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Insulin resistance a ‘hallmark’ of schizophrenia

Schizophrenia polygenic risk was significantly linked to insulin resistance in first-episode, antipsychotic-naive patients with schizophrenia regardless of demographic, lifestyle and clinical factors, according to a research letter published in JAMA Psychiatry.

These findings suggest that insulin resistance “is a hallmark of schizophrenia,” not a secondary effect of emerging symptoms, the researchers wrote.

“While family and genome-wide association studies have suggested a shared genetic vulnerability between schizophrenia and abnormal glucose metabolism, to our knowledge, a direct link between schizophrenia genetic risk and insulin resistance has not been investigated,” Jakub Tomasik, PhD, from the University of Cambridge, England, and colleagues wrote.

Researchers compared the link between insulin resistance, schizophrenia polygenic risk and treatment outcomes in 58 first-episode, treatment-naive patients with schizophrenia vs. 58 matched unaffected control individuals after controlling for covariates.

They calculated schizophrenia polygenic risk scores based on 108 genome-wide schizophrenia loci from genotyping data and used the Homeostasis Model Assessment (HOMA2) to determine insulin resistance, beta cell function and insulin sensitivity from clinical measurements of fasting serum glucose and insulin levels.

As seen in previous research, Tomasik and colleagues found that patients with schizophrenia had elevated HOMA2-insulin resistance (mean difference = 0.68; P = .004), beta-cell function (32.2; P = .02) and fasting insulin levels (5.5 IU/mL; P = .004) at baseline; however, insulin sensitivity and fasting glucose levels were not significantly different from control values. After adjustment, HOMA2-insulin resistance remained significantly increased in patients with schizophrenia (mean difference = 0.82; P < .001), according to the study.

Analysis revealed that HOMA2-insulin resistance was positively associated with schizophrenia polygenic risk score in patients with schizophrenia (beta = 3.74; P = .02). In addition, insulin resistance at baseline was linked to switching antipsychotic medication during the first year of treatment (adjusted OR = 1.77; 95% CI, 1.1-3.52), though schizophrenia polygenic risk score was not tied to medication switching status (aOR = 183; 95% CI, 0.48-504,931).

“Patients with schizophrenia presenting with [insulin resistance] might constitute a distinct patient subgroup and require personalized treatment tailored to this endophenotype,” the researchers wrote. “Future pharmacogenomic studies and more specific assays, such as the oral glucose tolerance and cortisol tests, are required to further examine the association between [insulin resistance], schizophrenia, and antipsychotic treatment response, in addition to determining the effects of other lifestyle factors such as diet and exercise.” – by Savannah Demko

Disclosures: Tomasik reports consulting for Psynova Neurotech, Ltd. Please see the study for all other authors’ relevant financial disclosures.