Sex-dependent habenular dysregulation across the continuum of stress exposure and depression severity: A systematic review of preclinical and clinical evidence.

BACKGROUND

Major depressive disorder (MDD) is diagnosed at roughly twice the rate in women as in men, yet sex is still routinely treated as a covariate rather than a biological variable of primary interest in depression research. The habenula (Hb), particularly the lateral habenula (LHb), is an increasingly implicated substrate of depression, but two recent systematic reviews found sex-stratified habenula data sparse and reported sex effects inconsistent in direction.

OBJECTIVE

To determine whether sex-related effects on habenula structure and function are patterned by stress intensity or chronicity in preclinical models, and by depression severity or chronicity in clinical populations, rather than arbitrary.

METHODS

This review builds on two parent systematic reviews (Cameron, Weston-Green and Newell, 2024; Fortin et al., 2025), extracting eligible sex-stratified studies and supplementing them with an independent, two-phase search (PubMed, Scopus, Web of Science) for comprehensive coverage of sex- and stress-related terms. Findings were synthesized narratively, organized by stressor chronicity (preclinical) and illness chronicity or severity (clinical), without meta-analysis.

RESULTS

Seventeen studies met eligibility criteria (10 preclinical, 7 clinical). In preclinical models, acute stressors produced modality-dependent, sometimes opposite-direction sex effects, while chronic stressors more consistently interacted with, and sometimes abolished, pre-existing baseline sex differences. In clinical populations, sex-dependent habenula abnormalities were largely absent in first-episode presentations and became more pronounced, often specifically in women, with greater illness chronicity, treatment resistance, or symptom severity.

CONCLUSIONS

Sex-dependent habenula dysfunction in depression shows a patterned, chronicity-linked structure in both literatures, though the evidence base remains small and several conclusions rest on a single study. These findings are hypothesis-generating rather than establishing sex as a confirmed driver of habenula dysfunction. Estrous cycle stage, baseline circuit-level sexual dimorphism, and sociocultural confounds are identified as testable moderators for future research.