Superior frontal and hippocampal structures associated with onset versus recurrence of mood disorders in monozygotic...

Mood disorders involve complex neurobiological trajectories, making it difficult to identify predictors of their onset and progression. This prospective study disentangled markers of vulnerability from markers of illness recurrence by leveraging monozygotic twins discordant for mood disorders. We followed 136 monozygotic twins (66 affected [AT], 39 high-risk, and 31 low-risk unaffected twins [UT]; mean age 37.4 ± 9.1 years; 69.9% females) for 7.1 ± 0.8 years after baseline MRI. Cox regression examined associations between regional neuroanatomy (bilateral hippocampus, precuneus, anterior cingulate volumes; superior frontal gyrus [SFG] thickness) and: (1) time-to-first onset (UT) or (2) time-to-recurrence (AT), adjusting for age, sex, intracranial volume, and symptoms. In UT, thinner bilateral SFG and smaller left precuneus were associated with greater onset risk (HR = 1.1, p < 0.04). These regions showed an approximately linear relationship across structural quartiles, with progressively higher 7-year episode-free probability from Q1 (lowest measures) to Q4 (highest measures). In contrast, in AT, smaller precuneus and bilateral hippocampal volumes predicted higher recurrence risk (HR = 1.1, p < 0.037), following a threshold-like pattern, with markedly higher 7-year risk of a mood episode for individuals in Q1 (lowest volume) compared to the higher quartiles (Q2-Q4). Our findings indicate distinct neuroanatomical risk profiles: prefrontal thinning of SFG marks vulnerability to initial onset, potentially reflecting impaired cognitive control, while hippocampal atrophy predisposes to recurrence, possibly via stress-related neurotoxicity. These stage-specific biomarkers, identified under rigorous genetic control, highlight targeted prevention strategies: cognitive interventions preserving frontal integrity in high-risk populations, and hippocampal neuroprotection to sustain remission.