Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Flawed reasoning in critique of child antidepressant trials
- Nicholas A. DeMartinis (10 April 2004)
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The quality of logical reasoning used in attacking an opponent's argument
- Jeffrey Mann (11 April 2004)
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Juredini et al use misleading evidence to support their claims
- David M Foreman (11 April 2004)
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Flawed conclusions
- Mark Berelowitz (12 April 2004)
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An important debate
- John F Corish (12 April 2004)
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What is the signal/noise ratio of antidepressant drug RCTs in children?
- Jeffrey Mann (13 April 2004)
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Most of the studies are underpowered: a meta-analysis is needed.
- Christopher K Gale (13 April 2004)
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Service to Humanity
- Grace E Jackson (13 April 2004)
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Caution: to avoid throwing the baby with the bath water
- L Duvika Mewasingh (16 April 2004)
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The Utility of Antidepressants in Pediatric Depression
- Sanjeev Pathak (17 April 2004)
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Another example of illogical reasoning and the non-provision of EBM evidence
- Jeffrey Mann (18 April 2004)
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How do the parents of adolescents and children make sensible decisions now?
- Malcolm VandenBurg, W1G 7JJ UK (19 April 2004)
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Adolescent depression - what do you do when treatment doesn't work?
- Andrew F Clark (20 April 2004)
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Conclusions not applicable to severe adolescent depression
- Bernadka W. Dubicka (20 April 2004)
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Sertraline Pediatric Depression Trial Met Highest Standards of Study Design and Reporting
- Cathryn M Clary, Steven J Romano (27 April 2004)
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Everybody has an agenda
- Chris. L. Manning (30 April 2004)
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What's your agenda?
- Alan G. Wade, Prof. Dr. med. Thomas E. Schläpfer (3 May 2004)
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What's your agenda/everybody has an agenda - further examples of illogical reasoning
- Jeffrey Mann (4 May 2004)
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CSM warning on risperidone and olanzapine: who takes the risks when patients lack capacity?
- Donald H R Mowat, Douglas Fowlie and Tom MacEwen (4 May 2004)
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Depression in children and adolescents: Diagnostic and treatment perspectives!
- Dr. Naseem A. Qureshi (5 May 2004)
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What is the definition of "clinical significance"
- Jeffrey Mann (6 May 2004)
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declaration of interests
- Grace E Jackson (17 August 2004)
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Response to Pfizer
- Peter R Mansfield (27 June 2005)
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Nicholas A. DeMartinis, Assistant Professor University of Connecticut School of Medicine, Farmington, CT 06030-6415
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Jureidini and coauthors repeatedly accuse investigators and the pharmaceutical industry of exaggerating the benefits of antidepressants and downplaying their adverse effects, criticizing methods of study design, analysis and interpretation by all (including scientific journals and the US FDA). Yet they fail to address or acknowledge the possibility that the methodology they criticize may actually be responsible for masking a true treatment effect of antidepressants in children via a Type II error. The authors also raise the use of non-drug treatments for depression, which they describe as "more effective psychological treatments with no known adverse effects" and "probably both safer and more effective." Surprisingly, the reference they give to support this claim (Harrington et al, 1998) is a meta-analysis of cognitive behavioral therapy that contains absolutely no information on adverse effects or safety from the trials studied. In fact, adverse events are rarely, if ever, reported in psychotherapy trials in children. The authors belief in the superior safety and efficacy of non-medication treatments compared to medication treatments has no basis in a direct, comparative, randomized trial as far as can be determined by searching the medical literature. Jureidini and coauthors condemn the scientific rigor of many investigators, editors, regulators, and clinicians, while apparently blind to their own scientific failings. The author's conclusions, like the MHRA's, fly in the face of years of clinical experience with tens of thousands of children and adolescents with major depression in many countries around the world. To deny children treatment for a condition that has a potentially fatal outcome based on studies with flawed design is outrageous and irresponsible. Nicholas A. DeMartinis M.D University of Connecticut School of Medicine Farmington, CT, USA References Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents BMJ 2004;328:879-883. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. BMJ 1998;316: 1559-63. Competing interests: ND has received clinical trial grants from Pfizer, Lilly, Bristol-Meyers Squibb, Wyeth, GlaxoSmithKline, Merck, Astra Zenica, Pharmacia, Synthelabo, and Cephalon. |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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Dr. DeMartinis states that Jureidini and coauthors "condemn the scientific rigor of many investigators, editors, regulators, and clinicians, while apparently blind to their own scientific failings", but he supplies us with very little substantive criticism of their critical analysis other than to vaguely say that they didn't exclude a type II error. He reasonably attacks Jureidini's unsubstantiated claim that psychotherapy may be more effective and safer than antidepressant drug use, but he doesn't attack the core arguments that form the heart of their critical meta-analysis. If Jureidini's critical analysis is invalid, then we have not discovered that fact from reading Dr. DeMartini's rapid response letter. What we learn from Dr. DeMartinitis' letter is that he believes that Jureidini's conclusions "fly in the face of years of clinical experience with tens of thousands of children and adolescents with major depression in many countries around the world." In other words, he seemingly suggests that the scientific truth can be more accurately established by anecdotal clinical experience and not the performance, and rigorous analysis, of clinical trials. If that were true, life would be much simpler. Unfortunately, confidence in the science of clinical medicine depends on clinical trials that have a high signal/noise ratio. He states that "to deny children treatment for a condition that has a potentially fatal outcome based on studies with flawed design is outrageous and irresponsible." I cannot understand the logic of this statement. In fact, I imagine that many clinicians would think that it is outrageous and irresponsible to prescribe a medical treatment that is based on flawed clinical studies, simply because some (or many) clinicians believe, based on anecdotal experience, that a particular medical therapy is effective. If Dr. DeMartini has scientific evidence (clinical trials which have a high signal/noise ratio) that antidepressant drugs are of value in major depression in children and adolescents, then he should quote the EBM evidence. Competing interests: None declared |
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David M Foreman, Consultant, Health Services Research Fellow & Hon. Sen. Lecturer in Child and Adolescent Psychiatry Skimped Hill Medical Centre, Market Place, Bracknell, RG12 1LH
