The September 27, 2011, edition of Reason Magazine reported on a “new working paper” from the National Bureau of Economic Research (NBER), suggesting that the FDA’s 2005 black box warnings concerning antidepressants and the risk of suicidal behavior in adolescents and teenagers caused a dramatic drop in antidepressant use and, consequently, a rise in teen suicides, not to mention a host of other maladies such as declining grades, binge drinking, use of illegal drugs, fighting, etc. Attributing any of these “consequences” to a lack of antidepressant use is erroneous (to say the least) for a number of reasons.
The article, written by Katherine Mangu-Ward, the managing editor for Reason Magazine, recycles unwarranted conclusions by pharma-funded academics which have been debunked by other scientists and by the authors themselves.
The view that lack of antidepressant use has contributed to an increase in youth suicides is an old argument put forward by pharma-funded “key opinion leaders” (or “KOLs”) such as Gibbons, Keller, Nemeroff, etc. (who figure prominently in the NBER’s working paper). [ i ]
A. Antidepressants Are Not Effective In Treating Adolescent Depression
The most glaring problem with NBER’s working paper is its presumption that antidepressants are effective in treating adolescent depression. Yet, antidepressants as a class have not been shown in clinical trials to be effective at treating adolescent depression [ ii ] Indeed, of the 36 antidepressants subject to the black-box warning, only two antidepressants – Prozac and Lexapro – have been approved for adolescent [ iii ] The other 34 antidepressants, which form the bulk of the market, have failed to show efficacy. NBER’s working paper fails to make any mention of this important fact and simply presumes that all antidepressants are effective in treating adolescent depression.
Exaggerated expectations of the efficacy of antidepressants have been fueled in part by selective publication of positive studies while negative studies remain hidden or misreported. Many failed clinical trials are never made public because they undermine the drug’s commercial profitability. For example, GlaxoSmithKline (“GSK”), the manufacturer of Paxil, conducted various clinical trials, all of which showed that Paxil was not effective at treating adolescent depression. When GSK became aware of the negative results, it made a concrete decision to conceal the information and, in an October 1998 internal memo (uncovered during litigation), an executive concluded “it would be commercially unacceptable to include a statement that efficacy has not been demonstrated as this would undermine the profile of [Paxil]. [ iv ] Years later, a Pennsylvania federal judge overseeing a case involving the suicide of a 16-year old boy cited the internal memo and other GSK documents concluding that the evidence showed that “GSK knew of the risk of pediatric suicidality as of 1998” and that “GSK documents suggest that [GSK] acted with a wanton and willful disregard for the safety of its consumers.”
Unfortunately, the concealment of negative clinical trial data is not unique to GSK. Rather, pharmaceutical manufacturers have for decades, through selective and biased publication of clinical trial data, managed to dupe the medical community into believing the efficacy and safety of their respective elixirs. As Jon Jureidini, a professor of psychiatry at Adelaide University and colleagues pointed out, “efficacy of newer antidepressants in childhood depression have exaggerated their benefits”; “adverse effects have been downplayed,” and; “antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression. [ v ]
Eric H. Turner, an assistant professor in the psychiatry department at the Oregon Health and Science University and colleagues, in their analysis of antidepressant clinical trials, found “bias toward the publication of positive results” and “studies that were not positive … were often published in a way that conveyed a positive outcome.” Turner concluded that “the efficacy of this drug class is less than would be gleaned from an examination of the published literature alone,” which “can lead doctors to make inappropriate prescribing decisions that may not be in the best interest of their patients and, thus, the public health.”
B. NBER’s Contentions Regarding the Level of Prescriptions and Suicides Are Factually Flawed
Moving past the efficacy issue, NBER’s contention that youth suicides have increased following the advent of the black-box warning is also factually flawed. The Reason article cites NBER’s fallacious working paper for the proposition that “Youth suicides had been flat or declining among 10-19-year-olds in the years preceding the warnings, but in 2004, 10-19-year-old girls experienced a sharp increase in suicides, of over 30 percent.” This is simply not supported by the data, which, as outlined below, reveal that suicide rates were not only rising prior to issuance of the black box warnings but actually went down following issuance of the black box warnings.
