Evidence-Based Reviews

The link between schizophrenia and diabetes

Current Psychiatry. 2012 October;11(10):28-46

Vigilant metabolic monitoring informs treatment decisions

References

1. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry Suppl. 2004;47:S64-S66.

2. Dixon L, Weiden P, Delahanty J, et al. Prevalence and correlates of diabetes in national schizophrenia samples. Schizophr Bull. 2000;26(4):903-912.

3. De Hert M, van Winkel R, Van Eyck D, et al. Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clin Pract Epidemol Ment Health. 2006;2:14.-

4. Juvonen H, Reunanen A, Haukka J, et al. Incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes mellitus. Arch Gen Psychiatry. 2007;64(8):894-899.

5. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull. 2001;60:5-20.

6. Ryan MC, Sharifi N, Condren R, et al. Evidence of basal pituitary-adrenal overactivity in first episode, drug naive patients with schizophrenia. Psychoneuroendocrinology. 2004;29(8):1065-1070.

7. Odawara M, Isaka M, Tada K, et al. Diabetes mellitus associated with mitochondrial myopathy and schizophrenia: a possible link between diabetes mellitus and schizophrenia. Diabet Med. 1997;14(6):503.-

8. Siuta MA, Robertson SD, Kocalis H, et al. Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice. PLoS Biol. 2010;8(6):e1000393.-

9. Strassnig M, Brar JS, Ganguli R. Nutritional assessment of patients with schizophrenia: a preliminary study. Schizophr Bull. 2003;29(2):393-397.

10. Daumit GL, Goldberg RW, Anthony C, et al. Physical activity patterns in adults with severe mental illness. J Nerv Ment Dis. 2005;193(10):641-646.

11. Ussher M, Stanbury L, Cheeseman V, et al. Physical activity p and perceived barriers to activity among persons with severe mental illness in the United Kingdom. Psychiatr Serv. 2007;58(3):405-408.

12. Cho NH, Chan JC, Jang HC, et al. Cigarette smoking is an independent risk factor for type 2 diabetes: a four-year community-based prospective study. Clin Endocrinol (Oxf). 2009;71(5):679-685.

13. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1-93.

14. Yu VL, Raphael D. Identifying and addressing the social determinants of the incidence and successful management of type 2 diabetes mellitus in Canada. Can J Public Health. 2004;95(5):366-368.

15. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116(2):151-157.

16. Colton CW, Manderscheid RW. Congruencies in increased mortality rates years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.-

17. Cohn T, Prud’homme D, Streiner D, et al. Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome. Can J Psychiatry. 2004;49(11):753-760.

18. Meyer JM, Stahl SM. The metabolic syndrome and schizophrenia. Acta Psychiatr Scand. 2009;119(1):4-14.

19. Chintoh AF, Mann SW, Lam L, et al. Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol. 2008;28(5):494-499.

20. Hahn MK, Arenovich T, Wolever T, et al. Single dose administration of olanzapine: effects on glucose metabolism, endocrine and inflammatory markers in healthy volunteers. Poster presented at: Schizophrenia International Research Society 3rd Biennial Conference; April 14-18, 2012; Florence, Italy.

21. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):S11-S63.

22. Little RR. Glycated hemoglobin standardization—National Glycohemoglobin Standardization Program (NGSP) perspective. Clin Chem Lab Med. 2003;41(9):1191-1198.

23. Keen H. The Diabetes Control and Complications Trial (DCCT). Health Trends. 1994;26(2):41-43.

24. American Diabetes Association. Symptoms. http://www.diabetes.org/diabetes-basics/symptoms. Accessed August 27 2012.

25. American Diabetes Association. Ketoacidosis (DKA). http://www.diabetes.org/living-with-diabetes/complications/ketoacidosis-dka.html. Accessed August 27 2012.

26. Grundy SM, Cleeman JI, Daniels SR, et al. American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-2752.

27. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23(5):469-480.

28. Rodbard HW, Blonde L, Braithwaite SS, et al. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1-68.

29. Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry. 2006;51(8):492-501.

30. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601.

31. Newcomer JW, Nasrallah HA, Loebel AD. The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol. 2004;24(5 suppl 1):S1-S6.

32. Khoury A, Sproule BA, Cohn TA. Development and implementation of the Metabolic Health Monitor at the Centre for Addiction and Mental Health. Poster presented at: BC Psychopharmacology Conference; February 15-16 2008; Vancouver, British Columbia, Canada.

33. Koller EA, Doraiswamy PM. Olanzapine-associated diabetes mellitus. Pharmacotherapy. 2002;22(7):841-852.

34. Zipursky RB, Gu H, Green AI, et al. Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol. Br J Psychiatry. 2005;187:537-543.

35. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45(7):771-791.

36. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302(16):1765-1773.

