Trial Analyst Finds Embarassing Inconsistencies in NIMH Flawed Safety Study

In the wake of the extraordinary acknowledgement this month by
GlaxoSmithKline that the clinical trial evidence shows that not only
children and adolescents are at increased risk of suicidal behavior if they
take its antidepressant, Paroxetine / Paxil (or any other "new generation"
antidepressant). Adults too are at increased risk of suicide if they take
Paxil–and that risk is six-fold compared to those given a placebo.

Our colleague in the UK, Charles Medawar, of Social Audit,  has been closely
monitoring British public officials, drug company executives and leading
academic psychiatrists–almost all of who have a financial / professional
stake in protecting the reputation of SSRI antidepressants. His primary
focus has centered on the British cast of characters in this tedious and
insidious shadow play. GSK’s acknowledgement confirms that the
"authorities"–academic, government regulators and industry–have denied,
deceived, and concealed evidence of drug harm.

The claimed findings reported by Dr. Gregory Simon and colleagues about
their epidemiological study, Suicide Risk During Antidepressant Treatment,
in The American Journal of Psychiatry  163:41-47, January 2006, vol.
163.1.41 are unsupported by the data. Dr. Simon reported that there was no
increased suicide risk during the first week of treatment with an SSRI. This
claimed finding from a methodologically flawed, uncontrolled study was
widely disseminated in the major press–"Depression Drugs Safe, Beneficial,
Studies Say" (Washington Post).

Uncritical reporters transcribed the investigators’ claims without
understanding that these were scientifically invalid.  

However, Charles Medawar found egregious inconsistencies in that published
report.  He inquired, ever so politely, of  Dr. Simon, the lead author to
explain the inconsistencies.

The one sided correspondence reveals that academic psychiatrists have
misrepresented what the data actually shows.
"In agreement with Jick and colleagues (15), we found a significantly higher
risk of suicide attempts in the first week of antidepressant treatment than
in subsequent weeks".

In Dr. Simon’s initial response, he conceded: "Risk in week 1 was not higher
than in weeks 2, 3, and 4.  But risk in week 1 was higher than in subsequent
weeks (from week 5 onward)."

Uncorrected,  inconsistent statements of findings confuse many readers: they
serve to deflect from the very troubling evidence that these widely
prescribed drugs pose a serious threat to those who take them–especially
throughout the first month.   Such misleading reports served industry’s
interests. http://www.socialaudit.org.uk/6060521.htm#ANTIDEPRESSANTS

The release simultaneously of two "positive" SSRI studies–both financed by
the National Institute of Mental Health–seems suspiciously calculated. Our
suspicions are validated by the accompanying editorial in the Amer. J of
Psychiatry which questioned the need for the black box label warnings! (see
below).  It is especially troubling that that most of the uncritical media
had accepted the claimed "positive" results on faith. But the report–like
most of the scientific literature about SSRI antidepressant safety and
efficacy provides false and misleading information tailored to conceal that
these drugs induce suicides.

Since SSRIs have failed to demonstrate an antidepressant effect–given that
in controlled clinical trials placebo has matched and even outperformed
SSRIs–critics are beginning to wonder on what basis the FDA approved these
drugs as "antidepressants"?   This may be a case of misbranding. 

Simon G, et al http://ajp.psychiatryonline.org/cgi/content/abstract/163/1/41
See also: http://www.ahrp.org/cms/content/view/94/94/ ;
http://www.ahrp.org/cms/content/view/23/28/

 
Contact: Vera Hassner Sharav
veracare@ahrp.org
 
http://ajp.psychiatryonline.org/cgi/content/full/163/1/A34  
American Journal of Psychiatry 163:34A, January 2006
doi: 10.1176/appi.ajp.163.1.A34
C 2006 American Psychiatric Association
<http://ajp.psychiatryonline.org/misc/terms.shtml>

Is the FDA Warning About Antidepressants Wrong?

A 2004 advisory by the Food and Drug Administration (FDA) warns that
suicidal behavior may emerge after antidepressant treatment is begun. A
10-year population-based study by Simon et al. (p. 41
<http://ajp.psychiatryonline.org/cgi/lookup?lookupType=volpage&vol=163&fp=41
&view=short> ) indicates just the opposite. Among 65,103 patients in a large
health plan who filled prescriptions for antidepressants during 1992-2003,
the number of suicide attempts fell dramatically after antidepressant
treatment began and then declined more slowly. Completed suicides were few
and did not vary over the first 6 months of treatment. Adolescents had more
suicidal behavior than adults, but attempts decreased by over 60% in the
first month of treatment (see figure
<http://ajp.psychiatryonline.org/cgi/content/full/163/1/A34#F1> ).

