Re: Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
The study is not reliable
Lu et al. reported that suicide attempts in young people increased after the FDA warned in 2003 and 2004 that SSRIs can increase just that: the risk of suicidal behaviour in young people (1). They found substantial reductions in antidepressant use after the warnings and believe that this caused the increase in suicide attempts.
This is contrary to what would be expected. The FDA’s large meta-analysis of 100,000 patients who had participated in placebo-controlled randomised trials found that antidepressants increase suicidal behaviour up till about the age of 40 (2), and in young people, the risk was doubled, as Lu et al. also report (1). This result was found despite the fact that many suicides and suicide attempts on active drugs were missing in the FDA analysis (3).
It is therefore a highly convincing finding that antidepressants increase the risk of suicide in young people, and randomised trials are far more reliable than the before-after analysis that Lu et al. presented, which seemed to find the opposite result. There must therefore be major problems with their research, and indeed there are.
1. The authors didn’t study their primary outcome, suicide attempts on SSRIs, but used a proxy, which was “poisoning by psychotropic agents” (ICD-9 code 969). This is a very poor surrogate. It covers all psychotropic agents, not only SSRIs, and people on SSRIs who attempt to commit suicide don’t usually poison themselves (and cannot really do it with SSRIs). Suicides on SSRIs are often violent, e.g. death by hanging, gun shots or caused by vehicles. Further, many suicide attempts and much suicidal behaviour don’t lead to hospital admission and might therefore not be detected and coded.
2. Most importantly, the authors don’t seem to know that any dose change with SSRIs increase the risk of suicide. Treatment with SSRIs leads to dependency in many people (3,4) and it is well-known that withdrawal from SSRIs can lead to terrible symptoms, which increase the risk of suicide. Thus, if people suddenly stop taking SSRIs because of the FDA’s warnings, suicide attempts might increase, but this is likely due to the withdrawal symptoms, not certainly because SSRIs protect against suicide in young people, which they don’t (3).
3. The authors used complicated statistics with quadratic terms to make their point (1), and we should therefore look at their raw data instead. The authors’ figures are not convincing. For example, psychotropic drug poisonings and suicides continued to rise markedly in adolescents, with no difference in trend, after the decline in use of SSRIs had stopped and even after the use started to go up again (their Figure 1).
4. The authors’ seem to be biased in favour of antidepressants. For example, they conclude that “Undertreated mood disorders can have severe negative consequences.” As they focus on young people, it would have been more correct to say that treatment of mood disorders can have severe negative consequences, which is what the FDA analysis showed. They also downplay the FDA findings by saying that the trials included in the meta-analysis were never designed to estimate the risk of suicidality. This is true, but the effect of this is the opposite of what the authors think, namely that the suicidality risk was much underestimated. For example, the FDA asked the companies to only report events that occurred within the first 24 hours after the randomised phase stopped, although we know that the suicide risk is increased for much longer than 24 hours. Worst of all, the FDA had informed the companies that it wouldn’t check their reports of suicidality, despite the fact that the FDA was aware that several companies had manipulated the suicidality data they had submitted to the FDA earlier (3)!
The findings in the report by Lu et al. should be ignored. SSRIs don’t decrease suicidal behaviour in young people, as they claim. SRRIs increase it, and it seems that the risk increases with dose, as would be expected (5).
References
1. Lu CY, Zhang F, Lakoma MD, et al. Changes in antidepressant use by young people and
suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ 2014;348:g3596.
2. Laughren TP. Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory
Committee (PDAC). 2006 Nov 16. Available online at: www.fda.gov/ohrms/dockets/ac/06/
briefing/2006- 4272b1- 01- FDA.pdf (accessed 22 October 2012).
3. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013.
