Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Transl Psychiatry. 2020 Feb 4;10(1):56. doi: 10.1038/s41398-020-0727-8.
As ketamine is increasingly used as an effective antidepressant with rapid action, sustaining its short-lived efficacy over a longer period of time using a schedule of repeated injections appears as an option. An open question is whether repeated and single administrations would affect convergent neurocircuits. We used a combination of one of the most robust animal models of depression with high-field neuroimaging to perform a whole-brain delineation of functional mechanisms underlying ketamine's effects. Rats from two genetic strains, depressive-like and resilient, received seven treatments of 10 mg/kg S-ketamine (N = 14 depressive-like, N = 11 resilient) or placebo (N = 12 depressive-like, N = 10 resilient) and underwent resting-state functional magnetic resonance imaging. Using graph theoretical models of brain networks, we compared effects of repeated ketamine with those of single administration from a separate dataset of our previous study. Compared to single treatment, repeated ketamine evoked strain-specific brain network randomization, resembling characteristics of the depressive-like strain and patients. Several affected regions belonged to the auditory, visual, and motor circuitry, hinting at possible cumulative side effects. Finally, when compared to saline, repeated ketamine affected only a few local topological properties and had no effects on global properties. In combination with the lack of clear differences compared to placebo, our findings point toward an inefficacy of ketamine's long-term administration on brain topology, making questionable the postulated effect of repeated administration and being consistent with the recently reported absence of repeated ketamine's antidepressant efficacy in several placebo-controlled studies.
由于氯胺酮作为一种有效的抗抑郁药，具有快速作用，因此通过重复注射的方案来维持其短暂的疗效似乎是一种选择。一个悬而未决的问题是，重复和单次给药是否会影响趋同的神经回路。我们使用了一种最强大的抑郁症动物模型之一，结合高场神经影像学，对氯胺酮作用的基础进行了全脑功能机制描绘。来自两种遗传品系（抑郁样和有弹性）的大鼠接受了七次 10mg/kg S-氯胺酮（N=14 抑郁样，N=11 有弹性）或安慰剂（N=12 抑郁样，N=10 有弹性）治疗，并进行了静息状态功能磁共振成像。我们使用脑网络的图论模型，比较了重复氯胺酮与我们之前研究的单独数据集单次给药的效果。与单次治疗相比，重复氯胺酮引起了与抑郁样大鼠和患者相似的脑网络随机化，具有菌株特异性。受影响的几个区域属于听觉、视觉和运动回路，暗示可能存在累积的副作用。最后，与盐水相比，重复氯胺酮仅影响少数局部拓扑性质，对全局性质没有影响。综合考虑与安慰剂相比没有明显差异，我们的发现表明氯胺酮长期给药对大脑拓扑结构没有效果，这使得重复给药的假定效果值得怀疑，并与最近报道的几项安慰剂对照研究中重复氯胺酮抗抑郁效果缺失一致。
