We found that the relation between exposure to SSRIs and the risk of suicide is influenced by age. Exposure to SSRIs decreased the risk of suicide by over 40% among adults and decreased the risk by over 50% among elderly people. However, among adolescents, exposure to SSRIs almost doubled the the risk of suicide. These results are consistent with the main conclusion of the recent FDA meta-analysis of clinical trial data.5
However, our risk estimates were very similar to those obtained by the FDA only for the elderly and adolescent groups. Although the FDA reported a neutral effect of SSRIs (or a promoting effect among adults aged 18–25), we found a strong protective effect associated with SSRI treatment.
We tested the robustness of these results in several ways. First, sensitivity analyses showed similar results when more homogeneous subgroups of studies (i.e., outcome measure, diagnostic criteria, control group and quality score) were included. This effect was maintained when only studies with data simultaneously about adolescents and adults were retained. Second, we found little or no effect of eliminating each of the studies from the analysis, which suggests that no individual study had excessive influence on the main results. Third, despite the heterogeneity that was observed in terms of study designs and characteristics, low or moderate levels of statistical heterogeneity were generally observed.
Observational studies have limited ability to adjust for baseline differences and are prone to bias and confounding; thus, alternative explanations for the results of this analysis cannot be excluded.51
All of the included studies enrolled individuals with major depression or used proxy measures of major depression, and, therefore, confounding by indication should not have occurred.
Confounding by severity of illness cannot be excluded. However, this confounder would have to have varied systematically with age to explain the very different findings in adolescents and adults. Among adolescents, SSRI treatment is often reserved for very severe cases, and prescription of antidepressant drugs might have been triggered by suicidal ideas. Thus, the excess risk might be explained by confounding by severity. That is, adolescents who received SSRIs might have been more severely depressed (or more suicidal) than adolescents who did not receive SSRIs. In contrast, among adults SSRIs may be similarly prescribed in severe and less severe cases, and confounding by indication might not have occurred. In some studies, confounding by severity has been taken into account. For example, Olfson and colleagues44
limited their analysis to individuals who received inpatient treatment for depression, thus ensuring a fairly comparable level of illness severity. In 2 other studies, comparability between groups was increased by the comparison of the risk of suicide during SSRI use with the risk during no antidepressant use in the same cohort.46,49
Although these designs likely limited the confounding effect of the severity of illness, we cannot exclude the fact that residual confounding might have inflated the excess risk found among adolescents.
The incidence of depression is higher among women than among men; however, the reverse pattern is observed for suicide.52
Thus, it would have been interesting to investigate the effect of sex on the risk of suicide. Similarly, the timing of the attempted or completed suicide in relation to the onset of exposure is another moderator variable that would have been clinically useful to analyze, because the risk of death by suicide may not be significantly higher in the month after starting medication than in subsequent months.53
However, information about these variables was not homogeneously reported, and re-analyses of aggregate data cannot answer issues related to patient-level moderators of treatment effect. Re-analyses of data from individual patients may have the potential to address these issues.
Differences between individual drugs need confirmation. Only 2 of the included studies provided data on specific antidepressants, and confounding by indication might have affected our results in unpredictable ways. Additionally, it is not clear why the use of some antidepressants, such as paroxetine and venlafaxine, increases the risk of suicide more than others. Intriguingly, previous re-analyses of randomized studies, including the FDA study, reported similar differences between antidepressants.38,54–56
Differences in long-term efficacy and safety should be confirmed in trials of head-to-head comparisons.57
Such an evidence base would assist clinicians in making choices about optimal antidepressant treatment.
Data from observational studies should reassure doctors that prescribing SSRIs to patients with major depression is safe. However, children and adolescents should be followed very closely because of the possibility of increased of risk suicidal thoughts and suicide. Paroxetine and venlafaxine may be better avoided based on the increasing evidence from randomized and observational studies that the risks might outweigh the benefits for most adolescents.
@@ See related commentary by Gibbons and Mann, page 270