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Biol Psychiatry:实验药物有望‘在数分钟内’帮助治疗抑郁

2012-12-18 Biol Psychiatry Biol Psychiatry

       12月3日在线发表于《生物精神病学》的新研究表明,尽管一种被描述为“友好版氯胺酮”的新型实验药物似乎可快速减少抑郁症状,但其效应可能不会长期持续存在。        由国立精神卫生研究所(NIMH)的研究者进行的一项小型随机交叉研究显示,单次滴注AZD6765后,近32%的难治性重性抑郁障碍

       12月3日在线发表于《生物精神病学》的新研究表明,尽管一种被描述为“友好版氯胺酮”的新型实验药物似乎可快速减少抑郁症状,但其效应可能不会长期持续存在。

       由国立精神卫生研究所(NIMH)的研究者进行的一项小型随机交叉研究显示,单次滴注AZD6765后,近32%的难治性重性抑郁障碍(MDD)患者80分钟后症状评分显著降低,相比之下15%接受匹配安慰剂治疗的患者症状评分显著降低。

       尽管接受实验药物治疗后评分总体下降仅持续30分钟,但是一些患者确实在长达2天后出现了残留的抗抑郁效应。
 
       AZD6765通过脑的谷氨酸化学信使系统起作用,这与抗抑郁药氯胺酮的脑部作用机制相同。此外,没有关于AZD6765治疗导致的致精神病副作用(氯胺酮常见)报告。

       “滴注小剂量该药物可在2小时内快速起效,相比而言,我们很多当前治疗需要很多周才能起效。”第一作者Carlos A. Zarate Jr医学博士(马里兰州贝塞斯达NIMH实验治疗学和病理生理学分所所长)在接受Medscape医学新闻采访时说。

       “此外,有反应的患者尝试了多种我们的药物。这证明了病情极重的患者可在极短的时期内出现抗抑郁效应。这可能会对公共卫生产生真正的影响。”Zarate医师说。

       他还指出,这是一项实验性概念验证研究,还需要进行更多研究。
 
       “从现在起,应该研究不同剂量、重复剂量,等等。该研究还为其他研究者和企业打开了投入之门,看看他们是否可研发出快速起效但无氯胺酮副作用的其他药物。”

       “友好版氯胺酮”

       “现有的处方抗抑郁药通过脑的5-羟色胺系统起作用,需要数周才能起效,因此会危及重性抑郁患者。”

       “氯胺酮需要数小时才能起效,但有可能导致分离性副作用,包括幻觉,这限制了其使用。”他们补充说。

       尽管AZD6765也可阻断“结合于神经元表面蛋白质”的谷氨酸,但是对N-甲基-D-天冬氨酸(NMDA)受体的阻断能力小于氯胺酮,这有可能解释该药耐受性较好的原因。

       “我们想寻找友好版的氯胺酮,即一种没有副作用的药物(例如体外经验),并且看到了希望。”Zarate医师说。

       在2009年12月至2011年12月之间,研究者纳入了22例MDD成年住院患者(平均年龄51.5岁,男性占55%)。

       所有参与者均被随机分配接受单次滴注150 mg AZD6765,1周后滴注生理盐水(安慰剂),或接受相反的操作:先滴注安慰剂,然后滴注活性药物。

       主要转归指标是基线和滴注后60、80、110和230分钟以及1、2、3和7天后随访时Montgomery-Åsberg抑郁评定量表(MADRS)的总抑郁症状。

       次要指标包括17项汉密尔顿抑郁评定量表(HDRS)。

       概念验证

       结果显示,与接受安慰剂治疗的患者相比,接受AZD6765治疗的患者在滴注后80分钟的MADRS评分显著改善(P<0.01)。再过30分钟,上述差异仍然显著(P<0.05)。

       与接受安慰剂后相比,患者在接受AZD6765治疗后80分钟、110分钟和2天后的HDRS评分显示治疗反应程度更大。

       所有患者均未报告严重的治疗相关不良事件,组间紧急副作用、心电图表现、生命体征或体重均未见显著差异。

       “我们的发现起到了概念验证的作用,由此我们可进入谷氨酸途径的一个重要成分,以开发出治疗抑郁的新一代安全、快速起效的实用疗法。”Zarate医师在新闻公告中说。

       研究者既往进行的研究显示,难治性MDD患者在接受氯胺酮滴注后“改善更为稳健和持久。”实际上,52%的上述患者显示80分钟后有反应,并且残余效应持续大约7天。

       尽管如此,当前这项研究的结果“进一步支持调节NMDA受体复合物有可能导致快速抗抑郁效应这一观点。”研究者们写道。

       需要合作

       Zarate医师在接受Medscape医学新闻采访时说,他们的研究结果需要进行更多有关该实验药物的试验,特别是要评估重复滴注或较大剂量是否会导致较长期效应。

       此外,“企业很了解不同的给药系统。例如,氯胺酮被视为鼻内给药,另一些药物则被视为片剂。因此,这些药物有可能被视为不同类型的给药方式并被开发。”他说。

       “我认为人们理解这点只是时间问题。但是对于病情非常严重的患者,即使他们每周滴注数次该药仍有益处。”

       他补充说,在过去数年,“企业放弃开发治疗精神疾病的药物”一直是让人真正担心的问题。
 
       “氯胺酮的研究目前已持续一段时间。我希望氯胺酮的研究加上这项研究以及明年进行的其他研究将十分令人振奋,并且促使人们重新开发所需的药物。这包括学术界、企业和政府形成的合作关系。”

抑郁相关的拓展阅读:



Background
The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).
Methods
In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.
Results
Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.
Conclusions
In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

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    2013-01-04 sunylz
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