Posted on 04/10/2004 7:43:31 AM PDT by neverdem
Pediatricians and family physicians should not prescribe antidepressants for depressed children and adolescents because the drugs barely work and their side effects are often significant, Australian researchers have concluded.
The researchers analyzed data from five published trials of three antidepressants, Prozac, Zoloft and Paxil, in depressed patients under age 18. They found that the drugs offered only a "very modest" benefit over placebos.
At the same time, the drugs carry significant risks, the researchers said in their report, published in today's issue of the British medical journal BMJ.
"If the drugs were highly advantageous over placebo, then you'd live with the risks," Jon Jureidini, a child psychiatrist in Adelaide and the study's lead author, said in an interview. "If the drugs were completely safe, then you might argue that there's nothing wrong with giving something that's only slightly better than a placebo."
However, Dr. Jureidini said, neither is true, so antidepressants should not be prescribed for children and adolescents except in extreme circumstances.
"We strongly want to say that non-child-psychiatrists should not be initiating the prescribing of" the antidepressants known as selective serotonin reuptake inhibitors or S.S.R.I.'s, a class that includes Eli Lilly's Prozac, Pfizer's Zoloft, and GlaxoSmithKline's Paxil, Dr. Jureidini said.
The study is the latest salvo in an increasingly bitter war over whether prescribing antidepressants to children and adolescents is appropriate.
Dr. Joseph Glenmullen, author of "Prozac Backlash" and a fierce critic of the pills, said the latest study further vindicated his view that antidepressants can be dangerous. "What this shows is that, on balance, there is no good reason to prescribe these pills," Dr. Glenmullen said.
However, Dr. Graham Emslie, a professor of psychiatry at the University of Texas Southwestern Medical Center, who was an author of some of the studies reviewed in the article, said the study was "illogical."
"I wish the effect size of these drugs was bigger, but at least there's some effect," Dr. Emslie said. "Some of these kids are severely depressed and we've got to do something."
Dr. Emslie, like many psychiatric researchers, is a consultant to pharmaceutical companies.
The Australian researchers suggested that psychiatrists offer children talk therapy in place of the drugs. But Dr. Emslie said that only one study had shown that talk therapy was beneficial.
"If people could offer better treatments than drugs, it'd be great," Dr. Emslie said.
British drug regulators have cautioned doctors against using any antidepressant but Prozac to treat depressed children and adolescents because the drugs have not proved effective against depression and may increase the risk of suicidal thoughts and behavior.
The Food and Drug Administration recently issued a warning that all patients taking antidepressants should be closely monitored by doctors, especially in the first weeks. But the agency emphasized that it had not concluded that the drugs caused suicidal thinking or behavior.
Dr. Laurence Greenhill, a professor of clinical psychiatry at Columbia University, said neither side in the debate had a monopoly on truth.
"I think that these medications are neither as much of a silver bullet as the advocates would have it nor as terrible as the critics would say," Dr. Greenhill said.
Yet a common effect does exist, and that is that the drugs are not so much anti-depressant as they are pro-daring.
The drugs mostly affect your anxiety-depression reaction (and sometimes cycle).
Depression is most often your body's attempt to subdue, as a response to stress. The more anxious you are, then the more your anxious chemicals build up and rummage around inside you.
Depression is your state caused by your body's attempt to "put out the fire" if such chemicals build up without your burning them off through action.
Basically, your anxious system was by design, meant for "fright and flight."
Without burning off that steam, your body will effectively respond to the anxious chemicals, by introducing "sedatives," so to speak, meant to "wind you down," they depress you, in addition to the fact that you still are not active.
At which point, you are "depressed."
The thing that you least seem to be able or willing to do, when depressed, is to act; but to act, is what you most need to do, to return balance to your system.
The modern anti-depressants screw around with your body's normal anxiety - fright and flight - depression system. Modern anti-depressants can strip you of some of the anxiety, while also masking the presence of the depressants in you.
You seem to be more active at times of the day, but quite often, you may find that you are "drowsy," when actually that is not the right word.
At that point, you are actually, because of the anti-depressant, less aware of the depressants in you --- you do not have a normal sense of the depressants in you.
So, instead of "being depressed," you seem to be "drowsy." Kind of a shift, really, instead of real anti-depression.
Your brain has a careless response to what is actually going on, instead of a careful response.
And there is the catch, that can be deadly.
You are not a drug-induced socio-path, yet you can feel a detachment from the, what you might say are, civil anxieties, your sense of how you should conduct yourself --- you can become a bit more daring, and sometimes reckless ... in some cases.
It's those cases, where we unfortunately read about somebody who does "something crazy," and then we find out that they were on some kind of anti-depressant.
Too many doctors prescribe these drugs without monitoring their patients, and without attenuating the strength of the medication for the patient, etc.
The drugs are still, too much a shotgun application in disregard for the patient's actual brain chemical state.
