In this article
View / Download pdf
version of this article
It's 2002; An 18-year old male patient, suffering from depression and anxiety is seeking treatment. You prescribe him
what evidence shows to be a safe and effective antidepressant - paroxetine.
Fast forward to 2008; does evidence suggest you prescribe this drug now? SSRIs have gone from being widely popular to
being associated with suicide risk, and then used again as the level of risk was outweighed by untreated depression. Now
a recent study claims that they do not work at all. The story is sure to continue.
The rate of antidepressant prescriptions in children and adolescents was steadily rising until 2003 when worldwide regulatory
agencies issued public health advice ("black box warnings") in response to reports that young people starting antidepressants,
especially SSRIs, were experiencing sudden onset of agitation and suicidal thoughts.1 After the warnings were
issued, antidepressant prescribing reduced considerably and some mental health professionals expressed concern that this
may result in increased levels of untreated depression and subsequent suicide.
Conflicting evidence of an increase in youth suicides
Since the black box warnings, there have been two major observational studies published which investigated the possible
association between antidepressant prescriptions and completed suicide or suicidal behaviour. These studies reached conflicting
Researchers from the USA and Netherlands studied national health records to identify suicide rates, before and after
the public health warnings were issued. In the Netherlands, the youth suicide rate increased by 49% between 2003 and 2005
and was significantly associated with the decline in SSRI prescriptions. The most significant association was for boys
under 15 years. In the USA, the youth suicide rate increased by 14% between 2003 and 2004, which was the largest yearly
change recorded since 1979. Prior to the warnings, SSRI prescription rates were increasing and suicide rates were decreasing
in both countries.2
Data from a recently released ecological time series study from the UK, using national prescribing, mortality and hospitalisation
data, contradicts these results. Researchers found no evidence of an association between trends in antidepressant prescribing
and suicide or hospital admissions for self harm, despite a large reduction in antidepressant prescribing since the warnings
in 2003. There were no obvious differences between the populations in either study that would explain this discrepancy.3
While causal associations drawn from ecological studies are often difficult to prove, the results of these studies raise
some important questions about the validity of the original black box warnings for SSRIs and perhaps more importantly,
whether antidepressants actually work for young people with depression.
Was the black box warning valid?
It appears now that the black box warning was a reaction to weak evidence, which had serious consequences if true. There
have been no observations of completed suicides in any of the SSRI trials to date.
There is a higher risk of suicide in real populations compared to study populations. In the trials, the rate of suicide
related behaviours was 5% for people using SSRIs and 3% for people using placebo.4 Community studies show that
over a fifth of young people report serious suicidal ideation and around 7% report suicide attempts.5 In most
trials of medication, those at risk of suicide are typically screened out. So the population on which the trials have
been done are at particularly low risk of suicide related behaviours and so are not those typically seen in clinical practice.
In addition, the studies were not set up to assess suicide risk and were not powered to do this. The ways in which suicide
related behaviours were assessed varied from study to study. In the Treatment of Adolescents with Depression (TADS) study,
a self-report measure of suicidal ideation was used and this showed a steady drop in suicide risk while on antidepressant
Are antidepressants effective treatments for depressive disorder
in children and adolescents?
The evidence is inconclusive at this stage. Tricyclic antidepressants are not effective for children and adolescents
with depression7 and there is limited evidence that SSRIs other than fluoxetine have anything more than a placebo
response.8, 9 Even for fluoxetine the overall response rate is low.10
It is unclear whether long-term use of antidepressants in children results in adverse effects. Some studies suggest
that children taking long-term antidepressants are at increased risk of developing bipolar disorder and other neurological
effects.1 Psychological therapies are recommended as first-line treatment for this age group.11
The example of the antidepressants "story" demonstrates the complexity of trying to practice evidence based medicine
when it keeps changing. In this case, the implicit consequence of the evidence, if proven true, has been the main influence
on the cycle of treatment.
What we know now is that antidepressants are unlikely to increase suicidal behaviour in young people, but there is doubt
over whether they work at all.