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In launching their attack on the biased reporting of antidepressant drug efficacy and safety for children, Juredini et al (1) also use misleading evidence to support their claims. They describe the effect size of .26 they found as ‘small’; however, recent adult reviews have given effect sizes between .15 (2) and .46 for Selective Serotonin Reuptake Inhibitors (SSRIs) (3). They call the 17% to 32% discontinuation rate they identified ‘high’, when it lies at the lower end of the 30%-70% discontinuation typical of adult studies (4), and the approximately 10% side effect rate they identify is similar to many adult rates (5). It would thus be equally true to claim that ‘trials of SSRIs in children show similar efficacy, side effect and dropout rates to those in adults’, a position far more supportive of their continued use than Juredini et al would have us take. They have combined the studies’ mood measures with measures of general well-being, so the effect size they quote should be interpreted as referring to overall symptomatic change, not simply change in mood. It thus includes a conservative bias, as childhood depression is known to be associated with other psychological and behavioural symptoms, but antidepressants are unlikely to impact on, for example, comorbid behaviour problems, which commonly occur. They do not, however, discuss this, or how they adapted their ‘random effects model’ to cope with the patients in the different studies being, in consequence, measured on differently weighted scales (c.f. 6). Their attempt to relate the effect size of total symptomatic change to scale change on an individual mood questionnaire is thus unwarranted and misleading. This paper demonstrates that self-serving bias can also infect those who seek to eliminate it in others. It is time the debate moved beyond the politics of blame, to how self-serving bias may be detected and removed. The publication of this paper continues to raise concerns that the current peer review system is not up to the job. References: 1. Juredini J, Doecke C, Mansfield,PR, Haby M, Menkes D, Tonkin A. Efficacy and safety of antidepressants for children and adolescents. British Medical Journal 2004;328:879-83. 2. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression (Cochrane Review). The Cochrane Library 2004;. 3. Joffe R, Sokolov S, Streiner D. Antidepressant treatment of depression: a metaanalysis. Canadian Journal of Psychiatry 1996;41:613-6. 4. Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R, Eccles M et al. . Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) (Cochrane Review). The Cochrane Library 2004;. 5. Trindade E, Menon D, Topfer L, Coloma C. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. Canadian Medical Association Journal 1998;159:1245-52. 6. Stangl D, Berry D. Meta-Analysis in Medicine and Health Policy. 2000;. Competing interests: Lilly have offered to help me evaluate different forms of service provision for children with ADHD. I work in a service which has a long waiting list for CBT for children with depression, but can prescribe antidepressants immediately on seeing a child. |
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Mark Berelowitz, Consultant Child and Adolescent Psychiatrist Royal Free Hampstead NHS Trust, London NW3 2QG
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Jureidini and colleagues (1) are right to caution us about the effectiveness and side effects of SSRIs. However, the authors go on to make a serious mistake in their reporting of other literature, a mistake which gives their own paper considerable potential to mislead. They say that there are available more effective psychological treatments with no known adverse effects, and quote an important paper by Harrington et al (2) in support of this statement. However, as Harrington points out, their review of the effectiveness of cognitive therapy for depression included only five papers that were studied in depth. Harrington says that the quality of the trials studied was moderate, most did not give an adequate explanation of the randomisation procedures, and most did not attempt to monitor possible lack of blindness in the outcome assessors. There is no substantive discussion of possible side effects of therapy. Indeed, Harrington goes on to suggest that neither cognitive therapy nor medication should be the first line of treatment for adolescent depression. This is hardly a ringing endorsement for cognitive therapy. As a practising clinician I have to continue to do what I can to help my depressed patients. Supportive psychotherapy, cognitive psychotherapy and medication will all continue to play a role. I will remain suspicious of anyone who tells me that we have available a treatment that is both highly effective and without side effects, and that is suitable for all comers. 1. Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents BMJ 2004;328:879-883. 2. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. BMJ 1998;316: 1559-63. Competing interests: None declared |
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John F Corish, Assistant Professor of Clinical Psychiatry St John's A1A 1T1
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Many baulk at the idea of giving psychoactive substances to children. However, if we accept that childhood depression is a real clinical entity then clinicians do have a duty to treat this with all means at their disposal. Many studies report that depression gets under-treated at primary care level. Most primary care practitioners are not well educated in the intelligent use of anti-depressant medication. The meta-analysis of Jureidini et al reveals high drop out rates, high incidence of side effects and relatively poor response in depressed children treated with anti-depressants. Is it not possible that these observations reflect more the competence of the treating clinicians than the efficacy or otherwise of anti-depressant medication when used in this population group? Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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I think that a recommendation to use antidepressant drugs in children should be based on valid scientific evidence -- RCTs that have a high signal/noise ratio [1]. Jureidini's critical analysis of six RCTs of antidepressant drug use in children, who have major depression, suggests that those RCTs have significant noise and a small/unclear signal. One can therefore conclude, if Jureidini's criticism is valid, that one cannot be confident in those RCTs' results, because they have a low signal/noise ratio. Dr. Foreman states that the effect size and the discontinuation rates are similar to studies on adults with major depression and that "it would thus be equally true to claim that ‘trials of SSRIs in children show similar efficacy, side effect and dropout rates to those in adults’, a position far more supportive of their continued use than Juredini et al would have us take". I cannot understand the logic of this statement. It would be seem to me that the statement is only true if one concludes that studies of antidepressant drugs in both adults and children have a high signal/noise ratio. The statement would not be true if the studies (in both adults and children) had a low signal/noise ratio, and Dr. Foreman does not provide any EBM evidence that demonstrates that RCTs in adults have a high signal/noise ratio. Dr. Foreman also criticises the Jureidini analysis on the basis that it does not accurately measure the signal (changes in mood) and that this reflects a self-serving bias. That criticism may (or may not) be valid, but Dr. Foreman has not provided an alternative analysis to demonstrate that the signal would be higher if an alternative signal-measuring methodology had been used. In the absence of definitive evidence that Jureidini has underestimated the size of the signal, one cannot therefore conclude that those RCTs had a high signal/noise ratio, which would support the use of antidepressant drug use in children. Dr. Cornish states-: "The meta-analysis of Jureidini et al reveals high drop out rates, high incidence of side effects and relatively poor response in depressed children treated with anti-depressants. Is it not possible that these observations reflect more the competence of the treating clinicians than the efficacy or otherwise of anti-depressant medication when used in this population group?" If Dr. Cornish's suggestion is plausible, then it still means that those RCTs are plagued by a low signal/noise ratio. If there are no other RCTs available to provide substantial EBM evidence supporting the use of antidepressant drug use in children, then we apparently have no EBM evidence (RCTS with a high signal/noise ratio) to allow us to be confident that antidepressant drugs are of positive value in children with major depression. References: 1. Sackett David. Why randomized controlled trials fail but needn't: 2. Failure to employ physiological statistics, or the only formula a clinician-trialist is ever likely to need (or understand!) CMAJ. 165(9):1226-1237, October 30, 2001. It is freely available online at http://www.cmaj.ca/cgi/content/full/165/9/1226. Competing interests: None declared |
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Christopher K Gale, Consultant Psychiatrist The Cottage, South Auckland Health, New Zealand
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Jureidini and co authors have critically analysed the data in these papers without considering if it is reasonable to expect a significant result from the study design. I was able to estimate the difference from placebo that one would need to reasonable expect a significant difference at 80% power (by proportions[1]) estimated detectable response rate from placebo at 80% power in dichotamous outcomes for two papers cited in the table. The first paper (Emilie et al) had but 20 participants per group. The response rate (CGI) in the placebo group was 33%. At 80% power, one would find a significant difference only if the treatment group response was 62%. It is thus unsuprising that a treatment response rate of 56% was non significant. Similarily, Keller (with 95 participants per group, and defining response at a 30% reduction in CDRS-R) had a response rate of 57%: one would find a significant difference only if the treatment group response was 72%, and the reported response rate of 65% is not unexepectedly not significant at the 0.05 level. The papers are probably undepowered. Either larger studies or a meta- analysis would be a reasonable next step Reference 1.R Development Core Team. R: A language and environment for statistical computing},2003R Foundation for Statistical Computing, Vienna. http://www.R-project.org Competing interests: Attended sponsored meetings Lilly and Astra Zenica. |