In 2004, the year suicides increased, “there was no significant drop in SSRI prescribing.” [ vi ] As Jureidini pointed out, Gibbons “incorrectly analyzed the relationship” between prescription rates and suicide rates among children and, when carefully examined, Gibbons’ suggestion of a clear causal association from the data analyzed “show no such association.” Id. Like Gibbons, the NBER working paper is making erroneous “[a]larmist predictions regarding the consequences of decreased prescribing.” Id.
Gibbons, himself, has since acknowledged that his data did not support a causal link: “We really need to see the 2005 numbers on suicide to see what happened.” [ vii ] (The alleged culprit of the NBER’s “list of terribles,” i.e., the black box warning, was implemented in early 2005, and antidepressant prescriptions did decrease that year.) The FDA’s Dr. Thomas Laughren confirmed at a 2008 hearing that antidepressant prescribing did not change until 2005 and the 2005 suicide numbers “are down from where they were in 2004.” [ viii ]
Moreover, one of the studies cited by the working paper authors by Gibbons et al. was so scientifically illegitimate that it was described by the British Medical Journal as “astonishing,” “misleading” and “reckless.” [ ix ] Further, one of the Gibbons study authors, Ron Herings admitted the study’s findings are “not right” and that it “doesn’t follow from the data, it is not true and serves just to scare people. It is hard to admit this, as I am one of the authors of the article and I attached my name to it …” [ x ]
Finally, NBER’s reliance upon ecological studies to support their arguments is methodologically flawed. Authors of ecological “studies” universally agree you cannot conclude that increasing or decreasing suicides (or any other malady) is the result of a lack of antidepressant consumption based on these types of analyses. [ xi ]
C. Selling Sickness
Another important issue in this debate is the over-promotion and subsequent indiscriminate prescription of antidepressants to as many people as possible. The marketing of depression and use of antidepressants has been called “a masterpiece of marketing.” [ xii ]
Prior to antidepressants hitting the market, “depression was considered a rare disease, affecting about 1 percent of the population (as opposed to 10 to 15 percent of the population today) …” Id. [ xiii ] According to Australian professor of psychiatry, Gordon Parker, the “[r]easons for the overdiagnosis [of depression] include … marketing of treatments beyond their true utility in a climate of heightened expectations.” [ xiv ]
Depression has “grown to epidemic proportions in modern, developed Western countries in particular. Within two decades the percentage of the population having depression that requires treatment has risen five-fold on average: in 2009 more than 5% of the general population.” [ xv ]
In his article Overprescribing Antidepressants, Christopher Lane, Ph.D., a research professor at Northwestern University, pointed to a Rand Corporation survey conducted in 2002, showing that just 20% of those surveyed who had received an antidepressant prescription “tested positive” for clinical depression. “Fewer than 30% of those receiving the medication had any depressive symptoms at all.” In other words, “70% of patients in the survey presented no medical need for antidepressant treatment, and a further 10% fell into a significant gray area, with an insufficient number of symptoms to warrant a DSM diagnosis.”
It has been said, “Every risk to public health seems to beget an equal and opposite effort at denial from the industry whose products are implicated.” [ xvi ]
Like the tobacco industry, which “helped invent the strategy of using scientists as third-party advocates” in order to “create doubt” (id. at 230) about the health risks associated with tobacco, drug manufacturers and their KOLs have used a similar strategy by propagating a steady stream of “studies” to counteract the impact of strengthened warnings about their drugs’ risks. The argument bears a remarkable resemblance to that put forward by tobacco companies in the 1960s – that deaths from respiratory and cardiac causes had been falling from 1900 through to the 1960s and life expectancy rising, all during a period when cigarette consumption was on the rise. [ xvii ]
While the NBER paper’s objective is not readily apparent, what is clear is that the presumptions and methodology are erroneous and the conclusions misleading. Relying on NBER’s paper, an unsuspecting mother might feel the cure to her child’s poor grades is an antidepressant and insist that he/she be placed on a drug that is not only clinically ineffective, but that has some potentially very serious side effects. Observing societal problems such as illicit drug use, violence, and poor grades and working toward workable solutions is a good thing, but believing a single magic pill will somehow cure all those ills is misguided.
