Objectives: Melancholic depression (MD) is a common subtype of major depressive disorder (MDD). It is difficult to treat because its neurobiological basis is poorly understood. Therefore, to investigate whether MD patients have any structural changes in gray matter (GM) and the molecular foundation of these changes, we combined voxel-based morphometry (VBM) analysis with neurotransmitter system-derived mapping from public data.Methods: 137 drug-naive MDD patients and 75 healthy controls (HCs) were recruited for structural magnetic resonance imaging. The imaging results were analyzed using VBM analysis. MDD patients were then divided into MD and nonmelancholic depression (NMD) subgroups according to their scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale. Next, we analyzed the spatial correlation between the changes in the gray matter volume (GMV) maps and the neurotransmitter receptor/transporter protein density maps provided by the JuSpace toolbox.Results: Compared to HCs, patients with MD had significant GMV reduction in the bilateral hippocampus, bilateral thalamus, right amygdala, and right posterior cingulate cortex (PCC)/precuneus. Compared to patients with NMD, MD patients had significant GMV reduction in the bilateral PCC/precuneus and lateral occipital cortex. Moreover, compared to HCs, changes in GMV introduced by MD were spatially associated with the serotonin transporter, cannabinoid receptor, and mu-opioid receptor. Compared to NMD patients, changes in GMV introduced by MD were spatially associated with the vesicular acetylcholine transporter.Conclusion: The present study discovered abnormal GMV alterations in patients with subtypes of depression. We also found a series of neurotransmitter receptors that may be associated with the alterations. The findings of the current study may provide a more comprehensive understanding of the molecular mechanisms underlying the structural abnormalities in subtypes of depression and potentially offer new insights into developing new therapeutic strategies.