Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

Abstract Background Gliosis is common among neuropsychiatric diseases but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO VT), measured with positron emission tomography (PET), mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO VT in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment resistant major depressive disorder (TRD). Methods 41 TRD subjects underwent one [18F]FEPPA PET to measure PFC and ACC TSPO VT. Open-label oral celecoxib 200 mg bid was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS). Results Cumulative mean change in HDRS between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO VT, showing a significant non-linear relationship. At low TSPO VT values, there was no reduction in HDRS, but as TSPO VT values increased, there was a reduction in HDRS, which then plateaued. This was modelled with a 4-parameter sigmoidal model in which PFC and ACC TSPO VT respectively accounted for 84% and 92% of the variance. Conclusions Celecoxib administration in the presence of gliosis labelled by TSPO VT is associated with greater reduction of symptoms. Given the predictiveness of TSPO VT on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for TRD.