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zoom RSS 自閉症の反復行動にSSRIセレクサは効果なし/米国医療事情

<<   作成日時 : 2009/06/03 20:14   >>

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画像 全国的な研究で citalopram は効果がなく、副作用が2倍であった。米国では自閉症の子どもの約1/3がセレクサと呼ばれる薬剤を服用している。
 自閉症の子供の反復性の行動をコントロールするのを手助けするとされる抗うつ剤は実際はプラセーボと変わらなかった。現在米国では自閉症と診断された子どもの約1/3がcitalopramやその類似薬の処方を受けている。
 米国には約150万人の自閉症患者がいる。強迫性反復性行動を特徴としており、制止されるとひどい癇癪をおこす。FDAにより認可されているのは自閉症の子どもの興奮や攻撃性に対して向精神薬のrisperidoneのみである。
 世界での自閉症治療薬使用は年間22-35億ドルと推計されている。ほとんど医薬品は自閉症の子どもに対して大規模な試験が行われていないので、強迫性障害やADHDなどでみられる似た症状の治療薬に医師は目を向けている。
 自閉症患者に見られる反復性行動が似ていることと、自閉症がセロトニンシステムに問題があると知られているために、成人の強迫性障害に対して使用される、選択的セロトニン再吸収阻害剤SSRIsと呼ばれる抗うつ剤の一群が、効果があると医師は期待していた。
 強迫症状と自閉症の反復性の行動の根本原因が同じ生物学的原因ならば、薬物は作動する可能性があるが、新しい研究ではそうではないことを強く示唆する。
 プラセーボの方がやや効果があったばかりでなく、薬の副作用--衝動性や不眠症などの--は少なくとも倍くらい悪かったという。
 米国ではセレクサとして売られている。
 UCLAを含め6つのメディカルセンターで177人の中等度以上の衝動性を持つ5-7才の自閉症児を2群に分け73人に12週間投与し、76人にプラセーボを投与し、反復性行動に対する効果を見た。投与群では33%の改善、プラセーボ群は34%の改善だった。ランダム化二重盲検の薬剤評価研究の重要性が強調される結果である。
 臨床試験で子どもに細かな注意がはらわれた場合は、行動が改善される傾向にある。
---------------------------------------------------
Study finds antidepressant doesn't help autistic children
http://www.latimes.com/news/nationworld/nation/la-sci-autism-drugs2-2009jun02,0,1928376.story
Nationwide research finds that citalopram is no more effective than a placebo and that its side effects are twice as bad. About a third of autistic kids take the drug, known as Celexa in the U.S.
By Karen Kaplan
June 2, 2009
An antidepressant commonly prescribed to help autistic children control their repetitive behaviors is actually no better than a placebo, according to a report published today.

Roughly a third of all children diagnosed with autism in the U.S. now take citalopram, the antidepressant examined in the study, or others that are closely related. The results of the nationwide trial, published in Archives of General Psychiatry, have some experts reconsidering the appropriateness of antidepressants and other mind-altering drugs used to treat children with autism spectrum disorders.

"There are tons of things being advocated as treatments for autism, some with appropriate caveats and careful explanations, others without any of that," said David Mandell, associate director of the Center for Autism Research at Children's Hospital of Philadelphia, who wasn't involved in the study.

An estimated 1.5 million Americans have autism, a group of poorly understood developmental disorders characterized by problems with communication and social interaction. One of the hallmarks of the disorder is obsessive, repetitive behavior such as flapping one's arms or hands or memorizing car makes and models. When those routines are interrupted, severe tantrums can result.

Only one medication -- the antipsychotic drug risperidone -- has been approved by the Food and Drug Administration for the treatment of irritability and aggression in children with autism. But doctors, frustrated by their limited options, haven't shied away from giving other pharmaceuticals a chance. Worldwide spending on drugs to treat autism is estimated to be $2.2 billion to $3.5 billion annually.