A wee bit of the stuff can be much more effective than what is being shoveled.
The part in bold is the key point. General practice pediatricians shouldn't be prescribing this stuff; they don't know enough. If they have a patient who they believe might need such treatment, they should refer the kid to an appropriately trained specialist.
While I am very dubious about drugging most kids, everyone must also remember that there are kids committing suicide. Reader beware. If you're not a professional, remember that a little knowledge can be dangerous. Before doing anything else, talk to the physician who wrote the prescrition if you have doubts raised by this article.
The article makes reference to "P" value when discussing statistical results. P = 0.05 or less is statistically sigificant. That means that such statistical correlations would be expected to be found on a random basis 1 out of 20 times(or more than 20). P = 0.01 means you would expect such a correlation to happen by chance only 1 time out of 100. Remember, haste can make waste.
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Collections under which this article appears: Mood disorders (including depression) Child and adolescent psychiatry Drugs: psychiatry |
1 Department of Psychological Medicine, Women's and Children's Hospital, North Adelaide, 5006 SA, Australia, 2 Quality Use of Medicines and Pharmacy Research Centre, University of South Australia, Adelaide, 5000 SA, 3 Department of General Practice, University of Adelaide, Adelaide, 5005 SA, 4 Department of Clinical and Experimental Pharmacology, University of Adelaide, 5 Health Surveillance and Evaluation Section, Public Health, Department of Human Services, Melbourne, 3000 Vic, Australia, 6 University of Wales Academic Unit, Wrexham LL13 7YP
Correspondence to: J N Jureidini jureidinij{at}wch.sa.gov.au
How safe and effective are antidepressants in children and adolescents? The authors of this review have found disturbing shortcomings in the methods and reporting of trials of newer antidepressants in this patient group
Introduction |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Methods |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Funding of trials |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Efficacy |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Two small studies found no statistically significant advantage for antidepressants over placebo on any of the outcome measures reported.5 6 Of the remaining four papers, two did7 9 and two did not3 8 show statistically significant advantages for antidepressants over placebo on primary outcome measures.
We meta-analysed the five published studies on selective serotonin reuptake inhibitors by using the standardised mean difference (Hedges' g) as the measure of effect.3 5 7-9 We averaged relevant outcome measures within studies and then pooled them across studies by using a random effects model. We included all continuous outcome measures related to depression and health related quality of life. The effect size was small 0.26 (95% confidence interval 0.13 to 0.40). Assuming a standard deviation of scores of 11 to 14 on the revised children's depression rating scale in depressed children, an effect size of 0.26 is equivalent to a very modest 3 to 4 point difference on the scale, which has a range of possible scores from 17 to 113.
As regards unpublished studies, we note from a report from the US Food and Drug Administration Center for Drug Evaluation and Research that only one of nine showed a statistical advantage for drug over placebo.11
Adverse effects of treatment |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Among 373 patients in the trial by Wagner et al, 9% (17/189) treated with sertraline withdrew because of adverse events, compared with 3% (5/184) in the placebo group.9 These authors also published no statistical analysis of this outcome or details of the adverse effects, but the difference in withdrawal rates was significant (Pearson's 2 = 6.62, df = 1, P = 0.01). Wagner et al reported seven adverse effects that occurred in at least 5% of the sertraline group, at least twice as often as in the placebo. Despite these results they concluded that, "sertraline is an effective, safe, and well tolerated short-term treatment for children and adolescents."
Other sources of data support the view that adverse effects might be more frequent than the authors of these studies imply. For example, children and adolescents with obsessive compulsive disorder exhibit a variety of treatment emergent effects of fluoxetine, including an "activation syndrome" affecting up to half of young patients; self injurious ideation or behaviour was seen in 6/42 patients.12 The failure of drug companies to disclose increased suicidal activity secondary to these drugs is also the subject of much debate.13
Study methods |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Use of categorical outcomes
Categorical outcomes (such as response and remission) are likely to inflate small differences between groups.14 As categorical outcomes are usually based on data from continuous measures, the difference in continuous measures should always be examined first and given priority. This approach has often not been followed in the childhood antidepressant literature, where three of six nominated primary outcome variables were categories created by dividing continuous measures.