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Grace E Jackson, contract psychiatrist, independent consultant Winterville NC
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Jureidini and co-authors have done a great service in the creation and distribution of this article. I would hope that those who criticize this paper will yet consider the following issues: a) using the philosophical principle of "utility" (risk vs. benefit), it is critical to appreciate the fact that the British CSM, MHRA, and DOH have all delivered resounding messages to British clinicians, RESONATING with the thrust of this paper namely: no efficacy has been established in children b) all of the RCTs that have been published have reflected serious problems which go beyond the conflicts of interest revealed in this paper: I) the miscoding of events: euphemistic language disguising suicidal events under the cloak of "emotional lability" or homicidal events under the cloak of "aggression" II) the false attribution of suicide to the placebo arm, when those events have occurred during the 1-2 week "lead-in" phase of each study, or in some cases -- when those events have apparently occurred several MONTHS AFTER the termination of the trial In all cases, the drug companies have attempted to maximize their profits by exaggerating product efficacy; and by minimizing risks. This has involved a willful misleading of the public. Equally disturbing has been the intentional misleading of clinicians, via such practices as Ghost Writing, Publication Bias / File Drawer Effect, and other manipulations (use of LOCF data, use of noncomparable dosing strategies, use of post-hoc cutoffs for assigning "efficacy"). The issue here is not JUST a debate about whether some chlidren have been able to tolerate the potential toxicities of these medications. That point has never been contested. Rather, the issue has been or should be a discussion of whether or not children should have been exposed at all, to a class of drugs which have never out-performed inert substances -- all the while, increasing the likelihood of harmful actions 2 to 3 fold, relative to placebo. The scope of this scandal cannot be understimated. Not since the thalidomide tragedy, perhaps, have so many unncesssary poisonings of young people occurred. That doctors continue to turn deaf ears and blind eyes to the fact that antidepressants are essentially "toxic placebos" is a fascinating phenomenon that speaks to two critical problems: 1) physicians have seldom been encouraged to develop or apply the critical thinking skills necessary to contemplate the "unthinkable" -- namely, that the wares they peddle frequently do more harm than good 2) the medical profession itself, and the governmental authorities charged with overseeing their practices, have all been deeply subverted by Big Pharma's current stranglehold over Western civilization [to the point that most objective data have now been twisted or concealed] The cognitive dissonance which arises from the revelations of the kind made by Jureidini's team may be as painful for physicians to bear, as it is for their clients [ a phenomenon not unique to psychiatry by any means, given the latest revelations about Hormone replacement therapy and stroke, or in an earlier time: DES and cancer]. It would seem that we are all in this lifeboat together, and whilst the problems of antidepressant suicidality and lack of efficacy are significant "trees" in their own right, we would do well not to forget the larger "forest" that remains burning: something deeply horrible has happened to medicine, as coroporate profiteering appears to have replaced the ethics of physician non-maleficence and treatment rendered upon a truly "informed consent" to care. For too long, the psychiatric "standard of care" has been built upon a foundation of sand. It is heroic that Juriedini has had the courage to expose this. Competing interests: None declared |
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L Duvika Mewasingh, Resident in paediatric neurology Hôpital Universitaire des Enfants Reine Fabiola, Ave JJ Crocq 15, 1020 Brussels
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The numerous responses elicited by Jureidini et al paper have been to a lesser or greater extent emotional. The bottomline remains that as physician one wishes first and foremost to do no harm (primum nocere). Is there adequate evidence to help in that regard? I dont purport to answer that but do believe that this same line of questioning exists for several if not the majority of drugs used in the paediatric age group; even more so for neonatal drugs, often used outside licensed indications or in adapted dosage regimes that vary from unit to unit. How should one deal with this issue...? If EBM is to be the answer then there is a huge bulk of work to be done; placebo controlled studies involving children are not easy to design or recruit for and ethically...? Competing interests: None declared |
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Sanjeev Pathak, Assistant Professor CCHMC, University of Cincinnati College of Medicine, Cincinnati, OH-45040
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Dear Editor,
I disagree with Jureidini et al’s conclusion that “confidently recommending” antidepressants would be inappropriate”1. Psychotherapy is the first line therapy for mild/ moderate depression2. However, it cannot be recommended as first line treatment for severe depression as severe depression predicts non response to psychotherapy2. It would be reasonable to prescribe fluoxetine for severe depression, given that no other intervention has scientific evidence of efficacy in severe depression in children and adolescents2. In addition, untreated depression can be disabling and life threatening. Furthermore, epidemiological data suggests that increase in prescriptions of antidepressants is associated with reduction in youth suicide rates3. The authors indicate that psychotherapy is more effective and safer intervention compared to antidepressants1. However, so far results of comparative trials of selective serotonin reuptake inhibitors (SSRI) and psychotherapy in pediatric depression have not been published. Therefore, it remains to be determined if any of these treatments can be considered superior to the other. In addition, several other arguments in the article need further clarification: 1. The authors fault pharmaceutical trials due to financial conflict of interest. Psychotherapy trials suffer from the same pressures as successful psychotherapy trials assist in getting publications leading to additional funding, tenure, job security, and promotions for the principal authors. Despite these pressures, several scientists conduct psychological and pharmacological research with the highest ethical standards. 2. Unblinding is a potential problem and can bias results. However, active (i.e. symptomatic) placebos have produced similar results like inactive placebos, in contrast to what the authors assert4. Unblinding is a bigger problem for psychotherapy trials where a double blind trial is impossible, and unblinding of single blind status occasionally happens as patient may inadvertently disclose the name of their clinician to the rater. Moreover, psychotherapy trials have used wait list or attention placebo (such as art therapy) which is suboptimal compared to a pill placebo2. In conclusion, I will like to add that the authors Jureidini and Tonkin are members of “Health Skepticism, Inc” as disclosed in another publication5. The mission of this organization is to “encourage skepticism about misleading pharmaceutical drug promotion”. I am concerned that due to this affiliation, the authors go fishing for weaknesses in pharmaceutical trials, and thus bias the results of their analysis. Clinicians must take a pro-patient stance, understand that both antidepressant and psychological trials have limitations2, and advocate for any treatment (psychotherapeutic or pharmaceutical) with evidence for efficacy and effectiveness without any prejudice. 1. Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328(7444):879-883. 2. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. Bmj 1998;316(7144):1559-63. 3. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60(10):978-82. 4. Quitkin FM. Placebos, drug effects, and study design: a clinician's guide. Am J Psychiatry 1999;156(6):829-36. 5. Jureidini J, Tonkin A. Paroxetine in major depression. J Am Acad Child Adolesc Psychiatry 2003;42(5):514; author reply 514-5. Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103.
