Antidepressants: Youth Suicide Warnings Increasingly Questioned

FDA advisories warning of increased suicide risk among children and adolescents beginning antidepressant therapy have alarmed the health care community. But emerging evidence suggests that this may not be the case--and that it may actually be a disservice to withhold these medications from persons who need them.

Recent observational evidence of reduced suicide risk in persons beginning antidepressant therapy stands in direct opposition to FDA advisories associating these agents with suicidality. This finding also raises the question of whether more patients will be at risk if FDA advisories and the “black box” warning serve to discourage antidepressant use, rather than--as intended--to encourage their careful monitoring.

Simon and colleagues¹ evaluated health plan data (1992 to 2002) for more than 65,000 patients receiving their first antidepressant for a depressive episode. For both adults and adolescents, the risk of suicide was highest in the month before starting the antidepressant, and decreased progressively with continued treatment. “The patterns . . . appear more consistent with a decline in suicide risk after initiation of treatment, than they are with a medication-induced increase,” the investigators observed. “The decline in suicide attempts . . . closely parallels the trend in depressive symptoms seen in patients who receive new antidepressant prescriptions.”

The month before this study appeared in the literature, Donald Klein, MD, of the New York State Psychiatric Institute, Columbia University, published his concern about an “uncertain public health impact” from the sharp decrease in antidepressant prescriptions that followed issuance of a blackbox warning in October 2004 advising physicians of possible increased suicide risk in children.^2,3 “There is no convincing evidence that antidepressants specifically increase suicide attempts,” Klein declared. “The [FDA] committee's decision was probably influenced by the paucity of data, except for fluoxetine, demonstrating a specific benefit. In terms of a risk-benefit ratio, the lack of specific benefit became misleadingly translated into a high specific risk.”²

Investigating suicide

Amid disputes over issues of suicide risk and data validity, researchers continue to investigate whether antidepressants can be deadly. The randomized clinical trial is the gold standard for discerning drug effect, but the trial size necessary to detect a relatively rare event--along with the ethical necessity and methodologic difficulty of establishing a valid surrogate marker of suicidality, rather than waiting to detect a suicide attempt--make it unlikely that a clinical trial can resolve the question. Multiple trials can provide a large number of persons to assess, but measures may be inconsistent across studies and the behavioral measures may be unreliable markers of suicide.

In his article, Klein faulted the FDA for issuing suicide warnings about antidepressants based on the results of diverse clinical trials using inconsistent, post hoc determinations of suicidality as surrogate markers for completed suicide. “It was only by the amalgamation of diverse trials and questionable variables, of unlikely clinical or predictive significance, that statistical sanctification was approached,” he asserted.

An alternative approach, used by Simon's group and others, is to examine patterns of antidepressant use and suicide in large populations over time. However, confirming or excluding a causal relationship remains difficult, especially if the alleged drug effect could also be caused by the condition the drug is designed to treat (“confounding by indication”), as is the case with suicide and depression.⁴ The observational studies that control for selection bias related to particular drug use and non-drug-related risks of suicidal behavior can provide only partial insight into the issues, according to Simon and colleagues.¹ “For a study of suicide death or serious suicide attempts, it will be necessary to rely on multiple sources of data,” they indicated, “including both large observational studies and randomized trials.”¹

Acknowledging such limitations, Simon and associates sought to distinguish events occurring in patients receiving the tricyclic antidepressants (TCAs) from those occurring in patients receiving 1 of the 10 newer agents cited in a March 2004 FDA advisory for possible worsening of depression and or emergence of suicidality in adults and children.⁵ The incidence of attempted suicide in their study was 129 and 76 per 100,000 persons for old and new agents, respectively. The incidence of death from suicide was also higher with the old than the new agents: 51 versus 34 per 100,000.

Acknowledging such limitations, Simon and associates sought to distinguish events occurring in patients receiving the tricyclic antidepressants (TCAs) from those occurring in patients receiving 1 of the 10 newer agents cited in a March 2004 FDA advisory for possible worsening of depression and or emergence of suicidality in adults and children.⁵ The incidence of attempted suicide in their study was 129 and 76 per 100,000 persons for old and new agents, respectively. The incidence of death from suicide was also higher with the old than the new agents: 51 versus 34 per 100,000.

