Fwd: JAMA: Antipsychotics pose Ominous long-term health implications for children

[Guest guest]

ALLIANCE FOR HUMAN RESEARCH PROTECTION A Catalyst for Public Debate: Promoting Openness, Full Disclosure, andAccountability http://www.ahrp.org FYIA study published in the current issue of The Journal of the AmericanMedical Association [1], confirms that children and adolescents who areprescribed second generation neuroleptics are put at high risk of severeharm: prominent psychotropic drug investigators acknowledge that the rapidonset of "cardiometabolic risks" is "alarming." They recommend thatconsideration be given for lower-risk alternatives.This government-sponsored study is the largest ever conducted on first-timeusers of neuroleptics (a.k.a. antipsychotics). It sought to document theassociation of second-generation neuroleptics (antipsychotics) with bodycomposition and metabolic parameters in patients not previously exposed toantipsychotic drugs. The four drugs in the study—Zyprexa (olanzapine), Risperdal (risperidone)Seroquel (quetiapine) and Abilify (aripiprazole)—are the most popularantipsychotic medications. They are industry blockbusters, with combinedsales of $12.7 billion last year.Two hundred and fifty seven young children and adolescents, aged 4 to 19, inthe New York study added 8% to 15% to their weight after taking one of fourneuroleptics for only 11 weeks. All but Abilify showed rapid and significant increases in one or moremetabolic markers, which can presage adult obesity, hypertension and Type 2diabetes. The metabolic markers included glucose, insulin, triglycerides andcholesterol."Adverse baseline-to-end-point changes reached statistical significance forolanzapine and quetiapine for total cholesterol, triglycerides, non-HDLcholesterol, and ratio of triglycerides to HDL cholesterol. [ sic] Withrisperidone, levels of triglycerides increased significantly. Metabolicbaseline-to-end-point changes were not significant with aripiprazole or inthe untreated comparison group. Patients receiving quetiapine had modestlyhigher incidence rates of hyperglycemia and the metabolic syndromeand patients receiving olanzapine experienced the highest incidence rates(eTable 3). Pubertal status was unrelated to metabolic changes in anyantipsychoticmedication group.In this short-term study of youth naïve to antipsychotic medications,aripiprazole, olanzapine, quetiapine, and risperidone were each associatedwith rapid and significant increases in body composition, whereas metabolicchanges were less uniform. Effect sizes for body composition changes werelarge (eTable 2). Altogether, 10% to 36% of patients transitioned tooverweight or obese status within 11 weeks. "The lack of significant changes in weight and metabolic parameters inpsychiatric comparison patients and short inpatient stays (10-18 days isequal to 14%-25% of treatment time) indicates that the observed alterationsare not likely due to a newly developing or worsening psychiatric disorderor hospitalization. "The results are concerning because they include fat mass and waistcircumference, which are associated with the metabolic syndrome in adultstreated with antipsychotic medications and heart disease in the generalpopulation. Moreover, abnormal childhood weight and metabolic statusadversely affect adultcardiovascular outcomes."The findings, led Dr. Wayne K. Goodman, chairman of psychiatry at MountSinai School of Medicine and head of an FDA advisory panel that had beencharged with assessing these drugs risk for children last summer, expressedshock. He told The New York Times: “The degree of weight gain is alarming.The magnitude is stunning.” And Dr. Judith Rapoport, chief of the child psychiatry branch at theNational Institute of Mental Health, acknowledged in an interview with TheNew York Times, “It’s by far the best documentation of not just weight gainand metabolic changes…” In an editorial accompanying the study [2], child psychiatrists, Dr.Christopher K. Varley (Seattle Children’s Hospital) and Dr. Jon McClellan(University of Washington School of Medicine) wrote that “ominous long-termhealth implications” arise from weight gain and changes in blood fat levelsearly in life: "These data confirm prior findings that children and adolescents are highlyvulnerable to antipsychotic medication–induced weight gain and metabolicadverse effects. The magnitude of weight gain is particularly concerning, asis the implication that metabolic adverse events may be underestimated instudies in which participants have had prior atypical antipsychoticmedication exposure. Furthermore, the development of clinically