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In a rapid response letter to the bmj [1] Dr. Pathak argues as follows:- “I disagree with Jureidini et al’s conclusion that “confidently recommending” antidepressants would be inappropriate”. Psychotherapy is the first line therapy for mild/ moderate depression. However, it cannot be recommended as first line treatment for severe depression as severe depression predicts non response to psychotherapy. It would be reasonable to prescribe fluoxetine for severe depression, given that no other intervention has scientific evidence of efficacy in severe depression in children and adolescents. In addition, untreated depression can be disabling and life threatening. Furthermore, epidemiological data suggests that increase in prescriptions of antidepressants is associated with reduction in youth suicide rates.” Dr. Pathak argues that psychotherapy cannot be regarded as first line therapy for major depression, which is a reasonable argument. He then argues that fluoxetine would be a reasonable choice given that no other intervention has scientific evidence of efficacy in severe depression in children and adolescents. That is illogical reasoning because one has to justify a positive recommendation for fluoxetine based on its own merits, and not because no other drug has proven efficacy. Jureidini has argued that the RCTs of fluoxetine have a low signal/noise ratio due to a weak signal and considerable noise, and that one cannot therefore be confident that fluoxetine has any proven efficacy in major depression in children. Dr. Pathak has not provided any EBM evidence that Jureidini’s analysis is flawed or that there are other positive fluoxetine RCTs with a high signal/noise ratio. Dr. Pathak also argues as follows-: “In conclusion, I will like to add that the authors Jureidini and Tonkin are members of “Health Skepticism, Inc” as disclosed in another publication. The mission of this organization is to “encourage skepticism about misleading pharmaceutical drug promotion”. I am concerned that due to this affiliation, the authors go fishing for weaknesses in pharmaceutical trials, and thus bias the results of their analysis.” An inherent skepticism about drug-sponsored clinical trials is indeed an ‘a priori’ bias, but Dr. Pathak provides no evidence that Jureidini’s analysis is flawed as a result of that bias. All human beings have inherent biases, but that doesn’t automatically mean that their analytical thinking is flawed as a result of that inherent bias. Critics of Jureidini’s analysis should focus their criticism on their logical reasoning and/or statistical analysis. I have still not read a single rapid response letter that has identified a major flaw in Juredini’s analysis, or that has provided substantial EBM evidence to justify a confident recommendation for fluoxetine for major depression in children. References: 1. Pathak S. The Utility of Antidepressants in Pediatric Depression - Rapid response letter - http://bmj.bmjjournals.com/cgi/eletters/328/7444/879#56873 Competing interests: None declared |
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Malcolm VandenBurg, Physician and founder of Parents under Pressure workshops 114 Harley Street London, W1G 7JJ UK
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I have for many years supported the parents and carers of children and adolescents who have mental illness. Indeed in the worksops I have run for General Practitioners to help them cope with their own innapropiate responses to stress, mental illness of their offspring has been identified as a major stressor in their lives. I now run support groups for these parents including one for The Capio Nightingale Clinic's Adolescent Unit in Chelsea for parents and carers of those children admitted to the hospital. One of the reccuring themes they want to discuss is the evidence base for all the therapies that ther children recieve, both psychological and pharmacological. It is indeed a poor reflection on the whole medical proffession that this evidence base is not extensive for any of the therapies that are used. As has been pointed out by many of the rapid responses there may be as many flaws in the research governing the use of psychological therapies in this age group, as pharmacological ones . If the children are denied pharmacological treatments for depression, will the others be sufficient? Is there a difference in the safety of the drugs if they are used in hospital rather than on outpatients? Is the risk/benefit profile altered by the use of the drugs by adolescent psychiatrists compared to use by General practitiners? Are the outcomes different when drugs are prescribed at the same time as frequent psychotheraputic contact? Surely these matters are of such importance that large scale studies should be carried out to assess the comparative risk/benefit ratio of all theraputic modalities which may be offered to this age group. These studies would have to be large and multicenter,if not multinational. Who will fund them especially if the new European Clinical Trials Directive has to be followed?. They must exclude the possibility of a type 11 error. Metanalysis should be carried out as a matter of urgency. We need to understand why there is a difference between risk/benefit in those above and below 18 (if indeed there is). We need a biological marker independant of age if possible so that those aged 16-17 who may derive benefit are not precluded a useful treatment, and those aged 19-20 who may be harmed are not given such therapy. If indeed as this paper suggests some doctors lack the skills to understand the evidence base and trials what chance the parents. Perhaps more importantly what chance the children who do not wish their parents to be involved in their theaputic decisions following the lines of the 'Gillick Competencies' The parents of this age group want to be totally involved in the theraputic decisions coccerning their children, because they both care desperately and also as a way of dealing with thier own axnieties. Indeed some spend many hours performing literature searches worthy of a PhD. This itself helps them and is a common coping strategy. There needs to be transparency in all theraputic research. In research concerning children there needs to be super transparency both on the part of researchers and those performing reviews. Anything less is unnaccceptable. Competing interests: Malcolm VandenBurg runs support groups for the parents of children who have mental illness. He is also a Pharmaceutical Physician who has been funded by the industry to carry out research on antidepressants. |
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Andrew F Clark, Senior Lecturer & Consultant in Adolescent Psychiatry Bolton Salford Trafford Mental Health NHS Trust, M25 3BL
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Research suggests that over 90% of UK child and adolescent psychiatrists prescribe antidepressants to children under their care (Phillips et al, 2003) and that this prescription of antidepressants represents over 30% of their prescribing of any medication for any disorder (Clark, 2004). Higher levels of prescribing of one class of medication (e.g. SSRI antidepressants) are correlated with higher levels of another class (e.g. stimulants) despite a relative lack of overlapping indications or patient groups (Clark, 2004). This suggests that some psychiatrists are more likely than others to prescribe medication even when presented with similar clinical dilemmas. Judeirini et al's paper and the recent guidance from the FDA in the US and the MHRA in the UK highlight the lack of robust evidence to guide the clinician when faced with a teenager with a depressive disorder which fails to respond to environmental and psychological interventions. In the face of such lack of evidence and yet a teenager with enduring suffering and impairment surely the appropriate strategy is to openly and honestly discuss the conflicting research interpretations with the young person and their parents/carers and to aim to reach a collaborative decision as to whether for that individual the potential risks or benefits favour a trial of antidepressant medication. References: Clark AF (2004) Incidences of new prescribing by British child and adolescent psychiatrists: a prospective study over twelve months. Journal of Psychopharmacology, 18, 115-120. Phillips T, Salmon G & James AC (2003) Prescribing practices in child and adolescent psychiatry: change over time 1993-2000. Child and Adolescent Mental Health, 8, 23-28. Competing interests: I have managed an NHS research grant for a study into the prescribing practices of child and adolescent psychiatrists. I have received honoraria and travelling expenses from pharmaceutical companies, including manufacturers of antidepressants. I recieve NHS clinical referrals of teenagers with depressive disorders that have failed to respond to treatment |
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Bernadka W. Dubicka, honorary clinical research fellow Royal Manchester Children's Hospital, Dept of Child Psychiatry, Hospital Rd, Manchester M21 8UU