The investigators determined that the highest rate of suicide attempts occurred in the 7 days preceding antidepressant treatment. The frequency of suicide attempts was relatively consistent throughout the month after treatment was started. During this period, the investigators found an increased risk with the older antidepressants, but they suggested that this could reflect the longer dose escalation period needed to attain therapeutic but tolerated amounts of these more discomforting agents. They concluded that “the results of the month-by-month comparison of newer and older drugs certainly argue against any increase in risk specific to newer antidepressants.”

In this study, the time pattern of suicide attempts was similar for adolescents and adults, although the rate in the teens was substantially higher. Adolescents constituted too small a portion of the sample size to enable their risk-benefit balance to be analyzed, however, and any increase in suicide attempts after receiving antidepressants was too small to separate statistically from the general decline.

Simon and colleagues could not exclude the possibility that antidepressants exacerbate or precipitate suicidality in a subgroup of vulnerable individuals. “Our data contribute nothing to the debate regarding the efficacy or clinical appropriateness of antidepressant treatment for adolescents,” they added.

The Simon study follows 2 casecontrol observational studies that used the General Practice Research Database (GPRD) in the United Kingdom. One identified approximately 160,000 patients receiving 1 of either 2 TCAs or 2 selective serotonin reuptake inhibitors (SSRIs) between 1993 and 1999.⁶ The match control design distinguished between persons with and those without suicidal behavior before index antidepressant treatment.

The antidepressants did not differ significantly in terms of patients' risk for suicidal behavior. The investigators did find a 4-fold greater risk of suicide within the first 9 days of antidepressant treatment than after 90 days of maintenance therapy, but this could have reflected the lag before medication onset. As in the Simon study, the data were insufficient to provide an answer to the question of increased risk in adolescents.

Another case-control study with GPRD data compared nonfatal selfharm and suicide in patients receiving TCAs and those receiving SSRIs between 1995 and 2001.⁷ Again, there was no statistically significant difference in risk between the newer agents and the TCAs, although there was a weak suggestion of increased risk in patients younger than 18 years who were taking an SSRI. The investigators noted that patients at higher risk for suicidal behavior might have preferentially received SSRIs, but a different drug response in this age group could not be ruled out.

In an effort to evaluate risk in a sufficiently large adolescent population, an observational study accessed the managed care claim records compiled in the PharMetrics Integrated Outcomes database.⁸ This database represents 58 million insured patients and 74 managed care plans in the United States. About 24,000 adolescents were identified to have received a diagnosis of major depression and/or a prescription for an antidepressant between January 1998 and March 2003. Even with this large sample, however, only 45 patients received TCA monotherapy. About 5000 were treated with an SSRI, 2000 received an antidepressant combination or other type of medication, and 17,000 received no medication for the diagnosed major depression. The investigators calculated “propensity scores” to adjust for bias in treatment selection and then applied the Cox proportional hazards approach to estimate the effect of antidepressant treatment on the probability of a suicide attempt. Their analysis indicated that the SSRIs had no significant independent effect on suicide risk. Risk was decreased in patients receiving an antidepressant for at least 6 months.⁸ The possibility remains that antidepressants can provoke suicide but that it occurs too infrequently to be detected by such observational studies. In Klein's2 view, the detection of this phenomenon may require a sophisticated postmarketing surveillance program to supplement or supplant the current FDA MedWatch program of volunteer adverse drug reaction reporting.

“The creation of effective postmarketing surveillance must be brought to the forefront of public discussion,” Klein argued, “to deal with the confusing barrage of horror stories that spark regulations, warnings, and changes in medical practice, with unclear net effects.”

References:

References1. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry. 2006;163:41-47.
2. Klein DF. The flawed basis for FDA post-marketing safety decisions: the example of anti-depressantsand children. Neuropsychopharmacology. December 14, 2005; [Epub ahead of print].
3. FDA public health advisory: suicidality in children and adolescents being treated with antidepressant medications. October 15, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm. Accessed February 22, 2006.
4. Didham RC, McConnel DW, Blair HJ, Reith DM. Suicide and self-harm following prescriptions of SSRIs and other antidepressants: confounding by indication. Br J Clin Pharmacol. 2005;60:519-525.
5. FDA public health advisory: worsening depression of suicidality in patients being teated with antidepressant medications. March 22, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm. Accessed February 22, 2006.
6. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292: 338-343.
7. Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and nonfatal self harm in first episode depression: nested case-control study. BMJ. 2005;330:389.
8. Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensityadjusted retrospective cohort study. CNS Drugs. 2004;18:1119-1132.