Biomarkers of Neuroinflammation in Psychiatric Illnesses and their Relationship to Anti-inflammatory Medication

Major depressive disorder (MDD) is a leading cause of death and disability worldwide, with inadequate response to current pharmacotherapies being present in over 50% of cases. A logical explanation for treatment resistance is that MDD and other similarly treatment resistant psychiatric illnesses such as obsessive-compulsive disorder (OCD), may have multiple pathologies which present treatments do not effectively target. Interestingly, neuroinflammatory and immunological abnormalities have been documented in some patients with psychiatric disorders, leading to a theory of inflammatory processes affecting the brain and contributing to the pathogenesis of psychiatric illnesses. Positron emission tomography (PET) imaging enables the quantification of gliosis by measuring the level of translocator protein (TSPO), which is increased during neuroinflammation. Accordingly using [18F]FEPPA PET, in study one, we examined the relationship of TSPO distribution volume (VT), in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula (INS) to duration of untreated MDD. In study two, we determined whether TSPO VT is elevated in the cortico-striato-thalamo-cortical circuit of OCD. In study three, we assessed a serum blood marker to predict PFC, ACC, and INS TSPO VT in unmedicated MDD and treatment resistant depressed (TRD) participants and dorsal caudate TSPO VT in OCD participants. In study four, we determined whether oral minocycline can reduce elevated PFC, ACC, and INS TSPO VT in TRD participants. In study five, we determined the relationship of PFC TSPO VT to reduction in symptom severity associated with celecoxib administration. In study one, the results suggest that there is an increasing glial response in MDD reflecting neuroprogression of this illness. In study two, the results strongly argue that neuroinflammation, in particular glial activation is a pathological abnormality of OCD. In study three, the results suggest systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO VT. In study four, the results suggest that oral minocycline is not effective enough to elicit a change in TSPO VT in MDD. In study 5, we demonstrate that oral celecoxib has a differential effect on depression symptom severity, depending on the level of microglial activation as indexed by the baseline TSPO VT value.Ph.D.2021-11-11 00:00:0