Disclosure: Baum Hedlund has litigated antidepressant suicide and suicide attempt cases for approximately 20 years. As a result, the firm (in conjunction with research consultants and leading experts in psychopharmacology) have conducted a great deal of research on the issues presented in the NBER paper, and, further, the firm has obtained confidential pharmaceutical company documents which shed further light on the issues. Baum Hedlund has but a handful of antidepressant suicide cases remaining in its inventory, thus, any financial motivation in responding to Reason’s article is limited. We believe, however, that it is important to continue to share our knowledge base when we become aware of research that could mislead the public.
i. See Paul Basken, “As He Worked to Strengthen Ethics Rules, NIMH Director Aided a Leading Transgressor” (i.e., Charles Nemeroff), The Chronicle of Higher Education, June 6, 2010, http://chronicle.com/article/While-Revising-Ethics-Rules/65800; Silverman, “Grassley Targets Brown’s Keller Over Grants,” Pharmalot.com, July 14th, 2008,
Firestone and Kelsh, “Keller’s findings on Paxil disputed by doctors, FDA,”The Brown Daily Herald, September 24, 2008,
http://www.browndailyherald.com/campus-news/keller-s-findings-on-paxil-disputed-by-doctors-fda-1.1669707#.ToN-EYIa-dA; Firestone and Kelsh, “Senator targets professor’s ties to big pharma,” The Brown Daily Herald, September 24, 2008, http://www.browndailyherald.com/campus-news/senator-targets-professor-s-ties-to-big-pharma-1.1669703#.ToN98oIa-dA; Silverman, “Antidepressant Use And Conflicts Of Interest,” Pharmalot.com, September 7, 2007
ii.See September 13, 2004 Psychopharmacological Drug Advisory Committee transcript, http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004‑4065T1.htm, p.445; September 14, 2004 PDAC transcript, http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004‑4065T2.htm, p. 83. See also Jureidini, Doecke, Mansfield, Haby, Menkes, Tonkin, Efficacy, and safety of antidepressants for children and adolescents, BMJ 2004;328:879‑883 (10 April), doi:10.1136/bmj.328.7444.879 available in full at http://www.bmj.com/cgi/content/full/328/7444/879; Newman, A Black‑Box Warning for Antidepressants in Children? N Eng J Med, Vol. 351:1595‑1598, October 14, 2004, abstract available at http://content.nejm.org/cgi/content/short/351/16/1595
iii. Even so, both Prozac’s and Lexapro’s efficacy for the treatment of children and adolescents is dubious. As Dr. Thomas Newman, an epidemiologist from UC San Francisco and an FDA advisor, explained during the September 14, 2004 PDAC, “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 pediatric] trial, just as an example, … the improvement over placebo was really very, very small, and I would say not detectable by a clinician treating individual patients. …” See September 14, 2004 PDAC transcript at
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004‑4065T2.htm, p. 338. With respect to Lexapro, its approval for children ages 12-17 in March 2009 came, curiously enough, amidst charges by the Department of Justice that its manufacturer, Forest Labs, illegally marketed Lexapro for children and paid pediatricians kickbacks to prescribe the drugs off-label. Forest labs ended up paying over $313 million to settle the unlawful marketing allegations and pled guilty to felony obstruction of justice, two misdemeanor counts and paying kickbacks to doctors. See: Department of Justice press release, “Drug Maker Forest Pleads Guilty; To Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations,” September 15, 2010, http://www.justice.gov/opa/pr/2010/September/10-civ-1028.html. Another oddity about Lexapro’s approval is that it was approved based on only one favorable clinical trial of Lexapro (the FDA normally requires two well-controlled clinical trials). The FDA accepted the company’s combination of one positive Lexapro trial and one positive trial of Lexapro’s “sister” drug Celexa, which, on its own, Forest was never able to prove effective. Two other pediatric clinical trials (one Lexapro and one Celexa) failed. Forest was also unable to prove that Lexapro was effective for maintaining treatment for depression in children and/or adolescents.
