yuyun 2009-11-30 11:27
使用非典型抗精神病藥物會增加小孩的心血管風險
作者：Caroline Cassels
出處：WebMD醫學新聞
November 10, 2009 — 有更多研究確認最近一篇大型世代研究的結果，心智疾病和行為異常的孩童與青少年，使用非典型抗精神病藥物(atypical antipsychotics，AAPs)時，體重顯著增加的風險會提高，而且會有各種代謝方面的改變。
在美國兒童與青少年精神科學院第56屆年會中，Christoph U. Correll醫師等人首次發表登載於10月28日美國醫學會期刊(Journal of the American Medical Association)中的兩篇新研究，研究指出，這些藥物會引起體重增加，且與各種不良代謝變化有關。
第一篇研究中，加拿大英屬哥倫比亞大學、兒童與婦女健康中心的研究者發現，代謝症候群(metabolic syndrome，MetS)的整體盛行率，在以AAP治療的病患中為27%，而未使用AAP的青年，此盛行率為2.9%。此外，研究者發現，以AAP治療的青年，各種MetS特徵的比率都較高。該研究也顯示，以AAP治療的病患，其他代謝參數也顯著上升。
【以AAP治療和未使用AAP病患的各種MetS特徵比率 】
[table][tr][td][align=center]MetS 特徵 [/align][/td][td][align=center]以 AAP 治療之病患百分比 [/align][/td][td][align=center]未使用 AAP 治療之病患百分比 [/align][/td][/tr][tr][td][align=center]肥胖 [/align][/td][td][align=center]32.7 [/align][/td][td][align=center]16.3 [/align][/td][/tr][tr][td][align=center]過重 [/align][/td][td][align=center]23.6 [/align][/td][td][align=center]12 [/align][/td][/tr][tr][td][align=center]腰圍增加 [/align][/td][td][align=center]49.1 [/align][/td][td][align=center]17.9 [/align][/td][/tr][tr][td][align=center]高三酸甘油脂血症 [/align][/td][td][align=center]42.6 [/align][/td][td][align=center]22.4 [/align][/td][/tr][tr][td][align=center]空腹血糖值不佳 [/align][/td][td][align=center]16.1 [/align][/td][td][align=center]2.6 [/align][/td][/tr][tr][td][align=center]血壓升高 [/align][/td][td][align=center]53.7 [/align][/td][td][align=center]17.6 [/align][/td][/tr][/table]
主要研究者、Dina Panagiotopoulos醫師在訪問中向Medscape Psychiatry表示，相較於未曾使用非典型藥物治療者，最令人吃驚的發現之一是那些使用非典型藥物孩童的代謝症候群盛行率。我認為，這次首次有這麼高的盛行率報告。
【證據越來越多】
根據Panagiotopoulos醫師指出，在成人，有越來越多證據顯示，AAPs會引起體重增加、高脂質血症、胰島素阻抗性，增加了醫界對於一般人、特別是精神病患者的考量，以及這些藥物是否會增加孩童與青少年的早熟性心血管疾病的風險。
Panagiotopoulos醫師表示，估計美國約有將近20%的青少年有心智疾病，而其中有許多人使用AAP治療。
Panagiotopoulos醫師表示，我們決定進行此研究，是我們觀察發現，服用這些藥物、特別是quetiapine的年輕病患有突發的糖尿病。
Panagiotopoulos醫師指出，根據美國糖尿病學會、美國精神病協會與其他團體在2004年發布的指引，建議對使用AAPs的成年人定期監測代謝參數，她的研究團隊決定發展一種針對孩童與青少年代謝副作用的系統方法。目前，對於服用AAPs的孩童並沒有此類指引可用。
Panagiotopoulos醫師表示，我們知道未曾有人以一致性或系統性方法完成這個，所以我們發展並執行一種代謝監測協定。我們如此關注的原因，不單單是因為糖尿病風險，還包括其他風險因素，如血脂異常與腰圍增加，會持續到成年且增加心血管疾病和其他併發症風險。
【代謝監測協定】
為了評估AAPs對青少年的代謝影響，研究者使用他們發展的一套代謝監測協定，比較使用AAP治療的青少年和未使用AAP者。MetS的小兒科定義包括以下參數中的至少3項：
* 三酸甘油脂≧1.24 mmol/L (110 mg/dL)
* HDL ≦1.03 mmol/L (40 mg/dL)
* 腰圍高於年紀與性別指標的第90百分位
* 收縮壓或舒張壓高於年紀、性別與身高指標的第90百分位
* 空腹血糖 ≧ 5.6 mmol/L (100 mg/dL)
