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Misapplying Population Trends - No Competing Interests?
Posted by plosmedicine on 30 Mar 2009 at 23:59 GMT
Author: Vera Hassner Sharav
Position: No occupation was given
Institution: ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Submitted Date: September 04, 2006
Published Date: September 5, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.
The authors of "Modeling of the Temporal Patterns of Fluoxetine Prescriptions and Suicide Rates in the United States" claim that Prozac "may have contributed to the prevention of as many as 33,600 suicides since the drug was introduced" and they declare that "no competing interests exist."  Both claims are refuted below.
The scientific evidence--from controlled clinical trials conducted by manufacturers of Prozac and the other marketed selective serotonin reuptake inhibitors (SSRIs)--supports a positive relationship between treatment with SSRI antidepressants and attempted and completed suicide.  Several recent re-analyses of the data from these trials, confirmed the risk, and have resulted in revisions of these drugs' warning labels.  Antidepressants now carry highlighted and Black Box warnings about an increased risk of treatment-related suicidality in children and adults.  Indeed, the most recent analysis of the adult paroxetine (Paxil) controlled trial data by GlaxoSmithKline acknowledged a six-fold increased risk for patients taking the drug compared to placebo.  Randomized trials are widely considered to constitute the highest level of scientific evidence and are the only evidence sufficient to obtain regulatory approval.
The drugs have consistently caused a clinically significant treatment emergent cluster of frequently occurring severe adverse psychiatric and behavioral effects now disclosed in the drugs' label: "The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric." In pediatric trials a twofold increased risk of suicidal acts--1 in 50--is now acknowledged on the drugs' label. "Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms." 
Suicide--or rather the marketing of suicide prevention--through screening and increased prescriptions of antidepressants--has become a Big Business --despite a complete lack of evidence that screening and/or antidepressants prevent suicide.  Those who profit from expanded use of mental health interventions--drug manufacturers and those whom they support--however, are threatened by public disclosure that the most widely prescribed antidepressants have triggered suicide and violence in some patients. The conundrum for industry and psychiatry is the lack scientific evidence to support the safety and clinical effectiveness of these drugs: First, the exceedingly high placebo effect (80%) demonstrated in controlled clinical trial data submitted to the FDA   shows the drugs don't offer a clinically significant benefit greater than placebo--thereby belying the claimed benefit attributed to them.
The desperation induced by mounting evidence has led influential psychiatrists whose career and financial interests are invested in maintaining the primacy of drug centered treatment regimens to turn to ecologic data--the lowest rung on the evidentiary ladder.   Indeed the authors acknowledge that FDA's required "black box warning" on antidepressant labels made it "timely to examine temporal trends in suicide and to study the potential impact of antidepressants on mortality caused by self-harm."  They are attempting to overturn the scientifically solid findings from randomized controlled trials with ecologic correlations that are not a valid substitute for randomized, replicated findings. However, though their scientific methods may be questionable, their widely publicized invalid conclusions support the drugs benefit as a suicide prevention salvo.
Another epidemiological study in the Journal of the American Medical Association  compared U.S. suicide statistics during a 10 year period (between 1990-1992 and 2001-2002). The finding: "Despite a dramatic increase in treatment, no significant decrease occurred in suicidal thoughts, plans, gestures, or attempts in the United States during the 1990s." The authors note: "There are approximately 3000 suicide ideators per 100 000 population and 500 suicide attempters per 100 000 population in the United States each year compared with only 14 suicide completers per 100 000 population."
Since increased treatment did not reduce suicide thoughts, gestures and attempts--symptoms which are far more prevalent than completed suicides--there is no justification for attributing the 6% drop in completed suicides during that 10 year period to the increase in treatment. Indeed, if correlation proved causality, the adverse effects of antidepressants would be proved by Utah, which has one of the highest suicide rates and also the highest sales of antidepressants.
