Behavioural brain research · 2026
Sex-dependent habenular dysregulation across the continuum of stress exposure and depression severity: A systematic review of preclinical and clinical evidence.
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Ferreira-Vorkapic Camila, Coelho Renato Ramos, Wiech Monika, Tocco Filippo, Todde Francesco
Аннотация
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.
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.