A research team from the Sant Pau Research Institute (IR Sant Pau) has published a scientific review proposing a paradigm shift in the way depression is understood and studied. The study highlights the need to move beyond traditional psychiatric diagnoses based on broad categories and toward a dimensional approach focused on specific symptoms and their underlying neurobiological mechanisms.
The article, published in the journal Translational Psychiatry , provides a comprehensive review of the existing evidence on resting-state functional brain connectivity and its relationship with key clinical dimensions of depression, including anhedonia, rumination, insomnia, and suicidal behavior. The findings show that these dimensions are associated with distinct connectivity patterns, reinforcing the idea that depression is not a homogeneous condition from the perspective of brain function.
The Limitations of the Traditional Diagnosis of Depression
In clinical practice, the diagnosis of major depressive disorder is based on a combination of symptoms defined by international diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders, the reference manual developed by the American Psychiatric Association and widely used to classify mental disorders. This system establishes a minimum number of symptoms required for diagnosis but allows for multiple possible combinations under the same clinical label.
This diagnostic flexibility creates substantial heterogeneity among patients who share the same formal diagnosis but present very different clinical profiles. This diversity has direct implications for both research and clinical practice, as it makes it more difficult to identify consistent brain biomarkers and predict treatment response. "When we use a single diagnostic category for people with very different symptoms, it becomes much more difficult to identify clear brain correlates or anticipate which treatment may work best in each case," explains Dr. Marta Cano, a researcher with the Mental Health group at IR Sant Pau and co-author of the study.
She adds, "Analyzing depression through specific clinical dimensions allows us to examine more precisely the brain mechanisms underlying each symptom and better understand why the experience of the disorder differs so much from one patient to another."
Four Clinical Dimensions With Distinct Neurofunctional Signatures
The review is based on studies that have used resting-state functional magnetic resonance imaging, a technique that makes it possible to analyze how different brain regions communicate with one another when a person is not performing a specific task. This approach is particularly well suited to studying persistent and self-referential mental processes that are relevant to depression and has enabled researchers to identify connectivity patterns associated with specific symptoms.
Based on this evidence, the study focuses on four specific clinical dimensions of depression that have been extensively investigated from this perspective: anhedonia, rumination, insomnia, and suicidal behavior. The combined analysis of these dimensions indicates that each is associated with distinct connectivity profiles, reinforcing the idea that depression has a heterogeneous neurobiological basis.
In this context, "the aim of this study is to change the way we interpret depression from the perspective of the brain, moving from a single diagnosis toward the identification of circuits associated with specific symptoms," says Dr. Marta Cano. "This approach allows us to better account for the clinical diversity we see every day in patient care."
In the case of anhedonia, defined as difficulty experiencing pleasure, the studies reviewed distinguish between two components with partially distinct neurobiological profiles. Consummatory anhedonia, related to immediate pleasure, is consistently associated with reduced connectivity between the ventral striatum and regions of the prefrontal cortex involved in hedonic valuation. By contrast, anticipatory anhedonia, linked to motivation and reward expectation, shows more complex and heterogeneous connectivity patterns, suggesting that the two processes rely in part on different brain circuits.
Rumination, one of the most characteristic features of depression, is described as a pattern of repetitive, self-referential thinking, but it is not a uniform phenomenon either. The review distinguishes between maladaptive rumination, or brooding, associated with persistent negative thoughts, and reflective rumination, which is more oriented toward analysis and problem solving. The studies show that brooding is primarily associated with increased connectivity within the default mode network, which is involved in self-referential thought, whereas reflective rumination also involves executive networks related to cognitive control.
Insomnia emerges in the review as a core dimension of depression rather than a secondary symptom. The studies analyzed show alterations in the connectivity of key regions of the default mode network, including the hippocampus and medial prefrontal cortex, which are involved in memory, self-referential processing, and regulation of the sleep-wake cycle. These findings reinforce the idea that sleep problems in depression have a specific neurobiological basis.
Finally, suicidal behavior is analyzed as a continuum ranging from suicidal ideation to suicide attempts. The review identifies common alterations in the connectivity of the orbitofrontal cortex, a key region involved in decision-making and emotional regulation, but also clear differences between ideation and attempts. While suicidal ideation is mainly associated with alterations in cognitive control and self-referential circuits, suicide attempts more prominently involve regions related to the processing of emotional pain and salience.
Implications for Precision Psychiatry
According to Dr. Narcís Cardoner, also a researcher with the Mental Health group and a co-author of the article, "The findings of this review reinforce the idea that there is no single form of depression from a neurobiological perspective, but rather a set of clinical dimensions involving partially distinct brain circuits." This approach challenges traditional diagnostic models and highlights the need for more refined frameworks to understand the disorder.
From a clinical perspective, this dimensional approach may help explain why patients with the same diagnosis experience very different disease trajectories or respond differently to the same treatment. "Identifying connectivity patterns associated with specific symptoms is a key step toward more precise and personalized psychiatry," says Dr. Cardoner. "It allows us to begin considering interventions that are better tailored to each patient's clinical and neurobiological profile."
The authors also emphasize that these findings open up new opportunities for the development of brain biomarkers with prognostic and therapeutic value, as well as for the design of treatments targeting specific neural circuits, including neuromodulation strategies. Although further research is still needed before these advances can be incorporated into routine clinical practice, the study provides a solid conceptual framework to guide future research.
Overall, the review lays the groundwork for a brain-based psychiatry aimed at improving the diagnosis, prognosis, and treatment of depression through an approach that better reflects the complexity and diversity of patients.
