Weston Ridge G, Fitzgerald Paul J, Watson Brendon O
Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.
Front Psychiatry. 2021 May 11;12:659052. doi: 10.3389/fpsyt.2021.659052. eCollection 2021.
The anesthetic drug ketamine has been successfully repurposed as an antidepressant in human subjects. This represents a breakthrough for clinical psychopharmacology, because unlike monoaminergic antidepressants, ketamine has rapid onset, including in Major Depressive Disorder (MDD) that is resistant to conventional pharmacotherapy. This rapid therapeutic onset suggests a unique mechanism of action, which continues to be investigated in reverse translational studies in rodents. A large fraction of rodent and human studies of ketamine have focused on the effects of only a single administration of ketamine, which presents a problem because MDD is typically a persistent illness that may require ongoing treatment with this drug to prevent relapse. Here we review behavioral studies in rodents that used repeated dosing of ketamine in the forced swim test (FST), with an eye toward eventual mechanistic studies. A subset of these studies carried out additional experiments with only a single injection of ketamine for comparison, and several studies used chronic psychosocial stress, where stress is a known causative factor in some cases of MDD. We find that repeated ketamine can in some cases paradoxically produce in immobility in the FST, especially at high doses such as 50 or 100 mg/kg. Several studies however provide evidence that repeated dosing is more effective than a single dose at immobility, including behavioral effects that last longer. Collectively, this growing literature suggests that repeated dosing of ketamine has prominent depression-related effects in rodents, and further investigation may help optimize the use of this drug in humans experiencing MDD.
麻醉药物氯胺酮已成功地被重新用作治疗人类抑郁症的药物。这代表了临床精神药理学的一项突破，因为与单胺能抗抑郁药不同，氯胺酮起效迅速，在对传统药物治疗有抗性的重度抑郁症（MDD）患者中也是如此。这种快速的治疗起效表明其作用机制独特，目前仍在啮齿动物的反向转化研究中进行探究。大部分关于氯胺酮的啮齿动物和人类研究仅关注单次给予氯胺酮的效果，这就产生了一个问题，因为MDD通常是一种持续性疾病，可能需要持续使用这种药物来预防复发。在此，我们回顾了在强迫游泳试验（FST）中使用重复给予氯胺酮的啮齿动物行为学研究，着眼于最终的机制研究。这些研究中的一部分还进行了仅单次注射氯胺酮的额外实验以作比较，还有几项研究使用了慢性心理社会应激，在某些MDD病例中，应激是已知的致病因素。我们发现，在某些情况下，重复给予氯胺酮会反常地导致FST中的不动时间增加，尤其是在高剂量如50或100mg/kg时。然而，几项研究提供的证据表明，重复给药在减少不动时间方面比单次给药更有效，包括行为效应持续时间更长。总体而言，这些不断增加的文献表明，重复给予氯胺酮在啮齿动物中具有显著的与抑郁相关的效应，进一步的研究可能有助于优化该药物在MDD患者中的使用。
