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Antidepressant risks: With children and adolescents

   

Thinking of starting your child on an antidepressant?

   
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Maybe you, the teacher, and/or your doctor think your child is depressed and might benefit from medication. If so, you may find this helpful to know.

Doctors place their trust in particular medications on the basis of the evidence of published studies. But the trouble is, studies intending to prove that antidepressant drugs are safe and effective for children and adolescents have been shown to be seriously biased and flawed. Patients and doctors are being misled as drug companies mostly only publish the most favourable data and hold back on studies that show the drugs in a poor light.

pillsAny parent considering starting their child on medication needs to know if the drugs are safe and effective. Every child has the right to be treated with medicines that are known to be safe and are likely to be helpful too.  Where there are risks, families need to know whether these risks are worth taking. Here we take a closer look at some of these studies. As you will have realised by now, this website is not telling you what to do or what not do. This information is intended to support the making of informed choices. 

Learning from history

We will first take a look at the antidepressant Seroxat (US Paxil, also known as paroxetine) as this is a drug that was marketed as safe for children but soon proved hazardous. Although Seroxat was known by the makers (GlaxoSmithKline, GSK) as both risky and a poor performer when used with children/adolescents – the company (GSK) supported the publication of a misleading study report in a prestigious journal to cover up the serious risks and encourage widespread use. Until the truth came out, this drug was prescribed widely for paediatric use by countless doctors. Tragically, the cost was high in that children have killed themselves in what are claimed to be adverse reactions to this drug. Had the truth not been concealed by deceptive reporting and marketing, doctors and the public would have known that this drug was associated with the onset of suicidal thinking and actual suicide.

It is far too easy to claim that this was a one-off and things are now fine as Seroxat is no longer to be prescribed for youngsters. But that is far too simplistic: misinformation and deception continue.  As Prozac/fluoxetine is now the recommended drug for paediatric use we will also take a closer look at some of the flaws in studies that appear to support its use with children and adolescents. Here too, serious risks are being played down. My purpose here is not to provide the most in-depth research evidence; but rather, to show that there are more concerns surrounding the benefits and risks of antidepressant use with children and young people than is widely accepted. To make informed choices we need to be informed.

Seroxat - No longer to be prescribed to children for depression

Some antidepressants are known to have ill-effects on children and adolescents; in some cases, leading then to become violent towards others and even to kill themselves. One such antidepressant drug that has been associated with these serious adverse effects with children is Seroxat (US Paxil, also known as paroxetine). Seroxat was heralded as a wonder drug in the 1990s and was being used ‘off label’ (prescribed at the doctor’s discretion but not formally approved for paediatric use) for children and adolescents.

Doctors were confident that Seroxat was safe and effective for youngsters as GSK (previously SmithKlineBeecham, SKB) had commissioned a study which concluded that: “paroxetine is generally well tolerated and effective for major depression in adolescents” 1. This message was widely promoted by GSK sales reps that were primed to tell potential prescribers that Seroxat “demonstrates REMARKABLE efficacy and safety in the treatment of adolescent depression.”

But there was a BIG problem here: the large clinical trial conducted by GSK in the 1990s did not actually show that Seroxat was safe or effective, and GSK knew this full well. We know this as an internal document at the time stated: “Essentially the study did not really show [Seroxat] was effective in treating adolescent depression, which is not something we want to publicize.” What’s more, at least 8 adolescents had self-harmed and/or had suicidal thoughts /intentions during the clinical trial (known as Study 329) 2. But still GSK continued to promote Seroxat for paediatric use.

