Assessment of Insulin Resistance Among Drug-Naive Patients With First-Episode Schizophrenia in the Context of Hormonal Stress Axis Activation | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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Table 1.  Demographic Data, Clinical Scores, and Laboratory Parameters Related to Insulin Resistance and Hormonal Stress Axis Activation (Cortisol and Catecholamine Metabolites)a
Demographic Data, Clinical Scores, and Laboratory Parameters Related to Insulin Resistance and Hormonal Stress Axis Activation (Cortisol and Catecholamine Metabolites)a
Table 2.  Correlation of Homeostasis Model Assessment of Insulin Resistance With Demographic Data, Clinical Scores, and Laboratory Parameters
Correlation of Homeostasis Model Assessment of Insulin Resistance With Demographic Data, Clinical Scores, and Laboratory Parameters
1.
Pillinger  T, Beck  K, Gobjila  C, Donocik  JG, Jauhar  S, Howes  OD.  Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis.  JAMA Psychiatry. 2017;74(3):261-269.PubMedGoogle ScholarCrossref
2.
Sakel  M.  Insulin therapy in the future of psychiatry.  Can Med Assoc J. 1938;39(2):178-179.PubMedGoogle Scholar
3.
Berger  M, Kraeuter  AK, Romanik  D, Malouf  P, Amminger  GP, Sarnyai  Z.  Cortisol awakening response in patients with psychosis: Systematic review and meta-analysis.  Neurosci Biobehav Rev. 2016;68:157-166.PubMedGoogle ScholarCrossref
4.
Jordan  W, Dobrowolny  H, Bahn  S,  et al.  Oxidative stress in drug-naive first episode patients with schizophrenia and major depression: effects of disease acuity and potential confounders [published online December 2, 2016].  Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-016-0749-7PubMedGoogle Scholar
5.
Steiner  J, Bernstein  HG, Schiltz  K,  et al.  Decrease of serum S100B during an oral glucose tolerance test correlates inversely with the insulin response.  Psychoneuroendocrinology. 2014;39:33-38.PubMedGoogle ScholarCrossref
6.
Kirkpatrick  B, Miller  BJ, Garcia-Rizo  C, Fernandez-Egea  E, Bernardo  M.  Is abnormal glucose tolerance in antipsychotic-naive patients with nonaffective psychosis confounded by poor health habits?  Schizophr Bull. 2012;38(2):280-284.PubMedGoogle ScholarCrossref
Research Letter
September 2017

Assessment of Insulin Resistance Among Drug-Naive Patients With First-Episode Schizophrenia in the Context of Hormonal Stress Axis Activation

Author Affiliations
  • 1Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
  • 2Center for Behavioral Brain Sciences, Magdeburg, Germany
  • 3Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine (AITHM), Townsville, Australia
  • 4College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, Australia
  • 5Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Australia
  • 6Laboratory of Neuroproteomics, Institute of Biology, University of Campinas, Cidade Universitária Zeferino Vaz, Campinas, Brazil
  • 7Institute of Clinical Chemistry and Pathobiochemistry, University of Magdeburg, Magdeburg, Germany
  • 8Department of Forensic Psychiatry, Psychiatric Hospital of the Ludwig-Maximilians-University München, Munich, Germany
JAMA Psychiatry. 2017;74(9):968-970. doi:10.1001/jamapsychiatry.2017.1983

Before the introduction of antipsychotics, links between schizophrenia and abnormal glucose metabolism levels were found in the late 1800s as an increased prevalence of diabetes in families with a history of “insanity.”1 Furthermore, it is known that some patients with psychosis require higher dosages than other patients when applying insulin therapy, suggestive of insulin resistance.2 A recent meta-analysis by Pillinger et al1 assessed insulin resistance and found an elevated homeostatic model assessment of insulin resistance (HOMA-IR) among drug-naive patients with first-episode schizophrenia (n = 560) compared with controls (n = 450).1 They highlighted hormonal stress axis activation and lifestyle factors as potential confounders.1 Stress hormones, such as cortisol and catecholamines, are catabolic and functional antagonists of insulin. Antipsychotic-naive individuals with first-episode psychosis exhibit higher baseline cortisol levels and a blunted cortisol awakening response compared with controls.1,3 To test whether insulin resistance in schizophrenia can be discerned from stress-related and medication effects, we assessed HOMA-IR and stress hormone levels among drug-naive patients with first-episode schizophrenia and matched controls.

Methods

Morning urine and blood samples (taken at 8 am after the patients fasted) were obtained from 24 acute, drug-naive patients with first-episode schizophrenia and 24 controls. All participants were white and matched for sex, age, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), and waist-hip ratio (Table 1). All procedures were approved by the local institutional review board and written informed consent was obtained. Methodological details, inclusion/exclusion criteria, a psychopathology assessment (Positive and Negative Syndrome Scale [PANSS]), and the measurement of serum cortisol and urinary metanephrine/normetanephrine levels are available in Jordan et al.4 Insulin and glucose levels were determined as described in Steiner et al.5 Homeostatic model assessment of insulin resistance, a measure of basal insulin resistance, was calculated using the formula (insulin [mU/L] × glucose [mmol/L])/22.5. Group differences were detected applying Mann-Whitney U tests, and associations of HOMA-IR with other measures were determined using the Spearman rank test. An analysis of covariance using an aligned rank transformation of the data (http://www.r-project.org) was performed to control for the diagnostic group effects regarding HOMA-IR for the covariates BMI, waist-hip ratio, cortisol levels, metanephrine levels, normetanephrine levels, and smoking.

