A letter to NIMH - 04.30.2004

[Guest guest]

From: Vera Hassner Sharav, President Cohen, Ph.D. Secretary

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Friday, April 30, 2004

To: Insell, MD, Director, NIMH Benedetto Vitiello, MD Swedo, MD

Eve Moscicki, MD (NIMH)

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.

NIMH STATEMENT

http://www.nimh.nih.gov/press/StmntAntidepmeds.cfm

>>>>>>>>>>>>>>Begin Statement

April 23, 2004

Antidepressant Medications for Children:

Information for Parents and Caregivers

" Depression is a serious disease that causes significant problems at home,

in school, and with peers. It increases a child's vulnerability to substance

abuse, and puts them at risk for suicidal behaviors. Previous research has

shown that depression in children and adolescents is a treatable condition.

Psychological therapies, such as cognitive-behavioral therapy and

interpersonal therapy, have been shown to be helpful for adolescents with

depression. Medications, particularly the serotonin reuptake-blocking

medications (SSRIs), have been shown to be of benefit in adults. Recently,

however, concerns have been raised that antidepressant medications

themselves may induce suicidal behavior and be ineffective in treating

depression in youths. The National Institute of Mental Health (NIMH) offers

the following information to help families and caregivers make treatment

choices based on the best currently available information.

Use of SSRIs has risen dramatically in the past several years in children

and adolescents age 10-19. Some research points out that this increase 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.

Fluoxetine has also been shown to be safe and helpful in treating depression

in children 8 years and older in two different studies-one supported by NIMH

and the other supported by Eli Lilly, the manufacturer of the drug. The

studies found that it reduced depression for many children better than a

placebo (a fake pill) and it did not increase suicide or suicidal thinking.

However, fluoxetine failed to improve depression in at least one third of

patients. Also, about one in 10 children experienced adverse side effects

such as agitation and mania.

The other SSRIs, such as sertraline, citalopram, paroxetine, and

venlafaxine, have not been approved for treatment of depression in children

or adolescents, though they have often been prescribed to children by

physicians in " off-label use " -a use other than the approved use.

Some forms of psychotherapy, such as cognitive-behavioral therapy, have

proven useful for adolescents with depression.

What Do We Know About Antidepressant Medications?

The SSRIs (serotonin reuptake inhibitors) include:

fluoxetine (Prozac)

sertraline (Zoloft)

paroxetine (Paxil)

citalopram (Celexa)

escitalopram (Lexapro)

fluvoxamine (Luvox)

venlafaxine (Effexor)-another antidepressant closely related to the SSRIs

SSRIs (serotonin reuptake inhibitors) are considered an improvement over

older antidepressants because they are better tolerated and are safer if

taken in an overdose (which is an issue for patients at risk for suicide).

They have been extensively tested in adult populations and have been proven

to be safe and effective for adults. Note: Fluoxetine, sertraline, and

fluvoxamine are approved by the FDA for the treatment of

Obsessive-Compulsive Disorder because studies have shown they are safe and

effective for adolescents with this disorder.

What Remains Unknown

Currently, there is no way of telling who may be sensitive to an SSRI's

positive or adverse effects. Results thus far are based on populations-some

individuals may show marked improvement, some may see no change, and some

may be vulnerable to adverse effects. The response to medication of an

individual patient cannot be predicted with certainty from the kind of

studies that have been done so far.

It is extremely difficult to prove whether SSRIs increase the risk of

suicide especially since suicide is already a significant risk in those who

are depressed. In fact, no suicide has been reported among the more than

4,100 subjects enrolled in pediatric clinical trials of SSRIs. Controlled

trials typically exclude patients considered at high risk for suicide, such

as those with a history of suicide attempts.

The FDA is now re-analyzing existing data to try to determine if SSRIs raise

the risk of suicide in children. It held a public advisory meeting in

February to discuss the issue and in March requested that a warning of a

possible association between use of SSRIs and suicidal behavior be inserted

in the labeling of these medications.

What Should You Do for a Child With Depression?

Major depression in children and adolescents is a serious condition that

should be adequately treated, which includes careful follow-up and

monitoring.

Psychotherapy appears to be a useful initial acute treatment for mild to

moderate depression according to practice parameters published by the

American Academy of Child and Adolescent Psychiatry (1998). 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. Psychotherapies include " cognitive behavioral

therapy " and " interpersonal therapy. "

Each child should be carefully and thoroughly evaluated by a physician to

determine if medication is appropriate. Those who are prescribed an SSRI

should receive ongoing medical monitoring, with particular care paid in the

first few weeks of taking the drug.

Should nervousness, agitation, irritability, mood instability, or

sleeplessness emerge or worsen during treatment with SSRIs, parents should

obtain a prompt evaluation by a clinician with expertise in these

medications.

Children already on any of the SSRIs should remain on the drug if it has

been helpful but they should also be carefully monitored by a physician for

evidence of side effects. Once started, treatment with these medications

should not be abruptly stopped, because the body can react with further

agitation and restlessness. Families should not discontinue treatment

without consulting with their physician.

All potentially effective treatments can be associated with side effects. A

careful weighing of risks and benefits, with appropriate follow-up to help

reduce risks, is the best that can be currently recommended.

What NIMH Is Doing

NIMH is conducting research to help clarify the potential value and risks of

antidepressants, and to explore how medications compare with psychotherapy

in adolescent depression. In particular, an NIMH-funded, multi-site

controlled clinical trial, the Treatment for Adolescents with Depression

Study (TADS), was launched in the late 1990s to directly compare the

efficacy of fluoxetine, cognitive-behavioral therapy, and a combination of

the two. Results are expected later in 2004.

Other studies are in progress to test the efficacy and safety of both

medications and psychotherapy for youths with treatment-resistant depression

and youths at increased risk for suicide attempts.

For more information on this topic, see: Antidepressant Medications in

Children. Vitiello, B, Swedo, S. National Institute of Mental Health,

Bethesda, MD. New England Journal of Medicine Apr 8;350(15):1489-91. See

also content.nejm.org

>>>>>>>>>>>>>>>End Statement

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, J Doecke, R Mansfield, M

Haby, 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, Fonagy, Cottrell,

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: 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. Mosholder, FDA's

own medical expert whose report and recommendations have been embargoed.

Other analysts include: Dr. Breggin, J. , Dr. Irving

Kirsch, and Dr. 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 GlaxoKline 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, J. , Alan Scoboria and 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. 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. 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. ,M. Al-Shabbout and N. , 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, 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 Cohen, Ph.D. The Alliance for Human Research

Protection

Contact: e-mail: veracare@...