4. Nielsen M, Hansen EH, Gøtzsche PC. What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction 2012;107:900–8.
5. Miller M. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med doi:10.1001/jamainternmed.2014.1053.
Rapid Response:
Re: Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
The study is not reliable
Lu et al. reported that suicide attempts in young people increased after the FDA warned in 2003 and 2004 that SSRIs can increase just that: the risk of suicidal behaviour in young people (1). They found substantial reductions in antidepressant use after the warnings and believe that this caused the increase in suicide attempts.
This is contrary to what would be expected. The FDA’s large meta-analysis of 100,000 patients who had participated in placebo-controlled randomised trials found that antidepressants increase suicidal behaviour up till about the age of 40 (2), and in young people, the risk was doubled, as Lu et al. also report (1). This result was found despite the fact that many suicides and suicide attempts on active drugs were missing in the FDA analysis (3).
It is therefore a highly convincing finding that antidepressants increase the risk of suicide in young people, and randomised trials are far more reliable than the before-after analysis that Lu et al. presented, which seemed to find the opposite result. There must therefore be major problems with their research, and indeed there are.
1. The authors didn’t study their primary outcome, suicide attempts on SSRIs, but used a proxy, which was “poisoning by psychotropic agents” (ICD-9 code 969). This is a very poor surrogate. It covers all psychotropic agents, not only SSRIs, and people on SSRIs who attempt to commit suicide don’t usually poison themselves (and cannot really do it with SSRIs). Suicides on SSRIs are often violent, e.g. death by hanging, gun shots or caused by vehicles. Further, many suicide attempts and much suicidal behaviour don’t lead to hospital admission and might therefore not be detected and coded.
2. Most importantly, the authors don’t seem to know that any dose change with SSRIs increase the risk of suicide. Treatment with SSRIs leads to dependency in many people (3,4) and it is well-known that withdrawal from SSRIs can lead to terrible symptoms, which increase the risk of suicide. Thus, if people suddenly stop taking SSRIs because of the FDA’s warnings, suicide attempts might increase, but this is likely due to the withdrawal symptoms, not certainly because SSRIs protect against suicide in young people, which they don’t (3).
3. The authors used complicated statistics with quadratic terms to make their point (1), and we should therefore look at their raw data instead. The authors’ figures are not convincing. For example, psychotropic drug poisonings and suicides continued to rise markedly in adolescents, with no difference in trend, after the decline in use of SSRIs had stopped and even after the use started to go up again (their Figure 1).
4. The authors’ seem to be biased in favour of antidepressants. For example, they conclude that “Undertreated mood disorders can have severe negative consequences.” As they focus on young people, it would have been more correct to say that treatment of mood disorders can have severe negative consequences, which is what the FDA analysis showed. They also downplay the FDA findings by saying that the trials included in the meta-analysis were never designed to estimate the risk of suicidality. This is true, but the effect of this is the opposite of what the authors think, namely that the suicidality risk was much underestimated. For example, the FDA asked the companies to only report events that occurred within the first 24 hours after the randomised phase stopped, although we know that the suicide risk is increased for much longer than 24 hours. Worst of all, the FDA had informed the companies that it wouldn’t check their reports of suicidality, despite the fact that the FDA was aware that several companies had manipulated the suicidality data they had submitted to the FDA earlier (3)!
The findings in the report by Lu et al. should be ignored. SSRIs don’t decrease suicidal behaviour in young people, as they claim. SRRIs increase it, and it seems that the risk increases with dose, as would be expected (5).
References
1. Lu CY, Zhang F, Lakoma MD, et al. Changes in antidepressant use by young people and
suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ 2014;348:g3596.
2. Laughren TP. Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory
Committee (PDAC). 2006 Nov 16. Available online at: www.fda.gov/ohrms/dockets/ac/06/
briefing/2006- 4272b1- 01- FDA.pdf (accessed 22 October 2012).
3. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013.
4. Nielsen M, Hansen EH, Gøtzsche PC. What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction 2012;107:900–8.
5. Miller M. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med doi:10.1001/jamainternmed.2014.1053.
Competing interests: No competing interests