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Neuroinflammation may be a culprit in the development of psychosis. What are the clinical implications?
The onset of schizophrenia is often preceded by a prodromal phase, characterized by attenuated psychotic symptoms and functional impairment. Persons who meet the standardized criteria for this phase are at ultra-high risk for the development of a psychotic disorder. Effective, early intervention during this phase may forestall the onset of a fulminant psychotic disorder. However, it is difficult to “spot” schizophrenia in its earliest stages: only about 35% of high-risk persons will develop a psychotic disorder, primarily schizophrenia, within 24 months.1
There is increasing evidence that immune system dysfunction, including inflammation, may be present in persons at high risk for psychosis and may play a role in the pathophysiology of some patients with schizophrenia. Microglia-the resident immune cells in the central nervous system-may have abnormal activity and density in schizophrenia. Microglial activity can be measured in vivo with positron emission tomography (PET) using radioligands specific for the translocator protein (TSPO), which is expressed on microglia.
Bloomfield and colleagues2 investigated whether microglial activity was elevated in subjects at ultra-high risk for psychosis using the novel TSPO radioligand [11C]PBR28. They hypothesized that microglial activity would be elevated in total gray matter, as well as in frontal and temporal cortical regions, in ultra–high-risk subjects compared with matched healthy controls.
The researchers recruited a total of 56 subjects in London, England: 14 who met ultra–high-risk criteria, based on the Comprehensive Assessment of the At-Risk Mental State (CAARMS); 14 with chronic schizophrenia; and 2 age-matched control groups of 14 subjects each. Subjects were screened using the Structured Clinical Interview for DSM disorders. All were age 18 or older and had no significant physical or psychiatric contraindications to PET scanning.
Excluded were subjects with exposure to any medications, including anti-inflammatory agents, in the past month; a history of substance use disorder; benzodiazepine use; a history of head injury with loss of consciousness; low-affinity binding TSPO genotype; antipsychotic medication exposure (in the ultra–high-risk and control groups); or significant prior radiation exposure; or who were pregnant or breastfeeding.
Microglial activity-as measured by the [11C]PBR28 binding ratio in total, frontal, and temporal gray matter-was elevated in ultra–high-risk subjects compared with age-matched controls with a large effect size (d = 1.2). It was also positively correlated with symptom severity based on the CAARMS (r = 0.730) but was not correlated with symptom duration or depressive symptoms. Interestingly, one ultra–high-risk subject in the study who subsequently developed a psychotic disorder had the highest total gray matter [11C]PBR28 signal.
Patients with schizophrenia also demonstrated elevated microglial activity in total, frontal, and temporal gray matter relative to matched controls with a large effect size (d = 1.7). However, there was no relationship between microglial activity, psychotic symptoms, or depression in patients with schizophrenia.
The researchers concluded that [11C]PBR28, a marker of microglial activity, is elevated in subjects at ultra-high risk for psychosis and is independent of the effects of previous psychotic illness or its treatment. Furthermore, this marker was associated with subclinical psychotic symptoms, but not depression, which suggests an association that is specific to psychosis rather than to psychiatric symptoms in general.
The bottom line
This study suggests that persons at high risk for psychosis have evidence of neuroinflammation that may be involved in the development of psychotic disorders. Replicated findings would indicate that anti-inflammatory treatment might be effective in preventing the transition to psychotic disorder in these persons.
Dr Miller is Associate Professor in the Department of Psychiatry at Georgia Regents University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
1. Fusar-Poli P, Bonoldi I, Yung AR, et al. Predicting psychosis: metaanalysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry. 2012;69:220-229.
2. Bloomfield PS, Selvaraj S, Veronese M, et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. Am J Psychiatry. 2016;173:44-52. doi: 10.1176/appi.ajp.2015.14101358.