AAGP 2009：尼古丁貼片可能對於認知功能受損有益

作者：Caroline Cassels  
出處：WebMD醫學新聞

　　March 11, 2009（夏威夷檀香山）－ 新研究結果顯示，經皮尼古丁貼片可能幫助輕微認知功能受損（MCI）病患改善記憶。
　　
　　這項來自一項大型、雙盲、多中心的先驅研究，發表於美國老年精神學學會2009年年會，結果顯示尼古丁貼片可以改善專注力、記憶與速度，還有許多其他評量也顯示出有明顯改善的趨勢。
　　
　　主要研究者、來自布靈頓Vermont大學醫學院的Paul Newhouse醫師向Medscape精神學表示，尼古丁刺激改善認知功能表現，經皮吸收尼古丁貼片改善這個族群病患延遲單字記憶回想正確率，且加快記憶運行的速度。
　　
　　在過去的20年間，Newhouse醫師與其同事致力於研究尼古丁作為改善許多疾病認知功能的一個可能途徑。
　　
　　在1980年代時，他與其他的團隊開始針對刺激尼古丁受體作為改善罹患阿茲海默氏症、其他失智症形式、以及注意力缺乏/過動異常，還有MCI病患，改善認知功能的一個可能方法。
　　
　　他指出，他的許多研究重點放在研發治療這些疾病的全新尼古丁致效劑，這項研究目前仍持續進行中。
　　
　　【理想標的】
　　目前的這項研究由國家高齡化機構（NIA）贊助，目的在於確認經皮吸收尼古丁貼片是否可以改善MCI病患的認知功能，這是一個從正常認知功能至之後發展成失智症的轉換期。
　　
　　他表示，我們知道尼古丁受體功能對於整體膽鹼激性功能來說是關鍵部分，我們想要看是否展現刺激尼古丁受體功能可以增進MCI病患的認知功能；從許多方面來看，MCI確實是個尼古丁治療的良好標的，因為有此狀況的病患並未完全喪失這些尼古丁受體。
　　
　　來自Vermont大學、杜克大學以及喬治城大學三個不同中心的研究者們，共收納了74位未吸菸且合乎失憶MCI標準的受試者；受試者被隨機分派在試驗的前6個月接受雙盲的尼古丁或是安慰劑貼片，接著是6個月的交換期，在這段期間所有受試者都接受藥物治療。
　　
　　在雙盲期中，受試者們在試驗前、91與182天時接受認知功能檢驗，以認知藥物研究電池（一種電腦化評估）、康納氏連續表現任務（CPT）以及臨床整體改變印象（CGIC）來進行評估。那些被隨機分派接受尼古丁的受試者，在不知情的情況下於3週間逐漸增加使用劑量，從每天5毫克增加到15毫克。
　　
　　Newhouse醫師表示，我們發現，在6個月的試驗期間，治療組中有23%、控制組中有9%受試者的整體評估分數是增加的。這差一點達到統計上顯著差異，但我們相信這是因為這項研究沒有足夠的統計力量去偵測到顯著差異。
　　
　　除此之外，受試者自我評分的認知功能受損以及靈敏度顯示偏好尼古丁治療的強烈趨勢。
　　
　　【出乎意料的降血壓作用】
　　以受試者的APOE e4狀態治療效果分析顯示一種基因型效應，對沒有這個對偶基因的受試者，在CGIG評分與表現評量上有很強的治療反應。
　　
　　Newhouse醫師指出，不良反應是輕微的，且最終在安慰劑組與治療組之間是相仿的。他表示，這並非意料之外，相較於安慰劑組受試者，在尼古丁組的受試者體驗到微小但顯著的體重下降；有趣的是，那些在藥物治療組的受試者體驗到統計上顯著的收縮血壓下降，這是個意料之外的發現。
　　
　　一般的情況下，你聽到尼古丁對於心血管健康有負面影響，因此這個血壓的下降是意料之外的；他表示，除了這可能與腦幹機轉有關的說法之外，我們目前無法解釋這樣的發現。
　　
　　來自這項研究開放標記的數據分析目前尚未完成。然而，Newhouse醫師表示，來自雙盲期的發現提供了需要進行較大型研究足夠強度的訊號。
　　
　　我們已取得更多的數據，以持續與NIA進行及計畫一項更大型的研究，來看經皮吸收尼古丁貼片是否為失智型MCI病患適當的治療；他表示，，如果這樣的療法有效，我們將有安全、便宜且有效的治療。
　　
　　這項研究由國家高齡化機構贊助。

AAGP 2009: Nicotine Patch May be Helpful in Mild Cognitive Impairment

By Caroline Cassels
Medscape Medical News

March 11, 2009 (Honolulu, Hawaii) — Transdermal nicotine treatment may help improve memory in patients with amnestic mild cognitive impairment (MCI), new research suggests.

