Markowitz (2001), commenting on a study by Donovan et al (2000), which indicated that selective serotonin reuptake inhibitors (SSRIs) were more associated with presentations of deliberate self-harm to accident and emergency departments than were other antidepressants, suggested that it was ‘ astounding’ that Donovan et al had not taken into account the fact that their results might stem simply from a preferential prescribing of SSRIs to patients with borderline personality disorder — a patient group particularly prone to self-harm. Dr Markowitz's points about the Donovan et al study come down essentially to two — that this study was not randomised and that there was no placebo control. There are, however, data in the public domain bearing on these points to which he may not have had access.
Khan et al (2000) published a meta-analysis of randomised controlled trials submitted to the US Food and Drug Administration (FDA) showing suicides and suicide attempts on a number of recently licensed antidepressants. Requests to the FDA under freedom of information provisions (further details available from the author upon request) indicate that three of five suicide attempts characterised as placebo suicide attempts in the sertraline trial programme reported by Khan et al occurred during washout rather than while on placebo. Similarly, in the paroxetine trial programme reported by Khan et al, both suicides and three of six suicide attempts characterised as placebo suicides and attempts appear to have been washout rather than placebo suicides or attempts. Taking this information into account and analysing the drug v. ‘ true placebo’ data for absolute numbers of patients reveals a statistically significant general increase in the risk of suicide acts on novel antidepressants compared with placebo and a specific increase for paroxetine.
In the light of these randomised, placebo-controlled findings it would seem that Dr Donovan et al were cautious and understated in their discussion of their results.
- © 2002 Royal College of Psychiatrists
Response from Pfizer
The possible association between SSRIs and suicidal behaviour has been the subject of intense discussion throughout the 1990s, following the publication of case reports of suicidal behaviour suspected to be associated with fluoxetine.
Healy states that three of five suicide attempts characterised as placebo suicide attempts in the sertraline trial programme reported by Khan et al occurred during the washout period rather than while on placebo. All of the five suicide attempts to which he refers occurred while patients were on placebo, three of which occurred during the washout period. Healy similarly states that three of six suicide attempts and two completed suicides also occurred during washout rather than while on placebo in the paroxetine trial programme. Pfizer does not have access to data regarding other companies' products and cannot therefore comment whether this is accurate or not. Healy concludes that taking this information into account and reanalysing the data, there is a statistically significant general increase in the risk of suicidal acts in patients taking novel antidepressants when compared with placebo. However, since this is based on inaccurate information, at least as regards sertraline, it is not a justifiable conclusion.
Pfizer has submitted information specific to when deaths occurred to the Medicines Control Agency (MCA) as well as other regulatory bodies, in compliance with worldwide regulatory requirements.
As with all medicines, the safety of the SSRIs is continually monitored by the MCA and the independent expert advisory body, the Committee on Safety of Medicines (CSM). Since 1992 a number of epidemiological studies and analyses of clinical trial data have failed to establish a causal association between the SSRIs and suicidal behaviour, and the CSM has reviewed this issue on a number of occasions. The most recent review, conducted in 2001 and discussed at the CSM on 12 December 2001, concluded that ‘the current evidence is insufficient to confirm a causal association between SSRIs and suicidal behaviour’ (Commons Hansard Written Answers, 2002) and advised that the issue should be kept under review.
The product information and the British National Formulary warn that patients should be closely monitored for suicidal impulses, and an article emphasising this advice was also published in the MCA/CSM drug safety bulletin in September 2000.
References
Response from GlaxoSmithKline
Dr Healy responds to concerns raised by Markowitz (2001) about the potential for misinterpretation of the Donovan et al (2000) study. Markowitz points out that the patient populations receiving SSRIs and tricyclic antidepressants were not similar, and accordingly that comparisons of the effects of the two classes of antidepressants on suicide risk are not meaningful. Dr Healy suggests that there are data in the public domain bearing on this issue, citing the meta-analysis performed by Khan et al (2000) and data obtained from the US Food and Drug Administration. Khan et al found no difference in suicide or suicide attempts with the use of antidepressants compared with placebo. Dr Healy claims that suicides and suicide attempts during ‘ washout rather than while on placebo’ invalidate the results of Dr Khan et al's analysis.
With respect to paroxetine, Dr Healy misstates the scope of the Khan et al meta-analysis, and the conclusions he draws lack scientific substantiation. Dr Healy fails to recognise that the exposure time of patients on paroxetine in the clinical studies was substantially different and far greater than that on placebo — under these circumstances an analysis of absolute numbers of patients with no consideration of time of exposure is not meaningful. Furthermore, contrary to Dr Healy's implication, the Khan et al report was not limited to randomised, placebo-controlled studies. In the case of paroxetine, the studies covered included open label extensions, studies without placebo arms, and studies that were not randomised. When one considers only the randomised, controlled portions of the placebo-controlled trials (excluding events occurring during placebo run-in) included in the Khan et al analysis, there are no statistically significant differences in suicides or suicide attempts between paroxetine and placebo, either in absolute numbers of patients or when adjusted for time of exposure.
Donovan et al caution about the conclusions that should be drawn from the study. They point out that physicians are following guidance to prescribe antidepressants that are purportedly ‘safer in overdose’ to patients who are perceived to be at greater risk of deliberate self-harm. Consistent with Dr Markowitz's comments, this prejudices against SSRIs when associations are made between their use and deliberate self-harm. Donovan et al also note that it is problematic attributing the cause of deliberate self-harm to antidepressant treatment when such behaviour occurs as a symptom of depressive illness itself and that establishment of cause and effect is ‘almost impossible’.
The ‘drug v. “true placebo” ’ analysis Dr Healy describes is not only scientifically invalid, but also misleading. Major depressive disorder is a potentially very serious illness associated with substantial morbidity, mortality, suicidal ideation, suicide attempts and completed suicide. Unwarranted conclusions about the use and risk of antidepressants, including paroxetine, do a disservice to patients and physicians.