Data from the FDA Adverse Event Reporting System (MedWatch) from 1998 to 2004 for all antidepressants and completed suicide were analyzed by our group.5 The dataset comprised a total of 28,317,382 records, including all reported adverse events and drug combinations. A national prescription rate for each antidepressant by year is the denominator in the analysis. Figure 1 presents a plot of the estimated rate multipliers and confidence limits for each drug. As a class, both SSRIs and SNRIs have rate multipliers that are significantly less than 1.0 (ie, lower than the national average suicide adverse-event report rate for antidepressants as a class). By contrast, TCAs have rate multipliers that are significantly above the national average suicide rate for antidepressants. TCAs have a significantly higher risk of suicide adverse-event reports than do SSRIs and SNRIs.
This is striking because one might anticipate an increase in reports related to SSRIs given the highly publicized concern over a possible link between suicide and the use of SSRIs. However, TCAs are much more toxic than SSRIs on overdose and are much more likely to produce a medically serious outcome. Therefore, it may be important to separate reports of medically serious overdoses using TCAs or SSRIs. Comparing the incidence of other types of suicide-related reports for these classes of medication may clarify the situation.
Ecological studies. For very rare events, such as those that occur at rates of 1 in 10,000 or less (eg, death by suicide), there are few options for routine drug surveillance because very large populations of patients are needed to detect enough events to be informative. One approach is to use ecological data that relate changes in drug prescription rates to suicide rates in large populations.
Decreases in suicide rate over time have been shown to correlate with increased antidepressant use in many studies around the world, including those in Europe, Scandinavia, the US, and Australia. In Sweden, the doubling of prescriptions for SSRIs correlated with a 25% decrease in the suicide incidence.6 In an analysis of 27 countries, Ludwig and Marcotte7 showed that an increase of 1 pill per capita (a 13% increase over 1999 levels) was associated with a 2.5% reduction in suicide rates, a relationship that was more pronounced in adults than in children.
Japan is a curious anomaly. Researchers there found a positive association between suicide rates and antidepressant prescriptions.8Figure 2 clearly shows an overall positive association between SSRI prescriptions and suicide rates; however, stratification by age reveals that within each age stratum, an inverse association is observed. This is a classic illustration of Simpson’s paradox. What it indicates is that in Japan, both suicide rates and use of antidepressants increase with age; however, for a given age-group, suicide rates have decreased with increasing SSRI prescriptions over time.
Another anomaly is Iceland, where antidepressant prescription rates seemed unrelated to lower suicide rates. Part of the reason for this are the traditionally extremely low suicide rates in Iceland. This is a floor effect; there is so little room for a further decline in suicide rates that the relationship to prescription rates is extremely hard to detect. Italy has had a decline in suicide rates linked to prescriptions for women but not for men. Most antidepressants in Italy are prescribed for women, and so the ability to detect such a relationship is greater in women.
Ecological modeling from large numbers of small areas can also provide a stronger basis for understanding the association between antidepressant medication use and suicide completion. US county-level data on suicide rates and antidepressant prescription rates were analyzed for 1996 to 1998.9 After adjusting for sex, race, age, income, and unobservable county-level effects, the analyses revealed that increases in SSRI and SNRI prescriptions were associated with decreases in suicide rates both between and within counties over time. Conversely, counties with higher rates of TCA prescriptions were associated with higher suicide rates; this may be because of the greater toxicity of this class of agents and/or their more frequent use in areas with poorer access to quality mental health services. This finding has been replicated in children and young adolescents (aged 5 to 14 years) and indicates that the relationship is robust and manifest across the life cycle, from childhood to adulthood.10
Large-scale observational studies. Valuck and colleagues11 examined the effects of antidepressants on 24,119 adolescents with a first diagnosis of major depression. At least 6 months of follow-up data were available, which showed that treatment with SSRIs, other antidepressants, or combinations of antidepressants did not increase the risk of suicide attempts. Similar results were seen by Simon and colleagues.12,13
In contrast, Olfson and associates14 conducted a case-control study in depressed children and found a significant association for both suicide attempts (n = 263) and suicide completion (n = 8) in children treated with antidepressants. Tiihonen and colleagues15 found that current antidepressant use was associated with increased risk of suicide attempts but lower risk of suicide completion in youths who had been treated with an antidepressant.
Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.
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