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In their detailed analysis of the efficacy of antidepressants in juvenile depression(1), Jureidini et al have crucially failed to point out that most of these trials have been conducted on both children and adolescents, some as young as 6 years (2). In addition, suicidality is often an exclusion criteria, as are numerous comorbid disorders. Therefore, we do not know the effect of these drugs in the depressed, suicidal adolescent population who frequently present with associated comorbidity, as this sample have not been analysed separately. This group would be more representative of the typically depressed adolescent that may be treated with antidepressants in the UK, and just as antidepressant drugs cannot 'confidently be recommended as a treatment option for childhood depression', neither can we confidently conclude that antidepressants are not effective in this group. Likewise, cognitive behavioural therapy (CBT) has not been trialled in severe adolescent depression with associated suicidality and comorbidity. The quoted study by Harrington et al (3) found that psychological treatment was an effective intervention for depressive symptoms and mild depression only, therefore we cannot conclude that this will also be effective in severe depression, and free of adverse effects. More non-industry treatment trials of severe adolescent depression are urgently needed to address these issues. 1. Jureidini et al, Efficacy and safety of antidepressants for children and adolescents, BMJ, 328: 879-83, 2004. 2.Wagner et al, Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. JAMA, 290, 1033-1041, 2003. 3. Harrington et al, Psychological treatment of depression in children and adolescents. A review of treatment research. BJP, 173, 291-298, 1998. Competing interests: BD is a research fellow in a government funded treatment study of adolescent depression, involving antidepressants and cognitive behavioural therapy. |
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Cathryn M Clary, Pfizer Inc Pfizer Inc 235 E 42nd Street New York NY 10017, Steven J Romano
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We wish to address the methods used by Dr. Jureidini and his co- authors in their recent review (Jureidini et al, 2004) of SSRIs in children, as well as to take issue with one of the important conclusions they make relating to the potential public health value of drugs with modest effect sizes in the treatment of pediatric depression, a serious illness. Specifically, we would like to disagree with several misstatements that are made in the Jureidini article about our report of 2 placebo- controlled clinical trials of sertraline in pediatric depression (Wagner, JAMA, 2003), and with the overall conclusion, which suggests that this article exhibited “disturbing shortcomings in the methods and reporting…” Methods used in the clinical review
Application of this checklist to our trial that studied the efficacy and safety of sertraline results in a Jadad score of 5, which is the highest possible score. Similarly, medical journal editors have agreed upon standardized methods for reporting clinical trials (the Consort Guidelines; Moher et al, 2003). A review of the sertraline study against the Consort reporting guidelines (Moher et al, 2003) indicates that we complied with all 22 of the reporting guidelines. Thus, objective consensus guidelines indicate that the quality of the sertraline clinical trial (Wagner et al, 2003), as well as the quality of how it was reported, both met the highest consensus standards. Use of double-blind methodology
Sertraline: Review of Safety and Tolerability
The authors then go on to deplore “The failure of drug companies to disclose increased suicidal activity secondary to these drugs…” For sertraline in the treatment of childhood depression (Wagner et al, 2003) this statement is false, and we would request that the authors make a correction in BMJ. The article in JAMA provides the following data on suicidal related ideation and/or activity (p.1038): “Seven sertraline- treated patients and 6 placebo patients had adverse events that met the established criteria for a ‘serious’ adverse event, including suicide attempt (2 sertraline and 2 placebo), suicidal ideation (3 sertraline), and aggressive reaction (1 sertraline)…” On p.1039 of the JAMA article, there is further discussion of the issue of suicide as follows: “Our trials show a lack of significant difference in suicidal ideation between sertraline-treated and placebo patients, as measured by the CDRS-R. In patients who continued the 24-week open-label extension study, only 1 episode of suicidal ideation was reported, and the investigator attributed this event to teasing by classmates.” Sertraline: Review of Efficacy
General Comments
We are not sure why the non-specific effect of placebo is so high in childhood depression, though it is likely to be due to a high expectancy effect in a highly suggestible patient group. We do know, though, that placebo will not be prescribed by any physician for the treatment of major depression in children. We also believe that there are sufficient safety concerns with the TCAs (eg, cardio-toxicity and overdose lethality) that make them a poor first-line treatment, especially since evidence for their efficacy is even weaker than the SSRIs. Also, as we have indicated, the evidence for the efficacy of psychological therapies is based on relatively small studies, none of which used a double-blind methodology. Thus, a response rate of 69% on sertraline (despite only a 10% advantage over placebo) makes it understandable why physicians in the past decade might have made the clinical judgment that the benefit-risk ratio was tipped in favor of SSRI treatment, even though regulatory approval is lacking for most SSRIs (including sertraline) in childhood depression. When one puts the issue of childhood depression in context, then we feel less able than the authors are to dismiss a 69% response rate on sertraline, even if it is only 10% superior to placebo. Cumulative rates of major depression and suicide in childhood and adolescence are staggering. In Western Europe alone, an estimated 10.1 million children will develop major depression by age 18, and more than 50,000 will have committed suicide (Birmaher et al, 1996; Olfson et al, 2003; US Census Bureau). While a 10% advantage over placebo may seem trivial to the authors, the sheer magnitude of the suffering makes us wonder about their unwillingness to “lower the threshold for accepting a new intervention.” Even 10% improvement in response to this devastating illness, while small in absolute terms, translates into substantial relief of suffering for hundreds of thousands of children and potentially saving the lives of some patients. Daily, clinicians face the difficult question of how to treat these patients, for whom the data are often confusing or inconclusive. We stand by the reported results from the sertraline study, and welcome objective and fair discussion on this topic. However, reports containing inaccurate or misleading statements such as that by Dr. Jureidini and colleagues only cloud the issue and impede successful patient treatment. References Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B. Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry 1996;35:1427- 1439. Cook EH, Wagner KD, March JS, Biederman J, Landau P, Wolkow R, Messig M. Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 2001;40:1175-1181. King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30:179-86. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. BMJ 1998;316:1559-1563. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of randomized clinical trials: is blinding necesssary? Control Clin Trials 1996;17:1–12. Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328:879-883. March JS, Biederman J, Wolkow R, Safferman A, Mardekian J, Cook EH, Cutler NR, Dominguez R, Ferguson J, Muller B, Riesenberg R, Rosenthal M, Sallee FR, Wagner KD, Steiner H. Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA 1998;280:1752-1756. Moher D, Schulz KF, Altman DG; CONSORT Group. The CONSORT statement: revised recommendations for improving the quality of reports of parallel- group randomised trials. Clin Oral Investig 2003;7:2-7. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60:978-982. US Census Bureau, Global population estimates, 2002, Table A-7a Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290:1033-1041. Competing interests: Drs. Clary and Romano are full time employees and shareholders of Pfizer Inc |
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Chris. L. Manning, CEO primhe (primary care mental health and education) Twickenham
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Dear Sir I defer to the analytical abilities of those who have contributed to this debate; they all clearly demonstrate that this subject area, and more importantly, those affected by it, are demanding of far greater focus and attention than they have received to date. Perhaps, it is time to turn down the heat on some old favourites, like diabetes, asthma and CHD, and put the brain highest on the list for deserving our attentions? As a former front-line "jobbing Joe", I was relieved to be able to start prescribing non-cardiotoxic products in the treatment of depression, and can also report that taking an SSRI, after having taken a TCA, has given me a life free of the latter's paralysing and life-enfeebling side- effects. As a patient, and service user, I am also pleased that my own narrative has value, whether it is supportive of the evidence gleaned from the highly artifical environment of RCTs or flies in the face of it. I am also convinced that the term depression does not, in any way, do justice to the complexity of the brain and that, attempting to strain everyone through such an outwardly-derived diagnosis, is like trying to claim that the Amazonian Forest complexity of the brain can be understood using 4 theories stating that it has at least 7 moving parts. Furthermore, as I have witnessed the various UK and US actings-out on this, admittedly, crucial matter, I have realised that a lot of what has happened to date is also about the varied agendas of all of those involved, not just the industry. I am also sure that most of us now know what we are AGAINST in all of this: the potential for the over-marketing of any medicine, however achieved, and especially to vulnerable groups and desperate practitioners. The challenge now is surely how we all work together TOWARDS achieving the best possible outcomes for those who suffer from a genuine illness ("if you can describe it, then you have never had it" Prof. Lewis Wolpert), which itself has high comorbidities and often tragic outcomes. I was well trained by a Teutonic Professor of Pharmacology who instilled in all of us the varying degress of toxicity associated with ALL medicinal products. We need to move forwards in a both...and way now, not an either...or one. Taking sides, for whatever reason, either personally or organisationally, is the worst possible way forward and compounds the damage already done to the community we are tasked with serving here. Many of us spend every day working to drive these issues up the national agenda in the UK. It is still highly confounding, however, that mental health is taken to be synonymous, at worst, with mental illness (or, at best, its absence)and is seen as a 'soft-touch' in terms of funding. It figures, for example, next to nowhere in the Government's current consultation on public health and services for CAMH, especially in primary care, have their own extremely chequered history of low-level provision, long-waiting times and people being referred back as "inappropriate referrals". By way of closure, I can well remember psychotherapists and counsellors phoning me up about clients/patients who had just started in therapy (either referred by me or not)and who had become agitated and suicidal, sometimes at the very first session. If we cannot appreciate that taking a meta/unstable situation and throwing ANY intervention at it (including 'just' a listening ear)is going to be fraught with some difficulties (and I defer to the analysts to tease that one out), then we will simply continue in our either..or shismatic thinking and behaviours. Many of us go into health and social care to make a positive difference to the lives of those who suffer; there is no valid point in continued witch-hunts and professional bashing. We need to start working now on agreeing the way forwards, not endlessly re-iterating where we have been. Yours Faithfully Dr Chris Manning CE Primhe Hon Vice President Depression Alliance National MH Taskforce Competing interests: I have depression. I have treated depression in primary care in adolescents and two children. I have designed and run educational and training programmes for primary and secondary care professionals, at which whole-systems and whole-person approaches have been advocated and, as part of which ,medical treatment may or may not be appropriate. These programmes have, to date, been funded mostly by the pharma. industry in the absence of any coherent or available funding from elsewhere. At all times, a line has been drawn, and that line is the drug product and its marketing. The activities of Depression Alliance and Primhe are funded from supportership fees, the Department of Health and the industry. Both charities look forward to the time when England is not at war and can spend time focussing on the 'crying' needs of its citizens. |
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Alan G. Wade, Medical director CPS Research 1 Todd Campus, Glasgow G20 0XA UK, Prof. Dr. med. Thomas E. Schläpfer
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Depression in children is a serious and life threatening illness justifying aggressive and sustained treatment. Most medications used for children are only tested in adults and therefore used “off-label”. In general it is accepted that benefit in adults is assumed to confer benefit in children. This is at least in part due to difficulties of obtaining consent and conducting studies in children. In the absence of evidence to the contrary this should also apply to antidepressants. At present there is an apparent campaign against SSRI antidepressants and this paper, if not in actual content, then certainly in implication, seems to follow this trend. It is worth remembering that the prescribing information clearly states that these drugs have not been tested in children and to our knowledge no attempt has been made to licence these drugs for children. While in the light of commercial interests a raised bar in term of judgement is necessary, we have to be careful not to raise the bar so high that nothing gets over What do Jureidini and colleagues find is wrong with the evidence available? 1. Exaggeration of benefits – selective publication of positive results is well recognised throughout medicine – this applies equally to psychotherapy so strongly recommended with no evidence in this paper. We strongly believe that the scientific process of peer review, publication and replication or lack of it will eventually bring out the truth. 2. Improvement in control groups – a large placebo response is not only seen in treatments of depression – including psychotherapy – but is common to many areas of medicine such as asthma, pain and hypertension 3. Adverse effects – these cannot be taken in isolation, risk/benefit must be assessed and depression in unstable adolescents is a serious illness with potential lethal outcomes 4. Antidepressants cannot reliably be recommended (in children) – based on published evidence fluoxetine can, other SSRI’s simply have insufficient data for us to make such a judgement. This recommendation is reinforced by a recent review in the Lancet. 5. A more critical approach to published data is needed – no one could possibly disagree with this sentiment - this paper too? It is important to recognize that different agendas play a role in psychiatric pharmacotherapy: companies want to sell their drugs, patients want to get efficacious and safe treatments, third parties want to get acceptable effects at a minimum of costs. It’s a difficult task for physicians to mediate between these interests and to stay away from additional less legitimate ideological agendas. The conclusion in this case must be that the evidence of benefit does not exist, not that lack of benefit exists. It is important that we do not needlessly dismiss potentially useful drugs when viable alternatives are thin on the ground. Reference Whittington et al Lancet 2004; 363: 1341-45 Competing interests: Both authors heave received research grants, consultancy fees and support to attend conferences from a number of pharmaceutical companies which produce antidepressant drugs. |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103.
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Alan Wade in his rapid response letter to the bmj [1] states "The conclusion in this case must be that the evidence of benefit does not exist, not that lack of benefit exists. It is important that we do not needlessly dismiss potentially useful drugs when viable alternatives are thin on the ground." I cannot understand how the second sentence follows logically from the first sentence. If there is no RCT evidence of benefit of SSRIs in major depression in children/adolescents, then one cannot conclude that the drug is potentially useful unless there is other EBM evidence that proves that the drug is effective and clinically useful. The author supplies no additional (ancillary) EBM evidence that proves that SSRI's are beneficial for major depression in children/adolescents. Also, the lack of viable alternative drugs does not alter the EBM validity/invalidity of EBM studies of SSRIs in major depression in children and adolescents. I think that it is irrational to question Jureidini's agenda, when one should really question the scientific valididy of his particular analysis. Wade also suggests that the benefits have been exaggerated with respect to other therapies (other than SSRIs), and that there is a large placebo effect in other diseases, but those two comments have no pertinence with respect to the validity, or invalidity, of Jureidini's analysis, which should be criticised on its own merit (or lack of merit). Chris Manning in his rapid response letter [2] states with respect to the fact that a SSRI drug was of benefit in his personal case of depression-:"As a patient, and service user, I am also pleased that my own narrative has value, whether it is supportive of the evidence gleaned from the highly artifical environment of RCTs or flies in the face of it." I cannot readily understand how narratives of the anecdotal value of SSRIs can be of EBM evidentiary value when it comes to scientifically determining whether SSRIs are clinically effective in major depression. If a number of anecdotal reports suggest that SSRIs are of clinical value in major depression, then the psychiatric community has to devise a scientically valid method of determining whether the drugs really are of value by designing/performing a clinical research study that minimises systematic bias. If the evidence from RCTs does not provide significantly positive evidence of SSRI's efficacy, and mental health professionals regard those RCTs as being artificial (or otherwise invalid), then they should design and perform studies that can provide a higher level of EBM evidence. If they cannot design and perform a more scientically valid study than a RCT, then they are logically obliged to accept the results of RCTs as being the "best" EBM evidence presently available. This logic doesn't depend on any person's agenda, because the scientific validity of an EBM study should theoretically be independent of the personal bias of the person performing the study, or the personal biases of the community of mental health professionals who interpret the study. References: 1. Wade. Alan G. What's your agenda. bmj rapid response letter. http://bmj.bmjjournals.com/cgi/eletters/328/7444/879#58312 2. Manning Chris. Everybody has an agenda. bmj rapid response letter. http://bmj.bmjjournals.com/cgi/eletters/328/7444/879#58145 Competing interests: None declared |
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Donald H R Mowat, consultant in old age psychiatry royal cornhill hospital, Aberdeen AB25 2XS, Douglas Fowlie and Tom MacEwen
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Sir: On March 9, the Committee on Safety of Medicines (CSM) advised avoiding olanzapine and risperidone in the treatment of patients with dementia (1), reflecting concern over excess stroke risk. Anti-psychotics have long been used (off licence) in dementia to treat neuro-psychiatric disturbance and are highly effective (2). Atypicals have recently been favoured over older preparations to avoid anti-cholinergic and Parkinsonian side effects, but a recent study of elders on typical and atypical anti-psychotics has shown no significant difference in risk of stroke between pharmacological groups (3). Stroke, while potentially catastrophic, is a quantifiably rare "excess risk" event in an "already at risk" group (4), demanding balanced thinking against real reductions in agitation and aggression. We are concerned that anti-psychotic therapy will be unnecessarily withheld, and also that GPs will now adopt widespread usage of conventional anti-psychotic drugs. The Adults with Incapacity (Scotland) Act 2000 specifies that informed proxy decisions should made based on sound generalist and specialist advice, and in conjunction with relatives or carers (5). We regularly meet such carers in clinical practice who feel well served by medication, who are willing to engage in life’s realities of assessing and accepting risk, and who make those choices in conjunction with informed medical opinion. It seems to us that the blanket injunction issued by the CSM is oversimplified, and may prove detrimental to patient care. Yours sincerely Donald Mowat Douglas Fowlie Tom MacEwan Consultants in Old Age Psychiatry Royal Cornhill Hospital, ABERDEEN AB25 2ZH
References www.mca.gov.uk/aboutagency/regframework/csm/csmhome.htm Brodaty, H. et al. (2003): "A Randomised Placebo-Controlled Trial of Risperidone for the Treatment of Aggression, Agitation and Psychosis of Dementia". J Clin Psychiatry 64:2 134 – 143. Herrmann, N. (2003) Data on poster presented at International Conference on Geriatric Psychopharmacology Schneider, L. (2003) " Meta – Analysis of Atypical Anti-psychotics for Dementia Patients: Balancing Efficacy and Adverse Events". Proceedings of Eleventh Congress of the Interrnational Psychogeriatric Association, Symposium 078-004. Adults with Incapacity (Scotland) Act (2000): www.scotland.gov.uk/about/JD/CL/00016360/home.aspx Competing interests: TM has received support from Janssen Cilag to attend an international meeting; our Department has received limited educational support from various pharmaceutical companies. |
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Dr. Naseem A. Qureshi, Medical Director [A], Director, CME&R Buraidah Mental Health Hospital, Postcode.2292, Saudi Arabia
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Dear sir: Notably, there is a converging evidence that depression occurs in all age groups including children and adolescents (CAs) and for that matter CAs need proper diagnostic assessment and thereafter appropriate treatments, which may include either suitable drugs or psychotherapies or their combination. From symptoms and diagnostic perspectives, depression in CAs is often characterized by atypicalities such as decreased school performance, antisocial behaviors, withdrawal from friends, withdrawal from daily activities, excessive weight gain, excessive weight loss, aggressive spells, remarkable agitation, somatic symptoms and use of alcohol/other substances. In addition, recent research conducted among CAs documents alarmingly that the incidence of suicidal attempts and complete suicide is staggeringly high in this population and is on the increase. Notably, DSM-IV-defined depression could be found in children as young as six years of age. However, when aforesaid depressive psychopathological symptoms among CAs are recognized, they should have proper screening and some important scales are developed for this purpose; Children's Depression Inventory for 7-17 years; The Center for Epidemiological Studies Depression Scale for Children; Child Depression for 8-12 years; Adolescent Depression Scale for 13-18 years; and The Beck Depression Inventory for individuals 14 and older. The use of screening tools helps in the precise diagnosis of depression, guides its severity, and tracks therapeutic changes following the use of treatments and its outcome. Moreover, precise diagnosis of depression in CAs has major impact on the treatment outcome. It is documented that preschoolers (<7 years) also suffer from depression and DSM-IV criteria for depression in preschoolers may not be adequate, duration of symptom criteria, i.e, of two weeks may need modification. The most common symptoms among children of 2-5 years of age include irritability, angry spells, resentfulness, death/suicidal theme in play, feeling lonely, and high level of frustration. When children communicate death wishes, their parents must be interviewed. These children are reported to have high rate of comorbid disorders and moreover about 5% of them do have 4 or more of those aforesaid symptoms. The specific objective of presenting these defining psychopathological symptoms in CAs and preschoolers is to generate confidence among primary care physicians, pediatricians and mental health professionals who relatively lack adequate skills to recognize depression in CAs and preschoolers. At the same time, reportedly about 45% of physicians lack confidence in treating depression in this psychiatric population. In an interesting study of adolescents (9-13 years), heterotypic (versus homotypic) trajectory (continuity from one diagnosis to another diagnosis) was significant to depression to anxiety and from anxiety to depression and all heterotypic continuity was seen in girls (9 through 16 years). Now after introducing these clinical facts, I posit one question which is " Does precisely diagnosed depression in CAs need proper treatment?" The answer to this question is certainly "yes". If yes, are then the available drug treatments such as TCAs, SSRIs, mood stabilizers, and others really effective in CAs? Are these drugs fairly safe and cause no harmful effects in CAs? Are these drugs less expansive and easily accessible to all CAs globally? These questions are highly complex and if the answers to them are "yes", use them. But if the answers to these questions are "no", use them sparingly and keep on developing better drugs with better clinical profile to be used in children and adolescents with depression. Notably, we are beginning to develop and understand the complexities of pediatric psychopharmacology, and research efforts should continue in order to develop better psychotropic drugs for the treatment of depression in CAs, which is a very devastating mental disorder Finally, it looks fruitless to enter in the poignant debate related to the findings of Jureidini et al (2004) because supporters and opponents to those authors have already expressed their respective concerns. Reference: Jon N Jureidini, Christopher J Doecke, Peter R Mansfield, Michelle M Haby, David B Menkes, and Anne L Tonkin Efficacy and safety of antidepressants for children and adolescents. BMJ 2004; 328: 879-883 Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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Cathyrn Clary, a Pfizer Inc. employee, in a rapid response letter to the bmj [1] chides Jureidini for his criticism of the Pfizer-sponsored trial of sertaline for major depression in children/adolescents, which was originally reported by Wagner in JAMA [2]. Regarding the efficacy of sertaline, Clary criticises Jureidini as follows-:"Dr. Jureidini and his co-authors do not specifically summarize the efficacy results in the JAMA-sertraline article, except to note that they “doubt Wagner’s claim, and Varley’s editorial support for that claim, that their results are clinically, as well as statistically, significant.” Clary claims that the Wagner study's results are statistically and clinically significant. In particular, Clary states that the Wagner study demonstrated that sertaline produced a 69% response rate (in the primary efficacy endpoint) and that it was significantly better than placebo, which had a 59% response rate. That absolute risk difference (ARR) is equal to an absolute benefit of 10%, which Clary initially acknowledges is modest. However, at a later stage in her rapid response letter, she argues that the efficacy result is clinically significant. This is Clary's argument-: "Thus, a response rate of 69% on sertraline (despite only a 10% advantage over placebo) makes it understandable why physicians in the past decade might have made the clinical judgment that the benefit-risk ratio was tipped in favor of SSRI treatment, even though regulatory approval is lacking for most SSRIs (including sertraline) in childhood depression. When one puts the issue of childhood depression in context, then we feel less able than the authors are to dismiss a 69% response rate on sertraline, even if it is only 10% superior to placebo. Cumulative rates of major depression and suicide in childhood and adolescence are staggering. In Western Europe alone, an estimated 10.1 million children will develop major depression by age 18, and more than 50,000 will have committed suicide (Birmaher et al, 1996; Olfson et