A Lawyer's Response to the New York Times - Re: Antidepressant Dilemma

December 7, 2004

Friends,

This is the response that Barth-Menzies sent to Mahler and

the New York Times. It's my understanding that the Times did not publish

it. So, please help me get this into circulation!

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

In Response to the November 21, 2004 New York Times Magazine article:

" The Antidepressant Dilemma, " by Mahler

Properly researched, this article would have been entitled " The

Antidepressant Fraud: No Better Than Placebo. " However, the November 21,

2004 New York Times Magazine cover was the first clue that the article

inside was inadequately researched. The cover stated: " Warning:

Antidepressants increase the risk of suicidal thinking and behavior in

children and adolescents with major depressive and psychiatric disorder.

Caution: The very same antidepressants are helping thousands of kids who

might think of killing themselves - and now doctors are nervous about

writing prescriptions. "

In fact, only 3 out of 15 trials examined by UK regulators and the FDA,

which led to suicide warnings, demonstrated any efficacy in children and

adolescents. UK regulators were clear that their summer 2003 ban of the

antidepressants for use in children and adolescents was due in part (in

addition to the suicide risk) to the fact that the drugs had not been shown

to be effective. FDA itself has stated that " effectiveness has not been

demonstrated. " Notwithstanding, the article quotes Graham Emslie, one of

the authors of the " TADs " (Treatment for Adolescents With Depression Study)

Prozac study as stating: " This study should put to rest doubt about whether

these drugs work in teenagers with severe depression. "

On the other hand, one of the FDA advisory committee experts evaluating the

antidepressant suicide connection more recently pointed out:

I think we have to come back to the issue of efficacy. We have I think very

strong evidence of harm and really not very good evidence of efficacy, and

although I know many practitioners are convinced that these drugs work, if

you look very closely at the [Prozac] trial, just as an example, at the

Childhood Depression Rating Scale, the improvement with placebo was 19

points, and the improvement with the drug was 23.4 points. You bring

people in, you start a medication, and you see an improvement, you are very,

very likely to believe that the drug is effective, and the reason why we do

randomized, double-blind trials is because personal experience, however

compelling, is not a reliable way to tell whether drugs work. In the study

where they worked, in the [Prozac study], the improvement over placebo was

really very, very small, and I would say not detectable by a clinician

treating individual patients. ...

The chairman of the FDA advisory panel seconded these views, stating " there

is a dearth of data on efficacy. " The advisory panelist's point was further

articulated when he wrote: " It is easy to see why the personal experience of

clinicians and patients would lead them to believe the drug to be effective,

since they would have no way of knowing that more than 85 percent of the

benefit they observed would also have occurred with placebo. " In fact, the

lack of proof of effectiveness was a consistent theme throughout both FDA

advisory panel meetings, in February and September 2004, and the

Congressional hearings that took place in September 2004 concerning the

FDA's handling of the antidepressant suicide issue.

Any perception that the drugs work is likely reinforced by the

pharmaceutical influenced medical literature. A good illustration of this

point is a September 1, 2003 published study conducted by Dr. Dineen

Wagner, et al., which proclaimed that " Zoloft appears to work for children,

with no major side effects. " The study was highly publicized; however, its

conclusions received considerable criticism through letters to the journal

editor. One doctor wrote: " The relative benefit increase of sertraline

[Zoloft] over placebo . . . suggests that there might in fact be no benefit

from sertraline for these patients. " Another doctor stated: " [Zoloft]

barely achieved a statistically significant improvement over placebo . . .

I would appreciate more information about the degree of influence the

sponsor [Pfizer] had over the presentation of the data and interpretation of

the results. . . . Given the safety and efficacy precautions recently raised

about [Paxil], another selective serotonin reuptake inhibitor with a similar

mechanism of action (at least in adults), I believe that more convincing

data are needed before [Zoloft] can be recommended as first-line treatment

for major depression in children and adolescents. " Another doctor

complained that Dr. Wagner's claims about the study " reach[] well beyond the

trial's results " and concluded " this trial suggests that [Zoloft] shows

little to no perceptible benefit compared with placebo in the treatment of

depressed youths. " It was recently learned that the Wagner study was, in

fact, ghostwritten by a Pfizer employee.

The issue of " lack of efficacy " should come as no surprise. In fact, the

FDA expressed internal concern over the lack of efficacy, related to adults,

as early as 1991. According to an internal FDA memo dated August 26, 1991,

Dr. Leber, formerly of the FDA, stated: " In recommending [approval], I

have considered the fact that the evidence marshaled to support [Zoloft's]

efficacy as an antidepressant is not as consistent or robust as one might

prefer it to be. "

A later FDA memo, dated December 24, 1991, also from Dr. Leber states:

" everal foreign national drug regulatory authorities ... presumably

provided with the same body of information [as the FDA], have not yet been

willing to allow [Zoloft's] marketing in their respective countries ...

