Schizophrenia polygenic risk score (PRS) was significantly associated with insulin resistance (IR), per study results published in JAMA Psychiatry. Such data indicate that insulin resistance may be a “hallmark” of schizophrenia, rather than a secondary effect.

First-episode, antipsychotic-naive patients with schizophrenia (n=58) were recruited from the University Hospital Marqués de Valdecilla in Santander, Spain, and matched with 58 control individuals by age, sex, and body mass index. Genotyping was performed on patient blood samples; schizophrenia polygenic risk scores were calculated on the basis of 108 genome-wide significant schizophrenia loci. The updated Homeostasis Model Assessment (HOMA2) was used to infer IR, β-cell function, and insulin sensitivity from clinical measurements of fasting serum glucose and insulin levels. Switching antipsychotic medication at least once during the initial 12 months of treatment was used as a long-term treatment outcome measure.

Related Articles

Patients with schizophrenia displayed increased baseline HOMA2-IR (P =.004), HOMA2 β-cell function (P =.02), and fasting insulin levels (P =.004). HOMA2 insulin sensitivity and fasting glucose levels, however, did not differ between patients and control individuals. After adjusting for body mass index, HOMA2-IR remained significantly increased in patients with schizophrenia (P <.001). HOMA2-IR was positively associated with schizophrenia PRS in patients with schizophrenia (P =.02), although not in control individuals. Body mass index was the most significant risk factor for HOMA2-IR in control individuals (P <.001). Baseline HOMA2-IR was significantly associated with switching antipsychotic medication during the initial 12 months of treatment (odds ratio, 1.77; 95% CI, 1.10-3.52; P =.02). All patients who at baseline met fasting insulin criteria for IR required a medication change within the following 12 months. Schizophrenia PRS, however, was not significantly associated with medication switching.

These data support the hypothesis that schizophrenia and diabetes may share susceptibility genes, although further research with larger patient cohorts are necessary. Insulin resistance may also predict resistance to antipsychotic therapy, a finding relevant to clinicians developing patient treatment plans.


Tomasik J, Lago SG, Vázquez-Bourgon J, et al. Association of insulin resistance with schizophrenia polygenic risk score and response to antipsychotic treatment [published online April 3, 2019]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.0304