Schizophrenia Risk and Insulin Resistance Intrinsically Linked

Megan Brooks

April 04, 2019

New research provides more evidence of genetic ties between schizophrenia and insulin resistance and suggests that patients with insulin-resistant schizophrenia may constitute a distinct subgroup with diminished response to antipsychotics medications.

"Because these patients show diminished response to antipsychotic medication, they might require personalized treatment tailored to their endophenotype," lead researchers Sabine Bahn, MD, PhD, and Jakub Tomasik, PhD, from University of Cambridge, UK, told Medscape Medical News.

The study was published online April 3 in JAMA Psychiatry.

Shared Genetic Factors?

Patients with schizophrenia are at increased risk of impaired glucose metabolism, yet the comorbidity between the two conditions cannot be fully explained by known risk factors such as obesity, smoking, stress, or antipsychotic medication.

Previous family and genome-wide studies have suggested that the co-occurrence between schizophrenia and impaired glucose metabolism may be due to shared genetic factors, as illustrated by increased risk of diabetes in first-degree relatives of patients with schizophrenia, but the biological mechanisms underlying this association remain unknown.

Bahn and colleagues studied the association between insulin resistance, schizophrenia polygenic risk, and response to treatment in 58 drug-naive patients with schizophrenia and 58 matched healthy individuals while controlling for a range of demographic (age, gender, body mass index), lifestyle (smoking, alcohol and cannabis use) and clinical (psychopathology scores, treatment drug) factors.

They found that insulin resistance significantly correlated with schizophrenia polygenic risk score in patients, with higher genetic risk of schizophrenia associated with increased insulin resistance. They also found that patients with higher insulin resistance were more likely to switch antipsychotic medication during the first year of treatment (adjusted odds ratio 1.77; 95% confidence interval, 1.10 - 3.52; P = .02), which implies lower clinical response.

"Future large-scale pharmacogenomic studies in drug-naive patients with longitudinal clinical follow-up will help 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, identifying specific genetic variants underlying shared susceptibility to schizophrenia and insulin resistance, and potentially guiding the development of novel, personalized treatment approaches," the investigators said.

Alternative Explanations?

Commenting on the findings for Medscape Medical News, Toby Pillinger, MRCP, from the Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK, noted that the study's outcomes are "consistent with a theory that was first proposed over 100 years ago — that risk of developing both schizophrenia and type 2 diabetes are intrinsically linked."

There are, however, other potential explanations for the outcomes, he noted.

"For example, the influence of diet and exercise was not assessed. Increased genetic risk for schizophrenia is associated with worse symptoms and functioning, so you might expect patients with higher polygenic risk scores to have worse diet and reduced exercise levels, which would increase insulin resistance," he said.

Similarly, the observation of increased insulin resistance predicting nonresponse to treatment may simply be explained, Pillinger said, by patients with more severe symptoms at baseline (which will respond less well to treatment) having poorer lifestyle factors that increase insulin resistance.

"In other words, these outcomes may not actually be directly (intrinsically) related," Pillinger said. "So, while the findings are novel and interesting, future studies need to consider the influence of confounders such as lifestyle before we can make definitive statements regarding intrinsic links and causality."

The study was supported by grants from the Stanley Medical Research Institute. Tomasik was a consultant for Psynova Neurotech Ltd, until April 2016. Bahn is a director of Psynova Neurotech Ltd and Psyomics Ltd. Pillinger has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online April 3, 2019. Abstract


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