significanthyperlipidemias and insulin resistance after only 12 weeks of treatmentportends severe long-term metabolic and cardiovascular sequelae.""These results challenge the widespread use of atypical antipsychoticmedications in youth."In view of these indisputable, confirmatory alarming findings, not only theauthors of the study, but the authors of the JAMA editorial, the chief ofchild psychiatry at the NIMH, and even the chairman of the FDA advisorypanel who in June 2009 voted to approve the use of three of the drugs forchildren--all acknowledge the need to reassess the use of these drugs inchildren: “These results challenge the widespread use of atypicalantipsychotic medications in youth.” But, will the evidence that these drugs pose “ominous long-term healthimplications” for children, provide the necessary political will to ban theuse of antipsychotics for children??? These drugs’ hazardous effect on weight and metabolism—in adults andchildren—had been previously detected and reported. [3] Indeed, theprinciple investigator, Dr. Crisoph Correll, is a leading expert on themetabolic and cardiovascular ill effects of the second generationneuroleptics, whose critical scientific appraisals have been publishedwidely. [4--9] However, the alarming speed and magnitude of the effects found in thispediatric study were greater than previously reported. The findings are allthe more compelling because the children were new patients who had notpreviously been exposed to neuroleptics. Given the "ominous long-term healthimplications," we venture to say, the children's health would have been farbetter served without these drugs.Yet, psychiatrists' practice disregards the drugs' harmful effects: A 2008study found that patients under 19 years old accounted for 15% ofantipsychotic drug use in 2005, compared with 7% in 1996. Since 2005, thatpercentage has skyrocketed.Why are these toxic drugs so widely prescribed by US psychiatrists?Because prominent psychiatrists at prestigious universities who have servedas paid consultants and speakers for drug manufacturers have promoted theoff-label use of these drugs for children and teenagers, despite a body ofknowledge documenting the severe adverse effects the drugs have onchildren’s physical health. Underscoring the abusive prescribing of these drugs for children is the factthat more than 70% of atypical antipsychotics prescribed for young childrenand teenagers have been for off-label—i.e., untested uses—mostly formisbehavior (e.g., attention deficit hyperactivity disorder). These drugsare being used as chemical restraints—the severity of their hazardouseffects is not justified by any medical benefit. The drugs’ beneficiaries are not those who ingest them: antipsychotic drug sales have enriched not only drug manufacturers, butpsychiatry’s leadership, leading medical institutions, the mental healthprovider industry, and so-called patient advocacy groups—all of who havesold their integrity, serving as industry’s partners in a despicable crime. The large number of industry-funded publications exalting the benefits ofsecond generation neuroleptics, penned by the pillars of Americanpsychiatry, should be discarded as fraudulent, mostly ghostwritten, industrypropaganda. Commercially-crafted reports masquerading as evidence-basedreports have undermined the integrity of the journals that published themand the profession whose practice was guided by them. Will the indisputable evidence of “ominous long-term health implications”from use of antipsychotics prompt the FDA to ban their use in children??? References:1. See: http://jama.ama-assn.org/cgi/content/abstract/302/16/1765Cardiometabolic Risk of Second-Generation Antipsychotic Medications DuringFirst-Time Use in Children and AdolescentsChristoph U. Correll, MD; Peter Manu, MD; Vladimir Olshanskiy, MD; BarbaraNapolitano, MA; John M. Kane, MD; Anil K. Malhotra, MD JAMA. 2009;302(16):1765-1773. 2. http://jama.ama-assn.org/cgi/content/full/302/16/1811Christopher K. Varley; Jon McClellanImplications of Marked Weight Gain Associated With Atypical AntipsychoticMedications in Children and AdolescentsJAMA. 2009;302(16):1811-1812 (doi:10.1001/jama.2009.1558)3. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychoticdrugs in patients with chronic schizophrenia. New England Journal ofMedicine 353:1209–1223,2005. The majority of patients in each medicationgroup discontinued their assigned treatment mostly due to inefficacy orintolerable side effects. Zyprexa (olanzapine) had somewhat lower drop-outrate, but the drug was associated with greater weight gain and increases inmeasures of glucose and lipid metabolism. 