   
   

While evidence was emerging that showed an increased suicide risk in adolescents prescribed
selective serotonin reuptake inhibitors for depression, GSK was actively encouraging off-label
prescription of paroxetine [seroxat] to individuals younger than 18 years. This was not an isolated
incident…Such behaviour is not only illegal, it is immoral. The Lancet (medical journal)

 
       

Over time, more and more people reported serious problems with this drug - with claims of children committing suicide as a reaction to this drug. These concerns were repeatedly dismissed by GSK, but in 2003 the UK Committee on Safety of Medicines issued a warning against the use of Seroxat in children. At around this time GSK issued a letter to all medical practitioners here in the UK actively discouraging the use of paroxetine in patients under 18 years of age as trial results showed “unacceptable risk of serious adverse effects, including hostility and suicidality.” 3

It took until 2012 for the law to catch up with GSK for misleadingly promoting this drug (and some other drugs too). GSK agreed to plead guilty and pay the US Government a settlement of $3 billion to resolve fraud allegations and their failure to report safety data.  The US Department of Justice’s complaint included the assertion that: “GSK published an article that misstated Paxil’s efficacy and safety for children and adolescents.” (More here).  A Lancet medical journal editorial neatly summarised the case against GSK: “What is particularly egregious about GSK's fraud is the calculated deceit and potential human cost of its aggressive and misleading marketing. For instance, while evidence was emerging that showed an increased suicide risk in adolescents prescribed selective serotonin reuptake inhibitors for depression, GSK was actively encouraging off-label prescription of paroxetine to individuals younger than 18 years. This was not an isolated incident… Such behaviour is not only illegal, it is immoral 4.”

I recognise that you may think I am overly cautious, even sceptical, when it comes to trusting drug company data. But Study 329 is a stark warning.  We need this healthy scepticism as we take a closer look at Prozac.

Prozac can be prescribed for children, but is it as safe and effective as claimed?

To many people it seemed that matters were resolved with the exposing of the risks and deception associated with Seroxat in paediatric use.  There is, however, one exception permitted: fluoxetine/Prozac. Here in the UK a doctor is advised, if prescribing an antidepressant to someone under 18, to make fluoxetine the first choice (in keeping with NICE Guideline 28 here). But there is a key problem that has not been resolved: a closer look at the evidence-base supporting fluoxetine’s use in youngsters is fraught with problems. It is true that doctors here in the UK are clearly informed of the potential risks of suicide by antidepressant drugs, including Prozac. Even so, I raise concerns that the data supporting the use of Prozac for paediatric use minimises the risks and thus misleads physicians and patients.

As we have seen, doctors are largely reliant on published studies (and drug company summary data) when deciding if a drug is worth prescribing.  Doctors were, quite rightly, outraged when a meta-analysis 5 (an analysis of data from a number of trials/sources) clearly showed that studies showing antidepressants (for children) in a positive light were being published – while those with negative findings were almost always remaining unpublished.  An editorial in the Lancet described this practise as “an abuse of the trust patients place in their physicians 6”. But the study (Whittington et al) central to this contention stopped short: it recognised risks of antidepressants in paediatric use, but still concluded that Prozac/fluoxetine “has a favourable risk-benefit profile”.  The problem is, a closer look at studies on Prozac show it too has been presented more favourably than the data shows to be true.

Graham Emslie was lead author of two studies that were submitted to the FDA in 2003 when Prozac was licensed as a treatment for children/adolescents 7, 8.  Emslie is in fact listed as one of the authors of the dubious and misleading Seroxat Study 329, which we referred to earlier. It is also noteworthy that neither of these studies on Prozac was independent: both were directly or indirectly funded by Eli Lilly, the maker of Prozac (For details see: Jureidini, J. et al. 2004). According to Professor Healy, one of these studies showed that “on the primary end-point measure, Prozac was no better than placebo…In addition, there was a 29% drop-out rate on Prozac and the rate of behavioural side effects was greater on Prozac than on placebo 9.”