Presented here at the American Association of Geriatric Psychiatry 2009 Annual Meeting, results from a large, double-blind, multicenter pilot study show that nicotine patches improve attention, memory, and speed, with several other measures showing strong trends toward improvement.

"There's a strong signal that nicotinic stimulation improves cognitive performance and that transdermal nicotine improves delayed-word-recall accuracy and the speed of memory processes in this patient population," principal investigator Paul Newhouse, MD, from the University of Vermont School of Medicine, in Burlington, told Medscape Psychiatry.

For the past 20 years, Dr. Newhouse and colleagues have been researching nicotine as apossible way of enhancing cognitive function in several different disorders.

During the 1980s, he said, his group and others began looking at stimulating nicotinic-receptor function as a possible method of improving cognitive function in individuals with Alzheimer's disease, other dementia types, and attention-deficit/hyperactivity disorder as well as MCI.

Much of this work, he said, focused on developing novel nicotinic agonists to treat these conditions — a research effort that is ongoing.

Ideal Target

The objective of the current study, which is funded by the National Institute on Aging (NIA), was to determine whether transdermal nicotine could improve cognitive function in MCI, a condition that is widely held to be a transitional stage between normal cognitive function and the subsequent development of dementia.

"We know that nicotinic-receptor function is a critical part of overall cholinergic function. We wanted to see whether we could demonstrate that stimulating nicotinic-receptor function enhances cognition in MCI patients. In many ways, MCI is really the ideal target for nicotine [therapy] because patients with this condition have not yet lost all of their nicotinic receptors," he said.

Investigators at 3 centers — the University of Vermont, Duke University, and Georgetown University — recruited 74 nonsmoking subjects who met the criteria for amnestic MCI.

Participants were randomized to receive either a double-blind nicotine or placebo patch for the first 6 months of the study, followed by a 6-month crossover phase in which all subjects received active treatment.

During the double-blind phase, subjects were cognitively assessed at baseline, 91, and 182 days using the Cognitive Drug Research battery (a computerized assessment), the Conners Continuous Performance Task (CPT), and the Clinical Global Impression of Change (CGIC). Those randomized to receive nicotine had their dose blindly titrated from 5 mg to 15 mg per day over 3 weeks.

"We found that over a 6-month period, 23% of those in the treatment group vs 9% of subjects in the placebo group were improved on the global assessment. This just missed statistical significance, but we believe this is because the study was slightly underpowered to detect statistical significance," said Dr. Newhouse.

In addition, subjects' self-ratings of cognitive impairment and alertness showed a strong trend in favor of nicotine treatment.

Unexpected BP-Lowering Effect

An analysis of treatment effect by subjects' APOE e4 status showed a genotype effect, with a stronger treatment response in CGIC ratings and performance measures in subjects without the allele.

Adverse events, said Dr. Newhouse, were mild and evenly split between the placebo and treatment groups. Not unexpectedly, he said, those in the nicotine group experienced a small but significant decline in weight compared with placebo subjects. Interestingly, he said, those in the active-treatment group experienced a statistically significant reduction in systolic blood pressure — an unexpected finding.

"Normally, you hear that nicotine has an adverse effect on cardiovascular health, so this drop in blood pressure was unexpected. We are at a loss to explain it, except to say it may be a brain-stem mechanism," he said.

Analysis of data from the open-label phase of the study is not yet complete. However, said Dr. Newhouse, the findings from the double-blind phase provide a strong enough signal of efficacy to warrant a larger study.

"We've got enough data now to go forward and propose a much larger study to the NIA to see whether transdermal nicotine may be an appropriate treatment for amnestic MCI. If it works out, we would have a treatment that is safe, cheap, and effective," he said.

The study was funded by the National Institute on Aging.

American Association for Geriatric Psychiatry 2009 Annual Meeting: Abstract NR 89. Presented March 6, 2009.