4. Correll C and Carlson HE. Endocrine and Metabolic Adverse Effects ofPsychotropic Medications in Children and Adolescents, J.Am Acad ChildAdolesc.Psychiatry, 2006;45:771-791.5. Correll CU, Penzner JB, Parikh UH, Mughal T, Javed T, Carbon M, MalhotraAK. Recognizing and monitoring adverse events of second-generationantipsychotics in children and adolescents. Child Adolesc Psychiatr Clin NAm. 2006 Jan;15(1):177-206. 6. Correll CU. Metabolic side effects of second-generation antipsychotics inchildren and adolescents: a different story? J Clin Psychiatry. 2005Oct;66(10):1331-2. 7. Saito E, Correll CU, Gallelli K, McMeniman M, Parikh UH, Malhotra AK,Kafantaris V. A prospective study of hyperprolactinemia in children andadolescents treated with atypical antipsychotic agents. J Child AdolescPsychopharmacol. 2004 Fall;14(3):350-8. Review.8. Kane JM, Barrett EJ, Casey DE, Correll CU, Gelenberg AJ, Klein S,Newcomer JW. Metabolic effects of treatment with atypical antipsychotics. JClin Psychiatry. 2004 Nov;65(11):1447-55. 9. Correll CU, Malhotra AK. Pharmacogenetics of antipsychotic-induced weightgain. Psychopharmacology (Berl). 2004 Aug;174(4):477-89. Contact: Vera Hassner Sharavveracare212-595-8974~~~~~~~~~~~~~ http://www.nytimes.com/2009/10/28/business/28psych.htmlTHE NEW YORK TIMESOctober 28, 2009Weight Gain Associated With Antipsychotic DrugsBy DUFF WILSONYoung children and adolescents who take the newest generation ofantipsychotic medications risk rapid weight gain and metabolic changes thatcould lead to diabetes, hypertension and other illnesses, according thebiggest study yet of first-time users of the drugs.The study, to be published Wednesday in The Journal of the American MedicalAssociation, found that 257 young children and adolescents in New York Cityand on Long Island added 8 to 15 percent to their weight after taking thepills for less than 12 weeks. The patients, ages 4 to 19, added an average of one to one-and-a-half poundsa week.“The degree of weight gain is alarming,” said Dr. Wayne K. Goodman, head ofa Food and Drug Administration advisory panel on the drugs last summer andchairman of psychiatry at Mount Sinai School of Medicine in Manhattan. “Themagnitude is stunning,” he said.Although the drugs’ influence on weight and metabolism had been previouslydetected, Dr. Goodman, who was not involved in the study, said the speed andmagnitude of the effects found in the study were greater than previouslyreported — findings he said were made possible by looking exclusively at newpatients.The four drugs in the study, the most popular antipsychotic medications, areindustry blockbusters, with combined sales of $12.7 billion last year. Andwhile all four caused weight gain, there were differences in the extent ofthe side effects. Among them, Zyprexa, made by Eli Lilly & Company, showedthe most severe effects on weight and metabolism. The study’s authors, andan accompanying JAMA editorial, called for closer monitoring of patientstaking the drugs, as well as additional long-term studies.The drugs are prescribed for schizophrenia, bipolar disorder and a broadrange of less serious psychological conditions. Their use by children andteenagers has been rising steadily. A 2008 study found that patients under19 years old accounted for 15 percent of antipsychotic drug use in 2005,compared with 7 percent in 1996.The study, financed by federal grants, is the largest yet published onchildhood use of the drugs. And because it is also the largest study offirst-time users of the drugs, whether children or adults, it provided anopportunity to analyze the cause and severity of near-term side effects.As a result, the study goes further than previous research in distinguishingvarying metabolic effects among the four drugs, according to Dr. Judith L.Rapoport, another expert who was not involved in the research.“It’s by far the best documentation of not just weight gain and metabolicchanges but also suggesting there might be differences among the drugs,” Dr.Rapoport, chief of the child psychiatry branch at the National Institute ofMental Health, said in an interview.The lead researcher, Dr. Christoph U. Correll of Zucker Hillside Hospital inQueens and the Feinstein Institute for Medical Research in Manhasset, N.Y.,said researchers had saved their blood work for future study of themolecular basis of the different drugs’ metabolic effects.