Antipsychotic Use in Children: FDA Panel Rejects FDA Soft-Peddle Approach

The New York Times reports that an FDA advisory committee deliberating over the safety of using antipsychotic drugs in children–e.g., Risperdal and Zyprexa–rejected agency officials’ effort to downplay these drugs’ documented hazards which are magnified in children.

"The committee’s concerns are part of a growing chorus of complaints about the increasing use of antipsychotic medicines in children and teenagers. Prescription rates for the drugs have increased more than fivefold for children in the past decade and a half, and doctors now use the drugs to settle outbursts and aggression in children with a wide variety of diagnoses, even though children are especially susceptible to their side effects."

Indeed, from 1993 through the first three months of 2008, 1,207 children given Risperdal suffered serious problems, including 31 who died. Among the deaths was a 9-year-old with attention deficit problems who suffered a fatal stroke 12 days after starting therapy with Risperdal.

The Times reports,

"Food and Drug Administration officials proposed that the committee endorse the agency’s routine monitoring of the safety of the medicines in children and support its previous efforts to highlight the drugs’ risks. But committee members unanimously rejected the agency’s proposals, saying that far more needed to be done to discourage the medicines’ growing use in children, particularly to treat conditions for which the medicines have not been approved."

Dr. Thomas Laughren, director of the FDA’s division of psychiatry products–the FDA official who had been most instrumental in providing the FDA seal of approval for antipsychotics without highlighting the very serious risks of harm the drugs posed–is quoted saying, "I’m a little puzzled about the statement that the label is inadequate…. the agency could do little to fix the problem."
This statement is disingenuous.

In point of fact, we believe evidence exists showing that Dr. Laughren actively promoted the increased use of antipsychotics in children. He did so when none of these had been approved by the FDA for use in children.

He promoted the use of these highly toxic drugs in ghostwritten publications as a co-author with influential academic psychiatrists whose financial conflicts of interest and biased reports have invalidated the psychiatric literature. Some of these authors’ financial conflicts of interest–Drs. Charles Nemeroff, Alan Schatzberg, Melissa DeBello– have been laid bare by Sen. Grassley.

Dr. Laughren also co-authored a book chapter with Leigh Thompson (then) Eli Lilly’s chief scientific officer. (Premarketing safety evaluation of psychotropic drugs.)

Dr. Laughren’s other influential industry-funded co-authors include Drs. Graham Emslie, Carole Tamminga, Peter Jensen, David Shaffer, Frederick Goodwin… as well as Dr. Trei Sunderland whose concealed conflicts of interest led to a criminal verdict.

Partial bibliography of Dr. Laughren’s publications:

1. Consensus Report on Impulsive Aggression as a Symptom Across Diagnostic Categories in Child Psychiatry: Implications for Medication Studies. SPECIAL COMMUNICATION. Journal of the American Academy of Child & Adolescent Psychiatry. 46(3):309-322, March 2007. Authors. JENSEN, PETER S. M.D.; YOUNGSTROM, ERIC A. Ph.D.; STEINER, HANS M.D.; FINDLING, ROBERT L. M.D.; MEYER, ROGER E. M.D.; MALONE, RICHARD P. M.D.; CARLSON, GABRIELLE A. M.D.; COCCARO, EMIL F. M.D.; AMAN, MICHAEL G. Ph.D.; BLAIR, JAMES M.D.; DOUGHERTY, DONALD Ph.D.; FERRIS, CRAIG Ph.D.; FLYNN, LAURIE B.A.; GREEN, EVELYN B.A.; HOAGWOOD, KIMBERLY Ph.D.; HUTCHINSON, JANICE M.D.; LAUGHREN, TOM M.D.; LEVE, LESLIE D. Ph.D.; NOVINS, DOUGLAS K. M.D.; VITIELLO, BENEDETTO M.D.