The FDA advisory names 10 newer antidepressants, but in this study the
decrease in suicide attempts after treatment began was actually greater with
newer agents than with older antidepressants. Reconsideration of the FDA
warning thus seems warranted, as it discourages use of an effective
treatment.
~~~~~~~~~~~~
 
10 January 2006
Dear Dr. Simon,

I’m sorry to trouble you, but I wonder if you could help with this query
arising from your recent paper (Am J Psychiatry 163:34A, January 2006) on
Suicide Risk During Antidepressant Treatment.

In the text immediately preceding Figure 5, you and your colleagues noted
that: "Suicide attempts during the first month of treatment were relatively
evenly distributed throughout the month", (as Figure 5 shows)
.

However, in paragraph two of the Discussion, you also noted that, "In agreement with
Jick and colleagues (15), we found a significantly higher risk of suicide
attempts in the first week of antidepressant treatment than in subsequent
weeks".

Forgive if I’ve missed something, but I am unable to reconcile these two
statements on the basis of the data and interpretations presented. I would
be most grateful if you could clarify the position and put me right. Thank
you for your attention and I look forward to hearing from you.

Sincerely,
Charles Medawar
Social Audit Ltd

11 January 2006
You are right – our language should have been more clear.  Risk in week 1
was not higher than in weeks 2, 3, and 4.  But risk in week 1 was higher
than in subsequent weeks (from week 5 onward).

Greg Simon

11 January 2006
Dear Dr Simon,

Thank you for your mail, but your response raised further questions in my
mind. If, as you say, the risk of serious suicide attempts in week 1 was not
higher than in weeks 2, 3, and 4, it would seem to follow that the risks in
first four weeks of treatment were greater than in subsequent weeks (from
week 5 onward). Does this honestly justify the headline of your press
release, "Suicide risk does not increase when adults start using
antidepressants"?

Your paper also states that, "Among those treated with newer antidepressants
(Figure 6) . risk in the first month of treatment was not significantly
higher than in months 2 – 6". You attribute the increased risk in the first
month of treatment to treatment with older antidepressant medications – yet
you also acknowledge that, "older drugs were more often prescribed at the
beginning of the study period, (1992 to June 2003) when the rates of
hospitalization were generally higher".  

Your paper noted that when you correct for this anomaly, "the risk of
suicide death and the risk of suicide attempt were not significantly lower
in patients treated with new drugs". Why was this seemingly important
qualification not mentioned in your press release? "The study also found
that the risk of suicidal behavior after starting 10 newer antidepressant
medications is less than the risk posed by older medications".  

I appreciate and share your general concern that people should not be
deterred from taking antidepressants because they over-estimate the risk of
drug-induced suicidal behaviour – but with these qualifications.  

    1.  The headline in your press release, "Long-term, population-based
study challenges FDA advisory" seemed unwarranted. It failed to acknowledge
the critical lack of any placebo or control group in your study and, as you
acknowledge in the small print of the paper, "our data certainly do not
exclude the possibility that antidepressant drugs may precipitate increased
suicidal ideation or suicide attempts in a sub-group of vulnerable
individuals", and "an observational study such as this one can neither
clearly establish nor clearly refute a causal relationship between
antidepressant use and risk of suicide".

    2.    In a paper on "suicide risk during antidepressant treatment"
(emphasis added), it did not seem appropriate to use as a prominent major
benchmark the inevitably very high rate of suicidal behaviour that occurred
in the month before drug treatment. That measure appears to be a cockshy:
suicidality emerging before (and leading to) treatment clearly has nothing
to do with the propensity of antidepressants to cause suicidal behaviour.

    3.    In the UK, and probably also in the US, about two-thirds of all
prescriptions for SSRIs are for ‘mild depression’ (only 3% are for ‘severe’
depression), yet there is still no good evidence that SSRIs are more
effective than placebo in treating cases of ‘mild’ depression. When there
can be no expectation of significant benefit, what justification could there
be for prescribing these drugs for people with mild depression, exposing
them to significant risks? Did your study explore this, and do the
prescribing practices recommended in the Group Health Cooperative take
account of severity of depression?

I apologise in advance if my understandings seem to you limited or
incomplete but considering the available evidence, alongside the
interpretations and emphases added, I feel far from persuaded that no
evidence of risk = evidence of no risk. I would welcome your comments on
these further points.

Sincerely,
Charles Medawar

11 January 2006
Could you please identify more clearly the purpose of your questions.  Is
this merely for our own information and interest?

Greg Simon

11 January 2006
Dear Dr Simon,