Professor Leo, writing about the same study (Emslie, G. et al. 1997) also points out that “There is no mention in the paper about any children attempting suicide” in the trials, even though evidence that there were “two suicide attempts in the group of 48 Prozac-treated patients” 10 was later to become evident. Furthermore, this and similar studies were designed to give Prozac a head start over placebo: this is not illegal but it produces misleading results (For more about this see Leo, J. 2006). Thus Prozac was initially approved for use with children by an inadequate representation of the facts. Dr Emslie is, by the way, also one of the TAD authors, that we will come to next (listed here under Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents With Depression).

Concerns have also been raised about later studies on Prozac for adolescents, including the TADS studies. The TAD (Treatment for Adolescents with Depression) series of studies were heavily influenced by the pharmaceutical companies in that so many of the authors had (or still were receiving) received funding from the drug companies – see the conflicts of interest with makers of antidepressants here – and therefore a biased investment in the outcome of the studies.

In the Suicidal Events in the Treatment for Adolescents with Depression Study (TADS) 11, there is a failure (observes the psychiatrist and retired academic Dr Mickey Nardo) “to mention that 82% of the suicidal events were in kids on Prozac and 94% of the suicide attempts were by kids on Prozac. What other explanation is there besides those conflicts of interest for leaving out the most obvious thing in their data?” (More here). Dr Nardo adds that: “the actual suicidality information is buried in layers of numerology” and this “is deliberately deceitful science” (More here). Dr Nardo’s clear analysis of the TAD study data shows an alarming risk of suicide with the use of Prozac in adolescents, as shown here (as copied from his more in-depth analysis here) in the chart below:Wrap text around image

And yet, the authors of the TADS study failed to produce a chart like this which is based on their data. Did they chose to deliberately try and conceal the data? When it comes to the studies of antidepressants and young people, it is evident that researchers not only have financial conflicts of interest with the makers of these drugs but some researchers seem determined to deliberately distort the data to show these drugs as less hazardous than they are.

Another study “reported the emergence of self-destructive phenomena in 14% (6/42) of children and adolescents (ages 10-17) who were being treated with fluoxetine” 12. It is worth noting that this particular study was with those youngsters being treated for with Prozac for so-called obsessive-compulsive disorder, so the self-destructive acts shouldn’t be attributed to depression.

Although we have focussed here on the suicidal risks, there are other significant side-effects produced by fluoxetine in paediatric use, including mania, “hypomania or restlessness, insomnia or sleep disturbance, general irritability or social disinhibition, and gastrointestinal distress 13”. A key concern here is that it would be far too easy to attribute these to the child/adolescent without recognising that they are adverse reactions to the drug. Furthermore, a child who becomes hyper is soon likely to be diagnosed as “Bipolar” and then prescribed further drugs (with additional side-effects).

Some concluding thoughts

Alarmingly, it transpires that drug companies have tried to play down the risks and to exaggerate the benefits of antidepressants for use with children (as detailed in this meta-analysis 5). An editorial in The Lancet medical journal reported this “Confusion, manipulation, and institutional failure” as “an abuse of the trust patients place in their physicians”.14

Antidepressant drugs cannot confidently be recommended as a treatment option for childhood
depression…We are concerned that biased reporting and overconfident recommendations in
treatment guidelines may mislead doctors, patients, and families. Many will undervalue non-drug
treatments that are probably both safer and more effective. Prof Jureidini and colleagues

As we have seen, the fact that Prozac is approved in England for use with children and young people does not mean that the risk is low or that the side-effects are tolerable. Various researchers/academics conclude that caution should be exercised when considering the use of antidepressants for the treatment of paediatric depression.

The authors of the study I have just cited (Sommers-Flanagan 1996) conclude: “Overall, we believe increased scepticism about the efficacy of antidepressant medications with youth may have positive ramifications for psychologists and for child and adolescent mental health care 13.”