該研究的研究對象包括，於2008年1至12月間，因為精神病或躁鬱症而短期住院到精神科病房的176名病患。
這些研究對象中，66人有服用AAPs (57.5% 為男性；年紀平均± SD為12.8 ± 2.7歲)，其他110人(54.5%為男性；年紀平均± SD為14.3 ± 2.4 歲)在入院時未曾用過AAP。
所有研究對象中，27人服用risperidone、23人服用quetiapine、13人服用olanzapine、2人同時服用risperidone和quetiapine。
該研究強度不足以發現這些製劑中的差異，不過，Panagiotopoulos醫師表示，研究團隊將繼續蒐集資料，之後以更大型的樣本進行分析，以回答此一問題和其他研究問題。
我們的初步分析認為，olanzapine比較可能有其他風險。我們進行迴歸分析，探討其他假設的獨立風險因素，包括心智疾病本身、種族或併用其他精神科藥物，如抗憂鬱劑或情緒穩定劑，但是並無證據支持。
她指出，不過，有一個顯著趨勢顯示，男性是一個獨立風險因素。Panagiotopoulos醫師表示，我們將以更大型的樣本來檢驗，看此發現是否依舊為真。
她指出，整體而言，此研究發現和Correll醫師最近在JAMA的研究相當一致，所以這些其實並不令人驚訝。
【令人驚訝的發現】
相對的，第一篇研究的共同研究者Margaret Weiss博士領導的另一篇研究，提出一個令人驚訝的發現。
研究者檢視極低劑量AAPs用於注意力不足過動障礙症(attention-deficit/hyperactivity disorder，ADHD)併有破壞性行為障礙孩童的代謝方面效果。他們發現，儘管劑量很低且服用這些AAPs小孩的身體質量指數也低，還是會發生代謝異常。
Weiss博士向Medscape Psychiatry表示，因為這些小孩很瘦，一般會認為不會有代謝問題，但實際上，我們發現超過16%有完整的代謝症候群，最引人注意的是，即使他們相當瘦，他們的腰圍仍增加，所以，證明代謝症候群的預測因子是腰圍而非體重。
該研究包括了在單一中心治療ADHD的194名孩童，其中，23人沒有服用藥物，134人只有服用ADHD藥物，37 人服用AAPs治療行為問題：活動、憤怒與情緒失調。
AAP組小孩的平均年紀為12.3歲，多數(86.5%)為男生。AAP組的小孩多數有服用risperidone、平均劑量為0.62 mg。平均治療期間為313天。
研究者發現，相較於其他兩個研究組，服用AAPs的小孩，其代謝異常風險顯著增加。這一組超過三分之二(68.0%)的腰圍高於第90百分位，且與體重增加無關。此外，18.5%的空腹血糖值不佳、12.5%血壓上升、11.1%三酸甘油脂增加、16.7%符合各種MetS指標。
【急需指引】
Weiss博士表示，我們關心的是，使用AAPs治療ADHD孩童的破壞性行為，這種非適應症用法相當普遍，本研究中，有五分之一的病患接受此種藥物治療。
需要後續研究來確認，此類病患廣泛使用這些藥物是否會有長期的健康後遺症。
同時，Weiss博士和Panagiotopoulos醫師都相信，一定要對服用這些藥物的年輕病患增加代謝方面進行監測。
這些是檢驗數據，它們是否真的就代表長期的心血管風險，還有待觀察。現在，最合理的因應措施是，發展縝密考量的實務指南。
Weiss博士表示，我們對使用興奮劑者發布監測心血管的實務指引，卻沒任何證據顯示是否有心血管風險，現在，我們有了明確的證據卻沒有發展實務指引，所以，服用這些藥物的多數孩童都沒有任何檢驗監測。
Panagiotopoulos醫師指出，精神科醫師也需要增加警覺，注意服用AAPs孩童之潛在的代謝影響，也須著手進行標準化的代謝監測。
她表示，目前的大挑戰之一是，心智健康照護不一定會使用藥物，多數孩童只是接受諮商而已，沒有支持代謝監測的基礎，所以我認為，有鑑於證據增加，我們必須改變模式，讓孩子們可以適當的進行長期監測。
Panagiotopoulos醫師指出，她的團隊目前正在發展AAPs用於孩童與青少年之代謝影響的相關教育資源，包括給小兒科住院醫師的手冊，目前正以一個先驅研究檢視該手冊。
她表示，我們希望將知識轉化為行動並改變實務，所以我們從小兒科住院醫師開始，希望可以幫助下一代的小孩和醫師。
Correll醫師和 Panagiotopoulos醫師皆宣告沒有相關財務關係。
美國孩童與青少年精神科學院：摘要3.40和4.25。發表於2009年10月29日和30日。
[size=4][b]More Evidence Atypical Antipsychotic Use May Boost Kids' Cardiovascular Risk[/b][/size]
[i]By Caroline Cassels
Medscape Medical News[/i]
November 10, 2009 — More research appears to confirm recent results of a large cohort study that the use of atypical antipsychotics (AAPs) increases the risk of significant weight gain and varied metabolic changes in children and adolescents with mental illness and behavioral disturbances.
