与米氮平治疗重度抑郁症反应相关的神经病理生理变化：自下而上多巴胺能通路和前额叶控制网络的见解

摘要(中文译文)

重性抑郁障碍（MDD）在症状和潜在病理生理机制方面均表现出显著的异质性，而缺乏基于生物学依据的亚型往往导致在选择有效治疗时经历漫长的试错过程。这促使研究者致力于寻找能够预测个体治疗反应的生物标志物。尽管米氮平在临床中广泛使用且其疗效已得到充分确立，但与其他抗抑郁药相比，针对其治疗反应的神经科学研究仍然有限。为填补这一空白，本研究考察了与后续米氮平治疗反应相关的治疗前病理生理性神经特征。67名重性抑郁障碍患者在完成条件性奖赏任务期间接受了功能性磁共振成像检查，随后接受米氮平单药治疗或两种对照抗抑郁药之一（阿戈美拉汀或选择性5-羟色胺再摄取抑制剂）治疗。米氮平应答者在治疗前表现出中脑边缘多巴胺能通路核心组分（尤其是腹侧被盖区和腹侧纹状体）的激活增强，以及在前额叶和功能连接区域中与奖赏评估、奖赏相关行为抑制和基于奖赏的决策相关的区域激活增强。重要的是，许多这些与应答相关的激活具有米氮平组特异性。这些发现提示，奖赏加工过程中中脑边缘多巴胺能通路和前额叶调控网络参与的异常改变可能构成一种对米氮平治疗敏感的重性抑郁障碍亚型，且此类模式可作为识别可能从该治疗中获益的患者的生物标志物。

Abstract

Major depressive disorder (MDD) shows striking heterogeneity in both symptoms and underlying pathophysiology, and the absence of biologically grounded subtypes often results in a prolonged trial-and-error process when selecting effective treatments. This has motivated efforts to identify biomarkers that may predict individual treatment responses. Although mirtazapine is widely used and its efficacy is well established in clinical settings, neuroscientific studies on its treatment response remain limited relative to other antidepressants. To address this gap, this study examined pre-treatment pathophysiological neural features associated with subsequent response to mirtazapine. Sixty-seven individuals with MDD underwent functional magnetic resonance imaging during a conditioned reward task and then received monotherapy with mirtazapine or one of two comparator antidepressants (agomelatine or a selective serotonin reuptake inhibitor). Mirtazapine responders demonstrated increased pre-treatment activation in core components of the mesolimbic dopaminergic pathway, particularly the ventral tegmental area and ventral striatum, as well as in prefrontal and functionally connected regions implicated in reward evaluation, reward-related behavioral inhibition, and reward-based decision-making. Importantly, many of these response-related activations were specific to the mirtazapine group. These findings suggest that altered engagement of mesolimbic dopaminergic pathways and prefrontal regulatory networks during reward processing may characterize an MDD subtype responsive to mirtazapine, and that such patterns may serve as biomarkers for identifying patients likely to benefit from this treatment.

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