Sunday, July 04, 2004

British Medical Journal Article:
Antidepressants and Suicide

There has been some concern about the possibility that antidepressant medication could actually increase the risk of suicide.  I have written about this a few times in the past; use the freefind search function in the sidebar if you care to find the earlier posts.  Recently, a few more items of interest have appeared on the 'net.  Gregg Easterbrook wrote an article on the New Republic entitled Pills Bury

Pills Bury
by Gregg Easterbrook
Post date 06.21.04

[...] So if antidepressant use is rising, and antidepressants are associated with suicide, then suicide must be rising, right? It's the other way around. Suicide in the United States is in decline, and the decline syncs almost exactly with increased use of antidepressants. This is a little detail that's been skipped in the coverage.

[...] I'm going to put my money on what seems the most obvious explanation--the decline in suicide is being caused by increased use of antidepressants.

Mr. Easterbrook is a senior editor and a distinguished fellow at the Fullbright Foundation.  He goes on to tell of his hypothesis about why antidepressants might reduce the suicide risk for the majority of people who take them, you cause a significant risk in a subset of the population.  I must say, his hypothesis doesn't really explain anything, but I agree with the gist of his article.  He goes on to make a good point:

Public-health experts have long worried that anger and lawsuits regarding the minority of people who have horrible adverse reaction to vaccines will result in the undoing of vaccination, which would lead to a big increase in suffering. The same fear may apply to antidepressants. If people stop taking them, or manufacturers stop making them, because a few have horrible adverse reactions, overall emotional suffering may rise, and there may be more total suicides.

 Later the same day, Mark A. Kleinman picked up on Easterbrook's article, and delineated his own thoughts on the matter:

Two kinds of suicide
June 21, 2004

Gregg Easterbrook makes an argument about suicide and the selective serotonin reuptake inhibitors (SSRIs -- the class of antidepressants including Prozac and Zoloft) that seems plausible, though I'm not qualified to judge the underlying factual claims:

1. The use of SSRIs precipitates suicide in a small but non-trivial number of patients.

2. But widespread SSRI use has coincided with a decline in the overall suicide rate.

3. Untreated depression is a major cause of suicide.

4. Therefore, SSRIs probably prevent many more suicides than they cause.

5. Therefore, scaring people into no using them, or scaring manufacturers into not making them, with a combination of publicity and lawsuits would result in more suicides, not fewer.

Again, I'm not sure that's right, but it might well be right, and it shows how poorly adapted our existing journalistic and legal mechanisms are to making policy about health care.

Dr. Kleinman is being a little bit modest here; although he is not a physician, he is a professor of Policy Studies at UCLA, and the director of the Drug Policy Analysis Program.  While not an expert per se  on the topic, clearly he has greater expertise than most bloggers.  He goes on to argue that not all suicides are bad:

[...]The bad suicide -- the part of suicide that can reasonably be conceived of as a public-health problem -- is the impulsive suicide, committed by a person who didn't want to kill himself last week and who won't want to kill himself next week if his current attempt is prevented or fails. Victims of that sort of suicide tend to be younger and to be suffering from various diagnosable mental health conditions, especially depression and anxiety. This class of cases ought to be managed with suicide prevention combined with treatment for the underlying disorders. (In addition, there are impulsive suicides stemming from sudden disasters; for these, prevention is still in order but there may be no underlying disorder to treat.)

But some suicides don't look like that at all. They're committed by people who, due to intense and prolonged misery, have decided that their lives would be happier if they ended now rather than later. The subjects -- I see no reason to call them "victims" -- of such acts of voluntary termination tend to be older, have more physical and social problems, and to have fewer psychiatric problems than those who submit to a transient impulse to kill themselves. [...]

Update:  A reader points out that the distinction between considered and impulsive acts is at least partly misleading, since someone in the grip of depression or anxiety disorder may plan a suicide carefully over a long period. A suicide committed not on impulse, but with impaired decision-making capacity, can be just as tragic and just as preventable as an impulsive act. So the right distinction is between "well-considered" acts, planned over time with relatively unimpaired mental faculties, and "poorly-considered" acts done either rashly or under the burden of mental illness.

Ideally, those judgments would be made looking only at the form of the decision rather than its content. In fact our judgment about whether a suicide is well-considered or not will have to depend to some extent on the substance of the reasons assigned for it. 

This is an interesting point, although it is not pertinent, directly, to the question of whether antidepressant medication could actually increase suicide risk for some people.  I believe that the reader to whom he refers in his update was Lindsay Beyerstein, who has a related post:

[...] Patients with clinical depression may retain their rational faculties, but and yet be suffering from a biochemical brain disorder which distorts their affective responses. A depressed patient may rightly conclude that her current life isn't worth living. Nothing seems worth having or pursuing, she's unable to take pleasure in things she once enjoyed, etc. Unless the patient realizes that her condition is treatable, she may undertake a considered suicide based on her distorted view of the world.

