Heterogeneity in Depression: evidence for distinct clinical and neurobiological profiles

Addressing heterogeneity in depression is critically important to overcome replicability challenges and gain insights into neural etiology. We developed a novel hierarchical framework to systematically disentangle clinical and neurobiological sources of heterogeneity utilizing population data from the UK Biobank. Firstly, we defined patient subgroups who uniquely shared isolated clinical characteristics of depression (e.g., symptoms of anhedonia, depressed mood, and somatic disturbance; severity indices of lifetime chronicity and acute impairment; and late onset). Our results revealed distinct neurobiological features robustly associated with each clinically isolated subgroup, providing symptom-level insights into the neural etiology of depression, and supporting a one-to-one mapping between clinical and neurobiological sources of heterogeneity. Secondly, we investigated residual neurobiological heterogeneity within each subgroup using data-driven clustering. Our findings revealed stable neurobiological clusters that differed in cognitive ability within two clinical subgroups (chronicity and acute impairment), providing evidence that multiple neurobiological mechanisms may give rise to the same clinical presentation (many-to-one mapping). ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Janine Bijsterbosch is supported by the NIH (R34 NS118618; R01 MH128286) and the McDonnell Center for Systems Neuroscience. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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. Yes 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). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes UK Biobank data is available following an access application process. For more information: . .