“People should think twice before they actually prescribe the medications,”Dr. Correll said in a phone interview. The drugs studied are in a classknown as atypical antipsychotics, which are second-generation psychiatricdrugs that in some cases regulate the receptors in the brain that interactwith the mood-altering hormones serotonin and dopamine.Abilify and Risperdal are the only two of the four drugs approved aspediatric treatments, for the severe mental conditions schizophrenia andbipolar disorder — and in Risperdal’s case, for some children with autism.More than 70 percent of atypical antipsychotics’ use in young children andteenagers has been off-label prescriptions for nonpsychotic conditions likeattention deficit hyperactivity disorder, according to Stephen Crystal, aRutgers University professor who studies the drugs.Dr. Rapoport said Lilly’s Zyprexa drug, introduced in 1996, had been soheavily marketed that it was in widespread use before physicians began torecognize the severity of its side effects a few years ago. Zyprexa hascontinued selling in the range of nearly $3 billion a year in the UnitedStates even as concerns emerged about its tendency to cause patients to gainweight.Abilify, from Bristol-Myers Squibb, showed the least metabolic effects amongthe four drugs in the study. “It’s considered a very good but weaker drug,”Dr. Rapoport said.The other two drugs in the study, whose weight-related side effects fellbetween Zyprexa and Abilify, were Risperdal and Seroquel. Seroquel, fromAstraZeneca, had United States sales of $2.2 billion in the first six monthsof this year, according to IMS Health, a research company. Abilify had salesof $1.9 billion during that period; Zyprexa, $1.5 billion; and Risperdal,from Johnson & Johnson, $660 million.A Lilly spokesman, Jamaison R. Schuler, said the new research echoed Lilly’sown findings and previous studies about weight gain and metabolic changesthat led to a label warning being placed on Zyprexa in October 2007. But inan interview, he said the drug was still essential to sparing children alifetime of psychological suffering.“It’s important to recognize that severe mental illnesses, includingschizophrenia and bipolar 1 disorder, often strike during adolescence andare devastating,” Mr. Schuler said.In an editorial accompanying the study in the journal, Dr. Christopher K.Varley and Dr. Jon McClellan, child psychiatrists at Seattle Children’sHospital and the University of Washington school of medicine, wrote that“ominous long-term health implications” arise from weight gain and changesin blood fat levels early in life. “These results challenge the widespreaduse of atypical antipsychotic medications in youth,” they wrote.Dr. Varley said in a phone interview Monday that doctors had been loath touse the older antipsychotic medicines, like Thorazine and Haldol, because ofneurological side effects. But he said the new data indicated that the newerones should be prescribed more cautiously.“In the course of less than 12 weeks, the weight gains are startling,” hesaid. “If you look at Zyprexa, the kids are gaining a pound and a half aweek. Even with the drug Abilify, which is one that was not so prone toweight gain, kids still gained a pound a week. In addition, they hadevidence in a very short period of time of other metabolic problems.”The study covered 272 patients visiting clinics in Brooklyn, Queens and LongIsland from 2001 to 2007. Fifteen patients who stopped taking their medicinewere used as a control group. Their weight stayed level. The 257 patientswho stayed on their drugs took detailed tests, including a fasting bloodtest to check for high glucose levels.Their mean weight at the start of the study period was 118 pounds. But afterabout 11 weeks, those who took Zyprexa had gained 18.7 pounds; Seroquel,13.4 pounds; Risperdal, 11.7 pounds; and Abilify, 9.7 pounds.Their waists typically expanded three inches with Zyprexa, and two incheswith the others.All but Abilify showed rapid and significant increases in one or moremetabolic markers, which can presage adult obesity, hypertension and Type 2diabetes. The metabolic markers included glucose, insulin, triglycerides andcholesterol.The authors noted that the study had limitations. Patients were not randomlyassigned, so the baseline starting weights differed. Clinicians, given thechoice, started heavier patients on Seroquel and those with the lowest fatmass on Zyprexa, who then gained the most, the data show. Also, the studydid not control for dosing or other medications, which can affect outcome.Copyright 2009 The New York Times CompanyFAIR USE NOTICE: This may contain copyrighted (© ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit. _____________Infomail1 mailing listto send a message to Infomail1-leave =====In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.