A 2005 study found that 16% of top-cited clinical research articles on medical interventions published in the last fifteen
years have been contradicted by subsequent clinical studies. In addition, a further 16% of research was found to have
initially stronger effects than later research found.12 This is a worrying statistic for those who strive to
practice evidence based medicine.
There is a huge volume of research published in medical journals each year but only a small minority of papers receive
attention and dominate scientific thought and practice. Original highly cited articles are published almost exclusively
in three general medical journals - the New England Journal of Medicine, the Journal of the American Medical Association
(JAMA) and Lancet.12
High impact research may be further influenced by several biases. "Publication bias" and "time lag bias" favour rapid
and prominent publication of positive findings.12 "Wish bias" is when researchers are selective in the results
they choose to publish or the research they choose to refute due to their desire for their own beliefs to be true.13
The strength of a study's findings should be measured by the amount of supporting research. Observational studies are
often contradicted by randomised controlled trials and small studies are contradicted by studies with much larger sample
There are several reasons why researchers may get it wrong.
- Statistical significance is not always equal to clinical significance. Level of significance is arbitrary; traditionally
a P value of <0.05 is considered significant, however significance should be interpreted in the context of the study.
- Initially stronger effects may be due to chance variability.
- Evidence from a unique trial may be refuted with subsequent study in the area.
- Studies may not be able to be replicated and therefore results cannot be confirmed.
There is no proof that subsequent contradictory studies are themselves true. However the overall effect is that it generates
uncertainty for clinical practice.12 In the course of developing both the HRT and antidepressant articles for
this edition of best practice, evidence changed and advice had to be updated.
Trying to make sense of research evidence can be complex and time consuming and as seen here, even the experts get it
wrong. It is often unavoidable to follow latest evidence, especially when it receives much media attention. However wherever
possible, an informed but pragmatic approach is "best practice".
Thank you to Dr Sally Merry, Werry Centre for Child and Adolescent Mental Health, for expert guidance on this article.
- Leckman J. A developmental perspective on the controversy surrounding the use of SSRIs to treat pediatric depression.
Am J Psychiatry 2007;164(9):1304-6.
- Gibbons R, Brown H, Marcus S, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions
and suicide in children and adolescents. Am J Psychiatry 2007;164(9):1356-63.
- Wheeler B, Gunnell D, Metcalfe C, et al. The population impact on incidence of suicide and non-fatal self harm of
regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological
study. BMJ 2008;[Epub ahead of print].
- Hetrick S, Proctor M, Merry S, et al. Selective serotonin reuptake inhibitors (SSRIs) for depression in children
and adolescents. Cochrane Database Syst Rev 2007.
- Watson P, Clark T, Denny J, et al. A health profile of New Zealand youth who attend secondary school. NZ Med J 2003;116(1171).
- March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents
with depression treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA 2004;292(7):807-20.
- Tricyclic drugs for depression in children and adolescents. (Cochrane Review) [program]. Oxford: Update Software.
- Hetrick S, Proctor M, Merry S, Sindahl P, Ward A. Selective serotonin reuptake inhibitors (SSRIs) for depression
in children and adolescents. Cochrane Database of Systematic Reviews 2007.
- Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors
in childhood depression: systematic review of published versus unpublished data. The Lancet 2004;363(9418):1341-5.
- Jensen P. After TADS, can we measure up, catch up and ante up? J Am Acad Child Adolesc Psychiatry 2006;45(12):1456-60.
- Cheung A, Zuckerbrot R, Jensen P, et al. Guidelines for adolescent depression in primary care (GLAD-PC): II. Treatment
and ongoing management. Paediatrics 2007;120(5):1313-26.
- Ioannidis J. Contradicted and initially stronger effects in highly cited clinical research. JAMA 2005;294(2):218-28.
- Tatsioni A, Bonitsis N, Ioannidis J. Persistence of contradicted claims in the literature. JAMA 2007;298(21):2517-26.