Thanks for your mail. Well, I hope my questions don’t seem irrelevant, but
no, they weren’t simply for your own information and interest. You and your
colleagues published a paper that reached conclusions with important
implications, and I wrote to you because [a] I’ve been involved with and
interested in this topic for some time; [b] I wasn’t convinced that your
research supported the main conclusions of your paper, let alone some of the
interpretations and headlines arising from the GHC’s press release; and [c]
I thought you and your colleagues, having undertaken such a major study,
might welcome feedback and the opportunity to further explain and justify
your findings. Moreover, some of the points I raised – notably about the
limitations of SSRI and other antidepressants in the treatment of mild
depression – might perhaps be relevant to many GHC patients.

I have today posted to you a copy of Medicines out of Control? a study of
psychotropic and antidepressant drug prescribing; this will give you more
information about my interests and activities. You might also want to refer
to our website (www.socialaudit.org.uk); though it has been rather neglected
over the past six months, it still gets around 500,000 visitors/year. I
might of course want to consider reporting on the issues your paper deals
with and naturally it seemed sensible to first check with you about some of
the queries I have.

I hope that this deals satisfactorily with your query and look forward to
hearing from you.

Sincerely,
Charles Medawar
Social Audit Ltd

20 February 2006
Dear Dr Simon,

It’s been some weeks since I wrote, I hope explaining the reasons for the
questions I raised about your paper. I also sent you by airmail a copy of
the book, Medicines out of Control? and I hope this arrived safely.

I am now writing to ask if and when I might expect a reply from you. I would
appreciate your response on the points I raised.

Sincerely,
Charles Medawar

19 May 2006
Dear Dr Simon,

I’ve been meaning to write to you for some time and the recent publicity
about paroxetine provides a good opportunity to do so. This is to advise you
that I shall shortly be posting a note on the Social Audit website about our
correspondence earlier this year. You will see that the emphasis is on the
need for accountability, rather than lack of courtesy. That seemed
appropriate, given my views on the quality of your paper, and your
conviction that there was never any need to defend it.

Sincerely,
Charles Medawar

19 May 2006
Mr. Medawar –

I receive approximately 300 email messages a day.  I simply can’t respond at
length to them all.  If you would choose to raise questions about our paper,
the usual method in the scientific community would be to write a letter to
the editor of the journal publishing the paper.  Please feel free to do
that.  I have responded to all questions raised through public channels.  I
do not have the time to repond to all private correspondence.  If you value
accountability, then you would certainly want all correspondence (including
this message) to be public.

Greg Simon

21 May 2006
Dear Dr Simon,

Thank you for your mail. I appreciate that you would not be able to respond
at length to 300 emails/day, but suspect you need a good spam filter. Thank
you for telling me about protocol in the scientific community: I meant no
offence when writing to first check with you about some of the queries I had
about your paper, before writing to the journal concerned. However, I have
now done so: see attached. I shall of course include our correspondence when
I post to our website, and if you would like to comment further, of course
you have the opportunity to do so.

Sincerely,
Charles Medawar

 
Financcial Disclosure  See:
http://ajp.psychiatryonline.org/cgi/content/abstract/163/1/41

>From the Center for Health Studies, Group Health Cooperative; the Department
of Health Care Policy, Harvard Medical School, Boston; and the Department of
Psychiatry, Brigham and Women’s Hospital, Boston. Address correspondence and
reprint requests to Dr. Simon, Center for Health Studies, Group Health
Cooperative, 1730 Minor Ave., Number 1600, Seattle, WA 98101;
simon.g@ghc.org (e-mail). Supported by NIMH grants R01 MH-51338 and R01
MH-61941.

Dr. Simon was principal investigator with primary responsibility for study
design, data analysis, and drafting of this manuscript. Dr. Savarino was
responsible for data extraction and participated in data analysis, data
interpretation, and critical revision of this manuscript. Ms. Operskalski
and Dr. Wang participated in study design, data analysis, and critical
revision of the manuscript. During the past 3 years, Dr. Simon has received
a research grant from Eli Lilly and Co. (manufacturer of fluoxetine) and has
received consulting fees for contributions to a patient education program
developed by Pfizer Pharmaceuticals (manufacturer of sertraline).
 Dr. Wang has provided expert testimony regarding paroxetine and risk of
suicide.
Dr. Savarino and Ms. Operskalski have no relevant financial interests to
disclose.
Dr. Simon had full access to all data used for this study and had final
responsibility for the decision to submit this manuscript.
The funder (NIMH) had no role in study design, data collection, data
analysis and interpretation, or preparation of this report.