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 anhedonia and depressed mood, but not the reverse. This progressive motivational decline was driven by cumulative physical burden, rather than underlying genetic neurodegenerative risk (APOE ε4 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.

The authors have declared no competing interest.

S.Z. and M.H. were funded by the Wellcome Trust (226645/Z/22/Z). M.H. was also funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre. The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht programme of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and is supported by participating universities and mental health care organisations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos Institute)). The Netherlands Study of Depression in Older persons (NESDO) is funded by the Netherlands Organisation for Health Research and Development (ZonMw, grant number 31160004) and is supported by participating universities and mental health care organisations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Radboud University Nijmegen Medical Centre and Pro Persona).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocols of NESDA and NESDO were approved centrally by the Ethical Review Board of the VU University Medical Center, and subsequently by the local ethical review boards of the participating centres: University Medical Center Groningen and Leiden University Medical Center for NESDA; and Leiden University Medical Center, University Medical Center Groningen, and Radboud University Medical Center Nijmegen for NESDO. Written informed consent was obtained from all participants at the start of baseline assessment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data that support the findings of this study are not publicly available due to ethical and legal restrictions on sharing potentially identifying clinical participant information. Data from the Netherlands Study of Depression and Anxiety (NESDA) are available to researchers outside the consortium upon reasonable request and after approval of a formal analysis plan; further information on the data access procedure is available at https://www.nesda.nl/. Data from the Netherlands Study of Depression in Older Persons (NESDO) are similarly available to researchers upon reasonable request and after approval of an analysis plan by the NESDO steering committee; further information is available at https://nesdo.onderzoek.io/. The analyses in this paper were carried out under NESDA data access project DAP2543 and NESDO DAP2676.