Researchers Chastise Am J Psychiatry Over Skewed Celexa Study

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[sSRI-Research] Researchers Chastise Am J Psychiatry Over

Skewed Celexa Study

 

 

 

Researchers Chastise Am J Psychiatry Over Skewed Celexa Study

 

Thu, 31 Mar 2005

 

 

 

http://www.ahrp.org/infomail/05/03/31.php

 

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.

 

======================

======================

 

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]