Abstract: Objective: To determine whether impulsive aggression (IA) is a meaningful clinical construct and to ascertain whether it is sufficiently similar across diagnostic categories, such that parallel studies across disorders might constitute appropriate evidence for pursuing indications. If so, how should IA be assessed, pharmacological studies designed, and ethical issues addressed?

Method: Experts from key stakeholder communities, including academic clinicians, researchers, practicing clinicians, U.S. Food and Drug Administration, National Institute of Mental Health, industry sponsors, and patient and family advocates, met for a 2-day consensus conference on November 4 and 5, 2004. After evaluating summary presentations on current research evidence, participants were assigned to three workgroups, examined core issues, and generated consensus guidelines in their areas. Workgroup recommendations were discussed by the whole group to reach consensus, and then further iterated and condensed into this report postconference by the authors.

Results: Conference participants agreed that: A is a substantial public health and clinical concern, constitutes a key therapeutic target across multiple disorders, and can be measured with sufficient precision that pharmacological studies are warranted. Additional areas of consensus concerned types of measures, optimal study designs, and ethical imperatives.

Conclusion: Derived from scientific evidence and clinical experience, these consensus-driven recommendations can guide the design of future studies.

2. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry. 2005 Aug 1;58(3):175-89. Review. Authors: Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, Nemeroff CB, Bremner JD, Carney RM, Coyne JC, Delong MR, Frasure-Smith N, Glassman AH, Gold PW, Grant I, Gwyther L, Ironson G, Johnson RL, Kanner AM, Katon WJ, Kaufmann PG, Keefe FJ, Ketter T, Laughren TP, Leserman J, Lyketsos CG, McDonald WM, McEwen BS, Miller AH, Musselman D, O’Connor C, Petitto JM, Pollock BG, Robinson RG, Roose SP, Rowland J, Sheline Y, Sheps DS, Simon G, Spiegel D, Stunkard A, Sunderland T, Tibbits P Jr, Valvo WJ.

3. Methodological issues and controversies in clinical trials with child and adolescent patients with bipolar disorder: report of a consensus conference. J Child Adolesc Psychopharmacol. 2003 Spring;13(1):13-27. Review. Authors: Carlson GA, Jensen PS, Findling RL, Meyer RE, Calabrese J, DelBello MP, Emslie G, Flynn L, Goodwin F, Hellander M, Kowatch R, Kusumakar V, Laughren T, Leibenluft E, McCracken J, Nottelmann E, Pine D, Sachs G, Shaffer D, Simar R, Strober M, Weller EB, Wozniak J, Youngstrom EA.

4. Developing strategies for psychopharmacological studies in preschool children. J Am Acad Child Adolesc Psychiatry. 2003 Apr;42(4):406-14. Review. Authors: Greenhill LL, Jensen PS, Abikoff H, Blumer JL, Deveaugh-Geiss J, Fisher C, Hoagwood K, Kratochvil CJ, Lahey BB, Laughren T, Leckman J, Petti TA, Pope K, Shaffer D, Vitiello B, Zeanah C.

5. Developing novel treatments for mood disorders: accelerating discovery. Biol Psychiatry. 2002 Sep 15;52(6):589-609. Review. Authors: Tamminga CA, Nemeroff CB, Blakely RD, Brady L, Carter CS, Davis KL, Dingledine R, Gorman JM, Grigoriadis DE, Henderson DC, B Innis RB, Killen J, Laughren TP, McDonald WM, M Murphy GM Jr, Paul SM, Rudorfer MV, Sausville E, Schatzberg AF, Scolnick EM, Suppes T.

posted by Vera Hassner Sharav

THE NEW YORK TIMES
November 19, 2008
Use of Antipsychotics in Children Is Criticized
By GARDINER HARRIS

WASHINGTON – Powerful antipsychotic medicines are being used far too cavalierly in children, and federal drug regulators must do more to warn doctors of their substantial risks, a panel of federal drug experts said Tuesday.

