Mapping neurophysiological biotypes of postpartum depression and underlying neural and molecular basis

Postpartum depression is a common and disabling condition that differs from major depressive disorder and shows marked variation in symptoms and outcomes. Identifying distinct biological subtypes could improve diagnosis and treatment. The present study aims to uncover neurophysiological subtypes of postpartum depression and explore their underlying neural and molecular features.

We analyzed structural brain images from a cohort of postpartum women recruited at the West China Second Hospital, Sichuan University, including 76 patients with postpartum depression (age range: 24-39 years) and 62 healthy postpartum women (age range: 23-40 years). An unsupervised clustering approach was applied to gray matter volume patterns to identify neurobiological subtypes. Individualized structural covariance networks were then constructed to compare subtype-specific connectivity. Transcriptomic profiles and neurotransmitter density maps were further integrated to examine molecular mechanisms underlying the structural alterations.

Here we show that postpartum depression can be divided into two neurobiological subtypes. Subtype 1 displays reduced gray matter volume in the dorsal attention network, consistent with cognitive impairments. Subtype 2 shows increased gray matter volume in the default mode network, reflecting emotional dysregulation. Subtype 2 also exhibits weaker structural connectivity between the middle temporal gyrus, parahippocampus, and amygdala. Molecular analysis indicates that Subtype 1 is related to energy metabolism and the neurotransmitter receptor mGluR₅, whereas Subtype 2 is associated with synaptic regulation, neuroplasticity, and neurotransmitter receptors such as 5-HT_1B, dopamine D₂, cholinergic M₁ and μ-opioid receptor (MOR).

These findings suggest that postpartum depression comprises two biologically distinct forms with different cognitive and emotional characteristics. Recognizing these subtypes may enhance our understanding of its neuropathology and support the development of personalized therapeutic strategies.