In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study

Abstract

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.

Kinetics of Cytokine Levels during Antipsychotic Treatment in Schizophrenia: A Meta-Analysis

“…This could be reversed through antipsychotic medications. The possible antiinflammatory involvement could be illustrated by a recent study (Holmes et al, 2016) using positron emission tomography and radioligands that bind to the 18-kDa translocator protein that shows a direct interaction between antipsychotic medication and microglial activation in medicated patients with schizophrenia. The antiinflammatory effect of antipsychotic treatment may produce microglial activation (Holmes et al, 2016).…”

“…The possible antiinflammatory involvement could be illustrated by a recent study (Holmes et al, 2016) using positron emission tomography and radioligands that bind to the 18-kDa translocator protein that shows a direct interaction between antipsychotic medication and microglial activation in medicated patients with schizophrenia. The antiinflammatory effect of antipsychotic treatment may produce microglial activation (Holmes et al, 2016). There are 2 possible explanations for this normalization: the direct impact of antipsychotic treatment on the immune system or the indirect effect of antipsychotic treatment on the immune system by the improvement of the clinical symptoms of schizophrenia.…”

TSPO expression and brain structure in the psychosis spectrum

“…Three of the latter studies, however, used the first-generation radioligand for TSPO, [ 11 C]PK11195, which is known to have several limitations including low signal-to-noise ratio and brain penetration 17–19 ; while the Bloomfield and colleagues study used distribution volume ratio (instead of total volume of distribution) as outcome measure which presents important limitations for data interpretation 21 . Also, in the study by Holmes and colleagues, increase in TSPO expression was only observed in medicated schizophrenia, not in drug-naïve patients 18 . It is noteworthy that a recent meta-analysis of individual data of previous PET studies with second-generation radioligands in psychosis suggests an overall reduction of TSPO expression in psychosis 22 .…”

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

“…Currently, positron emission tomography (PET) imaging of mitochondrial 18 kDa translocator protein (TSPO), which measures microglial activation, is the most valid approach for studying neuroinflammation in vivo [48]. Of nine studies that investigated in vivo brain neuroinflammation in schizophrenia to date [46,48,49,50,51,52,53,54,55], four studies reported higher neuroinflammation in medicated schizophrenia patients as compared to healthy volunteers [50,51,53,55]. However, three out of these four studies used a first-generation radioligand for TSPO, [ 11 C]PK11195, which is known to have important methodological limitations.…”