More than 389,000 children and teenagers were treated last year with Risperdal, one of five popular medicines known as atypical antipsychotics. Of those patients, 240,000 were 12 or younger, according to data presented to the committee. In many cases, the drug was prescribed to treat attention deficit disorders.

But Risperdal is not approved for attention deficit problems, and its risks – which include substantial weight gain, metabolic disorders and muscular tics that can be permanent – are too profound to justify its use in treating such disorders, panel members said.

"This committee is frustrated," said Dr. Leon Dure, a pediatric neurologist from the University of Alabama School of Medicine who was on the panel. "And we need to find a way to accommodate this concern of ours."

The meeting on Tuesday was scheduled to be a routine review of the pediatric safety of Risperdal and Zyprexa, popular antipsychotic medicines made, respectively, by Johnson & Johnson and Eli Lilly & Company. Food and Drug Administration officials proposed that the committee endorse the agency’s routine monitoring of the safety of the medicines in children and support its previous efforts to highlight the drugs’ risks.

But committee members unanimously rejected the agency’s proposals, saying that far more needed to be done to discourage the medicines’ growing use in children, particularly to treat conditions for which the medicines have not been approved.

"The data show there is a substantial amount of prescribing for attention deficit disorder, and I wonder if we have given enough weight to the adverse-event profile of the drug in light of this," Dr. Daniel Notterman, a senior health policy analyst at Princeton University and a panel member, said when speaking about Risperdal.

Drug agency officials responded that they had already placed strongly worded warnings on the drugs’ labels.

"I’m a little puzzled about the statement that the label is inadequate," said Dr. Thomas Laughren, director of the agency’s division of psychiatry products. "I’m anxious to hear what more we can do in the labeling."

Kara Russell, a spokeswoman for Johnson & Johnson, said, "Adverse drug reactions associated with Risperdal use in approved indications are accurately reflected in the label."

But panelists said the current warnings were not enough. While panel members spoke at length about Risperdal, they said their concerns applied to the other medicines in its class, including Zyprexa, Seroquel, Abilify and Geodon.

The committee’s concerns are part of a growing chorus of complaints about the increasing use of antipsychotic medicines in children and teenagers. Prescription rates for the drugs have increased more than fivefold for children in the past decade and a half, and doctors now use the drugs to settle outbursts and aggression in children with a wide variety of diagnoses, even though children are especially susceptible to their side effects.

A consortium of state Medicaid directors is evaluating the use of the drugs in children on state Medicaid rolls to ensure that they are being properly prescribed.

The growing use of the medicines has been driven partly by the sudden popularity of the diagnosis of pediatric bipolar disorder.

The leading advocate for the bipolar diagnosis is Dr. Joseph Biederman, a child psychiatrist at Harvard University whose work is under a cloud after a Congressional investigation revealed that he had failed to report to his university at least $1.4 million in outside income from the makers of antipsychotic medicines.

In the past year, Risperdal prescriptions to patients 17 and younger increased 10 percent, while prescriptions among adults declined 5 percent. Most of the pediatric prescriptions were written by psychiatrists.

From 1993 through the first three months of 2008, 1,207 children given Risperdal suffered serious problems, including 31 who died. Among the deaths was a 9-year-old with attention deficit problems who suffered a fatal stroke 12 days after starting therapy with Risperdal.

At least 11 of the deaths were children whose treatment with Risperdal was unapproved by the F.D.A. Once the agency approves a medicine for a particular condition, doctors are free to prescribe it for other problems.

Panel members said they had for years been concerned about the effects of Risperdal and similar medicines, but F.D.A. officials said no studies had been done to test the drugs’ long-term safety.

Dr. Dure said he was concerned that doctors often failed to recognize the movement disorders, including tardive dyskinesia and dystonia, that can result from using these medicines.

"I have a bias that extra-pyramidal side effects are being under-recognized with these agents," Dr. Dure said.

Dr. Laughren of the F.D.A. said the agency could do little to fix the problem. Instead, he said, medical specialty societies must do a better job educating doctors about the drugs’ side effects.