January 9, 2004
Paxil, Zoloft and Effexor are unsafe for children and adults
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
http://www.ahrp.org/
Contact: Vera Hassner
Sharav
Tel: 212-595-8974
e-mail: veracare@ahrp.org
FYI
At the
time that two manufacturers publicly acknowledged that their antidepressant
drugs (Paxil / Seroxat and Effexor) were unsafe, and ineffective for children,
the Journal of the American Medical Association (JAMA) published a clinical
trial report by the "Sertraline Pediatric Study Group" (i.e., Pfizer sponsored
investigators) claiming: "Sertraline [Zoloft] -treated patients experienced
statistically significantly greater improvement than placebo." See: http://www.ahrp.org/infomail/03/10/01a.html
The press uncritically swallowed those unsubstantiated claims, and proceeded
to mislead the public and treating physicians.
The disputed 'favorable
findings' claimed for Zoloft are challenged in letters published in the current
issue of JAMA (Jan 1, 2004). Five psychiatrists from the US and UK question the
validity of those claims and indeed, question the integrity of the method by
which those claims were obtained. In essence, the claimed 'positive' findings
were made by EXCLUDING noncompleters and nonresponders.
The British
authority, once alerted to how the methods by which drug manufacturers have
manipulated clinical trials to show 'positive findings,' took action to protect
children from the hazards of SSRIS. FDA, in sharp contrast, is fiddling while
children are needlessly being made to suffer. FDA is tinkering with the clinical
trial data, attempting to airbrush the evidence so as to neutralize the
negative.
Furthermore, FDA has refused to allow expert scientific testimony that updates the findings of the information received by the British Medicines and Healthcare Regulatory Agency.
As a result, American children prescribed SSRIS are at risk of developing
drug-induced mania, violence and suicidal behavior.
The JAMA
letters:
Drs. Maju, Manu, and Joanne Mathews from Dexel University, East Surrey
Hospital and West Suffolk Eng (respectively) noted: "[T]he authors excluded some
randomized patients from their analyses. According to the principle of mention
to treat (ITT), the authors could have assigned the 'worst-case outcome' to the
excluded patients."
Dr. David Price from Colorado Permanente Medical
Group questions the rationale for conducting 2 separate trials--that introduce
additional variability--rather than 1 large trial. He questions the rationale
for lowering the bar on the 'improvement' standard--from commonly used 50%
response rate to 40% which, as Dr. Price points out, "This seems to create a
bias for a favorable result for sertraline. And Dr. Price faults the authors for
using a questionable "last observation-carried-over method rather than the more
conservative analysis considering noncompleters
and
nonresponders."
Dr. Antal E. Solyom from the University of
Virginia questions the scientific and ethical justification of using children in
rigid double-blind controlled clinical trials inasmuch as thr pitfalls of
placebo-controlled trials in antidepressants have been acknowledged even by Dr.
David Kupfer, former president of the American College of
Neuropsychopharmacologogists. Dr. Solyom points out that "individual case
study designs that enroll patients with severe depression from which suicidal
patients are not excluded may be more appropriate.
Finally, Dr. Soyom
notes: "Most troubling is the uncritical duplication of all of these trials in
the even more heterogeneous and vulnerable child and adolescent psychiatric
populations. It would be more constructive to focus on the 40% of
depressed adolescents who do not respond to the initial trial and antidepressant
treatment."
Glen Spilmans a statistician from the department of
psychiatry, Indiana University, notes that the absence of evidence about the
validity of the two scales used to measure an improvement in outcome. "Because
of the small magnitude of difference between groups [on Zoloft compared to those
on placebo] and the failure to truly assess the degree to which the double blind
may have been penetrated, this trial suggests that sertraline shows
little to no perceptible benefit compared with placebo in the treatment of
depressed youth."
An unpublished letter by Dr. Jan Garland, Clinical
Professor, Psychiatry University of British Columbia and Clinical Head, Mood and
Anxiety Disorders Clinic BC's Children's Hospital appears below.
Letter
to Editor, JAMA:
As one of the many investigators in various sites who
was involved in the Pfizer sertraline pediatric depression trials published in
JAMA in August, 2003 (1), I was very concerned for a number of reasons about the
data analysis reported in this paper. The most striking feature was the pooling
of two trials which is not the orthodox way of handling trial data. The pooled
data, a sample size of 376 patients, showed a marginal superiority of medication
which is not likely to be clinically meaningful in terms of risk/benefit
balance. On selected improvement measures, only 10% more patients improved on
sertraline than on placebo, remission rates were not different, and there were
more discontinuations in the sertraline group due to adverse effects including
suicidality and aggression. Based on this report, it appeared very likely that
the individual trials were in fact negative, but this possibility was not
discussed by the authors. By pooling the data, what might have been reported as
two negative trials was instead converted into one marginally positive trial
with the conclusion that "sertraline is an effective and well-tolerated
short-term treatment for children and adolescents with MDD".
New
information about these trials is now available. The recent review of pediatric
antidepressant trials by the British regulatory agency includes the appropriate
separate analysis of these two trials, and the summary results are now in the
public domain (2). >From this analysis, it is clear that the two individual
trials each of a good size (almost 190 patients) did not demonstrate the
effectiveness of sertraline in treating major depressive disorder in children
and adolescents. Hence, the correct conclusion from the data reported by Wagner
et al should be that "sertraline is ineffective when compared to placebo and is
associated with increased adverse effects".
E. Jane Garland,
M.D.
1. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, et al.
Efficacy of Sertraline in the Treatment of Children and Adolescents With Major
Depressive Disorder: Two Randomized Controlled Trials
JAMA.
2003;290:1033-1041.
2. Committee on Safety of Medicines.
Medicines and Health Care Products Regulatory Agency. Selective Serotonin
Reuptake Inhibitors (SSRIs): overview of regulatory status and CSM advice
relating to major depressive disorder (MDD) in children and adolescents: Summary
of clinical trials