Different Brain Profiles, Same Symptoms: New Study Reveals Subtyping Patients Provides Key Insights into Depression's Complexities

A novel study aimed at disentangling the neurological underpinnings of depression shows that multiple brain profiles may manifest as the same clinical symptoms, providing evidence to support the presence of both one-to-one and many-to-one heterogeneity in depression. The findings of the study in Biological Psychiatry, published by Elsevier, highlight the layered and complex interactions between clinical symptoms and neurobiological sources of variation.

John Krystal, MD, Editor of Biological Psychiatry, comments, “Depression is a very heterogeneous medical condition. The inability to accurately subtype patients is a major obstacle to matching individual patients to treatments that are more likely to be effective for them. This study makes progress toward this objective. Of note, it unites clinical assessments and brain imaging findings to generate depression subtypes.”

Lead investigator Janine D. Bijsterbosch, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, explains, “Heterogeneity in depression, i.e., differences between patients with the same diagnosis, has been a topic of interest in our field for a long time. For example, patients with depression can differ from one another in clinical characteristics (e.g., what symptoms they experience, what age their depression first started, and how many episodes they have had), and patients can also differ in their neurobiology (e.g., what brain changes are linked to their depressive symptoms). Although prior studies have investigated both these clinical and neurobiological dimensions, we wanted to develop a more thorough understanding of these sources of variation in depression and their relationship.”

Using population-based data from the UK Biobank from multiple imaging sites, investigators tested whether clinical and neurobiological heterogeneity have a simple relationship (“one-to-one brain-symptom mapping,” in which one neurobiological profile is related to one clinical profile), or whether clinical and neurobiological heterogeneity have a more complicated relationship (“many-to-one brain-symptom mapping,” suggesting that multiple neurobiological profiles may give rise to the same depressive symptoms). The researchers grouped individuals with depression based on their specific clinical presentations and found unique groups of people who experienced one symptom (such as depressed mood) but not other common symptoms of depression (such as low motivation). They then compared the neurobiological profiles of these groups to a group with a mixed symptom profile.

Co-investigator Yvette I. Sheline, MD, Perelman School of Medicine, University of Pennsylvania, says, “Our findings showed that dividing people up into groups based on their clinical presentation of depression led to stronger and more distinct brain changes as compared to a group with a mixed clinical presentation. Our research also showed that more than one brain profile gave rise to the same clinical presentation in patients with acute depression, providing concrete evidence of many-to-one brain-symptom mapping for the first time. Notably, one of the neurobiological profiles we uncovered was associated with worse cognition, which is an important clinical outcome that can substantially impact individuals’ lives; an MRI scan of neurobiology may have the potential to predict clinical outcomes that depression symptom screening alone cannot capture.”

Depression is one of the most common mental health disorders, with 9.2% of Americans experiencing an episode each year. Despite its prevalence, depression often goes underdiagnosed, and treatment efficacy is poor; only 30% of patients respond to the first line of treatment.

Co-investigator Deanna M. Barch, PhD, Department of Psychological & Brain Sciences, Washington University, and Department of Psychiatry and Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, concludes, “We hope our findings will motivate future work attempting to disentangle the variations in depression, leading to the development of tools that address the layered and complex relationships between clinical and neurobiological sources of heterogeneity that we revealed. Identifying distinct subtypes of depression that may respond differently to treatment could greatly improve clinical care for patients with depression in the future. However, our findings show that identifying such subtypes of depression will only be achievable by addressing both clinical and neurobiological heterogeneity.”

Notes for editors

The article is "Parsing Clinical and Neurobiological Sources of Heterogeneity in Depression,” by Kayla Hannon, Ty Easley, Wei Zhang, Daphne Lew, Aristeidis Sotiras, Yvette I. Sheline, Andre Marquand, Deanna M. Barch, and Janine D. Bijsterbosch (https://doi.org/10.1016/j.biopsych.2025.04.025). It appears online in advance of volume 98, issue 7 (October 1, 2025) of Biological Psychiatry, published by Elsevier.

The article is openly available at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(25)01186-2/fulltext.

Copies of the full text and additional information are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the authors should contact Abeeha Shamshad, Senior Media Relations Specialist, WashU Medicine Marketing and Communications, at +1 925 998 0775 or [email protected].

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

This work is supported by the NIH (R01 MH128286).

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms, and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 6th^th out of 279 Psychiatry titles and 15^th out of 309 Neurosciences titles in Journal Citation Reports^TM published by Clarivate. The 2023 Impact Factor score for Biological Psychiatry is 9.6. www.sobp.org/journal

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