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 around 60% over the past decade, with over a million children and adolescents receiving what are called selective serotonin reuptake inhibitors (SSRI’s).
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 UK’s Medinces and Heathcare products Regulatory Agency (MHRA) advised that the risks outweighed the benefits for all SSRI’s (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 important 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The pediatric trial data released by the MHRA presented a unique opportunity to examine whether the unpublished data supported the findings from published studies of SSRI’s. My colleagues and I addressed this question in a review published in The Lancet in April 2004. The review showed that while the published data generally indicated minimal risk, the unpublished trial data were far less sanguine, and even suggested an increased risk of serious adverse events, including suicide-related behavior.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 SSRI’s in children and adolescents as industry-funded or non-industry funded. The results showed that 90% of industry-funded trials in the published literature were reported as positive, while only 55.6% of non-industry-funded trials were positive.
More recently, the US Food and Drug Administration (FDA) applied a ”black box” warning to all antidepressant drugs labelling, but fell short of restricting the use of any individual drug. This was done after an FDA commissioned re-analysis of safety data from all trials of the newer antidepressants demonstrated increased risk of suicidality (definitive suicidal behaviour/ ideation) and increased risk of treatment-emergent hostility or agitation in those treated with the active drug compared to placebo.
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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.
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 SSRI’s are safe and effective 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, not just those that are positive.
Such changes may well lead to a dramatic reduction in the use of SSRI’s in treating depressed children and adolescents. But whatever the outcome, it is urgent that doubts about the safety of these drugs are resolved.
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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 around 60% over the past decade, with over a million children and adolescents receiving what are called selective serotonin reuptake inhibitors (SSRI’s).
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 UK’s Medinces and Heathcare products Regulatory Agency (MHRA) advised that the risks outweighed the benefits for all SSRI’s (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 important 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 SSRI’s. 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 SSRI’s in children and adolescents as industry-funded or non-industry funded. The results showed that 90% of industry-funded trials in the published literature were reported as positive, while only 55.6% of non-industry-funded trials were positive.
More recently, the US Food and Drug Administration (FDA) applied a ”black box” warning to all antidepressant drugs labelling, but fell short of restricting the use of any individual drug. This was done after an FDA commissioned re-analysis of safety data from all trials of the newer antidepressants demonstrated increased risk of suicidality (definitive suicidal behaviour/ ideation) and increased risk of treatment-emergent hostility or agitation in those treated with the active drug compared to placebo.
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Access every new PS commentary, our entire On Point suite of subscriber-exclusive content – including Longer Reads, Insider Interviews, Big Picture/Big Question, and Say More – and the full PS archive.
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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.
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 SSRI’s are safe and effective 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, not just those that are positive.
Such changes may well lead to a dramatic reduction in the use of SSRI’s in treating depressed children and adolescents. But whatever the outcome, it is urgent that doubts about the safety of these drugs are resolved.