Our longitudinal [18F]FPEB-PET analysis delineates a pivotal role for the glutamatergic system, specifically the metabotropic glutamate receptor 5 (mGluR5), in the pathophysiology and therapeutic response of Major Depressive Disorder (MDD). We observed a marked reduction in mGluR5 availability in MDD patients before treatment compared to HCs. Significantly, post-antidepressant intervention, particularly within the dorsolateral prefrontal cortex (dlPFC), ventromedial prefrontal cortex (vmPFC), and caudate nucleus, a notable resurgence in mGluR5 availability was detected.
The global diminution of mGluR5 availability in MDD patients pre-treatment may suggest a widespread dysfunction within the glutamate system. This aligns with existing literature that implicates a dysregulation in the glutamatergic neurotransmitter system in MDD, especially in brain areas such as the dlPFC and vmPFC(30). The pivotal role of mGluR5 in neurotransmitter equilibrium, synaptic plasticity, and stress-related gene expression is well-documented(9–11). Downregulation of mGluR5 could impair neurotransmitter release and synaptic transmission efficiency, potentially leading to the emotional, cognitive, and stress-response alterations observed in MDD patients(6). Animal studies further corroborate this, linking reduced mGluR5 expression to changes in gene expression associated with stress adaptability and emotional stability, highlighting its crucial role in the development of depressive symptoms(7).
The recovery of mGluR5 availability post-treatment in specific brain regions such as the dlPFC, vmPFC, and caudate nucleus underscores the key biological effects of multimodal antidepressant therapy. These areas play significant roles in executive function, emotional regulation, and the reward system. Their functional recovery could signify the efficacy of antidepressant treatment(31, 32). The restoration of dlPFC and vmPFC functions is particularly crucial for ameliorating cognitive impairments and emotional dysregulation in MDD patients(31), while normalization of mGluR5 availability in the caudate nucleus may be related to the mood elevation and resurgence of pleasurable experiences(32). Vortioxetine, as a multimodal antidepressant, may enhance neurotransmitter release and promote neuroplasticity recovery by modulating mGluR5 in these regions(33–36).
Our study has certain limitations, one being the relatively small sample size. Although it is adequate to demonstrate large effect sizes, this limitation may still constrain the statistical robustness of our analyses.
In conclusion, our study reveals a significant increase in mGluR5 availability in the dlPFC, vmPFC, and caudate nucleus following antidepressant treatment in patients with MDD. These findings highlight the critical involvement of the glutamatergic system in MDD. The marked enhancement of mGluR5 availability post-treatment emphasizes the potential of mGluR5 as a novel target for therapeutic intervention, offering new insights into the pathophysiology of MDD and avenues for treatment development.