Nevertheless, the authors (UCLA psychiatrists, led by Dr. Julio Licinio), make precisely that claim: "Our findings strongly suggest that these individuals who committed suicide were not reacting to their SSRI medication. They actually killed themselves due to untreated depression. " Notwithstanding the authors' acknowledgement: "causal associations cannot be established with this type of ecologic data, " the conclusion they drew provided Eli Lilly with a widely publicized marketing pitch: "for the entire US population, a direct, inverse correlation exists between suicide rates and fluoxetine, and that treatment with fluoxetine (or possibly all SSRIs) for depression and other mood disorders may have contributed to the prevention of as many as 33,600 suicides since the drug was introduced". That pronouncement was clearly intended to draw wide media attention. In that regard, it succeeded: the "good news" published a year apart in two peer reviewed journals,   by academic authors who declared no competing interests, was broadcast far and wide. 
In media interviews Dr. Licinio claimed: "My concern is that when people don't get the treatment they need, the suicide rate is going to go up again" .The circularity of his reasoning is not merely wrong, it is very dangerous. If antidepressants cause rather than prevent suicide--as the randomized trials show--then administering drugs whose consequences can be dire as "the treatment they need" is diabolical. What if, as the controlled data suggests, exposure to the new antidepressants INCREASES the suicide risk, how many thousands of preventable suicides occurred as a result of the advice of psychiatrists such as Dr. Licinio?
A senior medical reporter, Lidia Wasowicz,  of United Press International, seriously questioned the validity of the claimed relationship between use of antidepressant drugs and fluctuating suicide rates. She showed how different studies assessing similar uncontrolled population data have led investigators to make various speculative assessments and draw inconsistent conclusions. And when pressed by Wasowicz about the scientifically inaccurate claim suggesting a causal connection, Dr. Licinio acknowledged: "you can't say suicide rates went down because of antidepressants." But that is exactly what the doctor said. So if the doctor admits to a reporter, "you can't say suicide rates went down because of antidepressants" how can Prozac "have contributed to the prevention of as many as 33,600 suicides since the drug was introduced? "Dr. Julio Licinio has been the UCLA coordinator for the International Society of Pharmacogenomics (ISP) and editor of its journal, Pharmacogenomics. Notwithstanding the ISP website claim: "The International Society of Pharmacogenomics is an independent body without any affiliation to institutions, and without direct institutional/administrative ties to any companies," ISP listed the following current sponsors in 2003: Eli Lilly, Novartis, Pfizer,and Wyeth--all of which produce psychotropic drugs. http://126.96.36.199/is...
In 2003, following ISP first meeting (October 2002, Paris), Dr. Licinio informed ISP members in a Newsletter how he actively sought funding for the ISP: "I was able to obtain annual company sponsorships from GSK (which gave us $15,000 for the period 2002-2005 thanks to the generosity of Allen Roses), Eli Lilly (which gave us $5,000 for 2002) and Pfizer (which will give us $7,500 for 2003). Note that in $5,000 I requested annual unrestricted contributions from industry for $5,000 per year. I increased those amounts to be $7,500. This increase was due to the fact that as I look into the details of putting this meeting together, I see the actual costs of things, and the need to secure more funds. Also note that ISP now offers companies two types of corporate memberships: Founding Regular ($7,500 per year) and Founding Gold ($15,000 per year)." http://www.pharmacogenomi...
According to RxPG News  Dr. Licinio, who moved from UCLA to The University of Miami Leonard M. Miller School of Medicine, "accepted an offer to consult for Eli Lilly after this research was accepted for publication."
1. Michael S. Milane, Marc A. Suchard, Ma-Li Wong, Julio Licinio. Modeling of the Temporal Patterns of Fluoxetine Prescriptions and Suicide Rates in the United States. PLoS Medicine, June 2006. http://dx.doi.org/10.1371...
2. Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Arch Gen Psychiatry 2000;57:311-7.
3. Laughren TP. The scientific and ethical basis for placebocontrolled trials in depression and schizophrenia: an FDA perspective.Eur Psychiatry 2001;16:418-23.
4. Healy D, Whitaker C. Antidepressants and suicide; risk-benefit conundrums. J Psychiatry Neurosci 2003;28:331-9.
5. Khan A, Khan S, Kolt S, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790-2.
6. Hammad TA, Mosholder A, Boehm G, Racoosin JA, Laughren T. Incidence of suicides in randomized controlled trials of patients with major depressive disorder. Pharmacoepidemiol Drug Safety 2003;12(suppl 1):S156.