Unblinding
The real proportion of effect attributable to a selective serotonin reuptake inhibitor may be less than apparent, given that the placebo versus drug difference is less where active placebo is used (that is, placebo with an active pharmacological principle that produces side effects).15 This finding suggests that part of the impact of an active drug might be due to unblinding as a result of detection of side effects by patients and doctors. No data are given in any paper reviewed here on the effectiveness of blinding. Blinding was "essentially" maintained for a subset of the participants in the Emslie (1997) study.7 16 However, the authors did not examine adverse events as a possible cause of unblinding, and they noted in their conclusions that "the role that minimal side effects for the active medication played undoubtedly contributes to these findings." Other work suggests that clinicians will have performed better than chance at predicting whether or not their patients were on the active drug,17 so that unintended bias may be a contributing or decisive cause of observed differences between the drug and placebo groups.18
Doubtful clinical implications of statistical superiority to placebo
Given the large placebo effect in all six studies reviewed, the clinical significance of the drug effect should be questioned. For example, in spite of a one week placebo lead-in and exclusion of initial placebo responders, Emslie et al (2002) found that, for the measure showing the greatest advantage of fluoxetine over placebo (revised children's depression rating scale), the improvement in the placebo group was 70% of the improvement seen in the fluoxetine group (22 point decrease for fluoxetine 15 points for placebo).8 Similarly, the fact that 87% of the improvement in the sertraline group was reproduced in the placebo group casts some doubt on Wagner et al's claim,9 and Varley's editorial support for that claim,19 that their results are clinically, as well as statistically, significant. This is illustrated by the graph from their paper (fig), which shows that, although they found a significant difference at 10 weeks, it was very small in size and unlikely to be clinically important.
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Quality of reporting |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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The two studies ultimately published by Emslie and colleagues in 1997 and 2002 (B1Y-MC-X065 and B1YMC-HCJE) were the subject of a "statistical review" by the US Center for Drug Evaluation and Research.21 That document showed that the prespecified primary outcome measure in the first Emslie study was proportion of completing patients who achieved recovery. The original definition of recovery in the study protocol was a score of 28 on the revised children's depression rating scale ("remission") and a clinical global impression-improvement score of 1 or 2. Two things are clear: firstly, this measure did not reach statistical significance (P = 0.339); secondly, when the study was published, new primary outcome measures were used (see table on bmj.com).
The authors chose a reduction from baseline of 30% on the revised children's depression rating scale (shown on post hoc analysis of the first study to show favourable advantage to fluoxetine21) as the single primary endpoint for the second study (B1Y-MC-HCJE).8 However, they found no statistical difference between fluoxetine and placebo on this measure. Although Emslie et al did state in the results section that significance was not reached on "response," they did not make it explicit that this meant a failure to show change on their stated primary outcome, and they make much more of the secondary endpoints that did favour fluoxetine. Whenever the failure to show superiority of fluoxetine over placebo in achieving 30% reduction from baseline on the rating scale is reported, mean improvement and "remission" are given equal weight in the published paper, implying that one or both of them was also a primary endpoint. The authors go on to make an unqualified claim of efficacy, even though the drug showed no significant advantage over placebo on the single primary outcome measure. The independent "statistical review," on the other hand, concludes that, "the sponsor did not win on these two pediatric depression studies based on the protocol specified endpoint. The evidence for efficacy based on the pre-specified endpoint is not convincing."21
No information is given that provides insight into why the US Food and Drug Administration ultimately approved fluoxetine for childhood depression. Nor is it clear why the UK Committee on Safety of Medicines exempted fluoxetine from its criticisms through accepting the published versions of these studies, when it did not do so in relation to sertraline.22
Wagner et al described their work as "two randomised controlled trials," but the methods are identical, and they and we treated them as a single trial.9 The trials when combined included a large enough number of participants (364) to have adequate statistical power to detect small differences between treatments. Neither trial showed a statistically significant advantage for sertraline over placebo in terms of the primary endpoint, which in this case was change from baseline in the revised children's depression rating scale score.22 Only when the trials were combined did a statistically significant difference emerge, although this was very small (about 2.7 points on a 113 point scale). Furthermore, we question Wagner et al's inference that because tricyclic antidepressants are no more beneficial than placebo, even a small advantage for newer antidepressants justifies their use. The availability of older interventions that are not beneficial should not lower the threshold for accepting a new intervention, especially given the availability of more effective psychological treatments with no known adverse effects.23
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Conclusion |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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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. Accurate trial reports are a foundation of good medical care. It is vital that authors, reviewers, and editors ensure that published interpretations of data are more reasonable and balanced than is the case in the industry dominated literature on childhood antidepressants. This is particularly true in the light of the increasing reliance on online abstracts by doctors who lack the time or the skills for detailed analysis of complete trial reports.
A table showing details of studies reviewed is on bmj.com
We thank Agnes Vitry, Dianne Campbell, and Brita Pekarsky for helpful comments on the manuscript.
Contributors: JNJ and ALT had the original idea for the work. JNJ undertook the primary literature review and drafted themanuscript. CJD and DBM undertook a secondary literature review. MMH conducted the meta-analysis. CJD, MMH, PRM, DBM, and ALT assisted in drafting the manuscript. JNJ is the guarantor.
Competing interests: JRJ and PRM are office bearers in Healthy Skepticism.
References |
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Top Introduction Methods Funding of trials Efficacy Adverse effects of treatment Study methods Quality of reporting Conclusion References |
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Collections under which this article appears: Mood disorders (including depression) Child and adolescent psychiatry Drugs: psychiatry |
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