Demchenko Ilya, Tassone Vanessa K, Kennedy Sidney H, Dunlop Katharine, Bhat Venkat
Interventional Psychiatry Program, Mental Health and Addictions Service, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
Center for Depression and Suicide Studies, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
Front Psychiatry. 2022 May 26;13:864902. doi: 10.3389/fpsyt.2022.864902. eCollection 2022.
Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of non-response. To address these challenges, preclinical and clinical studies have sought to characterize antidepressant response through monoamine-independent mechanisms. One striking example is glutamate, the brain's foremost excitatory neurotransmitter: since the 1990s, studies have consistently reported altered levels of glutamate in MDD, as well as antidepressant effects following molecular targeting of glutamatergic receptors. Therapeutically, this has led to advances in the discovery, testing, and clinical application of a wide array of glutamatergic agents, particularly ketamine. Notably, ketamine has been demonstrated to rapidly improve mood symptoms, unlike monoamine-based interventions, and the neurobiological basis behind this rapid antidepressant response is under active investigation. Advances in brain imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, enable the identification of the brain network-based characteristics distinguishing rapid glutamatergic modulation from the effect of slow-acting conventional monoamine-based pharmacology. Here, we review brain imaging studies that examine brain connectivity features associated with rapid antidepressant response in MDD patients treated with glutamatergic pharmacotherapies in contrast with patients treated with slow-acting monoamine-based treatments. Trends in recent brain imaging literature suggest that the activity of brain regions is organized into coherent functionally distinct networks, termed intrinsic connectivity networks (ICNs). We provide an overview of major ICNs implicated in depression and explore how treatment response following glutamatergic modulation alters functional connectivity of limbic, cognitive, and executive nodes within ICNs, with well-characterized anti-anhedonic effects and the enhancement of "top-down" executive control. Alterations within and between the core ICNs could potentially exert downstream effects on the nodes within other brain networks of relevance to MDD that are structurally and functionally interconnected through glutamatergic synapses. Understanding similarities and differences in brain ICNs features underlying treatment response will positively impact the trajectory and outcomes for adults suffering from MDD and will facilitate the development of biomarkers to enable glutamate-based precision therapeutics.
传统的基于单胺的药物疗法被认为是重度抑郁症（MDD）的一线治疗方法，但它存在诸多挑战，包括高比例的无反应情况。为应对这些挑战，临床前和临床研究试图通过单胺非依赖机制来表征抗抑郁反应。一个显著的例子是谷氨酸，它是大脑中最重要的兴奋性神经递质：自20世纪90年代以来，研究一直报告MDD患者体内谷氨酸水平发生改变，以及对谷氨酸能受体进行分子靶向治疗后具有抗抑郁作用。在治疗方面，这推动了一系列谷氨酸能药物的发现、测试和临床应用取得进展，尤其是氯胺酮。值得注意的是，与基于单胺的干预措施不同，氯胺酮已被证明能迅速改善情绪症状，并且这种快速抗抑郁反应背后的神经生物学基础正在积极研究中。包括功能磁共振成像、磁共振波谱和正电子发射断层扫描在内的脑成像技术的进步，能够识别基于脑网络的特征，这些特征将快速谷氨酸能调节与起效缓慢的传统基于单胺的药理学效应区分开来。在此，我们回顾脑成像研究，这些研究考察了与接受谷氨酸能药物治疗的MDD患者的快速抗抑郁反应相关的脑连接特征，并与接受起效缓慢的基于单胺治疗的患者进行对比。近期脑成像文献的趋势表明，脑区活动被组织成连贯的功能不同的网络，称为内在连接网络（ICN）。我们概述了与抑郁症相关的主要ICN，并探讨谷氨酸能调节后的治疗反应如何改变ICN内边缘、认知和执行节点的功能连接，以及其具有明确的抗快感缺失作用和增强“自上而下”的执行控制。核心ICN内部和之间的改变可能会对与MDD相关的其他脑网络中的节点产生下游影响，这些节点通过谷氨酸能突触在结构和功能上相互连接。了解治疗反应背后脑ICN特征的异同将对患有MDD的成年人的病程和预后产生积极影响，并将促进生物标志物的开发，以实现基于谷氨酸的精准治疗。
