Georgiou Polymnia, Farmer Cristan A, Medeiros Gustavo C, Yuan Peixiong, Johnston Jenessa, Kadriu Bashkim, Gould Todd D, Zarate Carlos A
Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA; Department of Psychology, University of Wisconsin, Milwaukee, WI, USA.
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
J Affect Disord. 2025 Mar 15;373:126-132. doi: 10.1016/j.jad.2024.12.036. Epub 2024 Dec 12.
Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans.
We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale.
We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body.
Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes.
亚麻醉剂量的（R，S）-氯胺酮（氯胺酮）已在抑郁症患者中显示出快速且显著的抗抑郁作用。然而，个体对氯胺酮的反应存在差异，目前对氯胺酮治疗反应的生物标志物尚未完全了解。临床前证据表明，下丘脑-垂体-肾上腺（HPA）轴激活（应激反应系统的一个决定因素）与氯胺酮在表现出增强抗抑郁反应的应激小鼠中的疗效之间存在联系。在此，我们评估了人类HPA轴、重度抑郁症特征与对氯胺酮的抗抑郁反应之间的关系。
我们对42名难治性抑郁症患者进行了研究，这些患者在药物洗脱后参加了一项接受静脉注射氯胺酮的随机、安慰剂对照、交叉试验。在基线时测量促肾上腺皮质激素释放因子（CRF）、促肾上腺皮质激素（ACTH）和皮质醇的血浆水平。使用蒙哥马利-阿斯伯格抑郁评定量表评估氯胺酮的抗抑郁效果。
我们发现基线HPA轴激素水平并未显著调节氯胺酮的抗抑郁效果。然而，观察到ACTH和CRF水平与抑郁发作的总持续时间之间存在负相关，这表明可能具有生物标志物意义。此外，观察到基线抑郁评分与发病年龄之间存在负相关，这表明如果抑郁症在较年轻时发作，其严重程度可能更大，这表明大脑和身体承受的压力更持久。
尽管我们未发现血浆HPA轴激素对氯胺酮抗抑郁效果的调节作用，但不能排除大脑HPA轴激素的调节作用，值得进一步研究。重要的是，我们的结果表明HPA轴成分可能是抑郁发作持续时间的潜在生物标志物。