[because of] what may be considered the 'lack of robustness' of the clinical

evidence supporting efficacy in the treatment of depression. " Dr. Leber

concluded: " Approval [of Zoloft] may ... for the reasons enumerated above,

come under attack by constituencies that do not believe the agency is as

demanding as it ought to be in regard to its standards for establishing the

efficacy of antidepressant drug products. "

Pfizer's difficulty in proving efficacy to foreign regulators is further

demonstrated through documents obtained in litigation. These documents

show, for instance, that Pfizer was surprised in 1991 that the FDA had not

questioned it about the lack of efficacy. The memo states: " I find it odd

that FDA did not at all questioning [sic] efficacy and there are significant

questions raised by several European companies. " Another memo states " we

have serious concerns regarding the approval of sertaline in key European

countries. "

Yet another 1991 memo states that Zoloft had " received an unfavorable review

in a number of countries. The common key issue is that regulators are not

convinced of sertraline efficacy versus placebo. " In response, Pfizer

withdrew the applications in those countries and planned studies that would

be sure to succeed. The memo goes on to state that the " lack of approval

[in Germany and France] will have devastating consequences on the commercial

potential of sertraline internationally. " What Pfizer needed was a

" strongly positive, placebo controlled study ... to ensure regulatory

success. " The Pfizer memo concludes: " To enhance the probability of success

in a timely manner, we recommend that the study: ... be designed to enhance

the probability of success. ... "

In fact, according to " The Emperor's New Drugs: An Analysis of

Antidepressant Medication Data Submitted to the U.S. Food and Drug

Administration, " which analyzed the efficacy data submitted to the FDA for

approval of 6 of the most widely prescribed antidepressants approved between

1987 and 1999, 75 percent of the response to antidepressants is duplicated

by placebo. FDA approval of these medications implies that the data were

strong enough and reliable enough to warrant approval. However, the authors

point out: " These data were the basis on which the medications were approved

by the FDA. If [the data] are suspect, then perhaps the decision to approve

the medications should be reconsidered. " The authors later wrote: " The

small difference between the drug response and the placebo response has been

a 'dirty little secret' [Hollon, DeRubeis, Shelton & Weiss, 2002), known to

researchers who conduct clinical trials, FDA reviewers, and a small group of

critics who analyzed the published data and reached conclusions similar to

ours (e.g. Greenberg & Fisher, 1989). It was not known to the general

public, depressed patients, or even their physicians. [Footnote omitted.]

We are pleased that our effort facilitates dissemination of this

information. " Antidepressants and Placebos: Secrets, Revelations, and

Unanswered Questions by Kirsch, , et al., Prevention & Treatment,

Volume 5, Article 33, posted July 15, 2002.

Not addressed in " The Antidepressant Dilemma " is the degree to which the

drug companies influence what doctors and the public think about these

drugs. As a case in point, the editors of The Lancet wrote a scathing

editorial in their April 2004 edition pointing out that: " The story of

research into selective reuptake inhibitor (SSRI) use in childhood

depression is one of confusion, manipulation, and institutional failure. "

The editors concluded that " these failings are a disaster " and suggested

that " [c]hanges are required at every level of the global health-care

infrastructure. " The underlying study that sparked this strongly-worded

editorial, also published in the April 2004 edition of The Lancet, found

that, after a systematic review of published versus unpublished

antidepressant clinical trial data involving children and adolescents, the

published data alone show a favorable profile while hidden and

unpublished data show the risk/benefit profile as unfavorable.

Another article, also published in April 2004, in the British Medical

Journal, similarly concluded: " [Clinical] investigators' conclusions on the

efficacy of newer antidepressants in childhood depression have exaggerated

their benefits " ; " Adverse effects have been downplayed " ; " Antidepressant

drugs cannot confidently be recommended as a treatment option for childhood

depression, " and; " A more critical approach to ensuring the validity of

published data is needed. "

There ought not be fear of frightening parents whose children could benefit

from Zoloft and similar drugs since there is scant evidence of benefit to

begin with. Nor is there proof that the drugs prevent suicide. In fact, in

a study of clinical trial data for drugs approved by the FDA between 1985

and 2000, all the selective serotonin reuptake inhibitors were examined.