Dr Joanna Moncrieff and Professor Irving Kirsch, having taken a close look at methodological issues in antidepressant drug trials, conclude that: “In children, the balance of benefits to risks is now recognised as unfavourable.” 15

In a statement by Professor Irving Kirsch with Professor David Antonuccio to the FDA regarding the efficacy of antidepressants with children, they state that “Clinically meaningful benefits have not been adequately demonstrated in depressed children…The highest possible standard should be applied to scientific data involving drug treatment of children because children are essentially involuntary patients 16.” (This statement includes a number of references that you may find helpful).

Professor Jureidini and co-authors conclude: “Antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression…We are concerned that biased reporting and overconfident recommendations in treatment guidelines may mislead doctors, patients, and families. Many will undervalue non-drug treatments that are probably both safer and more effective. 3

Maybe what we do not know is equally worrying. Do we know for sure that these drugs will not damage the eggs an adolescent girl is carrying for later pregnancy and childbirth? No. But we do know that antidepressants can damage cells 17. Is there any scientific certainty that antidepressants will not permanently damage the brain? None that I am aware off. Clearly the risks are high; especially when we consider that for most people placebo (sugar pills) work as effectively as do antidepressants. 18

Children and adolescents become sad for many different reasons. It may well be that the sadness and depression are a sign that something needs to change in that person’s life – they may have distress over what has happened in their lives, what is happening, and even fear the future. Medication cannot directly address or resolve these.

 

Children and adolescents become sad for many different reasons. It may well be that the
sadness and depression are a sign that something needs to change in that person’s life – they
may have distress over what has happened in their lives, what is happening, and even fear the
future. Medication cannot directly address or resolve these.

 
 

References - Bibliography - Further reading

1 Keller, M. et al. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: A randomised, controlled trial. Journal of American Academy of Child and Adolescent Psychiatry, 40, 762-772. Abstract here.

2 Jureidini, J. & McHenry, L. (2011) Conflicted medical journals and the failure of trust. Accountability in Research, 18:45-54, 2011

3 Jureidini, J. et al. (2004) Efficacy and safety of antidepressants for children and adolescents. BMJ Vol 328 10. Available here

4 The Lancet, Volume 380, Issue 9836, Page 2, 7 July 2012. Available here.

5 Whittington, C. et al. (2004) Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet  363: 1341-45. Full article available here.

6 Editors. (2004). Depressing research. The Lancet, 363, Issue 9418, Page 1335. Full text here.

7 Emslie, G. J. et al. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031–1037. Abstract here.

8 Emslie, G. et al. (2002) Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 4, 1205-15. Abstract here.

9 House of Commons Health Committee: The influence of the Pharmaceutical Industry 2004 Quoted section available here.

10 Leo, J. (2006) The SSRI Trials in Children: Disturbing Implications for Academic Medicine. Ethical Human Psychology and Psychiatry, Volume 8, Number 1. Available here.

11 Vitiello, D. et al. (2009) Suicidal Events in the Treatment for Adolescents with Depression Study (TADS). Journal of Clinical Psychiatry. 70(5): 741–747. Full study here

12 King, R. et al. (1991) Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry. Mar;30(2):179-86. Abstract here

13 Taken from: Sommers-Flanagan (1996) Efficacy of antidepressant medication with depressed youth: what psychologists should know.  Professional Psychology: Research and Practice, Vol 27. No. 2. 145-153. Available here.

14 Editors. (2004). Depressing research. The Lancet, 363, Issue 9418, Page 1335. Full text here

15 Moncrieff, J. & Kirsch, I. (2005) Efficacy of antidepressants in adults. BMJ 2005;331;155-157 The full article is available here.

16 FDA Testimony of Dr. Irving Kirsch and Dr. David Antonuccio on the efficacy of antidepressants with children. 
February 2, 2004.  Available here.

17 Jackson, G. (2009) Drug-induced dementia - a perfect crime.  USA: Anchor House

18 Kirsch, I. et al. (2008) Initial severity and antidepressant benefits: A meta-analysis of data submitted to the FDA. PLoS Medicine 2008 Vol 5 Issue 2. Available here