In 2003 and 2004, a controversy regarding the use of antidepressant medications in children and adolescents made the headlines. It was reported that these medications increased the risk of suicide. During the last four years, many studies have been conducted to assess whether antidepressants are beneficial or detrimental in the treatment of pediatric depression. Since the controversy, the topic has received little attention in the media, but the scientific community has been working hard to answer the public’s question: Should we worry?
It is estimated that approximately 3% of children and 8% of adolescents will go through a major depression (1), which seems to completely go against the idea of what childhood is supposed to be all about: happiness and fun. Indeed, children usually like to play and interact with other people, but depressed children often show no interest in playing, distance themselves from others, and can even have suicidal thoughts. When children experience major depression, one of the treatment options consists of prescribing antidepressants. But are these medications safe for the developing minds of children? More importantly, does the consumption of these drugs pose a threat to their lives?
What are these medications?
A little over 50 years ago, researchers investigating iproniazid as a treatment for tuberculosis discovered the drug also had psychoactive properties. It made even terminally ill patients cheerful, optimistic and more active (2). Intrigued by this discovery, Zeller (3) later found that iproniazid and other similar drugs inhibited the mitochondrial enzyme monoamine oxidase, whose function is to inactivate certain neurotransmitters in the nervous system such as norepinephrine (NE), serotonin (5-HT), and dopamine (DA). This class of drugs are called Monoamine Oxidase Inhibitors (MAOIs). The result of an MAOI such as iproniazid is that particular neurotransmitters remain longer in the brain and keep stimulating neurons for a longer period of time. This is important as lower levels of NE, 5-HT, and DA have been found to be related to depression. However, MAOIs were not used in the treatment of depression until a decade later. Soon after MAOIs started to be used as antidepressants, another kind of antidepressants, called Trycyclic Antidepressants (TCAs), was discovered. However, both types of antidepressants were only sparingly used as they were found to possibly interact dangerously with others drugs, left the patients with unpleasant side effects, and had significant toxicity and safety issues. Antidepressants called Selective Serotonin Reuptake Inhibitors (SSRIs) were later developed, and were finally approved for use with adult populations in 1987. SSRIs soon became the new trend in the treatment of depression. Indeed, they were found to be safer, easier to use, and better tolerated by patients (4).
Soon after, SSRIs were approved for children. Regulating agencies of different countries (such as the United States and United Kingdom) approved these new medications under the condition that pharmaceutical companies would have to conduct clinical trials in children and adolescent populations to insure the efficacy and safety of SSRIs.
Why are we worrying now? In 1990, Teicher and his colleagues (5) reported the case of 6 adults receiving the medication fluoxetine (FXT) as a treatment for their depression who started having suicidal ideas soon after starting to take their medication. However, an analysis of all the clinical trials of FXT, a SSRI better known as Prozac, indicated that the drug, compared to other antidepressant medications, did not significantly increase the risk of suicide (6).
In 2003, the controversy regarding the use of SSRIs resurfaced. At the time, as many as 50,000 children between the ages of 6 and 18 were taking antidepressants in the UK (7). That year, the Medicines and Healthcare products Regulatory Agency (MHRA) banned the use of all SSRIs for children and adolescents in the UK, except for Prozac. In 2004, the United States and Canada issued warnings for all SSRIs, and again, only Prozac was authorized as a treatment for depression in children in the United States (8, 9). It is important to note that in Canada, antidepressants were never authorized for use with children. The practice in place in Canada is called ‘off-label’ use, where doctors are expected to rely on their knowledge of their patients to decide what is best for them. Warnings were still issued to insure that doctors would be careful in their prescription of SSRIs for patients of all ages (8).
These sudden changes in the regulation stemmed from the publication of the firsts clinical trials of SSRIs with children and adolescents, years after the trials were actually conducted. Indeed, GlaxoSmithKline (GSK) carried its first clinical trial in 1995-1996, but the results were not published until 2001. This study (10) compared the use of their drug Seroxat (sertraline) to a placebo, and found that 11 children suffered from serious side effects (such as suicidal ideation and cardiovascular problems), for which 7 had to be hospitalized. Also, when the analyses were reconducted, it was found that the drug was not effective in reducing depressive symptoms in children. It is interesting to note that across the few clinical trials conducted, very different results were reported, which can be partly attributed to the fact that different medications were used in children of different ages, with different conditions.
Are there really reasons to worry ?In 2006, Kratochvil and his colleagues (11) reanalysed all the data regarding studies on antidepressants that had been conducted thus far in order to assess the risk/benefit ratio of the use of SSRIs in children. SSRIs paroxetine, sertraline, venlafaxine, citalopram, nefazadone, and mirtazapine all showed mixed or negative findings regarding the outcomes for children and adolescents treated with these medications. Kratochvil and his colleagues came to the conclusion that only FXT (Prozac) helped in the treatment of depression in children and adolescents. It is mainly because of this study that regulating agencies decided to only approve the use of FXT in this young population. Yet, an important finding was that FXT was related to an increase in suicidality in about 2% of children and adolescents treated with the drug. However, it was concluded that the risks did not outweigh the benefits.
