The notion that inflammation and immune signals may play a role in the pathophysiology of psychiatric conditions has been gaining considerable support. In no small part, this support was driven by imaging studies assessing neuroinflammation-related markers. In particular, microglia activation has been reported in several psychiatric conditions, including schizophrenia and clinical high risk (CHR) subjects, using PET ligands that bind to the 18 kDa translocator protein (TSPO) (Bloomfield et al, 2016). Despite the excitement the initial findings generated, studies have not been consistent. In the current issue, Hafizi et al (2017) report lack of differences in CHR subjects compared to controls. This is the largest study assessing neuroinflammation in this population so far, and the authors controlled carefully for genotype and other factors. The authors have also used a validated outcome measure, a two-tissue compartment model that provides total volume of distribution (VT). This contrasts with previous studies that used ligand distribution volume ratio (DVR), a measure considered unacceptable by most PET imagers (Innis et al, 2007). So, yet another negative finding with TSPO binding in a psychiatric condition raises a number of questions for the field.

One conclusion could be that there simply is no microglia activation in CHR subjects. But to make sense of the data (both presented in this issue and reported previously), we need to solve a few outstanding issues. First, we need to understand better what exactly TSPO ligands are binding to. TSPO is a mitochondrial protein that was reported elevated in the brain, initially in hepatic encephalopathy. Soon after, reports emerged of elevated TSPO binding in several neurodegenerative conditions, and more recently psychiatric conditions. It was assumed for quite some time that increased TSPO activity selectively reflects activation of microglia, the resident brain macrophages. However, it is now evident that TSPO is expressed in mitochondria of many brain cell types beyond microglia, including astrocytes (Lavisse et al, 2012) and neurons (Notter et al, 2017). Thus, increased TSPO binding may reflect the functional state of mitochondria in several cell types and not necessarily inflammatory processes. It could well be that conditions of strongly active microglia and immune activation, such as neurodegenerative disorders, show large and reliably measurable TSPO binding. If microglia were indeed activated in psychiatric conditions, this activation would likely be moderate and perhaps not easy to distinguish from the natural variability TSPO ligands. Unfortunately, it is becoming clear that the question of whether there is immune activation or neuroinflammation in psychiatric conditions cannot be answered with TSPO binding studies.

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