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 V(T)), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO V(T) 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. METHODS: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [(18)F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO V(T). Open-label oral celecoxib (200 mg, twice daily) 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 scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO V(T), showing a significant nonlinear relationship. At low TSPO V(T) values, there was no reduction in HDRS scores, but as TSPO V(T) values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO V(T) accounted for 84% and 92% of the variance, respectively. CONCLUSIONS: Celecoxib administration in the presence of gliosis labeled by TSPO V(T) is associated with greater reduction of symptoms. Given the predictiveness of TSPO V(T) 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 treatment-resistant major depressive disorder.