Do SSRIs Increase the Risk of Suicide among Depressives Even if They Are Taking Only Placebo?
Authors: Zoltán Rihmer
Journal: Psychotherapy and Psychosomatics (2003)

I have read with great interest the paper by Dr. Healy [1], reviewing an unselected cohort of randomised clinical trials (RCTs) and demonstrating a possible doubling of the relative risk of committed and attempted suicides on SSRIs, compared with older antidepressants (ADs) or placebo ‘treatment’. Analysing the data of table 1 of his paper, it can be seen that the rate of suicide behaviour (suicides and attempted suicides combined) among the SSRI trial placebo patients is 0.66% (16/2,401), whereas the same figure among the nonSSRI trial placebo patients is 0.23% (4/1,739). Does this mean that, compared with other ADs, SSRIs increase the risk of suicide behaviour almost threefold even if the patients are taking only placebo? Obviously, it does not. The result of this simple calculation, unfortunately missing from the table of Dr. Healy, is enough to question basically the main conclusions of his paper; yet this is not the point I should like to make here, for, in spite of this shortcoming, the paper merits further attention. The correct clinical interpretation of the findings presented by Dr. Healy calls for a more detailed analysis, taking into account the time of suicide behaviour and the responder/non-responder status of the patients at the time of their suicide event during the trial as well as the time and source of drop-outs among patients taking ADs or placebo. In other words, it would be important to secrete the data of the RCTs on: (1) suicide events occurring in the first 3 weeks of the trials (i.e. before the onset of the action of ADs), (2) suicide events occurring after the 3rd week of the trials among non-responders, (3) suicide events occurring after the 3rd week of the trials among responders, and (4) the time and source of drop-outs among patients taking placebo or ADs. Theoretically, the higher rate of suicide events after the 3rd week of treatment in patients on SSRIs compared with older ADs might be related to the higher rate of SSRI non-responders. If it were the case, the conclusion that SSRIs induce suicidality more often than older ADs is incorrect, and the formulation ‘among non-responders, SSRIs prevent less suicidal behaviour than older ADs’ would be more precise. It has been demonstrated, e.g. that lithium has an independent anti-suicidal effect, since the risk of suicide behaviour decreases significantly not only among prophylactic lithium responders, but also among partial responders and non-responders as well [2]. On the other hand, if the rate of drop-out because of suicidality among depressed patients taking placebo in RCTs were much higher than that of the patients taking ADs, it could be explained why suicide behaviour among depressed patients is the lowest on placebo. Since randomisation results in the same severity (including suicidality) of patients on placebo and on active treatment arms, the exact answers to the above-raised questions could resolve the contradiction between the logically correct conclusion and the clinically unacceptable interpretation of the findings presented by Dr. Healy, i.e. placebo treatment results in the lowest risk of suicide in depressed patients. As for suicide events occurring in the first few weeks of the trials, it should be noted that the well-known sedative (side-?) effect of older ADs (clomipramine and others) that cause several problems during long-term pharmacotherapy can decrease/prevent accompanying/newly emerging anxiety (or akathisia) in the early stage of the treatment; however, this is not the case for the SSRIs. On the other hand, because of the more favourable side-effect profile of SSRIs than that of older ADs, it is relatively easy to keep depressed patients on these drugs for many weeks or months, even if they are nonresponders. If an 8-week randomised, double-blind, placebo-controlled, fixed dosed antidepressant study were performed in the line of good clinical real practice (rather than in the line of good clinical trial practice), all non-responders would be dropped out between the 4th and the 6th week, and the final sample should contain only the responders (or, more precisely, the responders plus only a few percent of patients who were responders at the 6th week, but relapsed afterwards). I will, of course, not reject the possibility that SSRIs can induce suicidality in a quite small subsample of depressed patients, whereas they reduce/vanish it in the majority of the cases. Whether SSRIs provoke suicide behaviour in the first 3 weeks of the treatment, or after the 3rd week, but only among non-responders, is mainly a technical problem to be resolved by giving concomitant anxiolytics in the first few weeks for all depressed patients and switching to SSRI after the 3rd week in non-responders. Of the remaining 2 possibilities, namely that SSRIs can induce suicidality at any time of the treatment regardless of clinical response and that SSRIs can induce suicidality but only after the 3rd week and mainly among responders, the latter, I think, is the most unlikely. It should also be noted that the majority of RCTs on pharmacotherapy of depression exclude the most suicidal patients; therefore, their results are not representative of all depressives and have only a limited value regarding suicide prevention. Dr. Healy also concludes that the increasing use of ADs (primarily SSRIs) cannot lower national suicide rates, which seems to be rather premature. He only mentions the findings of Isacsson [3] on the significant inverse relationship between the use of ADs and suicide rate in Sweden, but does not consider the same significant negative correlation also reported for Denmark, Finland and Norway in the very same paper [3]. In addition, the more than 30% decrease in the very high suicide rate of Hungary in the last 15 years [4, 5] and the 20% decline in the suicide rate of England and Wales between 1960 and 1997 [6] as well as a marked drop of the suicide rates of Austria