What should we do now?Many studies have found an increased risk of suicidality in the first few days of treatment with SSRIs, but on a long-term basis, suicidal risk decreased. One should wonder why such an association between antidepressant use and suicidality might exist. Indeed, it has been suggested that the use of SSRIs is associated with suicide because patients get treatment at an acute phase of their illness, which without treatment, might lead to even greater risk of suicidality. People who have experienced depression in their childhood are more likely to be depressed and to commit a suicide attempt once they reach adulthood. Therefore, not treating depression cannot be an option, even if the treatment may increase suicidal tendencies temporarily (12). Taken together, these results show that there might be slight reasons to worry about the use of FXT in treating depression in children and adolescents. FXT seems to be a relatively good solution compared to other SSRIs and to the risk of non-treatment. So far, SSRIs other than FXT have not been found to relieve children and adolescent of their depressive symptoms. These other medications have been banned in most countries (for example in the USA and UK), but in Canada, they could still be prescribed if doctors feel they are the best option for their patient.
This points to what should really be the focus of this discussion, namely the way in which these drugs are prescribed to children and adolescents, and especially how patients are followed once on medication. Indeed, research suggests that Prozac (FXT) is safe for children, but only in the context of good clinical care, that is when the doctor knows the patient well, sees him/her regularly, and can easily manage side effects. In a context where medical appointments get shorter, and harder to obtain, how likely is it that good clinical care will be provided? Another important fact to consider is that pharmacotherapy is not the only available treatment for depression. Other treatments for depression are Cognitive-Behavioural (CBT) Psychodynamic, Family and Interpersonal Therapy. If giving drugs to children and adolescents is not necessary, then should this be the treatment of choice?
Are there other options?
In sum, what emerges from this discussion is that several drugs have not proven to be effective and safe for use in children. However, FXT (Prozac) may be appropriate for use in such a population, as long as certain standards of care are met. Regular and close follow-up by doctors must be the norm when patients are prescribed drugs such as SSRIs, and this is especially critical in children and adolescents who may show increased suicidal tendencies at the beginning of the treatment. It is important to note, that medication is not the only solution in the treatment of depression in children and adolescents. Indeed, there is growing evidence that cognitive behaviour therapy, psychodynamic therapy, interpersonal therapy and family therapy are effective in treating pediatric depression (13). Recent research has shown that CBT was more beneficial than SSRIs in the treatment of depression in children and adolescents (14). Therefore, there are other options for families who do not feel comfortable with the use of medications in their children.
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(2)Crane, George E. “The psychiatric side-effects of iproniazid.” American Journal of Psychiatry 112 (1956): 494–501.
(3)Zeller, E. Albert, James Barsky, and Elaine R. Berman. “Amine oxidases: inhibition of monoamine oxidase by 1-isonicotinyl-2-thiumispropyl hydrazine.” Journal of Biological Chemistry 214 (1955): 267–274.
(4 Lieberman III, Joseph A. “History of the Use of Antidepressants in Primary Care.”Primary Care Companion Journal of Clinical Psychiatry 5 (2003):6-10.
(5)Teicher, Martin H., Carol Glod, and Jonathan O. Cole. “Emergence of Intense Suicidal Preoccupation during Fluoxetine Treatment.” American Journal of Psychiatry147 (1990): 207-10.
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(7)Boseley, Sarah. (2003). “50 000 children taking antidepressants.” The Guardian. 2 Oct. 2007.
(8)Health Canada. Health Canada advises Canadians of stronger warning for SSRIs and other newer anti-depressants. (2004).2 Oct. 2007.
(9)FDA. Questions and Answers on Antidepressant Use in Children, Adolescent, and Adults. (2004). 2 Oct. 2007. http://www.fda.gov/CDER/Drug/antidepressants/Q&A_antidepressants.htm
(10) Keller, Martin B. Et al. “Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.” Journal of the American Academy of Child and Adolescent Psychiatry40 (2001): 762-72.
(11) Kratochvil, Christopher J., et al. “Selective serotonin reuptake inhibitors in pediatric depression: Is the balance between benefits and risks favourable?”Journal of Child and Adolescent Psychopharmacology16 (2006):11-24.
(12) Weissman, Myrna M., et al. “Depressed adolescents grown up.” Journal of the American Medical Association 281 (1999): 1707-13.
(13) Carr, Alan. “Depression in young people: Description, assessment and evidence-based treatment.” Developmental Neurorehabilitation11 (2008): 3-15.
(14) Perera, H. (2008). “Depression in children and adolescent” Ceylon Medical Journal 53 (2008): 65-7.
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