Because very few medications have been tested on autistic children in large, rigorous studies, doctors have looked to drugs that treat similar symptoms in other conditions, such as obsessive-compulsive disorder or attention-deficit hyperactivity disorder.

That's what led physicians to a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs, that help adults with obsessive-compulsive disorder. Their repetitive rituals, such as counting, cleaning or hand-washing, are reminiscent of the behaviors seen in autistic patients.

Doctors were also hopeful about SSRIs because the serotonin system is known to function improperly in people with autism.

But the medications will work only if the root causes of obsessive-compulsive disorder and autistic repetitive behavior involve the same biological pathways in the brain. The new study strongly suggests they do not.

"It just begs for a more careful understanding of the neurological underpinnings of the disorder," Mandell said.

Dr. Bryan King, director of psychiatry and behavioral medicine at Seattle Children's Hospital and leader of the study, said he was shocked to find that citalopram didn't help patients. Not only was the placebo slightly more effective, but the drug's side effects -- such as impulsivity and insomnia -- were at least twice as bad, the study found.

"I personally would have a healthy dose of skepticism about" prescribing citalopram or other SSRIs, King said. Citalopram is sold in the United States under the brand name Celexa.

In the study, King and his colleagues from six academic medical centers, including UCLA, enrolled 149 autistic children ages 5 to 17 whose compulsive behaviors were classified as moderate or worse. After 12 weeks, 33% of the 73 patients who took citalopram had improvements in repetitive behaviors as measured by clinicians and parents, versus 34% of the 76 patients who took a placebo.

If there hadn't been a control group for comparison, King said he would have been impressed by the improvement seen in the children who took the drug. "The decision would most definitely have been made to continue them," he said.

The study underscores the value of evaluating drugs in randomized, double-blind, placebo-controlled studies, which are considered the gold standard of medical research, Dr. Fred R. Volkmar, director of the Yale Child Study Center in New Haven, Conn., wrote in a commentary that accompanied the study. In such studies, neither patient nor doctor knows who is getting the drug and who is getting the placebo until all the results are in.

"We need more studies of this kind to advance research and guide clinical practice," Volkmar wrote.

Placebo-controlled studies are especially important in evaluating medications to treat behavior and mood because patients are typically in a crisis state when they enroll in a clinical trial and could improve on their own in time, Mandell said.

What's more, the attention focused on children when they are in a trial tends to improve their behavior all by itself, Volkmar said in an interview.

The study was funded by the National Institutes of Health. King and several of his colleagues have received research grants and other funding from pharmaceutical firms, including Forest Laboratories Inc. of New York, the maker of Celexa.

---------------------------------------------------
Lack of Efficacy of Citalopram in Children With Autism Spectrum Disorders and High Levels of Repetitive Behavior

Citalopram Ineffective in Children With Autism

Bryan H. King, MD; Eric Hollander, MD; Linmarie Sikich, MD; James T. McCracken, MD; Lawrence Scahill, MSN, PhD; Joel D. Bregman, MD; Craig L. Donnelly, MD; Evdokia Anagnostou, MD; Kimberly Dukes, PhD; Lisa Sullivan, PhD; Deborah Hirtz, MD; Ann Wagner, PhD; Louise Ritz, MBA; for the STAART Psychopharmacology Network

Arch Gen Psychiatry. 2009;66(6):583-590.

Context Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders.

Objectives To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders.

Design National Institutes of Health--sponsored randomized controlled trial.

Setting Six academic centers, including Mount Sinai School of Medicine, North Shore--Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School.

Participants One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders.

Interventions Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d).

Main Outcome Measures Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form.

Results There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P > .99). There was no difference in score reduction on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], --2.0 [3.4] points for the citalopram-treated group and --1.9 [2.5] points for the placebo group; P = .81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus.

Conclusion Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders.

Trial Registration clinicaltrials.gov Identifier: NCT00086645

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