In a population of 287 543 adults aged 18 years and older initiating antidepressant therapy in British Columbia between January 1, 1997, and December 31, 2005, we observed no clinically meaningful variation in the risk of suicide and suicide attempt by the type of antidepressant initiated. Most events occurred in the first 6 months after treatment initiation. We observed some variation in the effect size between individual agents to the extent that 95% CIs were not overlapping when comparing an-tidepressants using conventional propensity score methods. Effect sizes became more similar after restriction to subjects without any antidepressant use in the past 3 years; this population is much closer to a population of firsttime antidepressant users and an analysis within this population is less confounded by prior treatment experience and progression of the underlying condition, providing a more valid estimate of the causal treatment effects.
Our results are consistent with the findings of several other recent observational studies that reported small or no differences in suicides and suicide attempts between antidepressant classes10–12
and a meta-analysis of randomized controlled trial data that found no difference in suicide attempt rates between SSRI and TCA users.38
Similar to a cohort study using General Practice Research Database data, we found a higher rate of suicidal acts in venlafaxine users compared with SSRI users, even after adjustment for measured confounders. This effect was attenuated in secondary analyses restricted to treatment-naive users, suggesting some residual confounding in our primary analysis.14
In contrast to a case-control study in Ontario residents aged 66 years and older,15
we did not observe an increased risk of violent suicide among SSRI initiators relative to initiators of other antidepressants. This same article reported that SSRIs were associated with a nearly 5-fold increased risk of suicide during the first month of treatment compared with other antidepressants but found no difference between classes during subsequent periods. While our adjusted analyses did not specifically compare suicide rates between agents during the first month of treatment, our HRs appeared to be proportional over time and we did not observe an overall increase in the risk of suicide among patients treated with SSRIs relative to patients treated with other antidepressants.
During the 9-year study period, the suicide risk among all British Columbia residents aged 18 years and older averaged around 0.16 suicide deaths per 1000 people.39,40
The rate we observed after initiation of antidepressant therapy was almost 5 times higher, reflecting the current depressed state and greater degree of psychiatric co-morbidity in our population.
One of the major strengths of our study is that the large, stable study population allowed us to look at a variety of medications and at important subgroups. We had an adequate sample size to restrict our study to new initiators of antidepressants with a recorded depression diagnosis. An incident user design reduces the likelihood of missing early adverse events, allows for an evaluation of risks over time, ensures that the assessment of patient baseline characteristics is uninfluenced by any effects of antidepressant treatment, and reduces the likelihood that current treatment assignment is influenced by past drug-related experiences such as adverse effects and refractory symptoms. To have clearly identified exposure groups, we compared monotherapies with each other and censored patient follow-up as soon as the patient switched drugs or augmented therapy. This analytic strategy makes treatment groups more comparable with regard to initial health state and avoids analytic difficulties associated with comparing patients who escalate or change treatment in response to treatment failure or adverse effects vs those who do not. This will reduce the generalizability of our findings to patients receiving monotherapy, but the improvement in validity outweighs this reduction in generalizability. Similarly, we limited the follow-up time for the primary analysis to 12 months. Most events happened during that period, and longer observation would lead to increasingly selected populations in later months. Such patients would by definition not switch or discontinue their initial antidepressant for a 12-month period and their depression is likely well controlled without drug intolerance.
Nonrandomized studies using health care utilization data are particularly scrutinized for their limited control of confounding and their potential for misclassifying diagnoses.41
Confounding would occur if certain antidepressants were more likely to be given to patients with a greater background risk of suicide. We therefore controlled for sociodemographic, clinical, and health care utilization factors likely to be independent predictors of suicidality using traditional multivariate and high-dimensional propensity score techniques. Although we could show that with increasing adjustment (including high-dimensional propensity score adjustment36
) point estimates generally moved closer to the null result, our ability to fully adjust for mental health status is limited by the measurement and reporting of mental health conditions as ICD-9
diagnosis codes on insurance claims to the provincial government. Well-validated behavioral risk factors such as impulsivity and hopelessness, environmental factors such as access to lethal means, and family history of completed suicide42
would not be measured in claims data. Random misclassification of confounders in health care utilization databases leads to incomplete adjustment of confounding bias.43
For example, our finding that the apparent increased risk of suicide among venlafaxine users was attenuated when we restricted our analysis to subjects with no antidepressant use in the past 3 years suggests that there may have been residual confounding by the presence of treatment-resistant depression or other suicide risk factors in our initial analysis. Other studies have documented that venlafaxine tends to be prescribed to people with past SSRI treatment failure44,45
and with a greater burden of suicide risk factors.46
There are several limitations inherent in our definition of completed and attempted suicide outcomes. It is known that suicides are underreported by coroners, with an estimated 10% of suicides misclassified as other injuries in one US study.30
However, the specificity of suicide as a cause of death has been shown to be extremely high.30
Relative risk estimates are unbiased if outcomes are assessed with 100% specificity, even if sensitivity is far lower owing to nondifferential misclassification.47
While underreporting of suicide deaths is likely nondifferential, there is a possibility that patients treated with specific agents or having specific histories might attract closer scrutiny for potential suicide. Decedents using TCAs, which are known to be fatal in overdose, might be more likely to receive a suicide diagnosis. To make our analyses comparable to those presented by Juurlink et al,15
we analyzed the sub–end point of violent completed and attempted suicide. Because there is some evidence that suicide mechanism is not coded with perfect accuracy and intent is coded with greater accuracy for injuries due to poisoning than those due to firearms29
and because of the smaller number of violent events, we place the greatest weight on our overall findings.
In terms of the validity of our suicide attempt definition, intentional self-harm E-codes do not distinguish between suicidality and self-harm without suicidal intent despite their widespread use in research and surveillance to identify suicide attempts. However, a study of the validity of deliberate self-harm E-codes to identify suicide attempts reported a positive predictive value of 86% for these codes relative to the gold standard of medical record review.28
Ascertainment of intentional self-harm admissions within the British Columbia hospital discharge database is likely to be nearly complete as this database has an E-coding completeness rate greater than 95% for the years evaluated and does not have the E-coding completeness problems documented in some US claims databases.27
However, we did not have data on suicide attempts by patients who were seen in an emergency department, treated, and released without an inpatient admission. An analysis of 2006 US Web-Based Injury Statistics Query and Reporting System48
data showed that 70% of patients with nonfatal self-harm cases seen in the emergency department were admitted to the hospital, suggesting that our definition had a 70% sensitivity for nonfatal intentional self-harm. Our inclusion of only more severe attempts that require at least 1 night in the hospital is likely to increase the specificity.
Despite these limitations, our finding of equal event rates across antidepressant agents supports the US Food and Drug Administration’s decision to treat all antidepressants alike in their advisory. Treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent.