Researchers Chastise Am J Psychiatry Over Skewed Celexa Study

Researchers Chastise Am J Psychiatry Over Skewed Celexa Study

Thu, 31 Mar 2005

A letter by eight medical scientists (most from India, possibly all psychiatrists) have seriously challenged the scientific validity of an article published in the American Journal of Psychiatry. The lead author of the challenged study is one of the most influential opinion leaders in American child pshychiatry– Karen Dineen Wagner.

The letter states: “We would argue that the authors did not provide sufficient evidence to support their claim that “citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents” (p. 1082). We are surprised that the most respected psychiatric journal in the world published a study that is misleading to its readers in the extreme.”

Dr. Karen was similarly challenged about her claimed findings deeming Zoloft (sertraline) to be safe and effecive for childen. Her article was published in the Journal of the American Medical Association (2003). [1] Her claims were refuted last year by FDA’s Thomas Laughren. [2]

In light of the potentially fatal clinical harm suffered by children whose clinicians prescribed SSRIs without hesitation–because they were misguided by unsubstantiated, flawed clinical trial reports in the major medical journals– responsible editors should re-assess the reports in their journals, and purge those whose claimed positive findings are not substantiated by the data. [3, 4]

A comprehensive, independent evaluation of the findings and study designs of most clinical trial reports in psychiatry is long overdue. Particularly in light of evidence that the overwhelming number of leading investigators have substantial, ongoing financial ties to the companies whose products they have invariably found “safe and effective.”

Dr. Wagner served on the Texas Medication Algorithm Project (TMAP) panel whose treatment recommendations are not borne out by the scientific evidence. TMAP was finaced by the manufacturers of psychotropic drugs – in states that have adopted TMAP as their guideline, its list of recommended drugs is mandated by state mental health agencies. [5]

Dr. Wagner were hired by the state of Texas to make recommendations to the state mental health department for the treatment of depressed children. They recommended using the very drugs they knew to have serious risks without a demonstrable benefit greater than a sugar pill for children-as first line treatment in state funded facilities. Both Dr. Emslie’s and Dr. Wagner’s TMAP recommendations are not based on scientific evidence – but rather the consensus of the panel who was financed by psychotropic drug manufacturers.

References:

1. Wagner KD, Ambrosini P, Rynn M, et al: Efficacy of sertraline in the treatment of children andadolescents with major depressive disorder. JAMA 2003; 290(8):1033-1041.

2. Laughren T. Background Comments for February 2, 2004 Meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (Peds AC)

3. Whittington CJ, Kendal T, The Lancet (Vol 363, April 24, 2004);

4. Kendal T, Pilling, S and Wittington CJ. Are the SSRIs and Atypical Antidepressants Safe and Effective for Children and Adolescents? Curr Opin Psychiatry 18(1):21-25, 2005.

5. BARRY MEIER,Drug Testing Doesn’t Always Tell the Whole Story, THE NEW YORK TIMES, November 29, 2004, Front Page. At: http://www.ahrp.org/infomail/04/11/29.php

6. See: ongoing series of investigative reports by Nanci Wilson, Keye News (Texas CBS-affiliate): http://keyetv.com/investigativevideo/

See also: http://www.ahrp.org/infomail/03/10/01a.php

Contact: Vera Hassner Sharav
212-595-8974

Am J Psychiatry 162:818, April 2005
C 2005 American Psychiatric Association
Letter to the Editor
Child Psychopharmacology, Effect Sizes, and the Big Bang

MAJU MATHEWS, M.D., M.R.C.PSYCH., BABATUNDE ADETUNJI, M.D., F.A.S.A.M., JOANNE MATHEWS, M.D., BIJU BASIL, M.D., VINU GEORGE, M.D. Philadelphia, Pa., MANU MATHEWS, M.D., KUMAR BUDUR, M.D. Cleveland, Ohio, and SHINY ABRAHAM, M.D. Kottayam, India

To the Editor: We read with interest the study by Dr. Wagner et al. We have a number of concerns about this study. In the Method section, it is not clear how the patients were recruited. One is also left in the dark about the method of random assignment and if the random assignment list was concealed. The authors also give no indication of how they arrived at the sample size and if a power calculation was done.

Given the recent concerns about the risk of suicidal thoughts and behaviors in children treated with SSRIs, this study could have attempted to shed additional light on the subject. The authors called the analysis of data an intent-to-treat analysis, although four patients who were lost to follow-up were excluded. In a true intent-to-treat analysis, all patients are analyzed in the groups to which they were initially assigned, regardless of whether they received the treatment or not. We consider the use of the term “intent-to-treat” in this context misleading.

Dropouts from the study have been accounted for by using the last observation carried forward. Treatment response in depression is frequently followed by a subsequent return to original or baseline values on a scale such that the last observation carried forward may be an unduly optimistic estimate. The classification of dropouts as treatment failures is based on safer assumptions than the last observation carried forward.

Our greatest concern is with the results and conclusions drawn. There is no table showing the results in detail. The authors have only stated that 36% of citalopram-treated patients met the criteria for response, compared to 24% of patients receiving placebo. This response rate, while in itself marginal compared to other studies of antidepressants, does not in itself show that citalopram is better than placebo.

We calculated the absolute benefit increase of using citalopram as 0.12 (95%

confidence interval [CI]=-0.015 to 0.255). The relative benefit increase that could be attributed to citalopram was 50% (95% CI=-135% to 6%). The odds ratio, i.e., the odds of improving while taking citalopram compared to placebo was 1.75 (95% CI 0.92 to 3.43). The number needed to treat, i.e., the number of children who need to be treated with citalopram for one additional positive outcome was eight (95% CI=4 to infinity). None of these shows that citalopram is any better than placebo.

We would argue that the authors did not provide sufficient evidence to support their claim that “citalopram produces a statistically and clinically

significant reduction in depressive symptoms in children and adolescents” (p. 1082). We are surprised that the most respected psychiatric journal in the world published a study that is misleading to its readers in the extreme.

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The above is in response to the (abstract) of the following study:
http://ajp.psychiatryonline.org/cgi/content/abstract/161/6/1079
Am J Psychiatry 161:1079-1083, June 2004
C 2004 American Psychiatric Association

Article:
A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents

Karen Dineen Wagner, M.D., Ph.D., Adelaide S. Robb, M.D., Robert L. Findling, M.D., Jianqing Jin, Ph.D., Marcelo M. Gutierrez, Ph.D., and William E. Heydorn, Ph.D.

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression.

METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children (ages 7-11) and adolescents (ages 12-17) with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients (N=174) were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale-Revised; the response criterion was defined as a score of 28.

RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study (effect size=2.9). The difference in response rate at week 8 between placebo (24%) and citalopram (36%) also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively). Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.

CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

Dr. Wagner replies:

Letter to the Editor
Dr. Wagner and Colleagues Reply
KAREN DINEEN WAGNER, M.D., PH.D., ADELAIDE S. ROBB, M.D., ROBERT L. FINDLING, M.D., and JIANQING JIN, PH.D.
Galveston, Tex.

To the Editor: Dr. Mathews and colleagues request further information about the randomized, placebo-controlled trial of citalopram for treatment of depression in children and adolescents. Randomization was on a 1:1 basis and was stratified by age group. The random assignment list was concealed from the investigators, which is fundamental to the claim that the study was performed under double-blind conditions. The protocol-specified population for all efficacy analyses, defined as the “intent-to-treat” population, included all patients who received at least one dose of double-blind study medication and had at least one postbaseline efficacy assessment. The analyses we presented in the manuscript were not only conventional in nature; they were, in fact, defined a priori. The justification for defining this population for the efficacy analyses is that the primary analysis was the change from baseline, therefore requiring a postbaseline assessment.

Although recently a mixed-model approach has gained some currency for the analysis of efficacy in antidepressant trials, the last-observation-carried-forward method of analysis has always been conventionally considered the most conservative method of analysis. Certainly this was the case when the study protocol was being developed. In escitalopram trials in adult patients, last-observation-carried-forward analyses minimize the treatment effect that is demonstrated by observed-cases analyses of the patients who actually remain in treatment (1, 2). These analyses are considered more conservative than observed-cases analyses for acute treatment antidepressant studies because the onset of antidepressant effect is typically delayed for up to several weeks. Therefore, the last observation of patients who discontinue active treatment prematurely is not likely to capture the full potential antidepressant effect.

Regarding suicidality, it is helpful to note that the manuscript states clearly that no serious adverse events were observed in the trial for citalopram-treated patients. At the time the manuscript was developed, reviewed, and revised, it was not considered necessary to comment further on this topic.

Dr. Martin and colleagues inquire about the value of 2.9, which was calculated as the quotient of the least square mean, divided by the common standard error of the mean for each treatment group. With Cohen’s method, the effect size was 0.32.

In response to Dr. Barbe’s questions about the methods of this randomized clinical trial for the treatment of depressed children and adolescents, there were 75 subjects who were screened but not randomly assigned. The method for elicitation of adverse events was chosen because it was the accepted standard at the time the study was designed for multicenter, industry-sponsored clinical trials in juvenile depression.

It may be considered premature to compare the results of this trial with unpublished data from the results of a study that has not undergone the peer-review process. Once the investigators involved in the European citalopram adolescent depression study publish the results in a peer-reviewed journal, it will be possible to compare their study population, methods, and results with our study with appropriate scientific rigor.

We believe that the results of our study, which demonstrated a significant difference between citalopram and placebo beginning at week 1, is clinically meaningful, particularly at a time when there have been so few antidepressants shown to have superiority to placebo for depressed children.

Footnotes

Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

References

1. Burke WJ, Gergel I, Bose A: Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63:331-336[Medline]

2. Lepola UM, Loft H, Reines EH: Escitalopram (10-20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2003; 18:211-217[Medline]