New Studies to Address the Research Question

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Chapter: Pharmacovigilance: The Efficacy and Safety of Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Children and Adolescents

The main FDA clinical trial analysis (DNDP) looked at suicide ideation and attempts in relation to expo-sure to SSRIs although using ideation and attempts as surrogates for completed suicide is of unknown validity.


NEW STUDIES TO ADDRESS THE RESEARCH QUESTION

The main FDA clinical trial analysis (DNDP) looked at suicide ideation and attempts in relation to expo-sure to SSRIs although using ideation and attempts as surrogates for completed suicide is of unknown validity. The limitations of available data on attempts include a low level of specificity and accuracy of recall on self-reported rates of suicide attempts and variable and incomplete data on ATD doses, dura-tion of drug treatment, concomitant medications and drug switches. Furthermore, suicide attempts and self-mutilation are common in adolescence (Safer, 1997), and they often overlap; parent reports of suicide attempts in their offspring are underreported and suicide ideation and suicide threats in adoles-cence are much more common than serious suicide attempts. Consequently, for better precision it is preferable to have more definitive evidence of docu-mented medically serious suicide attempts in relation to SSRI treatment. Such evidence could be obtained from psychiatric-related hospitalizations and emer-gency department (ED) visits.

Survey data shed some light on the scope of the suicide-related medical service utilization. The self-reported suicide attempts and those resulting in medi-cal attention for adolescents (14–17 year olds) in the 2003 population-based high school CDC survey was 8.5% and 2.9%, respectively. Medical attention was not defined in the survey and presumably refers to outpatient care as well as hospitalization or ED visits (Grunbaum et al., 2004). By self-report then, approxi-mately 1.3 million US high school students have made suicide attempts during the previous year.

To obtain more precise information on suicide attempts resulting in medical attention, ED data may be a useful approach. Specifically, administrative data on ED visits for older youth (e.g. 10–18) could be examined. Suicide-related reports in the ED can be sorted by age group, gender, method of attempt (e.g. cutting, overdose) and disposition. In one study based on a multi-state epidemiologic examination of pooled E-coded discharge data and vital statistics (Spicer and Miller, 2000), the authors used E-codes 950–959.9 to calculate suicide attempts from hospi-talizations or ED visits and found the rate to be 21 per 100,000 for those less than 15 years and 259 per 100,000 among 15–19 year olds. Overdoses and cutting accounted for 85%–90% of attempts.

Estimates of the frequency of ED use for inten-tional self-injury by youths suggest that it is relatively low. In the state of Oregon from 1988 through 1993, suicide attempts by youths aged 10–17 as recorded in emergency rooms represented 0.3% of all youths in that age range (MMWR, 2005). In another emer-gency room report of 4072 adolescents (11–19 years old) presenting to an Arkansas Children’s Hospital ED during a 1 year period in 1985, 27 (0.66%) delib-erately injured themselves (Jay, Graham and Flowers, 2005). Thus, it is reasonable to assume that the intentional self-injury rate varies with the region and the completeness of identification and reporting. Another study indicates that of the youth who came to EDs related to suicidality, at least 40% came there because of suicidal ideation, not attempts (Stewart et al., 2001).

The data reviewed above suggest that administra-tive claims or computerized records data are likely to be a feasible approach to patient-level assess-ment of the association of psychiatric-related AEs with medication exposure. Evaluating youth who have been given ATDs as outpatients and then noting their ED and hospital visit rate is a feasible means of directly linking the AEs to the medication exposure. A more direct approach, the medical record audit, to assess emergency room records might be feasible if the staff routinely recorded in their data set prior and ongoing medication patterns of those admitted. Unfortunately, this is not generally recorded. Using a community-based data set across a 4-year period would allow those with a prescribed ATD (among three subclasses) over a given time period to be identi-fied. Total ATD-treated youth or those within selected diagnostic groups could then be evaluated for their rate of psychiatric admission to an ED or a hospital as well as the recorded reason for such an admis-sion (diagnostic codes and E-codes). The distinction between this study and the Simon study is essentially that youth rather than adults would be studied; youth and not episodes would be the unit of analysis; and only youth with a single ATD drug class would enter each group and children and adolescents would be separated.

The ideal study to assess the relationship between SSRI use and suicidality in youth requires a prospec-tive randomized cohort study design in a large usual practice community treatment setting. Now that there are serious concerns about the efficacy and safety of the SSRIs for youth treated for depression, the concern about depriving a youth of an effective marketed medication in a randomized protocol is balanced by the uncertainty of outcome. The usual ethical concern would be overcome in this instance. In a random-ized cohort study, three groups could be established: SSRI, other ATD or a waiting list placebo control. Following the cohort forward for 6 months would allow information to be collected on the effectiveness of treatment and reasons for discontinuation of drug. Most importantly, psychiatric-related ED or outpatient visits or hospitalizations related to hostility and acti-vation could be distinguished from depression-related events to shed light on the major confound of many psychotropic drug studies, namely, behavioural toxicity.

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