicide-related definitions (10
The whole continuum of suicidality was included in the system, given evidence that manifestations along the spectrum are linked (17
). For example, evidence suggests that suicide attempts with intent to die are predictive of completed suicide (16
), and individuals who engage in preparatory suicidal behaviors with intent to die are also at risk for future suicide attempts (20
) and completion (21
). Epidemiological and clinical studies of adolescents and adults have established that severe or pervasive suicidal ideation is a predictor of both future attempts (17
) and completed suicide (26
). Moreover, Brown et al. identified passive thoughts about wanting to be dead as a risk factor for completed suicide (27
). These studies provide the links between manifestations of suicidal process despite well-documented differences between them (28
In the present article, we describe the structure and reliability of the Columbia Classification Algorithm of Suicide Assessment (C-CASA), the classification system of suicidal adverse events that produced the data used by the FDA in their critical assessment of pharmacologic risk.