A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.
A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.
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DOI：
10.1038/mp.2015.83
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发表时间：
2016-03
影响因子：
11
通讯作者：
Mann JJ
中科院分区：
文献类型：
--
作者：
Milak MS;Proper CJ;Mulhern ST;Parter AL;Kegeles LS;Ogden RT;Mao X;Rodriguez CI;Oquendo MA;Suckow RF;Cooper TB;Keilp JG;Shungu DC;Mann JJ
NMDA受体拮抗剂氯胺酮可在数小时内改善重度抑郁症（MDD）。为了评价谷氨酸能和GABA能系统在氯胺酮抗抑郁作用中的假定作用，使用质子磁共振波谱法测量氯胺酮给药前、给药期间和给药后内侧前额叶皮质（mPFC）谷氨酸+谷氨酰胺（Glx）和γ-氨基丁酸（GABA）水平。氯胺酮（0.5 mg/kg i.v.）对11例抑郁症患者进行了研究。在8/11例患者中成功测量了Glx和GABA mPFC反应相对于未抑制体素组织水（W）的比值。11例患者中有10例在开始氯胺酮治疗后230分钟内缓解（24项汉密尔顿抑郁评定量表降低50%，总计≤ 10）。mPFC Glx/W和GABA/W在约26分钟内达到峰值，分别为基线水平的37.8% ± 7.5%和38.0% ± 9.1%。Glx/W（p = 0.025）和GABA/W（p = 0.005）的平均曲线下面积（AUC）增加并相关（r = 0.796; p = 0.018）。临床改善与90分钟去甲氯胺酮浓度相关（df = 6，r =-0.78，p = 0.023），但与其他指标无关。氯胺酮给药后MDD中Glx和GABA的快速增加支持谷氨酸的假定抗抑郁作用，并首次提出了GABA在氯胺酮抗抑郁作用中的作用问题。这些数据支持以下假设：氯胺酮给药可能导致谷氨酸的初始增加，这可能通过AMPA受体激活哺乳动物雷帕霉素靶点（mTOR）途径，因为氯胺酮阻断NMDA受体。GABA的同时激增的作用仍有待确定。
The NMDA receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg/kg i.v.) was administered to eleven depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total ≤ 10) within 230 minutes of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 minutes. Mean areas under the curve (AUC) for Glx/W (p = 0.025) and GABA/W (p = 0.005) increased and correlated (r = 0.796; p=0.018). Clinical improvement correlated with 90-minute norketamine concentration (df=6, r=−0.78, p=0.023), but no other measures. Rapid increases in Glx and GABA in MDD following ketamine administration support the postulated antidepressant role of glutamate and for the first time raises the question of GABA’s role in the antidepressant action of ketamine. These data support the hypothesis that ketamine administration may cause an initial increase in glutamate that potentially activates mammalian target of rapamycin (mTOR) pathway via AMPA receptors, since ketamine blocks NMDA receptors. The role of the contemporaneous surge in GABA remains to be determined.