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 [11C](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.
Highlights
Schizophrenia affects ~ 0.5–1% of the population worldwide.[1]
We found no evidence for increased translocator protein (TSPO) availability in antipsychotic-free patients in the 2–6 year period following diagnosis
Our finding suggests that schizophrenia is not associated with microglial activation, at least not in the relatively early stages
Summary
Schizophrenia affects ~ 0.5–1% of the population worldwide.[1]. It can be characterised by three symptom domains: positive symptoms (delusions and hallucinations), negative symptoms (lack of motivation, anhedonia, flat affect, social withdrawal) and cognitive impairments, all of which can have profound effects on functioning and quality of life. The efficacy of antipsychotics is predominantly against positive symptoms, whereas the negative and cognitive symptoms remain relatively poorly modified and contribute significantly to the impaired functioning and wider burden of the disorder. Novel avenues of research need to be explored to elucidate the pathophysiological mechanisms underlying all symptom domains, and to inform the development of more effective and tolerable medications. Convergent evidence suggests that inflammation may have a key role in the pathophysiology of schizophrenia and as a potential target for drug development.[2,3,4,5,6,7,8,9,10] In particular, peripheral markers of inflammation are raised in patients with schizophrenia[11] including first-episode antipsychotic-naive patients,[12,13] and there is some evidence for increased inflammatory markers post-mortem.[14,15,16] A crucial question though, is whether there is evidence of neuroinflammation in schizophrenia in vivo
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