A potential link between the use of two schizophrenia treatments – namely Novartis’ Clozaril (clozapine) and Zyprexa (olanzapine) from Eli Lilly – and an increased risk of developing diabetes has resurfaced in a study published in the journal Archives of General Psychiatry (2005;62:19-28).

The small, 41-patient trial found that schizophrenics treated with either Clozaril, or the structurally similar drug, Zyprexa, were more likely to show early signs of diabetes – insulin resistance and impaired glucose tolerance – compared to those treated with Johnson & Johnson’s Risperdal (risperidone).

The first indications that Clozaril and related drugs may be linked to diabetes emerged in 2001, when the Journal of the American Medical Association published a letter written by Dr Elizabeth Koller, a US Food and Drug Administration medical officer, and Dr P Murali Doraiswamy, a Duke University psychiatrist. This suggested that, according to the FDA’s MedWatch database, patients taking either Zyprexa or Clozaril were 10 times more likely to become diabetic than the general population. Additional studies have provided more evidence for this link, prompting the manufacturers to suggest that the insulin resistance is the result of the drugs’ tendency to cause weight gain and increase body fat. But in this latest study, the researchers matched non-obese patients in the Clozaril /Zyprexa and Risperdal groups according to their body mass index, yet still found the former group more likely to cause insulin resistance.

The firms have always disputed the diabetes link, saying schizophrenia have a two- to four-fold increased risk for diabetes when compared to the general population, irrespective of the antipsychotic prescribed. But this has not stopped class action lawsuits from patient groups claiming to have been damaged by the drugs [[24/05/04c]].

Analysts said that the new study would have limited impact as the risk of diabetes is already incorporated in labelling. In 2003, the FDA requested that Lilly and a number of other companies making atypical antipsychotics update their product labelling to include a warning about diabetes. The notification applied to all atypical antipsychotics and included Clozaril and Rispedal as well as AstraZeneca’s Seroquel (quetiapine), Pfizer’s Geodon (ziprasidone) and Bristol-Myers Squibb’s Abilify (aripiprazole) [[18/09/03a]]. The UK Medicines and Healthcare products Regulatory Agency and the Japanese Ministry of Health, Labour and Welfare have both warned about the risk of diabetes in patients who are prescribed Zyprexa.

Clozaril, also sold under the Leponex brand name, generated sales of around $78 million dollars in the third quarter of 2004, but its safety profile has always limited its use to high-risk patients and the new findings are unlikely to affect it greatly. Meanwhile, Zyprexa achieved sales of $1 billion in the same period, a decline of 9% that has been attributed to increased competition but also side effect concerns affecting demand in the important US market [[22/10/04b]].