Two new studies presented here for the first time at the American Academy of Child Adolescent Psychiatry 56th Annual Meeting confirm findings by Christoph U. Correll, MD, and colleagues published in the October 28 issue of the [i]Journal of the American Medical Association[/i] that these medications cause weight gain and are associated with varied adverse metabolic changes.
In the first study, investigators from the University of British Columbia, Children's and Women's Health Centre in Vancouver, Canada, found the overall prevalence of metabolic syndrome (MetS) was 27% in AAP-treated patients vs 2.9% in AAP-naive youth. In addition, the researchers found higher rates of all features of MetS in AAP-treated youth. The study also showed significantly increased rates of other metabolic parameters in AAP-treated patients.
[b]Rates of MetS Features in AAP-Treated and AAP-Naive Patients[/b]
[table][tr][td][b]MetS Features[/b] [/td][td][b]Percentage of AAP-Treated Patients [/b][/td][td][b]Percentage of AAP-Naive Patients[/b] [/td][/tr][tr][td]Obese[/td][td]32.7[/td][td]16.3[/td][/tr][tr][td]Overweight[/td][td]23.6[/td][td]12[/td][/tr][tr][td]Elevated waist circumference[/td][td]49.1[/td][td]17.9[/td][/tr][tr][td]Hypertriglyceridemia[/td][td]42.6[/td][td]22.4[/td][/tr][tr][td]Impaired fasting glucose level[/td][td]16.1[/td][td]2.6[/td][/tr][tr][td]Elevated blood pressure[/td][td]53.7[/td][td]17.6[/td][/tr][/table]
"One of the most startling findings was the prevalence of metabolic syndrome in kids treated with atypicals vs the non-treated kids. I think this is the first time such a high prevalence has been reported," principal investigator Dina Panagiotopoulos, MD, told [i]Medscape Psychiatry[/i] in an interview.
[b]Growing Body of Evidence[/b]
According to Dr. Panagiotopoulos, a growing body of evidence in adults demonstrating that AAPs cause significant weight gain, hyperlipidemia, and insulin resistance has raised concerns among the medical community in general, and the psychiatric community in particular, about whether these drugs may increase the risk of premature cardiovascular disease in children and adolescents.
It is estimated that approximately 20% of youth in the United States have a mental illness and many of them will be treated with an AAP, said Dr. Panagiotopoulos.
"We decided to undertake this research based on observations of sudden-onset diabetes in some of our young patients who were taking these medications — particularly quetiapine," Dr. Panagiotopoulos said.
Dr. Panagiotopoulos added that based on guidelines in adults issued by the American Diabetes Association, the American Psychiatric Association, and other groups in 2004 that recommended regular monitoring of metabolic parameters in adults taking AAPs, her research team set out to develop a systematic approach to look at the metabolic side effects in children and adolescents. There are currently no such guidelines for children taking AAPs.
"We knew this had never been done in a consistent or systematic way and so we implemented a metabolic monitoring protocol. The reason we are so concerned is not just because of the diabetes risk, but we know that some of these other risk factors, such as dyslipidemia and elevated waist circumference, can track into adulthood and increase the risk for cardiovascular disease and other complications," said Dr. Panagiotopoulos.
[b]Metabolic Monitoring Protocol [/b]
To assess the metabolic effects of AAPs in youth, the investigators compared AAP-treated and AAP-naive youth using the metabolic monitoring protocol they developed. The pediatric definition of MetS consisted of at least 3 of the following parameters:
[list][*]Triglycerides ? 1.24 mmol/L (110 mg/dL)[*]HDL ? 1.03 mmol/L (40 mg/dL)[*]Waist circumference ? 90th percentile for age and sex[*]Systolic or diastolic blood pressure ? 90th percentile for age, sex, and height[*]Fasting glucose ? 5.6 mmol/L (100 mg/dL)[/list]The study included 176 patients admitted for psychosis or bipolar disorder to a short-stay, inpatient psychiatric unit from January to December 2008.
