This is the largest study, to date, to examine the relationship between specific antidepressant agents and suicide death. Comprehensive longitudinal data for a large sample of high-risk patients allowed us to employ multiple analytic strategies to address potential treatment biases, 36,34
the major methodological issue for studies using observational data. Analytic approaches included conventional Cox models with covariate adjustment, Cox models with IPTW, propensity stratified Cox models, marginal structural models, and an instrumental variable approach.
The results from these different approaches converged in most instances and indicated that most antidepressant agents did not differ in their risks for suicide death.
However, conventional Cox models and the IPTW and propensity stratified Cox models all suggested lower risks with sertraline and fluoxetine than with paroxetine and suggested lower risks with bupropion than for several other antidepressants. MSM models confirmed the findings for sertraline and fluoxetine but not for bupropion.
IV models did not indicate any differences in suicide risks with specific antidepressant agents. Given appropriate instruments, the IV approach theoretically can better account for unmeasured confounders. However, the IV approach typically involves a loss of statistical power, because it is based on variation in treatment due to IVs rather than the full variation in treatment. This loss in power may limit the application of this approach where the event of interest (e.g., suicide) has a very low base rate and power is a pivotal issue. Nevertheless, the finding in IV analyses of no differences in risk across antidepressants is consistent with findings of Schneeweiss et. al, who used a high-dimensional propensity adjusted analytic approach.19
We note that the study findings of lower risks of suicide with fluoxetine and sertraline than paroxetine across several analytic approaches is consistent with a few observational studies that reported lower risks with fluoxetine than for other antidepressants among adults discharged from hospitals in Finland18
or a trend towards lower risks with sertraline among adult Medicaid patients discharged from the hospital.15
However, it may be more informative to compare the current study’s results to those of studies using data from RCTs, as RCT findings may be limited by sample size and use of proxy outcomes but are not subject to treatment selection biases. Of interest, the FDA meta-analyses of RCTs in adults which examined the relationship between a composite measure of “suicidality” and antidepressant use, also reported lower risks for sertraline than for other SSRI and non-SSRI agents when compared to placebo. In this meta-analysis, there was also a trend (p=.11) for decreased risk ratio for fluoxetine. However, the FDA analysis reported no particular signal for increased risks with paroxetine.
A re-analyses of FDA data from the meta-analysis for antidepressants among youth also reported a relationship between antidepressant half-life and suicide risks, with fluoxetine use being associated with the lowest risk (RR, 0.52).16
However, despite some degree of congruency of this study’s findings with the FDA meta-analysis of RCTs, study results may still be affected by residual confounding. The FDA meta-analysis did not find indications of lower risks with bupropion, and we suspect the present study’s limited findings regarding bupropion were due to remaining confounding. Bupropion is often used for smoking cessation, and despite the requirement of a depression diagnosis and adjustment for comorbid tobacco use disorder, patients with milder depression may still have been more likely to receive bupropion for smoking cessation and have also been at less risk of suicide due to milder symptoms. Schneeweiss et al. excluded patients receiving bupropion because of this alternative treatment indication.19
The VA study population consists predominantly of men and older individuals, and study findings may not generalize to other treatment populations. Overall suicide risks associated with antidepressant use differ by patient age, 5,17
and it is possible that risks associated with specific antidepressant agents may also vary with age.
We relied on antidepressant prescription fills to determine antidepressant exposure. Some patients may have used mental health services outside of the VA health system and have had antidepressant starts that were not recorded in our dataset. However, during the study period, patients eligible for VA coverage often exclusively used VA pharmacies because of the VA’s generous drug benefit.37
There are limited data on patient symptoms in administrative data and inclusion of more detailed patient data might have allowed improved adjustment for potential confounders.
We excluded patients who developed bipolar disorder or schizophrenia during the study period as we believed such patients may have been misdiagnosed as having a depressive disorder. However, this may have resulted in some misspecification of risk for specific antidepressants if patients with less certain depression diagnoses were given an agent preferentially and were also less likely to live long enough to receive a second, corrected diagnosis of bipolar disorder or schizophrenia.38
We also assessed most covariates for the 12 months prior to the index date of the new antidepressant but required only a 6-month clean period to define a new antidepressant start. This might have differentially affected some covariate values (e.g., number of outpatient visits) if specific antidepressant agents were more likely to be preceded by antidepressant exposure during the 12 to 6 month period before the index date.
Finally, we completed multiple comparisons for antidepressant agents, using several different analytic approaches to address selection biases. Given the low base rate of suicide, we did not correct for multiple comparisons, and instead emphasized results that were consistent across analytic approaches and that had substantial effect sizes.
Head-to-head comparisons of suicide risks of different antidepressant agents are difficult to conduct given the enormous sample sizes required. We completed the largest study to date, examining this relationship in over 500,000 high-risk VA patients. Across a variety of models, fluoxetine and sertraline appeared to have lower risks than paroxetine, findings that are reasonably congruent with those of the FDA meta-analysis of RCTs, which found indications that these agents might have lower risks than other antidepressants. However, we note that IV analyses did not provide additional support for these findings. The divergence observed in findings by analytic approach and the possibility of residual confounding suggests continued caution when using observational data to assess suicide risks associated with antidepressant agents.