Should Children Take Antidepressants?

Craig Whittington the last 12 months have witnessed radical changes and considerable controversy regarding how childhood and teenage depression is treated. Although few antidepressant drugs have been licensed for pediatric use, rates of prescribing in the under-18 age group have risen by 60 per cent over the past decade, with over a million children and adolescents receiving what are called selective serotonin reuptake inhibitors (SSRIs).

Now, however, concerns over these drugs safety and side effects in children and adolescents - including elevated suicide rates "have awakened regulators in many countries. After reviewing all relevant pediatric trials, the UKs Medicines and Healthcare products Regulatory Agency (MHRA) advised that the risks outweighed the benefits for all SSRIs (except fluoxetine), and that these products should not be prescribed as new therapy for patients under 18 years of age with depressive illness.

For the first time, the MHRA made public a summary of the review that this decision was based on, including both efficacy and safety data for all of the trials, regardless of whether they had previously been published or not. This was critical because about half of the trials had not been published in peer-reviewed journals. The pediatric trial data released by the MHRA presented a unique opportunity to examine whether the unpublished data supported the findings from published studies of SSRIs. My colleagues and I addressed this question in a review published in The Lancet in April 2004. The review showed that while the published data generally indicated minimal risk, the unpublished trial data were far less sanguine, and even suggested an increased risk of serious adverse events, including suicide-related behavior.

The MHRA was not alone in being concerned about pediatric trials. A review in the British Medical Journal (BMJ) in April 2004, claimed that most papers on SSRI trials overstated the evidence for efficacy and understated the risk of harm. An article by the Center for Science in the Public Interest classified all available published placebo-controlled trials of SSRIs in children and adolescents as industry-funded or non-industry funded. The results showed that 90 per cent of industry-funded trials in the published literature were reported as positive, while only 55.6 per cent of non-industry-funded trials were positive.

Taken together, it is not hard to see why some commentators argue that there has been little attempt by the pharmaceutical industry to properly assess the risks and benefits of their products in under 18's. Often, where trials have been conducted, only favorable results have been published.

The problem is widespread and not restricted to drug companies. Both regulators and clinicians who run trials have been criticized. But concern over the safety of SSRIs is not universally shared. For example, the American College of Neuropsychopharmacology produced a preliminary report in January 2004 that supported the use of SSRIs to treat depression in children and adolescents.

In contrast to UK drug regulators, Americas Food and Drug Administration (FDA) has not yet decided about the safety of SSRIs in treating pediatric depression. But it acknowledges potential safety issues, having commissioned a re-analysis of the SSRI trial data because of concerns that suicide-related behavior may have been misclassified originally. The re-analysis involves independent experts at Columbia University re-classifying the original trial safety data into suicidal (suicide attempt/ suicide ideation/ suicidal behavior without injury), non-suicidal, and indeterminate. Regulatory changes, if any, will not be made until a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the newly formed Pediatric Advisory Committee.

The FDA has faced criticism over its underlying motives in deciding to re-analyze the safety data. Some experts suggest that it will be difficult to make sense of the issue because of poor reporting in the original trials, thus making any decision based on the re-analysis tenuous at best. Furthermore, committees in both the US House and Senate are investigating the FDAs handling of this issue after concerns were raised over the original FDA review of the safety of SSRIs in pediatric depression. The concerns seem to stem from disagreement within the FDA itself, with at least one reviewer concluding that there was enough evidence in the trial data to suggest safety concerns.

My own synthesis of the data released so far by the FDA supports that claim. I found that across all trials of SSRIs in pediatric depression there is, on average, a 72 per cent increase in the risk of possibly suicide-related behavior and a 45 per cent increase in the risk of suicide attempts in children receiving the drug compared to those receiving a placebo. The researchers at Columbia will need to find substantial errors in the original reports before these risks are overturned. Adding further fuel to the fire, New York State Attorney General Eliot Spitzer recently filed a civil lawsuit against GlaxoSmithKline for potentially misleading doctors by publicizing a favorable study of paroxetine for pediatric depression while downplaying other unfavorable trials. In response, GlaxoSmithKline made full-trial reports of all studies involving paroxetine in patients under 18 available on their website.

The case points to several changes in the way data are collected and released that are urgently needed to determine definitively whether SSRIs are safe for treating pediatric depression. Tighter regulation of all clinical trials is needed, as is a public worldwide database that contains trial protocols and regularly updated information about trial status and publications. Moreover, both benefits and harms of all trials must be published within a reasonable timeframe, and properly designed, non-industry-funded trials are needed to confirm both safety and efficacy. Finally, product labels must reflect negative or equivocal results. Such changes may well lead to a dramatic reduction in the use of SSRIs in treating depressed children and adolescents. But whatever the outcome, it is urgent that doubts about the safety of these drugs are resolved.

Submitted By
Craig Whittington is Senior Systematic Reviewer, UK National Collaborating Centre for Mental Health.

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