Among the participants, 66 were taking AAPs (57.5% male; mean ± SD age, 12.8 ± 2.7 years) and 110 (54.5% male; mean ± SD age, 14.3 ± 2.4 years) were AAP naive on admission.
Of the total study group 27 were taking risperidone, 23 were taking quetiapine, 13 were taking olanzapine, and 2 were taking both risperidone and quetiapine.
The study was not powered to detect differences among agents. However, Dr. Panagiotopoulos said the research team will continue to collect data and then conduct further analyses in a larger sample size to answer this and other research questions.
"Our initial analysis suggests that olanzapine may be more likely to confer additional risk. We conducted a regression analysis looking at additional proposed independent risk factors, including mental illness itself, ethnicity, or the addition of other [psychotropic] medications, such as antidepressants or mood stabilizers, but there was no evidence that this was the case."
However, she added, there was a significant trend toward male sex being an independent risk factor. "We're going to have to see whether, with an increased sample size, this finding holds true," said Dr. Panagiotopoulos.
"Overall," she added, "the study findings were pretty consistent with Dr. Correll's recent study in [i]JAMA[/i] and so there really weren't any surprises here."
[b]Surprise Finding[/b]
In contrast, a second study led by Margaret Weiss, MD, PhD, who was also a coinvestigator on the first study, produced a surprising finding.
Investigators examined the metabolic effects of very low-dose AAPs in children with attention-deficit/hyperactivity disorder (ADHD) with comorbid disruptive behavior disorders. They found that despite very low doses and low body mass index children taking AAPs also developed metabolic disturbances.
"Because these children are always very thin, it was assumed that there would be no metabolic findings, but actually what we found was that more than 16% had full metabolic syndrome and what was most interesting was that even though they were very thin, their waste circumference grew — so it turned out it was waist circumference and not weight that was a predictor of metabolic syndrome," Dr. Weiss told [i]Medscape Psychiatry.[/i]
The study included 194 children being treated for ADHD in a single center. Of these, 23 were taking no medication, 134 were taking ADHD medications alone, and 37 were taking AAPs to treat behavioral problems, including reactivity, rages, and mood dysregulation.
The mean age of children in the AAP group was 12.3 years, and most (86.5%) were male. Most patients in the AAP group were taking risperidone, with a mean dose of 0.62 mg. The mean duration of treatment was 313 days.
The investigators found that compared with the other 2 study groups children taking AAPs were at significantly increased risk of metabolic disturbances. More than two-thirds of this group (68.0%) had a waist circumference ? 90th percentile independent of weight gain. In addition, 18.5% had an impaired fasting glucose level, 12.5% had elevated blood pressure, 11.1% had elevated levels of triglycerides, and 16.7% met full criteria for MetS.
[b]Urgent Need for Guidelines[/b]
Of concern, said Dr. Weiss, is that off-label use of AAPs to treat disruptive disorders in children with ADHD is common, with 1 in 5 patients in this study receiving these medications.
Further studies are needed to determine whether the widespread use of these drugs in this patient population has long-term negative health consequences.
In the meantime, both Dr. Weiss and Dr. Panagiotopoulos believe there is an urgent need for increased metabolic monitoring in young patients taking these medications.
"These are laboratory findings and whether they do in fact represent a risk for long-term cardiovascular risk remains to be seen. The most reasonable response right now is to develop well-thought-out practice guidelines.
"We put out practice guidelines for cardiovascular monitoring for the use of stimulants without any evidence whatsoever that there is a cardiovascular risk. Here, we have unequivocal evidence but no practice guidelines have been developed, so the vast majority of children taking these medications receive no laboratory monitoring whatsoever," said Dr. Weiss.
Dr. Panagiotopoulos added that there is also a need to increase awareness among psychiatrists of the potential metabolic effects in children taking AAPs and a need to institute standardized metabolic monitoring.
"One of the big challenges here is that mental health care is not 'medicalized.' Most kids just go in for counseling and that's it. There is no infrastructure to support metabolic monitoring, and so I think in light of this growing body of evidence we may have to change the model, so kids can be appropriately monitored over the long-term," she said.
Dr. Panagiotopoulos added that her team is currently developing educational resources about the metabolic effects of AAPs in children and adolescents, including a handbook for pediatric residents, which is currently being tested in a pilot study.
"We want to turn that knowledge into action and change practice, and so we figure by starting with pediatric residents we may be able to help the next generation of children and physicians," she said.
[i]Dr. Correll and Dr. Panagiotopoulos have disclosed no relevant financial relationships. [/i]
American Academy of Child & Adolescent Psychiatry: Abstract 3.40 and 4.25. Presented October 29 and October 30, 2009.