al, 2003; US Census Bureau). While a 10% advantage over placebo may seem trivial to the authors, the sheer magnitude of the suffering makes us wonder about their unwillingness to “lower the threshold for accepting a new intervention.” Even 10% improvement in response to this devastating illness, while small in absolute terms, translates into substantial relief of suffering for hundreds of thousands of children and potentially saving the lives of some patients." Before I discuss whether the 10% efficacy result is clinically significant, consider whether one can be confident that the 10% efficacy result is the "true value". Sackett, the guru of EBM, stated that confidence in a RCT's results is proportional to the RCT's signal/noise ratio multiplied by the square root of the sample size [3]. The Wagner study consisted of only 189 sertaline treated children. That is a small study when compared to cardiovascular RCTs that routinely enroll thousands of patients. Wagner reported [2] that-: "Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders (P = .05)". Is that result statistically significant and can one be confident in the internal/external validity of the study's results? Mathews questioned the statistical validity of the Wagner study's result in a letter to JAMA [4]. Mathew stated-:"The authors used P values to assess statistical significance. While this is at times useful, it is an arbitary value and the consensus now is that it does not convey much. The use of confidence intervals (CIs) would have conveyed more information about the clinical utility of the results. Based on the data in the article, we calculated that sertraline produced an absolute risk reduction for depression of 10% (95% CI, 0.15%-19.8%); the corresponding number needed to treat of 10 has a 95% CI of 5 to 540." In other words, Mathews is pointing out that the Wagner study was so small in size that one cannot be certain that the 10% absolute risk reduction is the "true value" and the ARR could be anywhere between 0.15-19.8%. I think that it would be difficult to cogently argue that an absolute risk reduction in the range of 0.15-10% (lower half of the estimated ARR range) is either statistically or clinically significant. I am particularly bothered by the fact that the Wagner study mainly recruited patients with moderate depression, and one cannot therefore be sure that the Wagner study's marginal efficacy results are applicable to children with severe depression. I personally think that it is difficult to accurately determine whether a drug is truly efficacious if the tested population of "sick" patients has a placebo response rate of 59%. I think that a high placebo response rate probably reflects a sample population of "less sick" MDD patients and I believe that one cannot automatically extrapolate the Wagner study's results to severely depressed children in clinical practice. Both Wagner and Clary argue that the 10% ARR is not only statistically significant; they also argue that a 10% efficacy result is clinically significant. Spielman in a letter to JAMA [5] questions the clinical significance of a 10% ARR. He states-: "Dr Wagner and colleagues stated that the "significance of the results is clinically as well as statistically relevant," an assertion that reaches well beyond the trial's results. The average improvement in the main outcome measure—the CDRS-R—was 22.84 points for the sertraline group vs 20.19 points for the placebo group. The authors did not report the standard deviation, however; thus, an effect size cannot be calculated. However, simple division shows that the gains made by the placebo group were 88.4% of those in the active medication group, leaving the active medication superior by less than a 12% margin compared with an inert placebo. The slight difference between active and inactive treatment in the main outcome measure, while statistically significant, is of questionable clinical relevance. Statistically significant differences were also found on the Clinical Global Impression (CGI) Improvement and Severity of Illness scales. While these scales are popular in clinical trial research, there is scant evidence about their validity. On the remaining 3 outcome measures, no statistically significant differences were observed." I have never seen a "gold standard" definition of clinical significance, but I find it difficult to understand how one can justify a 10% ARR as being clinically significant if the single RCT demonstrating a 10% efficacy result has a low signal/noise ratio (small signal of 10%, and high noise level due to the recruitment of patients with high placebo response rates which could theoretically vary from trial-to-trial, a subjective and questionably valid primary endpoint, and a questionable ITT analysis) AND a small sample size (189 treated patients), AND if one cannot be certain that more severely depressed children in clinical practice will respond as well as the moderately depressed children in the Wagner study (questionable external validity). Clary states that the cumulative suicide rate in childhood depression is staggering and she quotes an expected figure of 50,000 suicides among 10 million depressed children under the age of 18 in the USA. She therefore implies that sertaline would be of particular value in severely depressed children, who presumably are more likely to commit suicide. However, we have no guarantee that sertaline would have a 10% efficacy result in preventing suicide in severely depressed children. In fact, a number of people believe that sertaline may actually increase the suicide rate. Clary states that there was no difference in suicide rate between sertaline and placebo patients in the Wagner study. However, the Wagner study only consisted of a few hundred patients and was of limited duration (10 weeks). Clary also states that a trial of sertaline in OCD patients demonstrated that sertaline was not associated with an increased suicide risk. However, and by contrast, the Committee on Safety of Medicines [6] stated that sertaline is associated with a higher suicide risk. In particular, the Committee stated-: "Only one placebo-controlled trial has been performed with sertraline in children and adolescents with obsessive compulsive disorder (OCD), who were treated for 12 weeks. There were no reports of suicide, suicidal thoughts, or self-harm in patients treated with sertraline in this trial, and one report in a placebo-treated patient. There were, however, two reports of suicidal thoughts and one report of self harm in children and adolescents treated with sertraline for OCD in a 52-week open-label trial (giving a rate of 1.4 % (3/208)). In all controlled trials in MDD and OCD the rate of suicidal thoughts and self-harm in the sertraline group is 1.8% (5/281), the rate in the placebo group is 1.1% (3/279). In all sertraline-treated patients the rate of suicidal thoughts and self-harm in the sertraline group is 3.7% (23/616). This estimate takes into account the fact that in the extension trials only those patients who switched from placebo to sertraline were new to sertraline. Patients are only counted once in the denominator regardless of how many trials they may have participated in. In sertraline-treated patients with MDD the rate of suicidal thoughts and self-harm in sertraline-treated patients is 4.6% (20/435). Extension trials handled as above. In sertraline-treated patients with OCD the rate of suicidal thoughts and self-harm in sertraline-treated patients is 1.4% (3/208). Extension trials handled as above. The data show a consistently higher incidence of suicidal thoughts and self-harm in children and adolescents with depression treated with sertraline, which is in the region of twice the apparent placebo rate. Data on the risk of suicidal behaviour in OCD trials do not appear to indicate any unusual risk." I have personally never studied the relevant suicide literature, so I cannot personally judge whether sertaline actually increases the likelihood of suicide in severely depressed children. However, if sertaline actually increases the suicide rate, this would be a matter of great concern. Finally, should one prescribe sertaline because 69% of moderately depressed children may respond to the drug? Clary argues that one should prescribe the drug because physicians are not likely to prescribe a placebo agent. Clary acknowledges that 85% (59% divided by 69%) of the drug's antidepressant effect is due to a high "expectancy effect" in a highly suggestible group of patients. Then, I presume that Clary would agree that Pfizer should inform prospective pediatric MDD patients upfront that 85% of sertaline's antidepressant action is due to an "expectancy effect", and I think that this specific information should be included in the informational package insert document supplied with the drug, and in Pfizer's sertaline advertisments. I also think that many people may agree that Pfizer is ethically obliged to inform pediatric MDD patients that alternative psychiatric treatments may offer an equivalent "expectancy effect" (equal to 85% of sertaline's total therapeutic effect), and that use of those alternative treatments may avoid some of the adverse events associated with the use of sertaline. References: 1. Clary C. Sertaline Pediatric Depression Trial Met Highest Standards of Study Design and Reporting. bmj rapid response letter. April 27 2004. http://bmj.bmjjournals.com/cgi/eletters/328/7444/879#57741. 2. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290:1033-1041. 3. Sackett, David L. Why randomized controlled trials fail but needn't: 2. Failure to employ physiological statistics, or the only formula a clinician-trialist is ever likely to need (or understand!) CMAJ: 165(9):1226-123 | |||