憂鬱症的福音~快速作用的抗憂鬱藥物

快速作用的抗憂鬱藥物在未來可能是可行的

作者：Marlene Busko
出處：WebMD醫學新聞

　　December 20, 2007 — 根據一項發表於美國神經藥理學學會第46屆年會的研究結果，針對腦內麩氨酸受體的研究，可能在某天可以研發出新一代的快速作用抗憂鬱藥物；這項會議於佛羅里達博卡拉頓舉辦。
　　
　　主要研究者Husseini Manji醫師，他是馬里蘭班塞斯達情緒與焦慮異常計畫主任，他向Medscape神經學與神經外科學表示，我們不需要勉強接受抗憂鬱藥物需要幾個星期才有作用的特性，因為我們可能研發出僅要幾個小時就有作用的抗憂鬱藥物。
　　
　　他表示，這項研究將引導我們研發出新一代的抗憂鬱藥物。
　　
　　【作用起始時間：幾個小時比上幾週】
　　這些研究的動力是傳統的抗憂鬱藥物，這些藥物針對血清素與正腎上腺素，並不是對所有病患都有效的；大約僅有50%的病患對特定抗憂鬱藥物是有效的，而且當發揮效用時，其中又需要幾個禮拜才能生效，他表示，這段時間病患處於相當的壓力之下。
　　
　　過去的動物實驗，誘發動物發生類似憂鬱的症狀，接著給牠們服用傳統的抗憂鬱藥物，幾個星期之後顯示這些藥物會影響麩氨酸受體；Manji醫師表示，這代表直接調控麩氨酸受體的作用將可以跳過許多介入步驟，且可能這樣的抗憂鬱藥物作用會更好、更快。
　　
　　其他動物實驗顯示，阻斷N-甲基-D-天門冬酸鹽（NMDA）麩氨酸受體可以緩解憂鬱症狀。
　　
　　Manji醫師與其同事研究低劑量的ketamine，一種NMDA受體拮抗劑，該藥物經常以較高劑量用於麻醉。
　　
　　他們隨機分派了18位對治療反應不佳的病患，接受ketamine或是安慰劑輸注（Zarate CA等人，Arch Gen Psychiatry 2006;63:856-864）；平均來說，受試者已經有憂鬱症的症狀達3年，且已經接受其他6種抗憂鬱藥物治療，但效果不佳。
　　
　　研究者觀察到，接受ketamine病患的抗憂鬱效果在2小時內發生，在24小時時，71%接受ketamine治療病患達到有反應的條件，也就是漢米爾墩憂鬱指數下降50%，而29%病患達到症狀消退的條件，在7天時，35%病患持續有反應。
　　
　　Manji醫師指出，這樣的研究結果是非常令人印象深刻的，且導致後續有許多研究跟進。
　　
　　接下來的一項在小鼠身上進行的研究顯示，ketamine透過阻斷NMDA受體，增加阿法-3-氫氧根-5-甲基-4-異構唑丙酸鹽（AMPA）受體活性，這對於藥物的快速抗憂鬱效果是很重要的（Maeng S等人，Biol Psychiatry. 2007;DOI:10.1016/j.biopsych.2007.05.028）。
　　
　　在另一項研究中，初期的證據顯示，合併ketamine與riluzole，一種由美國食品藥物管理局核准用於治療多發性硬化症的抗癲癇藥物，可以延長ketamine的抗憂鬱作用。
　　
　　當ketamine本身因為其不良反應，包括產生幻覺，而可能無法作為一個抗憂鬱藥物，透過將重點放在更直接的標的，例如NMDA或是AMPA受體的藥物，科學家可能可以在未來研發出作用更快、更有效的抗憂鬱藥物。

Faster-Acting Antidepressants Might Be Feasible in Future

By Marlene Busko
Medscape Medical News

December 20, 2007 — Research targeting glutamate receptors in the brain might some day lead to a new generation of fast-acting antidepressants, according to findings presented at the American College of Neuropsychopharmacology 46th Annual Meeting, in Boca Raton, Florida.

"We don't need to settle for antidepressant treatments that take weeks to work, since it may be possible to develop an antidepressant that would work in hours," lead researcher Husseini Manji, MD, director of the mood and anxiety disorders program at the National Institute of Mental Health, in Bethesda, Maryland, told Medscape Neurology & Neurosurgery.

"This research is leading to some very real possibilities for a whole new generation of antidepressant medications," he said.

Onset of Action: Hours vs Weeks

The impetus for these investigations is that traditional antidepressants, which focus on serotonin and norepinephrine, are not effective for all patients. Only about 50% of patients respond to a given antidepressant, and when they do respond, there is a major lag of onset of weeks, during which the patient is under considerable distress, he noted.

Previous animal studies, in which depressionlike symptoms were induced in mice that were then given traditional antidepressants, showed that after several weeks, the drugs affected glutamate receptors. This suggested that manipulating glutamate receptors directly would bypass a lot of intervening steps, and maybe this antidepressant treatment would work better and faster, said Dr. Manji.

Other animal studies showed that blocking the N-methyl-D-aspartate (NMDA) glutamate receptor relieved symptoms of depression.

Dr. Manji and colleagues investigated the use of low-dose ketamine, an NMDA-receptor antagonist, which in higher doses is used as an anesthetic.

They randomized 18 patients with treatment-resistant depression to receive a single infusion of ketamine or placebo (Zarate CA et al. Arch Gen Psychiatry 2006;63:856-864). On average, the subjects had been depressed for the previous 3 years and had been treated unsuccessfully with 6 other antidepressants.

The researchers saw antidepressant effects in the ketamine-treated patients within 2 hours. By 24 hours, 71% of the ketamine-treated patients met the criteria for response — a 50% reduction in the Hamilton Depression Rating Scale score — and 29% met the criteria for remission. At 7 days, 35% of the patients maintained their response.

"That was very eye-opening at the time and led to a number of follow-up studies," said Dr. Manji.

A subsequent study in mice showed that ketamine, by blocking NMDA receptors, enhances the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which is crucial for the drug's rapid antidepressant actions (Maeng S et al. Biol Psychiatry. 2007;DOI:10.1016/j.biopsych.2007.05.028).

In another study, preliminary evidence suggests that combining ketamine with riluzole, an anticonvulsant that is approved by the Food and Drug Administration for amyotrophic lateral sclerosis, prolongs ketamine's antidepressant response.

While ketamine itself probably will not come into use as an antidepressant because of its adverse effects, including hallucinations, by aiming new medications at more direct targets such as NMDA or AMPA, scientists might be able to develop faster, more effective antidepressants in the future.

American College of Neuropsychopharmacology 46th Annual Meeting: December 9-13, 2007.