iv. Knipe v. GlaxoSmithKline, 583 F.Supp.2d 602, 640 (E.D.Pa. 2008).
v. Jureidini et al., Efficacy and safety of antidepressants for children and adolescents, Brit. Med. J., p. 879, 10 April 2004.
vi. See Jon Jureidini, The Black Box Warning: Decreased Prescriptions and Increased Youth Suicide?, 164 Am. J. Psychiatry 1907 (2007).
vii. See Alex Berenson & Benedict Carey, Experts Question Study on Youth Suicide Rates, N.Y. Times, September 14, 2007.
viii.See Joint Meeting of the Peripheral and Central Nervous system drugs advisory committee and the Psychopharmacological Drugs Advisory Committee, (“PDAC”) FDA (Beltsville, Maryland) (July 10, 2008), Hearing Tr. at 52.
ix. See Tony Sheldon, Dutch Academics Criticise Suicide Claims in American Journal, 336 Brit. Med. J. 112 (2008).
x. Interview with Ron Herings, Argos, VPRO/VARA, Radio 1 (December 7, 2007).
xi. See e.g., Jorgen Bramness et al., The sales of antidepressants and suicide rates in Norway and its counties 1980-2004, 102 Journal of Affective Disorders 1 (2007)Jorgen Bramness et al., The sales of antidepressants and suicide rates in Norway and its counties 1980-2004, 102 Journal of Affective Disorders 1, 6-7 (2007). (“Ecological studies cannot infer causality;” “the observed relationship [between declining suicide rates and antidepressant prescriptions] could be a spurious finding”); Gibbons et al., The Relationship Between Antidepressant Medication Use and Rate of Suicide, 62 Arch Gen Psych 165 (2005) Gibbons et al., The Relationship Between Antidepressant Medication Use and Rate of Suicide, 62 Arch Gen Psych 165 (2005) (“the aggregate nature of these observational data preclude direct causal interpretation of results.”)
xii. See Charles Barber, Comfortably Numb, How Psychiatry is Medicating a Nation 7 (2008).
xiii. Spending on antidepressants rose from $5.1 billion in 1997 to $13.5 billion in 2006. Id. at 8. Pieters and Snelders, Psychotropic Drug Use: Between Healing and Enhancing the Mind, 2 Neuroethics 63 (2009).
xiv. Gordon Parker, Is Depression overdiagnosed? 335 Brit. Med. J. 328 (2007). See also, Jureidini and Tonkin, Overuse of Antidepressant Drugs for the Treatment of Depression, 20 CNS Drugs 623 (2006); Pieters and Snelders, Psychotropic Drug Use: Between Healing and Enhancing the Mind, 2 Neuroethics 63 (2009).
xv. Pieters, Snelders, “Psychotropic Drug Use: Between Healing and Enhancing the Mind,” Neuroethics, 11 February, 2009.
xvi. See Rampton and Stauber, Trust Us, We’re the Experts – How Industry Manipulates Science and Gambles With Your Future 229 (2001).
xvii. See Tobacco and the Health of the Nation at
http://legacy.library.ucsf.edu/cgi/getdoc?tid=dxb34f00&fmt=pdf&ref=results and Smoking and Health Proposalat http://legacy.library.ucsf.edu/tid/rgy93f00, 690010954 (“Doubt is our product since it is the best means of competing with the ‘body of facts’ that exists in the mind of the general public. It is also the means of establishing a controversy … .”)