Early Neural Changes in the Dorsolateral Prefrontal Cortex Hold Promise as Biomarkers for Antidepressant Efficacy in Major Depression
In a groundbreaking new study published in Translational Psychiatry, researchers have unveiled compelling evidence that early changes in brain activity and connectivity within the dorsolateral prefrontal cortex (DLPFC) could serve as vital biomarkers for predicting antidepressant response in individuals with major depressive disorder (MDD). This work paves the way for more targeted treatment strategies and personalized psychiatry by leveraging neurophysiological markers to forecast clinical outcomes.
Major depressive disorder, a disabling and widespread mood disorder, remains a significant challenge within psychiatry due to the variability in patient responses to conventional antidepressant treatments. Current clinical approaches often rely on prolonged trial and error, leading to treatment delays and patient distress. Identifying objective biomarkers indicating early neural adaptations to antidepressants could revolutionize therapeutic decision-making and outcome prediction.
The study focused on quantifying the current density within the right DLPFC—one of the brain’s critical hubs for cognitive control and emotion regulation—during several time windows associated with event-related potential (ERP) components, specifically N1, N2, P2, and P3, triggered by oddball stimuli. The researchers noted that at baseline, individuals with MDD showed markedly diminished current density during the N2 and P3 windows compared to healthy controls, highlighting a potential neural deficit inherent to the disorder.
Using linear regression modeling, the investigators examined whether baseline DLPFC activity and functional connectivity, measured as seed-based functional connectivity (FC) within the DLPFC networks, could predict depressive symptom severity as assessed by the Hamilton Depression Rating Scale (HAMD-21) at 12 weeks post-treatment initiation. Results indicated no significant predictive power at baseline after controlling for age, gender, and initial symptom severity, suggesting that static measures prior to treatment may not hold predictive clinical value.
Intriguingly, the study revealed significant neural plasticity occurring within the first week of treatment. Specifically, there was a substantial reduction in right DLPFC current density during the N1 and P2 time windows in MDD patients at week one versus baseline. This change points to a dynamic response of cortical activity as an early neural adaptation to antidepressant therapy. Additionally, theta-band FC between the right DLPFC and the left insular cortex (IC) showed a notable decrease, while FC between the left DLPFC and right posterior cingulate cortex (PCC) increased during the same timeframe.
The relationship between these neurophysiological alterations and clinical improvements was further elucidated through Pearson correlation and linear mixed models correcting for demographic variables. Enhanced current density in the right DLPFC during early sensory and cognitive processing windows (N1, P2, N2) correlated negatively with changes in HAMD-21 scores, indicating that greater cortical engagement was associated with symptom reduction. Similarly, modulations in specific frequency bands of DLPFC connectivity with insular and cingulate cortices appeared intricately tied to symptom trajectory.
The significance of these findings was amplified when examining predictive biomarkers for remission status at 12 weeks. Logistic regression analyses revealed that early increases in right DLPFC current density across multiple ERP components (N1, P2, N2, and P3) almost quadrupled the odds of achieving remission. This robust association underscores the notion that rapid normalization or engagement of frontal cortical activity is a hallmark of effective antidepressant response.
Conversely, decreases in beta-band functional connectivity between the left DLPFC and bilateral PCC were linked to a higher likelihood of remission, pointing towards the complex interplay of synchrony across brain networks in mood recovery. These alterations were significantly more pronounced in remitters compared to non-remitters, indicating their potential as discriminative neural signatures for treatment outcome.
The study’s sophisticated approach leveraged high-density EEG combined with source localization and seed-based connectivity analyses to achieve a temporally and spatially precise characterization of dynamic brain responses. The oddball paradigm, with its well-established use in probing attentional and cognitive processing, served as an optimal stimulus protocol to uncover subtle neurophysiological changes during treatment onset.
Importantly, the findings highlight a nuanced temporal profile of DLPFC activity modifications, illustrating that shifts in early sensory components (N1), attentional processing (P2), and subsequent cognitive evaluation (N2, P3) collectively contribute to symptom improvement. This suggests that antidepressant-induced neuroplasticity engages multiple processing stages rather than isolated neural events.
Moreover, the differential directionality observed in functional connectivity changes across theta, alpha, and beta frequency bands reveals a multiplexed network reorganization underpinning therapeutic effects. The theta-band findings emphasize reduced connectivity with the insular cortex, a region implicated in emotion and interoception, while alpha- and beta-band variations involving the PCC underscore shifts in default mode network dynamics.
Collectively, this research advances our understanding of the neurobiological substrates mediating antidepressant efficacy and introduces early treatment-related neural changes in the DLPFC as powerful biomarkers. If validated in larger, multi-site cohorts, these biomarkers could serve to stratify patients likely to benefit from standard antidepressants, thereby enabling bespoke treatment plans.
The implications extend beyond diagnostics, offering targets for neuromodulatory interventions such as transcranial magnetic stimulation or neurofeedback aimed at enhancing DLPFC function to boost therapeutic outcomes. Furthermore, integrating these electrophysiological markers into clinical practice could shorten the latency to identifying effective treatment and reduce the burden of trial-and-error prescribing.
The study advocates for a paradigm shift in depression treatment research, emphasizing longitudinal neurophysiological monitoring during the critical early phase of therapy. This approach embraces the dynamic nature of brain function alterations and their predictive relevance for clinical response, providing a framework for next-generation personalized psychiatry.
While promising, the research acknowledges limitations including sample size and the need for replication across diverse depressive phenotypes and treatment modalities. Nevertheless, this work charts a compelling course for future investigations into brain-based biomarkers and their utility in transforming depression care.
As our understanding of brain circuitry in depression grows, the integration of EEG-derived measures of DLPFC activity and connectivity with clinical metrics holds considerable promise. Such advancements herald an era where tailored interventions guided by neurofunctional biomarkers become a clinical reality, ultimately improving outcomes for millions facing depression worldwide.
Subject of Research: Neural biomarkers in antidepressant response for major depressive disorder (MDD)
Article Title: Early treatment-related changes in dorsolateral prefrontal cortex activity and functional connectivity as potential biomarkers for antidepressant response in major depressive disorder.
Article References: Zhang, H., Li, C., Shi, K. et al. Early treatment-related changes in dorsolateral prefrontal cortex activity and functional connectivity as potential biomarkers for antidepressant response in major depressive disorder. Transl Psychiatry 15, 350 (2025). https://doi.org/10.1038/s41398-025-03576-0
DOI: https://doi.org/10.1038/s41398-025-03576-0