7. FDA. Antidepressant Use in Children, Adolescents, and Adults: Documents of current and background information. March 22, 2005. http://www.fda.gov/cder/d...
8. FDA. Template. Class Suicidality Labeling Language for Antidepressants. Revised 1/26/2005. http://www.fda.gov/CDER/D... ; FDA Reviews Data for Antidepressant Use in Adults, July 1, 2005: http://www.fda.gov/bbs/to....
9. GlaxoSmithKline. Important prescribing information. Letter to healthcare professionals, May 2006. www.gsk.com/media/paroxet...
10. TeenScreen http://www.ahrp.org/cms/c... ; Screening for Mental Health (SMH) http://www.ahrp.org/cms/c... ; JED Foundation, a pharmaceutical industry front, operates as a suicide prevention program on college campuses, see: http://www.ahrp.org/cms/c...
11. U.S. Preventive Services Task Force Ratings: Strength of Recommendations and Quality of Evidence. Guide to Clinical Preventive Services, Third Edition: Periodic Updates, 2000-2003. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clini...
12. Irving Kirsch, Thomas J. Moore, Alan Scoboria, and Sarah S. Nicholls The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration, Prevention and Treatment Volume Five July 15, 2002. Target article with 9 commentaries.
13. Joanna Moncrieff and Irving Kirsch Efficacy of Antidepressants in Adults, BMJ, 2005;331:155-157.
14. 12. Licinio and Ma-Li Wong, Nature Reviews Drug Discovery, February 2005; vol 4: pp 165-171.
15. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Archives of General Psychiatry. 2003 Oct;60(10):978-82, p. 979.
16. Trends in Suicide Ideation, Plans, Gestures, and Attempts in the United States, 1990-1992 to 2001-2003 Ronald C. Kessler, PhD, Patricia Berglund, MBA, Guilherme Borges, PhD, Matthew Nock, PhD, Philip S. Wang, MD, DrPH. JAMA. 2005;293:2487-2495
17. UCLA Press Release: New UCLA Study Disputes Antidepressant/Suicide Link; Scientists Fear Rise in Deaths From Untreated Depression, February 2, 2005: http://newsroom.ucla.edu/... WebMd, Suicide Rate Down Since Prozac, Feb. 2, 2005 http://www.cbsnews.com/st...
18. Sample press coverage of PLoS article: CBS News. Suicide Rate Down Since Prozac Feb. 2, 2005; Maggie Fox Depression drug suicide link challenged. Reuters Wednesday, 14 June 2006 http://www.abc.net.au/sci... US suicide rate drops as antidepressant prescriptions rise Jun 14, 2006, Reviewed by: Dr. Ankush Vidyarthi, RXPG News http://www.rxpgnews.com/m... Jim Rosack Suicide Rates Began to Drop With Advent of SSRIs. Psychiatric News April 1, 2005 Volume 40 Number 7, p. 29; 123. An Extensive Database Search on Antidepressants and Suicide. Science Today, University of California radio, August 1,2006 http://www.ucop.edu/scien...
19. LIDIA WASOWICZ Ped Med: Can Rx's cut suicide risk? United Press International. August 23, 2006: http://www.upi.com/Consum...
I have given testimony before national advisory panels, congressional committees, and AHRP has filed complaints with government agencies objecting to the use of non-consensual human beings as subjects in research. We oppose the use of trauma patients in artificial blood experiments; pesticide experiments targeting toddlers; psychotropic drug experiments on children; the use of prisoners in drug experiments; psychiatrists' use of patients with schizophrenia in chemical "challenge" experiments that induce psychosis in order to study the pathophysiology of schizophrenia. We have submitted an amicus brief against exposure of toddlers to lead paint to study the rising lead level in their blood.
All of these cases and others are documented on the AHRP website at: www.ahrp.org
AHRP has, so far, relied upon contributions from the public. We do not take money from the pharmaceutical industry or government--thus, we maintain absolute independence.