Kleinman is right that we shouldn't build pathology into our definition of suicide. Rational suicide is possible. See an earlier post of mine for a link to compelling case studies We should not discount the possibility of rational suicide, but if someone starts exhibiting suicidal tendencies, our default approach should be medically, rather than existentially oriented. Simply put, we should maintain a clinical high index of suspicion towards people considering suicide. We should help the distressed person to rule out the possibility that she is suffering from a treatable illness before she takes any irrevocable steps. 

The recent debate started in the UK late last year, so it is not surprising that the British Medical Journal would have some follow-up articles.  The latest issue has such an article.  It was co-authored by David Gunnell, professor of epidemiology, Deborah Ashby, professor of medical statistics.  Note that neither is likely to have any financial interest in the debate.

Antidepressants and suicide: what is the balance of benefit and harm
BMJ  2004;329:34-38 (3 July), doi:10.1136/bmj.329.7456.34

Prescribing of antidepressants has increased greatly in England and elsewhere in recent years.1-3 This increase has coincided with a fall in rates of suicide, leading some researchers to suggest a causal association.2 4-6 Meanwhile, others are concerned that antidepressants may precipitate suicidal behaviour.7 8 A recent review of evidence from paediatric trials by the Committee on Safety of Medicines in Britain led to most selective serotonin re-uptake inhibitors (SSRIs) being contraindicated in people aged younger than 18.9 So how safe are they? In this article, we assess the data on the risks and benefits.

[...] Surprisingly, direct evidence that antidepressants prevent suicide is hard to find. A meta-analysis of data on the SSRI fluoxetine, funded by its manufacturer, found no evidence that suicidal acts were less frequent among adults taking antidepressants; the pooled incidences were 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclics.14 In the most comprehensive synthesis of data from randomised trials, Khan and colleagues found no evidence of a beneficial effect of antidepressants on suicide.15 These findings are difficult to interpret as this was not a formal meta-analysis and relative risks were not derived separately for each trial on an intention to treat basis.

Suicide is rare, even among people with depression.16 Thus, most clinical trials have insufficient power to provide clear evidence on the effect of antidepressants on suicide.

The last point mentioned, in the above excerpt, may require some explanation.  The [phrase "insufficient power" refers to the concept of statistical power.  Statistical power is the probability that one can detect an effect if there really is one.  Let's say you wanted to determine if a coin toss really has an equal probability of coming up heads as opposed to tails.  If you conducted a study by flipping a coin ten times, you would not be able to detect any departure from randomness, because you did not conduct enough trials to see a small difference.  (In fact, it would take about 10,000 flips to detect the difference that does exist.)   Since the suicide rate is about 17 per 1000,000 persons per year, and most drug trials involve only a few hundred patients for a few months, a standard antidepressant drug trial is not going to be able to detect a risk with any reasonable degree of confidence. 

In the absence of clear evidence from clinical trials, researchers have investigated whether rises in antidepressant prescribing are associated with reductions in population suicide rates.2-6 17-19 With some exceptions,3 17 18 such studies conclude that recent rises in prescribing have contributed to falls in suicides. Interpretation of these findings is not straightforward. A range of factors influence population suicide rates.19 It is therefore challenging to distinguish the discrete effects of increased antidepressant prescribing from changes in other risk factors.

What they are saying is that Easterbrook's and Kleinman's analysis by intuition is not valid; it takes a complex statistical analysis to have any chance of establishing a causal relation between the rise in antidepressant prescriptions and the decline in suicide rate.  To provide an example, they point out one complicating factor:

The possible benefits of increases in SSRI prescribing are not limited to their effect on depression. Self poisoning accounts for around a quarter of suicides in England; 20% of these deaths are antidepressant overdoses.21 Tricyclic antidepressants are considerably more toxic in overdose than SSRIs.21 Consequently, it has been estimated that a switch from tricyclics to SSRIs as first line treatment for depression could prevent 300-450 overdose deaths a year through restricting access to the more toxic antidepressants.22 Of note, increased SSRI prescribing has not been accompanied by a fall in use of tricyclics (fig 2).

This raises another complication in the statistical analysis, one that the authors do not address.  Not all antidepressant prescriptions are given for the treatment of depression.  Quite a few of the prescriptions for tricyclic antidepressants are written fro treatment of chronic pain, migraine, urinary incontinence, or insomnia.  SSRI antidepressants are prescribed for migraine and anxiety disorders, in addition to the more common use for treatment of depression.  Antidepressants sometimes are used in persons with a primary diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder.  All of these conditions impose a risk of suicide, but the risk is different for different groups.  When analyzing aggregate antidepressant prescribing data, there is no way to know why any individual prescription was written.  This introduces a lot of statistical noise that would be difficult to factor out. 

Getting to the meat of the article:

Do antidepressants increase the risk of suicide?