The Psychiatric Times reported: " One striking finding was the elevated rate

of completed suicides for patients during these trials. Compared with the

rate of 11/100,000 persons per year for the population at large, the rates

of completed suicide were ... 718 in antidepressant trials. " According to

the author of the study: " This was particularly surprising in light of the

attempt, in most clinical trials, to exclude patients who are actively

suicidal. ... In the case of trials for depression and anxiety disorders,

suicide rates were in fact higher among those who received the

investigational drug than placebo. " Another recent study by Herman Van

Praag published in " World Journal of Biological Psychiatry " titled " A

Stubborn Behaviour: the Failure of Antidepressants to Reduce Suicide

Rates, " points out that despite the increased use of antidepressants

" completed suicide has remained quite stable " and " suicide attempts even

seem[] to have increased. " A study published in the July 2004 British

Medical Journal similarly concluded: " There is no strong evidence that

increases in antidepressant prescribing lie behind recent reductions in

population suicides. "

With respect to the evidence concerning the suicide risk in children and

adolescents, one of the FDA experts on the advisory panel, Dr. Newman

stated that the FDA's review of the clinical trials was " striking " and " such

a dramatic result would be expected to occur by chance only 1 time in

20,000. " Dr. Newman observed that " some FDA staff and committee members

expressed reservations about the data used for this analysis. For example,

there was a relatively small number of events, the trials had not been

designed to evaluate suicidality, and the methods of ascertainment and

classification of the events in the various trials were not uniform. " Dr.

Newman pointed out that " these concerns only made the results more

compelling. " He explained that " nadequate sample size and

misclassification of outcomes make it more - not less - difficult to detect

differences between groups in randomized, blinded trials. The fact that an

association emerged from the meta-analysis ... for an outcome that the

sponsors of the trials were not looking for, and presumably did not wish to

find, was quite convincing. "

Given the above, coming to the conclusion that there have been

" comparatively few failures " in those taking the drugs and that " lives have

been saved " by these drugs is insupportable. The bases for making such

statements appear to be the " anecdotal " stories claiming that " a number of

teenagers (and their parents) lives have been saved by antidepressants, "

provided to the New York Times by the heavily pharmaceutical company-funded

front organization, NAMI

Finally, the article failed to disclose the fact that Dr. Mann, who is

quoted as stating: " It would be ludicrous to think that antidepressants

could actually contribute to suicide in the United States in any kind of

significant way " has been a handsomely paid litigation expert witness for

at least three antidepressant manufacturers (Lilly, Pfizer, and GSK, all

makers of the antidepressants under question). The article also makes no

mention of Dr. Mann's testimony in the Tobin v. Kline Beecham trial,

which resulted in a 6 million dollar verdict for the plaintiff: " I still

think that akathisia has the potential when it is severe of contributing to

suicidality and aggression. " (The common mechanism through which much of

the violent and suicidal behavior stems is a drug-induced neurological

phenomenon called akathisia. The manifestations are extreme internal

restlessness, agitation and inner turmoil. The outward signs can be an

inability to sit still and pacing. Dr. Temple of the FDA told

reporters following the February 2, 2004 advisory committee meeting: " There

isn't any doubt that these drugs cause akathisia. That's not in doubt. " )

The article laments that " [n]ot prescribing these drugs may very well pose a

greater threat than prescribing them. " With the increased risk of suicidal

behavior, the lack of demonstrated efficacy, and no evidence that they

prevent suicide, how can one justify prescribing the drugs except in the

most extreme cases? This is not to mention the impact these drugs have on

the developing brain of a child or adolescent into young adulthood when the

brain is believed to end its development. In fact, according to a recent

study out of Columbia University, antidepressants may change " crucial phases

of brain development that might, paradoxically, predispose [children] to

depression and anxiety disorders later in life. " One of the study's

researchers warned that the widespread use of SSRIs is a " large scale

experiment with our nation's youth. I think that we don't really know

necessarily what the long-term effects are. "

The FDA's requested black box warning is an appropriate step in ensuring

public safety. How anyone can argue with providing information that

accurately reflects the benefits versus risks of these drugs is a mystery to

me. ly, when we heard that New York Times Magazine was soliciting

antidepressant success stories from NAMI, coupled with the large two-page

Zoloft advertisement placed in the magazine by Pfizer just weeks before this

article, we were rightfully concerned about the slant the article would

take. The New York Times has published some well researched and important

articles on the antidepressant suicide issue as well as other related

topics. Perhaps, in this instance, the author was misguided by sources with

close ties to the pharmaceutical industry.

Barth Menzies

Baum Hedlund

December 1, 2004

Barth Menzies is a partner in the national law firm , Baum Hedlund,

located in Los Angeles, which has been involved in pharmaceutical litigation

since the mid 1980s. She represents dozens of families including those whose

children have committed suicide or attempted suicide on one of the SSRI

antidepressants and is lead counsel of the Plaintiffs' Steering Committee in

charge of the multi-district litigation re Paxil Products Liability

Litigation and represents thousands of people who have suffered from Paxil

withdrawal/dependence. Ms. Barth Menzies testified twice this year before

the FDA's Psychopharmacologic Drugs and Pediatric Advisory Committee and

before the California State Senate regarding the risk of suicide in children

and adolescents taking antidepressants.

December 7, 2004