Diabetes mellitus and atypical antipsychotic drugs

• prevalence of diabetes mellitus among individuals with schizophrenia is around twice that in the general population

• traditional or atypical antipsychotics may further increase the risk of developing diabetes
  • these are major concerns for patients who, because of schizophrenia, may have difficulty in self-managing diabetes, and who often have other cardiovascular risk factors (e.g. smoking, being overweight, low physical activity)
  • there is evidence that atypical antipsychotic drugs are more likely than traditional drugs to impair glucose intolerance
    • it is not known whether or not this is solely due to weight gain
      • a consensus conference in the USA concluded that the risk for the development of type 2 diabetes was highest with clozapine and olanzapine (2)
        • atypical antipsychotic drugs, particularly clozapine and olanzapine, can cause much worse metabolic side-effects including body weight gain, obesity, hyperlipidaemia, insulin resistance, hyperglycaemia and diabetes (3)
        • exact mechanism by which clozapine can affect glucose regulation is unknown; however, substantial evidence indicates that clozapine use is associated with the greatest propensity for weight gain among the antipsychotic agents and dose-dependent insulin resistance (4)
        • clozapine has been shown to inhibit glucose uptake via interaction with glucose transporter proteins receptors with a toxic effect on pancreatic cells (8)
        • using a general practice research database in the United Kingdom, Koro and colleagues estimated the risk of hyperlipidemia and diabetes associated with olanzapine to be 3.4 (95% CI 1.8–6.4) and 4.2 (95% CI 1.5–12.2) times the risk associated with conventional antipsychotic agents, and 4.6 (95% CI 2.4–8.9) and 5.8 (95% CI 2.0–16.7) times the risk associated with no antipsychotic use (9,10)
      • for quetiapine and risperidone, the evidence was conflicting
      • there were too few data to assess the risk with amisulpride or zotepine, while limited data found no increased risk with aripiprazole
      • studies have shown that antipsychotic drugs cause not only greater weight gain in children/adolescents than in adults but also significant risk of type 2 diabetes (5)
      • there are limited reports linking atypical antipsychotics with diabetic ketoacidosis (DKA) in patients with type 2 diabetes mellitus and with very severe hypertriglyceridaemia (serum triglycerides >22 mmol/L) (6)
      • there is evidence that compared to women who discontinued before the start of pregnancy, those who continued olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with the treatment (11

Prior to initiation of atypical antipsychotic agents such as clozapine and olanzapine patients should have their baseline weight and BMI recorded with compulsory screening for the presence of diabetes mellitus and lipid abnormalities

• the American Diabetes Association/American Psychiatric Association published statements (7) recommended weight monitoring at 4, 8 and 12 weeks after initiating of therapy with new antipsychotic agents followed by quarterly routine visits to measure plasma glucose and lipids
• this should be followed by annual monitoring of fasting plasma glucose or HbA1c with lipid monitoring to occur at least every 5 years (7)

Reference:

1. Drug and Therapeutics Bulletin (2004); 42(8):57-60.
2. American Diabetes Association et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27: 596-601.
3. Stubbs B et al. The prevalence and predictors of type two diabetes mellitus in people with schizophrenia: a systematic review and comparative meta-analysis. Acta Psychiatr Scand. 2015 Aug; 132(2):144-57.
4. Melkersson K, Hulting AL. Antipsychotic drugs can affect hormone balance. Weight gain, blood lipid disturbances and diabetes are important. Lakartidningen 2001;98:5462-4, 5467-9.
5. Pramyothin P, Khaodhiar L. Type 2 diabetes in children and adolescents on atypical antipsychotics. Curr Diab Rep. 2015 Aug; 15(8):53.
6. Berglund L et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012 Sep; 97(9):2969-89.
7. 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;27:596-601
8. Dwyer DS, Donohoe D. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav 2003;75:255–60.
9. Koro CE et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study.BMJ. 2002 Aug 3; 325(7358):243.
10. Koro CE et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients.Arch Gen Psychiatry. 2002 Nov; 59(11):1021-6.
11. Park Y et al. Continuation of Atypical Antipsychotic Medication during Early Pregnancy and the Risk of Gestational Diabetes. Am J Psychiatry. 2018 Jun 1; 175(6): 564–574.