Antidepressants and Risks of Suicide and Suicide Attempts: A 27-Year Observational Study

On December 13, 2006, the Psychopharmacologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) considered the risk of suicidality among adults who took antidepressants by reviewing results of 372 industry-sponsored randomized controlled clinical trials with 99,839 participants for a range of indications.1 The FDA conducted its own meta-analyses that focused on the 77,382 adults from 295 randomized controlled clinical trials that evaluated treatments for major depressive disorder (MDD) and other psychiatric disorders.1 The primary outcome in the meta-analyses was suicidality, defined as suicidal ideation, preparatory acts, attempts, or completions, and the trials evaluated the 11 antidepressants approved by the FDA since 1985. About 70% of the suicidality was suicidal thoughts, but there were 8 suicide deaths in the adult trials (5 in participants randomized to the investigational agent, 1to an active comparator, and 2 to placebo). The meta-analyses showed a significant protective effect of antidepressants for ages ≥65 years and a marginal, yet nonsignificant, elevation in risk of suicidality for ages 18–25 years. The FDA briefing document1 displayed these results superimposed on their earlier meta-analyses, which showed a significantly elevated risk of suicidality for children and adolescents randomized to antidepressants. Overall, the document portrayed decreasing antidepressant protection against and increasing risk of suicidality for younger patients. On the basis of these analyses, the FDA issued a revised black box warning for all antidepressants on May 2, 2007, extending the coverage of the 2004 warning that applied to children and adolescents to include patients under 25 years of age.2 The warning label3 currently reads, "(A]ntidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders:' It further warns that "[d]epression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide': Moreover, the warning is not entirely age-specific in that it says, "[P]atients of all ages who are started on anti-depressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.' One limitation of the data that the FDA analyzed is that those results do not generalize to most patients treated with antidepressants. The data primarily came from clinical trials lasting 4 to 8 weeks involving participants in episodes of major depression and other psychiatric disorders. However, a vast majority of patients with major depression, for example, are excluded from clinical trials.4, 5 This occurs because the inclusion criteria of those trials had thresholds for illness severity and exclusion criteria that usually excluded patients who were recently or currently suicidal or psychotic. In addition, the trials usually excluded patients with medical or psychiatric comorbidity or those taking concomitant medications. Therefore, the results of the FDA meta-analyses do not necessarily apply to patients with suicidality, psychosis, comorbid illnesses, or those receiving maintenance therapy or polypharmacy. The objective of this article is to examine the risk of suicide attempts or suicide deaths associated with antidepressants in a broader range of participants that are more representative of the population of patients treated with antidepressants. Our goal was to focus exclusively on the FDA warning about antidepressant risk, not to examine the wide range of variables with hypothesized relationships to suicidality. The data come from the NIMH Collaborative Program on the Psychobiology of Depression-Clinical Studies (Collaborative Depression Study [CDS]), which began collecting prospective follow-up data in 1978.6 The study provides a unique opportunity to examine risk of suicidality with antidepressants due to the combination of methodological strengths of the study, including direct participant interviews, standardized diagnostic and follow-up instruments, frequent follow-up assessments, and up to 27 years of prospective follow-up. We include all study participants whether in a mood disorder episode or in recovery. We hypothesized that, on the basis of the FDA findings, there would be an elevation in suicide attempts and suicide deaths among participants who received an antidepressant compared with those who did not.