37. Nicol G, Newcomer J. Review: children and adolescents with schizophrenia spectrum disorders respond to antipsychotics but are susceptible to adverse events. Evid Based Ment Health. 2008;11(3):81.-

Discuss this article at www.facebook.com/CurrentPsychiatry

Although diabetes and schizophrenia are common companions, it is unclear how this association should influence our practice. What do we need to know about diabetes, and what are the key intervention points for psychiatrists?

This article is informed by my experience monitoring >1,000 patients with schizophrenia in a large urban mental health facility using an electronic metabolic monitoring system and consulting on hundreds of individuals with comorbid schizophrenia and diabetes in a mental health metabolic clinic.

A significant link

The association between schizophrenia and diabetes has been recognized for more than a century.¹ The prevalence of diabetes is increased 2- to 3-fold in patients with schizophrenia.^2,3 This relationship is specific to type 2 diabetes mellitus (T2DM); type 1 diabetes mellitus, an autoimmune disease, is less common in patients with schizophrenia.⁴ Factors that contribute to comorbidity between schizophrenia and T2DM include:

illness susceptibility: the mechanisms remain unclear but include the thrifty phenotype hypothesis,⁵ autonomic hyperactivity,⁶ and potential cellular and genetic links^7,8
lifestyle: diet, physical inactivity, and cigarette smoking^9-12
antipsychotic use¹³
social health determinants, such as income, housing, and food insecurity.¹⁴

The relative contribution of factors underlying this association is unknown; it is likely that they all contribute. Nevertheless, based on information from our facility’s metabolic monitoring database, depending on demographic variables, such as ethnicity and cigarette smoking, 20% to 30% of patients with schizophrenia will develop diabetes or prediabetes during the course of psychiatric treatment.

When evaluating a patient’s risk for a cardiac event, we consider having a diabetes diagnosis equivalent to having had a myocardial infarction.¹⁵ Likely, the high prevalence of T2DM among schizophrenia patients and challenges in managing diabetes and prediabetes underlies these patients’ reduced life expectancy.¹⁶ Self-care, a cornerstone of diabetes management, is challenging for patients with schizophrenia because of deficits in executive functioning, working memory, and motivation, coupled with negative symptoms and social and economic disadvantages that often accompany schizophrenia.

How diabetes impacts practice

What psychiatrists need to know. Insulin resistance—reduced biologic effectiveness of insulin—is the precursor of T2DM. Insulin is required to move glucose from the blood into cells. Weight gain, particularly abdominal adiposity, is the principal driver of insulin resistance. The body responds by producing more insulin (hyperinsulinemia) to maintain glucose homeostasis. Hyperinsulinemia underlies metabolic syndrome, an important risk marker for developing T2DM. Diabetes usually develops after many years when the pancreas fails to compensate for insulin resistance.

In most cases the development of diabetes in patients with schizophrenia follows this course. Weight gain, a consequence of lifestyle factors as well as antipsychotics and other psychotropics that promote obesity, leads to progressive insulin resistance. Consequently, metabolic syndrome is twice as prevalent among patients with schizophrenia compared with matched controls.^17,18

Occasionally patients develop T2DM within a few weeks or months of starting antipsychotic treatment—usually with clozapine or olanzapine—before they gain weight, which suggests a second mechanism may be involved. Animal studies have documented rapid development of insulin resistance after a single subcutaneous injection of antipsychotics that have high metabolic liability, possibly through a direct effect on insulin signaling.¹⁹ This phenomenon has been difficult to demonstrate in humans.²⁰

Clinical Point

Occasionally patients develop T2DM within weeks or months of starting antipsychotic treatment, usually with clozapine or olanzapine

Psychiatrists need to know how to diagnose diabetes (Table 1)^21-23 and the signs and symptoms of diabetes and diabetic ketoacidosis (Table 2).^24,25 Hemoglobin A1C diagnostic testing often is the preferred test because it does not require fasting.

Managing diabetes is complex and ideally involves a range of health practitioners who work with patients to provide education, promote self-care behaviors, and direct complex health care. These services are outside the scope of psychiatric practice, but given the functional deficits in seriously mentally ill patients, it is important to have an overview of diabetes care (Table 3).

In addition to diagnosing diabetes, psychiatrists should be able to identify patients at risk for developing diabetes and initiate prevention strategies. Interventions are focused on lifestyle—weight reduction, increased physical activity, diet, and smoking cessation—as well as pharmacologic strategies such as metformin.

Clinical Point

In addition to diagnosing diabetes, psychiatrists should be able to identify patients at risk for diabetes and initiate prevention strategies

Diagnostic criteria and strategies to manage prediabetes and metabolic syndrome are outlined in Table 4.^21,26,27 Prediabetes and metabolic syndrome predict development of T2DM. Additional risk factors include ethnicity (Hispanic, black, Native American, and South Asian), family history, gestational diabetes, and cigarette smoking.²⁸

What patients need to know. Similar to schizophrenia, a diabetes diagnosis may be difficult for patients to accept. Initially, a patient may have no manifestations or symptoms. However, untreated diabetes has serious long-term health consequences—including blindness, amputations, kidney disease, and early death from heart attacks.