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Schizophrenia and Insulin Resistance May Be Genetically Linked

April 12, 2019

By Marilynn Larkin

NEW YORK—Schizophrenia and insulin resistance (IR) may be genetically linked and patients with the two conditions may constitute a unique subgroup, researchers suggest.

"Previous family and genome-wide studies have suggested that the co-occurrence between schizophrenia and impaired glucose metabolism might be due to shared genetic factors, as exemplified by increased risk of diabetes in first-degree relatives of schizophrenia patients," Dr. Sabine Bahn of the University of Cambridge, UK, told Reuters Health by email.

To investigate the biological mechanisms underlying this association, Dr. Bahn and colleagues matched 58 first-episode, antipsychotic-naive patients with unaffected controls. Schizophrenia polygenic risk scores (PRS) were calculated based on 108 genome-wide schizophrenia loci; the updated Homeostasis Model Assessment (HOMA2) was used to infer IR, beta-cell function and insulin sensitivity from fasting serum glucose and insulin levels.

As reported online April 3 in JAMA Psychiatry, patients with schizophrenia had increased baseline HOMA2-IR, HOMA2 beta-cell function and fasting insulin levels. However, HOMA2 insulin sensitivity and fasting glucose levels did not differ significantly from controls.

After adjustment for covariates, including body mass index, HOMA2-IR remained significantly increased in patients with schizophrenia. Further, HOMA2-IR was positively associated with the schizophrenia PRS in patients with schizophrenia but not in controls, where BMI was the most significant IR risk factor

In addition, baseline HOMA2-IR was significantly associated with switching antipsychotic medication during the first year of treatment, with an adjusted (for ethnicity) odds ratio of 1.77. Specifically, among 41 patients for whom complete follow-up data were available, the eight patients who at baseline met the fasting insulin criteria for IR (25 mcg IU/mL or greater) had to switch.

By contrast, the PRS was not significantly associated with medication switching status (adjusted OR, 183).

"These results suggest that insulin resistance and schizophrenia are genetically linked and that schizophrenia patients presenting with insulin resistance might constitute a distinct patient subgroup," Dr. Bahn said. "This is consistent with previous findings of altered glucose metabolism in the brain and periphery in subsets of patients with schizophrenia. Because these patients show diminished response to antipsychotic medication, they might require personalized treatment tailored to their endophenotype."

She continued, "Future large-scale pharmacogenomic studies in drug-naive patients with longitudinal clinical follow-up will help to further examine (these associations), 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."

Her group is participating in clinical trials "aimed at repurposing a metabolic drug for schizophrenia in the Netherlands and targeting metabolic abnormalities in schizophrenia patients in Denmark," she said.

Dr. Lora McClain, a psychiatry researcher at the University of Pittsburgh experienced in the genetics of schizophrenia, told Reuters Health, "The authors present an intriguing study with potentially important results. Schizophrenia is likely a multifactorial disorder, where a combination of environmental and genetic risk factors contributes to risk for the disease."

"While the sample size is small," she said by email, "the results are tantalizing. These were 'first-break' patients, who had just recently manifested clear signs of schizophrenia. So, the finding of higher HOMA-insulin resistance in (those individuals) is notable."

Nonetheless, "there are some concerns about the interpretation and generalizability of the study as well, beyond its small sample size," she said. "Subjects were comprised of mainly white individuals...The schizophrenia PRS was built largely from prior studies using only European whites, and is known to work less well for other ancestry groups. This is also the case for measurements of HOMA-insulin resistance."

Further, she noted, "While these were first-break subjects, development of schizophrenia isn't necessarily as abrupt as its first diagnosis. What if individuals who are developing schizophrenia are also prone to lifestyle choices that increase risk for poorly controlled insulin resistance? That is a key challenge for all naturalistic studies - the distinction between correlation and causation is difficult."

"We should proceed cautiously until further studies, using larger sample sizes, wider sets of genetic ancestry, and more controlled designs, are performed," Dr. McClain concluded.


JAMA Psychiatry 2019.

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