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Apathy precedes worsening anhedonia in depression, but not the reverse

Zhao, S.; Paans, N. P. G.; Rhebergen, D.; Oude Voshaar, R. C.; Giltay, E. J.; Penninx, B. W. J. H.; Husain, M.

2026-05-06 psychiatry and clinical psychology
10.64898/2026.05.05.26352457 medRxiv
Show abstract

Apathy-loss of motivation associated with diminished goal-directed behaviour-is among the most prevalent yet undertreated neuropsychiatric syndromes. Whether it represents a downstream residual manifestation of chronic depression or an independent and potentially upstream process remains unresolved. Here, leveraging two large-scale longitudinal psychiatric cohorts (N=2,482; age 24-93), we demonstrate that multidimensional apathy is structurally and conditionally independent from anhedonia, depressed mood, anxiety and fatigue, using item-level factor analysis and partial correlation networks. Crucially, in the 6-year longitudinal subsample (N=292), cross-lagged panel models revealed an asymmetric temporal precedence: apathy strongly predicted subsequent worsening of depressed mood and anhedonia, but not the reverse. This progressive motivational decline was not explained by underlying genetic neurodegenerative risk (APOE {varepsilon}4 genotype) or cognitive decline. These findings overturn the assumption that motivational withdrawal follows loss of pleasure, and positions apathy as an upstream, independently targetable process in the evolution of depression.

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