Differential effects of TSPO ligands on functional connectivity and metabolism related to fear and anxiety in the human brain

• Applicants: Professorin Dr. Caroline Nothdurfter; Professor Dr. Rainer Rupprecht; Professor Dr. Jens Schwarzbach
• Subject Area: Biological Psychiatry ; Human Cognitive and Systems Neuroscience ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403161218

Endogenous and synthetic 3α-reduced neurosteroids are powerful positive allosteric modulators of GABAA receptors. Intriguingly, such compounds (brexanolone, zuranolone) may exert quite rapid antidepressant effects. These recent developments and the discrete neuroinflammation reported in depression have promoted the idea that TSPO ligands may constitute an attractive alternative to exogenous neurosteroids in the treatment of depression. Therefore, the current proposal aims to set up a proof-of-concept study to get first evidence whether the TPSO ligand etifoxine as add-on treatment to treatment as usual (TAU) may confer rapid antidepressant effects and which mechanisms of action, e.g., neurosteroidogenesis, modulation of distinct neuronal networks, HPA axis activity and microbiome composition, contribute to a putative antidepressant effect. Moreover, the project will study the effects of the TSPO ligand etifoxine regarding modulation of neuronal networks, HPA axis activity, brain metabolites and microbiome composition in relation to clinical and side effects. The project aims to address the following specific objectives by means of a single center placebo-controlled study in patients suffering from major depression or bipolar depression (n=50). 1. Does add-on treatment with a TSPO ligand for 14 days enhance or fasten the response to antidepressant treatment as usual (TAU)? 2. Is discontinuation of a TSPO ligand associated with relapse or withdrawal symptoms? 3. Does add-on treatment with a TSPO ligand differentially affect neurosteroidogenesis, TSPO expression and/or HPA axis activity in depressed patients compared to TAU? 4. Does add-on treatment with a TSPO ligand differentially affect functional neuronal networks and cognitive function as assessed by neuropsychological assessment and functional magnetic resonance imaging (fMRI) using resting-state and task-based paradigms (RSA and face name association learning) compared to TAU? 5. Does add-on treatment with a TSPO ligand differentially affect microbiome composition compared to TAU? 6. Can we predict the dynamics of changes in clinical outcome measures using behavioral, hormonal, imaging-, and microbiome-related parameters by machine learning paradigms? A positive proof-of-concept would delineate TSPO ligands as an attractive alternative to exogenous neurosteroids as a novel treatment approach in depression and constitute the basis for respective multicenter trials.

• DFG Programme: Research Units
• Subproject of: FOR 2858: Role of translocator protein (18 kDa) (TSPO) as a diagnostic and therapeutic target in the nervous system
• Co-Investigator: Professor Dr. Michael Koller