The MHRA's report presents summary data from 342 placebo controlled trials of SSRIs including 40 826 subjects and 16 suicides. An estimated 172 episodes of non-fatal self harm were reported in data from 477 trials including 52 503 subjects. For suicidal thoughts, data are presented from 477 trials of 45 704 subjects and an estimated 177 episodes ().
Table 1 Summary of clinical trial data abstracted from the Medicine and Healthcare products Regulatory Agency's review of the safety of SSRIs9
The pooled odds ratio (with 95% credible intervals) for all SSRIs compared with placebo treated subjects in relation to suicide was 0.85 (0.20 to 3.40). For non-fatal self harm, excluding paroxetine, the odds ratio was 1.57 (0.99 to 2.55), and for suicidal thoughts, excluding paroxetine, it was 0.77 (0.37 to 1.55). The I2 values were 27%, 3%, and 37%, respectively, indicating relatively little heterogeneity across the individual drugs for the first two outcomes. Three suicides in placebo treated patients (all in paroxetine trials) and one suicide among people treated with an SSRI (escitalopram) occurred after they had stopped treatment. Exclusion of these events from our meta-analysis resulted in a revised odds ratio for suicide of 1.24 (0.21 to 6.71). When we included paroxetine data for non-fatal self harm and suicidal thoughts in the meta-analysis, assuming half the events in each arm of the trial were non-fatal self harm and half were suicidal thoughts, the respective odds ratios were 1.29 (0.90 to 1.91) and 0.79 (0.48 to 1.28). These odds ratios may be biased towards null effects as our assumption of an even distribution of episodes of self harm and suicidal thoughts across placebo and control groups is not supported by our meta-analysis of these end points excluding paroxetine data.
All 95% credible intervals are compatible with no increase in risk. The 95% credible interval for suicide is wide because of the small number of events. However, while the credible intervals for the risk of non-fatal self harm are also compatible with at least a doubling of risk and little evidence of risk reduction, those for suicidal thoughts are compatible with up to a two thirds reduction or a modest increase in risk. For non-fatal self harm, the number needed to treat to harm, using the odds ratio without paroxetine, is 759 (based on the weighted prevalence of self harm in the placebo groups of 1 in 433). As the 95% credible intervals for the odds ratio for non-fatal self harm span 1.0 they are compatible with both harm and benefit. Following Altman's suggestion,13
the 95% credible intervals around the numbers needed to treat to harm are 759 (95% credible interval number needed to treat to harm 279 to ∞ to number needed to treat to benefit 43 300).
The shows the risk estimates for each SSRI in relation to suicide (a), non-fatal self harm (b), and suicidal thoughts (c). Because of the small number of suicides, the confidence intervals for the risk estimates are very wide. Of note, the Bayesian intervals are slightly wider than those in the figures, which have been calculated by using a classical approach, as the bayesian estimates reflect uncertainty about the precision between products.
Forest plots of suicide, non-fatal self harm, and suicidal thoughts in placebo controlled trials of SSRIs
The overall risk of suicide in both arms of the trials combined was 39 per 100 000 (16 suicides among 40 826 subjects). The risk of non-fatal self harm was about 10 times higher than that for suicide (328/100 000 (172 episodes of self harm among 52 503 subjects)); the risk of suicidal thoughts was similar to that for non-fatal self harm (387/100 000 (177 episodes of suicidal thoughts among 45 704 subjects)). As the mean duration of the trials included in the synthesis was eight to 10 weeks,9
the overall rates of suicidal behaviour and thoughts per person year at risk are likely to be some five times higher than the risks calculated here.
Size of trials needed to detect impact of SSRIs on risk of suicide and non-fatal self harm
We based our sample size estimates on the risk of suicide (39/100 000) and non-fatal self harm (328/100 000) among those taking part in the randomised trials of SSRIs, assuming a 20% decrease in risk is considered clinically important. About 1.9 million subjects would need to be recruited to a trial to detect a 20% decrease in suicide risk (assuming 80% power and 5% level of significance). For non-fatal self harm, the total sample size would need to be about 220 000. To detect a halving of risk of suicide and self harm, the sample sizes required would be 262 000 and 31 000 respectively.