Jenna Griffiths and Pascale Springuel, Bureau of Licensed Product Assessment, Therapeutic Products Directorate, Health Canada*

* Full text appears in Canadian Adverse Drug Reaction Newsletter, Volume 11, Number 4, October 2001.

The new atypical antipsychotics clozapine, olanzapine, quetiapine and risperidone are among first-line treatments for managing psychotic disorders mainly because they are associated with superior effectiveness in controlling the negative symptoms of schizophrenia - blunted affect, emotional and social withdrawal (1).

Some atypical antipsychotics have been associated with impaired glucose metabolism (2). Since 1994, there have been at least 29 published cases of impaired glucose metabolism associated with the use of clozapine and 26 with olanzapine (2, 3) and since February 1999, there have been two published cases in which risperidone was associated with diabetic ketoacidosis or elevated blood glucose levels (4, 5) and two published cases of new-onset diabetes mellitus with quetiapine (2, 6).

In 1999, the results of a cross-sectional study revealed a possible association between type 2 diabetes and antipsychotics (7). Specifically, diabetes was diagnosed in 15.5% of schizophrenic patients treated with clozapine, 11% of those treated with olanzapine and 6% of those treated with risperidone (7). Clozapine, olanzapine, quetiapine and risperidone were introduced in Canada in 1991, 1996, 1997 and 1993 respectively. By June 2001, a total of 37 domestic case reports of suspected impaired glucose metabolism associated with these drugs were reported to the Canadian Adverse Drug Reaction Monitoring Program. Patient characteristics and important adverse reactions are summarized in Tables 1 and 2 overleaf, respectively.

In 17 of the 37 cases, the reactions occurred within five months of treatment onset. Similarly, in published cases, impaired glucose metabolism associated with atypical antipsychotics often occurred relatively soon following the start of treatment, i.e. in as little as 10 days with clozapine, 15 days with olanzapine and one month with quetiapine (2). Of the 35 reports in which disorders of hyperglycaemia were denoted, there were four cases of pre-existing diabetes; 24 cases were considered to be new onset on the basis of the evidence in the report, with 14 clearly noted as being new-onset diabetes mellitus. One of the cases occurred 2 weeks after discontinuation of risperidone therapy and involved an intentional overdose. There were two reports of hypoglycemia; both patients had a prior history of diabetes before this reaction.

Of the 10 cases in which “diabetic ketoacidosis” or “ketoacidosis” was reported (Table 2), the possibility of alcohol consumption or substance use was noted in four cases, and abnormal liver function test results were reported in two cases. Three of these 10 patients died. Schizophrenic patients may be predisposed to diabetes mellitus and associated disorders due to factors such as reduced physical activity, poor diet and co-existing illnesses (8). In addition, the involvement of concomitant medications such as divalproex sodium, (9, 10) lithium, (10) and other drugs metabolized by the liver (11, 12) cannot be ruled out as contributing to the abnormal glucose metabolism associated with clozapine (12, 13) or olanzapine (10, 11). Other risk factors for hyperglycemia or ketoacidosis in patients taking clozapine or olanzapine may include being male, non-White and age of about 40 years (14).

Obesity is another major risk factor for diabetes (14) Among the Canadian reports, there was one case of a 33-year-old man who took olanzapine (15 mg/day) and gained between 22 and 45 kg over 1 year after starting olanzapine therapy. It was reported that diabetes developed as a result of this weight gain. It has been speculated that multiple receptor antagonism (dopamine, serotonin, histamine) may be involved in the development of non-insulin-dependent diabetes mellitus associated with atypical antipsychotics (2). Specifically, antagonism of histaminic and possibly serotonergic receptors may induce weight gain, which in turn, may lead to changes in glucose metabolism, and that these changes may have a causal role in neuroleptic-induced hyperglycemia (11). Serotonin antagonism may decrease the responsiveness of pancreatic cells, which would result in low insulin levels and ensuing hyperglycemia (11). Diabetes induced by atypical antipsychotics may be attributed to multiple factors, and the mechanism of action remains unclear (2). Atypical antipsychotics may be associated with new-onset diabetes mellitus and diabetic ketoacidosis. Patients may require glucose monitoring upon initiation and titration of antipsychotic medications, and regular monitoring thereafter (15, 16).

References

1. Markowitz, J.S., Brown, C.S., Moore, T.R. Atypical antipsychotics. Part 1: pharmacology, pharmacokinetics, and efficacy. Annals of Pharmacotherapy, 33: 73-85 (1999).

2. Liebzeit, K.A., Markowitz, J.S., Caley, C.F. New onset diabetes and atypical antipsychotics. European Neuropsychopharmacology, 11: 25-32 (2001).

3. Wehring, H., Alexander, B., Perry, P.J. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy, 20(7): 844-847 (2000).

4. Croarkin, P.E., Jacobs, K.M., Bain, B.K. Diabetic ketoacidosis associated with risperidone treatment? Psychosomatics, 41: 369-370 (2000).

5. Mohan, D., Gordon, H., Hindley, N., Barker, A. Schizophrenia and diabetes mellitus. British Journal of Psychiatry, 174: 180-181 (1999).

6. Procyshyn, R. New-onset diabetes mellitus associated with quetiapine. Canadian Journal of Psychiatry, 45 (7): 668-669 (2000).

7. Zoler, M.L. Antipsychotics linked to weight gain, diabetes. Clinical Psychiatry News, 27 (2): 20 (1999).

8. Mukhergee, S., Decina, P., Bocola, V. et al. Diabetes mellitus in schizophrenic patients. Comprehensive Psychiatry, 37 (1): 68-73 (1996).

9. Isakov, I., Klesmer, J., Masand, P.S. Insulin-resistant hyperglycemia induced by clozapine. Psychosomatics, 41 (4): 373-374 (2000).

10. Bonanno, D.G., Davydov, L, Botts, S.R. Olanzapine-induced diabetes mellitus. Annals of Pharmacotherapy, 35: 563-565 (2001).

11. Goldstein, L.E., Sporn, J., Brown, S. et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics, 40 (5): 438-443 (1999).

12. Kamran, A., Doraiswamy, P.M., Jane, J.L. et al. Severe hyperglycemia associated with high dose of clozapine. American Journal of Psychiatry, 151 (9): 1395 (1994).

13. Koval, M.S., Rames, L.J., Christie, S. Diabetic ketoacidosis associated with clozapine treatment. American Journal of Psychiatry, 151 (10): 1520-1521 (1994).

14. Mir, S., Taylor, D. Atypical antipsychotics and hyperglycemia. International Clinical Psychopharmacology, 16 (2): 63-74 (2001).

15. Haupt, D.W., Newcomer, J.W. Risperidone-associated diabetic ketoacidosis. Psychosomatics, 42: 279-280 (2001).

16. McIntyre, R.S., McCann, S.M., Kennedy, S.H. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Canadian Journal of Psychiatry, 46: 273-281 (2001).