Findings from a new study in Biological Psychiatry highlight the layered and complex underpinnings of depression, potentially leading to improved clinical care for patients

Philadelphia, June 19, 2025 – 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.”