Severe mental illness: biological effects

Exactly why first-episode drug-naïve patients with SMI have a higher than expected risk of developing T2DM remains elusive. Reports that predate the introduction of psychotropic medications show an association between ‘sugar intolerance’ and mental disorders such as ‘dementia praecox’ (schizophrenia). These appeared in several articles though the definitions of both conditions would not conform to modern criteria and there was little or no attempt to match different groups in terms of now known diabetes risk factors. Interestingly, in 10 studies of people with SMI pre-1954, the range of blood sugar levels following a glucose challenge ranged from 16-66%.


Antipsychotic naïve first episode people with schizophrenia have been shown to have impaired fasting glucose by a number of studies though not all[1][2][3][4][5]. The studies varied in that some had small sample sizes and inadequate matching of patients and controls. Furthermore, the fact that IFG is not as sensitive as the oral glucose tolerance test (OGTT) may also help explain these discrepancies. Those using the OGTT have shown that the rates of impaired glucose tolerance in first episode drug naïve people with schizophrenia have range from 8.0% to 22%, though the latter figure referred to ‘non-deficit’ (the presence of positive symptoms, such as hallucinations & delusions) patients and included those with T2DM as well as impaired glucose tolerance.

Potential reasons for the association between either pre-diabetic states or T2DM and schizophrenia include negative lifestyle choices (smoking, poor diet and lack of exercise), obesity and in particular increased visceral fat deposition, hypercortisolaemia, socioeconomic status and substance abuse[6]. However, studies that adjusted for such factors did not show a loss of significance of the 2-hour glucose between those with SMI and controls[2][3][4][5].

In these studies, proxy measures of abdominal obesity were used such as, waist circumference and waist to hip ratio. Yet, using imaging techniques such as CT and MRI, some studies, though not all, have shown that people with first episode drug naïve schizophrenia have higher levels of visceral fat compared to matched controls[7][8].

Studies have shown that excessive visceral fat can predict the development of pre-diabetes and T2DM[9]. An increase in visceral fat distribution occurs as a result of non-modifiable factors such as one’s age, sex or genes but can also be attributed to smoking, poor diet, poor physical activity substance abuse (e.g. alcohol), and stress related conditions such as serious mental illnesses. Studies have shown that patients with antipsychotic-naive new onset schizophrenia have a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis resulting in hypercortisolaemia, a hormone which is suspected to play a part in localizing fat deposition within the abdominal cavity.

Visceral fat is a potent source of pro-inflammatory cytokines that may be in turn responsible for low-grade inflammation that has been associated with insulin resistance and the development of T2DM.

In “The Pathology of the Mind”, (1879), Sir Henry Maudsley commented that ‘‘Diabetes is a disease which often shows itself in families in which insanity prevails’’[10]. This observation has been borne out in recent studies that show that unaffected family members of patients with schizophrenia have a higher than expected risk of having impaired glucose tolerance (18.5%) and in general have rates of T2DM that range between 27% and 49%, which is far higher than expected in the general population. Furthermore, gestational diabetes is associated with a 7-fold increase in the development of schizophrenia in the offspring as hyperglycaemia may result in prenatal oxidative stress, hypoxia and inflammation[11].

Bipolar Disorder

The rates of T2DM are three-fold higher in Bipolar Disorder though this figure is derived from studies performed in medicated patients[12]. One study has shown that the rates of T2DM is greater in Bipolar Disorder 1 (patients by definition have hypomanic episodes) (26%) and Schizoaffective Disorder (50%) (a condition in which mood and psychotic symptoms are present to an equal extent simultaneously) and was independent of medication usage but was related to BMI. People with drug naïve Bipolar Disorder 1 do not appear to have impaired fasting glycaemia while 40.8% of those with Bipolar Disorder 2 (by definition they will have had at least one manic episode) were overweight or obese[13][14]. A study has shown that Bipolar Disorder is associated with central obesity though this was related to the use of psychotropic medication[15]. Studies have shown that patients with Bipolar Disorder also smoke more than the general population, have a high energy intake and exercise little though these patients were all medicated. Hypercortisolaemia has been documented in drug naïve first episode patients with Bipolar Disorder who were predominantly dysphoric (irritable)[16]. Lastly, a family history of T2DM appears to be a risk factor for developing insulin resistance in patients with Bipolar Disorder[17].

In conclusion, SMI appear to be associated with T2DM. Therefore, it is imperative, that all patients with SMI are screened, offered advice and treated for T2DM irrespective of the medications that they may be prescribed.


  1. ^ Fernandez-Egea E et al. Diabetes or Prediabetes in Newly Diagnosed Patients With Nonaffective Psychosis? A Historical and Contemporary View. Schizophrenia Bulletin vol. 39 no. 2 pp. 266–267, 2013

  2. ^ Kirkpatrick B et al. Is Abnormal Glucose Tolerance in Antipsychotic-Naive Patients With Nonaffective Psychosis Confounded by Poor Health Habits? Schizophrenia Bulletin vol. 38 no. 2 pp. 280–284, 2012.

  3. ^ Spelman L et al. Impaired glucose tolerance in first episode drug naive patients with schizophrenia. Diabetes Medicine 2007 Mar 22;24(5):481-5.

  4. ^ Kirkpatrick B et al. Differences in glucose tolerance between deficit and nondeficit schizophrenia. Schizophrenia Research 2009 February ; 107(2-3): 122–127.

  5. ^ Ryan MCM et al. Impaired Fasting Glucose and Elevation of Cortisol in Drug-Naïve First-Episode Schizophrenia. American Journal of Psychiatry 2003 160; 284-289.

  6. ^ Thakore JH. Metabolic abnormalities in Schizophrenia. British Journal of Psychiatry 2005, 186; 455-456.

  7. ^ Ryan MCM et al. Atypical antipsychotics and visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sciences 2004; 74:1999-2008.

  8. ^ Zhang ZJ et al. Effects of antipsychotics on fat deposition and changes in leptin and insulin levels: Magnetic resonance imaging study of previously untreated people with schizophrenia. British Journal of Psychiatry 2004;184, 58-62.

  9. ^ Speaker KJ, Fleshner M. BMC Physiology 2012, 12:8.

  10. ^ Fernandez-Egea E et al. Parental History of Type 2 Diabetes in Patients with Nonaffective Psychosis. Schizophrenia Research 2008 January; 98(1-3): 302–306.

  11. ^ Cannon M et al. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002;159:1080-92.

  12. ^ Calkin CV et al. The relationship between bipolar disorder and type 2 diabetes: More than just co-morbid disorders Annals of Medicine, 2013; 45: 171–181.

  13. ^ Maina G et al. Prevalence and correlates of overweight in drug-naïve patients with bipolar disorder. J Affect Disord. 2008 Sep;110(1-2):149-55.

  14. ^ Hung Chi M et al. The prevalence of metabolic syndrome in drug-naïve bipolar II disorder patients before and after twelve week pharmacological intervention. J Affect Disord. 2013 Mar 20;146(1):79-83.

  15. ^ Fleet-Michaliszyn SB et al. A prospective observational study of obesity, body composition, and insulin resistance in 18 women with bipolar disorder and 17 matched control subjects. J Clin Psychiatry. 2008 Dec;69(12):1892-900.

  16. ^ Valiengo LL et al. Plasma cortisol in first episode drug-naïve mania: differential levels in euphoric versus irritable mood. J Affect Disord. 2012 Apr;138(1-2):149-52.

  17. ^ Natalie L Rasgona et al. Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus Bipolar Disord . 2010 August ; 12(5): 504–513.


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