An Open Letter to Officials of the National Institute of Mental Health

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting openness and full disclosure
http://www.ahrp.org

From: Vera Hassner Sharav, President
David Cohen, Ph.D. Secretary
The ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
   
To: Thomas Insell, MD, Director, NIMH
Benedetto Vitiello, MD
Susan Swedo, MD
Eve Moscicki, MD

The National Institute of Mental Health (NIMH) has issued an inaccurate, obfuscating, and misleading statement ON April 23, 2004 — Antidepressant Medications for Children: Information for Parents and Caregivers — that continues to encourage the use of antidepressants for children: “Many times, psychotherapy accompanied by an early follow- up appointment may help to establish the persistence of depression before a decision is made to try antidepressant medications.” This statement appears to demonstrate the inordinate influence of Big Pharma on NIMH. http://www.nimh.nih.gov/press/StmntAntidepmeds.cfm

The officials who formulated the NIMH statement failed to address the safety concerns of parents and failed to level with parents. NIMH DID NOT inform parents that in clinical trials these drugs have failed repeatedly to demonstrate a benefit for children, and that independently validated evidence shows that children who took the drugs in controlled clinical trials were at a two-to threefold increased risk of suicidal behavior compared to those on placebo.

AHRP finds it remarkable that the authors of the NIMH statement did not acknowledge that antidepressants have failed repeatedly to demonstrate a benefit for children in clinical trials. The omission is all the more remarkable given the FDA’s own acknowledgement, in a memorandum dated January 5, 2004, of “the preponderance of negative studies of antidepressants in pediatric populations.” The FDA noted that its analysis of the data contradicted published reports-such as by Keller, et al, 2001 and Wagner, et al, 2003–claiming positive findings, in fact failed to demonstrate a benefit greater than placebo.

The unnamed authors of the NIMH Statement on antidepressants for children FAILED TO CITE A SINGLE, SCIENTIFIC ANALYSIS OF THE PEDIATRIC SSRI CLINICAL TRIAL DATA.

Those independent, replicated analyses provide compelling scientific evidence invalidating previously published positive claims about the safety and effectiveness of these drugs for children. Those false claims, it has been shown, were made on the basis of partial data. When the concealed unpublished data was analyzed, SSRIs failed to demonstrate a benefit for children. The only studies the NIMH statement actually refers to are two trials concluding that Prozac had a marginally positive effect but a 10% rate of adverse effects such as mania and agitation.

If the nation’s premier psychiatric / behavioral research institute turns its back on science-based evidence and on scientific validation of that evidence, what does this say about the credibility of all its reports and guidelines? This apparent lack of respect for scientific validation raises questions about NIMH’s mission to base its advice for parents and caregivers on tested evidence.

Did NIMH officials take dictation from drug marketing agents when they formulated this inaccurate and misleading Statement about antidepressants?

The NIMH statement fails to mention:

(1) The scientific basis for the action taken by the British Committee on Safety in Medicines banning the use of these drugs for children under 18 has been validated by several recent independent meta-analyses of the published and unpublished clinical trial data. These reports, published in prestigious journals, confirmed that antidepressants consistently failed to demonstrate a benefit in youth, and that children taking antidepressants in controlled clinical trials had a two-to-threefold increased risk of suicidal and homicidal behavior compared to those on placebo.

See: Jon N Jureidini, Christopher J Doecke, Peter R Mansfield, Michelle M Haby, David B Menkes, Anne L Tonkin, Efficacy and safety of antidepressants for children and Adolescents, British Medical Journal, online free at: http://bmj.bmjjournals.com/cgi/content/full/328/7444/879?

See: Craig J Whittington, Tim Kendall, Peter Fonagy, David Cottrell, Andrew Cotgrove, Ellen Boddington. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. The Lancet. Volume 363, Number 9418, April 24, 2004, online free at: http://www.thelancet.com/journal/journal.isa

See: Peter R. Breggin. Suicidality, violence and mania caused by SSRIs: A review and analysis. International Journal of Risk & Safety in Medicine 16 (2003/2004) and

(2) Several independent expert analyses of the unpublished clinical trial antidepressant data submitted to the FDA validated earlier findings: Antidepressants failed to demonstrate a benefit for children but put children at increased risks of severe drug adverse effects. Except for two Prozac trials (whose design and findings are in dispute) the risks for children outweigh the (mostly nonexistent) benefits.

Among these expert reports is the analysis by Dr. Andrew Mosholder, FDA’s own medical expert whose report and recommendations have been embargoed.

Other analysts include: Dr. Peter Breggin, Thomas J. Moore, Dr. Irving Kirsch, and Dr. David Healy. All of whom separately found evidence of drug-related suicidal acts. See documents and references to additional documents at: www.ahrp.org

(3) In addition to the British MHRA action taken to protect children and adolescents from the hazards of SSRIs-informing physicians outright not prescribe SSRIs for youth– the European Medicines Evaluation Agency (EMEA) ordered GlaxoSmithKline to add still stronger warnings on the label of Paxil / Seroxat, including “a warning of severe withdrawal symptoms and that they were unsuitable for children and adolescents.”

(4) The NIMH statement overstates the benefits of SSRIs for adults. It fails to mention that meta-analyses show the drugs are barely superior to placebo. Khan, et al who analyzed FDA data found that 76% of the drug effect was met by placebo. Kirsch, et al who analyzed the efficacy data submitted to the FDA for the six most widely prescribed antidepressants found that 80% of drug response was met by placebo. These are not clinically significant results–especially when one considers the adverse side effects.

See: Khan, A., Warner, H. A., & Brown, W. A. (2000). Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: An analysis of the Food and Drug Administration database. Archives of General Psychiatry 57, 311-317.