Results

Homeostatic model assessment of insulin resistance increased 2-fold among patients (median [IQR], 0.72 [0.38-2.28]) compared with controls (median [IQR], 0.36 [0.26-0.84]) (P = .02) (Table 1). Serum cortisol levels increased approximately 1.4-fold (median [IQR], 26.65 [17.78-40.30]; P = .04) and urinary metanephrine (median [IQR], 71.5 [42.9-127.1]; P = .03) and normetanephrine (median [IQR], 147.7 [89.1-217.7]; P = .08) levels increased approximately 1.7-fold and 1.5-fold, respectively, although only the latter trended toward significance (P < .10). Homeostatic model assessment of insulin resistance was correlated with BMI (r = 0.463; P = .001), but no significant correlations were found between HOMA-IR and levels of cortisol (r = 0.097; P = .52), metanephrine (r = 0.123; P = .41), normetanephrine (r = 0.161; P = .28) or smoking (r = 0.094; P = .53) (Table 2). Homeostatic model assessment of insulin resistance was not related to PANSS-P (r = 0.086; P = .69), PANSS-N (r = 0.099; P = .65), PANSS-G (r = −0.183; P = .39), or PANSS sum (r = 0; P = .99). Additional testing showed that the schizophrenia-related HOMA-IR increase was present among nonsmokers (patients: n = 8, controls: n = 18; P = .02). The diagnostic group difference regarding HOMA-IR was confirmed by an analysis of covariance using an aligned rank transformation (F = 10.172, P = .003). Only the covariate BMI had significant influence in this model (patients: median [IQR], 22.2 [21.0-27.4]; controls: median [IQR], 24.7 [21.6-27.6]; F = 9.001, P = .005).

Discussion

We found that although serum and urinary stress hormone levels were increased in acute psychosis; this was not related to HOMA-IR. Notably, glucose metabolism is regulated redundantly and may be impaired by stress or biological insults in many ways (eg, central sympathetic control through multiple neurotransmitters). The patient and control groups were well-matched for sex, age, BMI, and waist-hip ratio to rule out the possibility that being overweight and visceral adiposity could be factors that explained increased HOMA-IR scores among patients. While the lifestyle factors “exercise,” “sedentary behavior,” and “diet” were not examined in this study, HOMA-IR was not related to smoking.

These results support the recently raised notion of impaired insulin/glucose homeostasis in drug-naive patients with first-episode schizophrenia, small sample and effect sizes notwithstanding.1,6 Reduced insulin sensitivity may arise independently from pharmacotherapy, hormonal stress axis activation, or obesity.6 Glucose metabolism levels should be assessed in larger samples and other psychiatric disorders to examine specificity for schizophrenia.

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Article Information

Corresponding Author: Johann Steiner, MD, PhD, Department of Psychiatry, University of Magdeburg, Leipziger Str. 44, Magdeburg, D-39120, Saxony-Anhalt, Germany (johann.steiner@med.ovgu.de).

Published Online: July 19, 2017. doi:10.1001/jamapsychiatry.2017.1983

Author Contributions: Drs Steiner and Dobrowolny had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Steiner, Berger, Schiltz.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Steiner, Guest, Schiltz, Sarnyai.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Berger, Dobrowolny, Schiltz, Sarnyai.

Administrative, technical, or material support: Steiner, Westphal, Schiltz.

Supervision: Steiner, Schiltz, Sarnyai.

Conflict of Interest Disclosures: Dr Sarnyai has been a speaker for Otsuka and Lundbeck. No other disclosures were reported.

Additional Contributions: We thank Anke Dudeck, Dipl-Psych, University of Magdeburg, Gabriela Meyer-Lotz, University of Madgeburg, and Jeanette Schadow, Dipl-Psych, University of Magdeburg, for participating in the sample characterization and collection. They were not compensated for their contributions.

References
1.
Pillinger  T, Beck  K, Gobjila  C, Donocik  JG, Jauhar  S, Howes  OD.  Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis.  JAMA Psychiatry. 2017;74(3):261-269.PubMedGoogle ScholarCrossref
2.
Sakel  M.  Insulin therapy in the future of psychiatry.  Can Med Assoc J. 1938;39(2):178-179.PubMedGoogle Scholar
3.
Berger  M, Kraeuter  AK, Romanik  D, Malouf  P, Amminger  GP, Sarnyai  Z.  Cortisol awakening response in patients with psychosis: Systematic review and meta-analysis.  Neurosci Biobehav Rev. 2016;68:157-166.PubMedGoogle ScholarCrossref
4.
Jordan  W, Dobrowolny  H, Bahn  S,  et al.  Oxidative stress in drug-naive first episode patients with schizophrenia and major depression: effects of disease acuity and potential confounders [published online December 2, 2016].  Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-016-0749-7PubMedGoogle Scholar
5.
Steiner  J, Bernstein  HG, Schiltz  K,  et al.  Decrease of serum S100B during an oral glucose tolerance test correlates inversely with the insulin response.  Psychoneuroendocrinology. 2014;39:33-38.PubMedGoogle ScholarCrossref
6.
Kirkpatrick  B, Miller  BJ, Garcia-Rizo  C, Fernandez-Egea  E, Bernardo  M.  Is abnormal glucose tolerance in antipsychotic-naive patients with nonaffective psychosis confounded by poor health habits?  Schizophr Bull. 2012;38(2):280-284.PubMedGoogle ScholarCrossref
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