Targeting BDNF to Overcome Treatment Resistance in Depression: Research Progress from Mechanism to Clinic

Depression ranks among the top causes of disability worldwide. About 40%-50% of the patients have insufficient response to conventional antidepressants, and treatment resistance has become a core clinical bottleneck. BDNF, as a key regulatory molecule of neuroplasticity, is regarded as the common final pathway of antidepressant action. This article systematically reviews the biological basis of the BDNF/TrkB signaling pathway and its differential mechanisms in treatment sensitivity and resistance. In the sensitive state, antidepressants up-regulate BDNF in the hippocampal dentate gyrus and TrkB signaling in the dorsal raphe nucleus through epigenetic modification, and promote neurogenesis and synaptic remodeling; in the resistant state, the high methylation of the BDNF promoter, the imbalance of pro-BDNF/mBDNF conversion, the disorder of TrkB conduction and the impairment of neurogenesis together constitute the molecular basis. In addition, this article sorts out the regulatory effects of genetic polymorphism, environmental stress, inflammation and the gut microbiota-gut-brain axis on the BDNF treatment response, and discusses the BDNF-based treatment stratification strategy, and holds that targeting the BDNF system is expected to provide a new strategy for the precise treatment of treatment-resistant depression.