See: 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 FDA, Prevention & Treatment, Volume 5, Article 23, posted July 15, 2002. http://journals.apa.org/prevention/volume5/pre0050023a.html

(5) The NIMH statement notes in passing that there has been an increase in the use of off-label prescriptions to children, it fails to express any CONCERN for the thousands of children who are put at increased risk of harm without a proven prospect of a benefit. Instead, the NIMH statement makes the undocumented suggestive claim–attributed to “some research points out”–that increased use of antidepressants in children “has coincideD with a significant decrease in suicide rates in this age group, but it is not known if SSRIs are directly responsible for this improvement.”

The facts, documented by the Center for Disease Control, refute that unsubstantiated claim. During the period in which children / adolescents have been increasingly prescribed antidepressants the suicide rate increased: “From 1980-1997, the rate of suicide among persons aged 15-19 years increased by 11% and among persons aged 10-14 years by 109%. Persons under age 25 accounted for 15% of all suicides in 2000. [i] For young people 15-24 years old, suicide is the third leading cause of death (9.9/ 100,000), behind unintentional injury and homicide. In 1999, more teenagers and young adults died from suicide than from cancer, heart disease, AIDS, birth defects, stroke, and chronic lung disease combined. http://www.cdc.gov/ncipc/factsheets/suifacts.htm

(6) The NIMH statement repeats the unsubstantiated claim that the SSRIs are better tolerated than the older tricyclic antidepressants they replaced, but-as acknowledged by FDA’s Dr. Robert Temple–every single tricyclic trial failed to demonstrate any benefit for children.

(7) Although the NIMH statement notes that no actual suicides have been observed in clinical trials, it fails to mention the documented increase in incidence of “suicidal thinking” and abnormal behaviors such as self-mutilation which occurred three times as often in children prescribed an SSRI compared to those who were in placebo arms of clinical trials. The investigators’ failure to report the outcome of those children who dropped out of clinical trials because of adverse drug effects, leaves the completed suicide question unresolved.

Furthermore, a body of evidence exists–first hand testimonies of parents whose children committed suicide shortly after taking an SSRI. See: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4006T1.htm Why has neither the NIMH or the FDA taken the lead in collecting and analyzing this first-hand evidence?

(8 ) Reports from clinical practice show the scope and severity of the problems associated with antidepressant drugs: For example, an examination of the medical charts of children and adolescents (age 8-19) who had been prescribed Prozac at a clinic staffed by University of Pittsburgh psychiatrists shows that 23% of the children or adolescents developed mania or “manic-like” symptoms, and another 19% developed drug-induced hostility and aggression, including a “grinding anger with short temper and increasing oppositionalism.” These dangerous effects may be precursors to suicidal or homicidal acts.

See: J. Jain, B. Birmaher, M. Garcia,M. Al-Shabbout and N. Ryan, Fluoxetine in children and adolescents with mood disorders: A chart review of efficacy and adverse reactions, Journal of Child and Adolescent Psychopharmacology 2 (1992), 259-265.

A chart review from Mass General Hospital showed that 74% of children who were prescribed an SSRI by expert Harvard child psychiatrists suffered serious adverse effects.

See: See: Wilens TE, Biederman J, Timothy E, Kwon A, Chase R, Greenberg L, Mick E, Spencer TJ. “Systematic Chart Review of the Nature of Psychiatric Adverse Events in Children and Adolescents Treated with Selective Serotonin Reuptake Inhibitors,” Journal of Child and Adolescent Psychopharmacology, 2003, 13: 143 – 152

(9) Indeed, the NIMH statement fails to mention very worrisome adverse effects of SSRIs in children as well as young adults, that continue to be reported in the medical literature. For example, a high incidence of manic reactions, growth retardation in children and adolescents, as well as apathetic/ lethargic “frontal lobe syndromes” in children and adolescents. And the NIMH statement fails to acknowledge the finding that 8.1% of psychiatric hospital admissions can be attributed to SSRI induced manic and/or psychotic behavior.

See: Preda A, McLean R, Mazure C, Bowers M. (2001). “Antidepressant- associated mania and psychosis resulting in psychiatric admission.” Journal of Clinical Psychiatry, 62, 30-33.

Weintrob N, Cohen D, Klipper-Aurbach Y, Zadik Z, Dickerman Z. (2002). “Decreased growth during therapy with selective serotonin reuptake inhibitors.” Archives of Pediatric and Adolescent Medicine, 156(7), 696- 701.

Garland EJ, Baerg EA. (2001). “Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents.” Journal of Child & Adolescent Psychopharmacology, 11(2), 181-186.

The NIMH Statement does not accurately reflect the state of knowledge regarding the potential harm antidepressants may cause. And the NIMH statement fails to address the safety concerns of parents, ducking the incontrovertible scientific evidence–as if it did not exist. Rather than demonstrate concern for the safety of children, NIMH officials exhibit a “business-as-usual” attitude.

It is significant that the most prestigious scientific journal in the world issued a scathing editorial to accompany the decisive analysis by Whittington, et al. The Lancet editorial begins by stating: “It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug’s use being based on the selective reporting of favourable research should be unimaginable.”

The final admonition to the biomedical research community reminds them: “People around the world understand the desire to achieve success and to work in a profitable environment. They will not, however, tolerate the notion that in biomedical research this could be at the expense of their children’s lives.” http://www.thelancet.com/journal/vol363/iss9418/full/llan.363.9418.editorial_and_review.29416.1

We at The Alliance for Human Research Protection believe that parents and caregivers in America deserve better information, analysis, and caution from the NIMH–America’s children deserve no less protection from drug hazards than British children.

Vera Hassner Sharav and David Cohen, Ph.D.
The Alliance for Human Research Protection

Contact: 212-595-8974