Gambini Matteo, Gurrieri Riccardo, Russomanno Gerardo, Cecchini Gianmatteo, Mucci Federico, Carbone Manuel Glauco, Marazziti Donatella
Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, 56100 Pisa, Italy.
Medical Center Le Cascine, 56122 Pisa, Italy.
Brain Sci. 2025 Sep 10;15(9):971. doi: 10.3390/brainsci15090971.
Major depressive disorder (MDD) represents a leading cause of global disability, with approximately one-third of patients exhibiting treatment resistance (TRD) despite adequate pharmacological interventions. This treatment gap underscores the urgent need for novel therapeutic strategies. Recently, a series of data suggests that botulinum neurotoxin of type A (BoNT-A), traditionally used for neuromuscular and cosmetic indications, could constitute a potential antidepressant tool. This narrative review critically examines the current preclinical and clinical findings of BoNT-A in MDD. A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to June 2025, including randomized controlled trials, observational studies, animal models, and mechanistic investigations. Search terms included "Botulinum Toxin," "BoNT type A", "Depression", "Major Depressive Disorder", "Facial Feedback", and "Neurobiology". Some randomized and observational studies would indicate that glabellar BoNT-A injections might lead to significant reductions in depressive symptoms in patients with MDD and TRD. Proposed mechanisms include both peripheral modulation of emotional expression and brain effects, such as reduced amygdala hyperactivity, increased BDNF expression, and enhanced monoaminergic transmission. Preclinical studies confirm that BoNT-A modulates limbic and brainstem circuits, possibly implicated in affective regulation. The few comparative studies suggest therapeutic efficacy comparable to that of SSRIs, with a more rapid onset. Preliminary data also support its application in bipolar depression and comorbid anxiety disorders. : The available literature would indicate that BoNT-A might constitute a promising candidate at least as an adjunctive treatment in MDD, although the impact of current findings is limited due to the methodological heterogeneity and the small sample sizes of patients examined. Further large-scale, placebo-controlled trials are warranted to elucidate the mode of action of BoNT-A and to validate or not its clinical effectiveness.
重度抑郁症（MDD）是全球致残的主要原因之一，尽管进行了充分的药物干预，仍有约三分之一的患者表现出治疗抵抗（TRD）。这种治疗差距凸显了对新型治疗策略的迫切需求。最近，一系列数据表明，传统上用于神经肌肉和美容适应症的A型肉毒杆菌神经毒素（BoNT-A）可能构成一种潜在的抗抑郁工具。这篇叙述性综述批判性地审视了BoNT-A在MDD中的当前临床前和临床研究结果。截至2025年6月，对PubMed、Scopus和Web of Science进行了全面检索，包括随机对照试验、观察性研究、动物模型和机制研究。检索词包括“肉毒杆菌毒素”、“A型BoNT”、“抑郁症”、“重度抑郁症”、“面部反馈”和“神经生物学”。一些随机和观察性研究表明，眉间注射BoNT-A可能会使MDD和TRD患者的抑郁症状显著减轻。提出的机制包括情绪表达的外周调节和大脑效应，如杏仁核过度活动减少、脑源性神经营养因子（BDNF）表达增加和单胺能传递增强。临床前研究证实，BoNT-A可调节边缘和脑干回路，可能与情感调节有关。少数比较研究表明，其治疗效果与选择性5-羟色胺再摄取抑制剂（SSRI）相当，且起效更快。初步数据也支持其在双相抑郁症和共病焦虑症中的应用。现有文献表明，BoNT-A可能至少作为MDD的辅助治疗是一个有前景的候选药物，尽管由于方法学的异质性和所研究患者样本量小，目前研究结果的影响有限。有必要进一步开展大规模、安慰剂对照试验，以阐明BoNT-A的作用方式，并验证其临床有效性。