Soon after the launch of fluoxetine, the most commonly prescribed SSRI, a series of reports were published suggesting worsening of depression and emergence of suicidal thoughts in some people.23 24 The issue has been hotly debated.7 8 Disentangling the evidence is problematic as much of the research is sponsored by the pharmaceutical industry.25 Review of data from paediatric trials of SSRIs shows that published findings present a more favourable risk-benefit profile than unpublished trials sponsored by industry.12 Table 1 summarises the evidence from clinical trials on the adverse effects of SSRIs on suicidal behaviour in children, abstracted from information recently released by the Medicines and Healthcare Products Regulatory Agency.26 No suicides occurred in these trials. The pooled estimate of increased risk of suicidal thoughts or behaviour from these data is 1.66 (95% credibility interval 0.83 to 3.50). Interpretation of this apparent increase in risk is problematic as people taking SSRIs may be more likely to report adverse effects, perhaps because the drugs could have a disinhibiting effect. In addition, response to treatment may lead to reactivation among people whose depression previously prevented them from acting on suicidal impulses.27 Furthermore, any increased risk may be counterbalanced by a longer term reduction in suicidal behaviour; such benefits would not detected in the trials as they generally lasted 10 weeks or less, whereas the mean duration of treatment in clinical practice is three to four months.28

Reassuringly, time trends for suicide (England and Wales)29 and non-fatal self harm (Oxford)30 in children and adolescents provide no consistent evidence of adverse trends paralleling increased prescribing in the 1990s, although there is some evidence of a rise in non-fatal self harm in young females. Furthermore, in the United States, recent research suggests that areas with the largest increases in antidepressant prescribing to 10-19 year olds experienced the greatest falls in suicide.6

If rare adverse effects of antidepressants on suicide exist, recent large scale increases in prescribing might be expected to affect suicide trends. But, as detailed above, recent suicide trends have generally been favourable, and so it is likely either that benefits outweigh the risks in adults or that any excess risk is small. Nevertheless, antidepressants may have precipitated some suicides in susceptible individuals, and it is important to estimate the number of such deaths. Table 2 outlines a model to estimate the number of excess deaths that may have occurred in 2002 compared with 1991 as a result of their increased use in England.

The authors then go into a moderately complex analysis of the statistics they used, leading them to these conclusions:


There is no strong evidence that increases in antidepressant prescribing lie behind recent reductions in population suicides. Furthermore, data from paediatric trials suggest that SSRIs are associated with an increased risk of suicidal behaviour and most SSRIs seem to be ineffective for childhood depression. However, current concerns about the safety of SSRIs come from clinical trials both of too short duration (< 10 weeks) to identify longer term beneficial effects and are carried out in children and adolescents, among whom suicide is rare.

From the population perspective, the balance sheet of risks and benefits of SSRIs is unclear. Any antidepressant induced suicides may be offset by the beneficial effects of antidepressants on depression and long term suicide risk associated with untreated depression. The low toxicity of SSRIs in overdose will have prevented some suicides. The balance of risks and benefits may vary depending on an individual's underlying suicide risk. For patients with conditions that have a high risk of suicide, such as severe depression,33 the risk-benefit balance may be more favourable than for patients with conditions such as anxiety and mild depression, in which suicide is rare. It is in these lower risk conditions, however, that much of the recent rise in prescribing has probably occurred.

Depression is a common and disabling condition, and so the safety of drugs used in its management is crucial. Future trials of antidepressants should be of sufficient duration to detect longer term benefits of this class of drug and balance these against possible risks. They should also systematically collect data on suicidal thoughts and behaviour. Long term studies are required to assess the effect on population health of recent rises in antidepressant prescribing.

There are two elements missing from their conclusions.  First, the usual way of assessing a risk vs. benefit balance is to assess both the risks and the benefits.  The authors allude to the benefits of the medications, but make no attempt to compare the risk versus the benefit.  I do not fault them for this: after all, how does one weight the risk of suicide in one group versus the improved level of function and quality of life experienced by a different group -- those who have a positive response to the medication? 

Second  -- and this is an even thornier issue -- if you assume their worst-case estimates of risk are correct, but if you also acknowledge that psychiatry is a field that is advancing rapidly, how do you then weight the current risks of treatment against possible future benefits from subsequent treatment advances?  If we declare that the risks right now are not worth the benefits, does that mean we should just stop what we are doing, and forego any future advancements? 

Today, there are a lot of people walking around, leading normal lives, because of great technological advances in orthopedic surgery.  If our ancestors had looked at the problems that surgical patients had 100 years ago -- using the same kind of critical analysis that is now being applied to psychiatry, they might very well have decided that surgery was not worth it, and put an end to it.  If they had, all those people walking around today would have no legs.  Or maybe only one leg. 

Some persons with depression will respond to treatment with placebo, or to psychotherapy, or to lifestyle interventions such as improved nutrition.  But many will not.  Are we going to just let them suffer, or do we want to give them another chance? 

This leaves us with the most important question of all: if there is another chance to be given, who gets to decide whether or not the chance is worth the risk?

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