MDD—affecting >300 million people worldwide—is associated with dysfunction in the prefrontal cortex (PFC), hippocampus, amygdala, and cingulate cortex. Convergent imaging and molecular data implicate reduced hippocampal neurogenesis, dendritic atrophy, loss of synaptic connectivity, and altered long-term potentiation/depression (LTP/LTD). Neurotrophic factors—including BDNF, IGF-1, and NGF—govern neuronal survival, synaptogenesis, and plasticity and are dysregulated in MDD.

Narrative review of PubMed/Google Scholar literature on MDD, neuroplasticity, neurotrophic signaling, antidepressant mechanisms, and neuromodulatory therapies. Studies spanning molecular, circuit, imaging, and behavioral outcomes were prioritized for mechanistic convergence (neurogenesis, dendritic remodeling, synaptic density, LTP/LTD; BDNF/TrkB, CREB, PI3K-AKT-mTOR pathways).

Across preclinical and clinical studies, conventional antidepressants (SSRIs/SNRIs/TCAs) generally increased BDNF and TrkB signaling, enhanced hippocampal neurogenesis, and improved dendritic complexity and synaptic density in PFC/hippocampus, changes that paralleled symptom improvement. Multimodal agents (e.g., vortioxetine) augmented glutamatergic transmission, LTP, and dendritic spine maturation; MAOIs elevated BDNF/IGF-1 and supported LTP. Rapid-acting NMDA antagonists (ketamine/esketamine) produced swift, durable antidepressant effects with increases in AMPA throughput, p-TrkB/c-CREB, and spine formation. Some drug classes showed heterogeneity (e.g., duloxetine/milnacipran with region-specific or inconsistent plasticity effects; sertraline with mixed LTP findings). Non-pharmacologic neuromodulation (rTMS, ECT) consistently upregulated BDNF/TrkB signaling, increased neurogenesis and synaptogenesis, and restored PFC–limbic connectivity.

Neuroplasticity dysfunction is a core substrate of MDD, and therapeutic benefit tracks with restoration of plasticity—particularly via BDNF/IGF-1/NGF pathways. Targeting neurotrophic signaling (e.g., BDNF mimetics, IGF-1 analogs), pairing plasticity enhancers with standard antidepressants, and integrating neuromodulation may yield more durable remission and reduced relapse. Future work should standardize plasticity biomarkers (imaging, serum/csf neurotrophins) to stratify patients and optimize sequencing/combination of pharmacologic and device-based interventions.