Impairments in memory are associated with worse function outcomes and quality of life in patients with schizophrenia.1 Alterations in glucose metabolism, which are found in patients with schizophrenia,2 are also associated with memory impairment.3 Levels of insulin signaling molecules in blood extracellular vesicles (EVs) of neuronal origin can be measured as a marker of neuronal-specific insulin resistance.4 Complementary to this approach, magnetic resonance spectroscopy (MRS) is a non-invasive technique to measure brain glucose levels.
Wijtenberg and colleagues5 performed a study of EV biomarkers of neuronal insulin resistance and brain glucose levels using MRS, and their relationship to memory function, in 22 patients with schizophrenia and 24 healthy controls. Patients with schizophrenia were clinically stable with no changes in symptoms or medications in the past four weeks. Exclusion criteria were contraindication for MRI scanning, major medical illness affecting brain structure, diabetes, and current substance use disorder (excluding nicotine). Verbal and visuospatial learning and memory were assessed using the Hopkins Verbal Learning Task-revised (HVLT) and the Brief Visuospatial Memory Test (BVMT).
Functional capacity and quality of life were assessed with the UCSD Performance-Based Skills Assessment (UPSA). Fasting morning blood samples were collected for EV biomarkers, using an established protocol to isolate EVs enriched for neuronal origin. A principal component score representing six EV biomarkers was used as a measure of neuronal insulin resistance. All subjects also had a morning brain scan on a 3T MR system for glucose levels. Between-group differences were analyzed using Pearson Chi-square test for categorical variables, and Wilcoxon rank-sum or Wilcoxon-Mann-Whitney tests for continuous variables. Linear regression analyses were used to examine relationships between brain glucose, neuronal insulin resistance, and memory function.
The mean age of participants was 38 years; 63% of were male; and 18% were smokers. Patients with schizophrenia had a mean duration of illness of 19 years, and the majority was taking second-generation antipsychotics. Blood samples were available for EV biomarkers for 19 patients with schizophrenia and 16 controls. Patients with schizophrenia had significantly lower scores on the HVLT, BVMT, and UPSA compared to controls. There were no statistically significant differences in neuronal insulin resistance biomarkers between subject groups.
In patients with schizophrenia, neuronal insulin resistance biomarker scores were associated with higher brain glucose levels and poorer performance on the HVLT, but not the BVMT. Patients with schizophrenia had higher brain glucose levels than controls, and brain glucose levels were associated with poorer BVMT scores. In participants with schizophrenia, several individual neuronal insulin resistance biomarkers were significantly correlated with HVLT, but not BVMT scores. In controls, insulin resistance biomarker scores were not associated with HVLT scores or brain glucose. Furthermore, individual insulin resistance markers were not correlated with memory function in controls.
The authors concluded that poor glucose utilization, reflected by higher brain glucose levels, is evident in patients with schizophrenia. Furthermore, they found evidence of schizophrenia-specific interrelationships between neuronal insulin resistance biomarkers, brain glucose, and memory impairment. Limitations of the study include the relatively small sample size, the impact of antipsychotic medications on brain insulin resistance in schizophrenia is unclear, diabetes status was based on subject self-report, and peripheral metabolic markers were not measured.
The bottom line
Findings from this preliminary study suggest that brain insulin resistance may be an underlying cause of memory impairments in schizophrenia, and a novel potential treatment target.
Dr Miller is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is the Schizophrenia Section Editor for Psychiatric Times.
This article was originally published on 7/8/19 and has since been updated.
The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
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