Neuroinflammation in Major Depressive Disorder and Schizophrenia: a PET study

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Abstract

Background: Mounting evidence suggests that inflammation is involved in the pathophysiology of both Major Depressive Disorder (MDD) and schizophrenia. The presence of inflammation in the brain, however, is less clear. Microglial activation, a measure of neuroinflammation, can be quantified using PET ligands that bind to the Translocator Protein (TSPO) which is overexpressed by activated microglia. Previous PET studies using TSPO radioligands have shown some evidence for neuroinflammation in both MDD and schizophrenia. However some of these studies have been confounded by antidepressant/antipsychotic medication, low numbers and mild severity. We aimed to address some of these issues and investigate the relationship between neuroinflammation and peripheral inflammation, medication status, symptom severity and cognitive function.Method: Fourteen patients in a Major Depressive Episode (MDE) of at least moderate severity, sixteen patients with a diagnosis of schizophrenia of at least moderate severity and a total of eighteen age and gender-matched healthy volunteers underwent a 60 minute dynamic PET scan with the TSPO radioligand [11C](R)-PK11195 on the High Resolution Research Tomograph (HRRT). Parametric maps of binding potential (BPND) were generated using the simplified reference tissue model and a grey matter cerebellum input function. All of the MDD patients were antidepressant-free for at least eight months prior to scanning. Of the sixteen schizophrenia patients, eight were antipsychotic-free (for at least twelve months) and eight were on a long-acting injection of risperidone or paliperidone. All patients and healthy volunteers were medically healthy and had drug or alcohol abuse within the previous year. Results: We found a 26% mean increase in BPND values, indicative of microglial activation, in MDD patients compared to healthy volunteers. Exploratory analysis revealed significantly higher [11C](R)-PK11195 binding in the anterior cingulate cortex (ACC). We found no significant correlations between [11C](R)-PK11195 binding and peripheral markers of inflammation or with symptom severity. We also found a mean 27% increase in BPND values in the schizophrenia patients compared to healthy volunteers. There were significant correlations between [11C](R)-PK11195 and negative symptoms across multiple brain regions. When breaking the cohort down according to medication status, there was no difference between antipsychotic-free patients and healthy volunteers. However, mean BPND values were 30% higher in the ACC. The medicated patients exhibited higher BPND values than healthy volunteers, with a mean increase of 48%. Exploratory t-tests revealed significant increases in dorsolateral prefrontal cortex and ACC.Conclusions: Our findings are largely consistent with previous PET findings of increased microglial activation in a sample of antidepressant-free patients in a moderate-to-severe MDE, suggesting that neuroinflammation is present in MDD. We also investigated neuroinflammation in antipsychotic-free patients for the first time and found no evidence of microglial activation. However it is likely that the subgroup sample was underpowered. The medicated patients exhibited a 48% increase in [11C](R)-PK11195 binding compared to controls, suggesting that either medication or duration of illness might potentiate microglial activation. Our findings also point to an association between neuroinflammation and the negative symptoms of schizophrenia. The PET findings from both cohorts are largely overlapping, suggesting that neuroinflammation is not specific to either disorder but rather a common mechanism. This could reflect a common aetiology and/or an overlap in symptoms. Our findings suggest that inflammation could be used as a potential biomarker as well as a target for novel treatment strategies in both MDD and schizophrenia.

Keyword(s)

Depression; Inflammation; Positron Emission Tomography; Schizophrenia

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