Advancing PRecise Interventions for resistant DEpression: rebalancing brain networks and investigating the trajectories of antidepressant effect with non-psychedelic psilocybin and personalized neuromodulation
Progetto This proposal seeks to address the global challenge of treatment-resistant depression (TRD), that leaves 30-50% of patients with major depression (MDD) unresponsive to conventional treatments. The persistent nature of TRD, despite therapeutic advances, underscores an urgent need for more precisely targeted and personalized strategies .
Our primary objective is to investigate the effectiveness of two promising interventions for TRD: psilocybin, administered in a novel, non-psychedelic form, and advanced neuromodulation (i.e., accelerated transcranial magnetic stimulation (rTMS) with customized fMRI-guided targeting). Though both have shown efficacy in TRD, a better understanding of their precise mechanisms of action, their impacts on brain networks implicated in MDD, and their optimized usage methods is crucial for effective translation into clinical practice.
We aim to translationally explore the specific effects of psilocybin and personalized rTMS on neural networks (Aim 1). Psilocybin has the potential to reorganize connectivity within and among brain networks implicated in MDD, such as the Default Mode Network (DMN), thereby "resetting" DMN connectivity. In contrast, rTMS targeting the prefrontal cortex modulates interactions between the central executive and reward networks, possibly improving cognitive control over emotional stimuli, thus alleviating anhedonic symptoms.
We will also compare the effectiveness of psilocybin and personalized rTMS in addressing TRD through a head-to-head non-inferiority trial (Aim 2). Using animal models that mimic specific features of MDD we will explore their efficacy across different MDD endophenotypes. The ultimate goal is to identify patient characteristics/endophenotypes predictive of treatment response or non-response, an area currently lacking robust scientific evidence.
The final aim is to bridge the research-practice gap by implementing advanced theoretical knowledge on MDD through easy- to-use methods for clinical practice (Aim 3). This includes integrating EEG-fMRI data and psychometric scales to identify distinct antidepressant trajectories, thus minimizing trial and error in clinical practice. We intend to promote feasibility of psilocybin use in the SSN by investigating the potential of minimizing its psychedelic effects, thereby reducing costs/drawbacks .
In conclusion, this project represents a significant step towards understanding brain networks associated with specific MDD symptom domains and their responses to different treatments. Findings will potentially guide the development of personalized treatment strategies for TRD, significantly contributing to global efforts in combating MDD. Furthermore, this research explores the potential of using psilocybin as a "clean" therapeutic tool, devoid of psychedelic effects, and the implementation of advanced neuromodulation techniques into everyday clinical practice. Importantly, the translational nature of the project, namely the use of preclinical models associated with distinct depressive endophenotypes and differing antidepressant trajectories, stands as a core strength. These preclinical investigations will provide crucial insights into disease mechanisms and therapeutic effects, paving the way for their translation into clinical trials and, ultimately, into routine clinical practice. The successful completion of this study will contribute to the development of more effective, individualized treatment approaches in the future.