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Risk of DM associated with atypical antipsychotic use among patients with Bipolar Affective Disorder (BAD)

By Jeff J. Guo, Paul E Keck, Patricia K Corey Lisle, Hong Li, Dongming Jiang, Raymond Jang, Gilbert J. L’Italien

J Clin Psychiatry. 2006 Jul; 67 (7): 1055-61

Summary and Important Issues addressed in this Article:

Brief outline of how the study was conducted

  • Introduction: Atypical antipsychotic agents with different mechanism of action from conventional antipsychotic have been widely adopted in the treatment of bipolar disorder since mid 1990s, they have a different spectrum of side effects, including weight gain, alterations in glucose metabolism, increased concentrations of blood cholesterol and lipids, myocarditis and cardiomyopathy
  • Evidence has shown an association between some antipsychotics (clozapine, olanzapine and risperidone) and DM in patients with schizophrenia. DM is a known and infrequent adverse effect of olanzapine and risperidone.
  • This is a retrospective, population-based case control study which recruited from multi-state managed care claims database from U.S during 1st January 98- 31st December 02 (5 calender year) to examine the association of atypical antipsychotics with diabetes mellitus in bipolar patients.
  • 920 of Diabetes with BAD (identified using ICD-9 codes or diabetic medication) were matched with 5258 controls ( by age, sex and bipolar index month and year). People with Diabetes had a minimum 3-month exposure to any medications (as published reports show that drug-induced diabetes usually occurs with recent or current use of antipsychotic drugs) or at least 3 prescriptions for their bipolar or co-morbidity treatment.
  • Patients with a diagnosis of depression only or schizophrenia or history of DM before the prescription of antipsychotic medications during the study period were excluded from this population.
  • Cox proportional hazard regression was conducted to assess the risk of diabetes associated with antipsychotic use. 2 different groups were compared. 1st group included all patients except those receiving the specific atypical antipsychotic drug of interest. 2nd group (control) included patients taking conventional antipsychotic.
  • Use of different medications was not mutally exclusive for one patient (e.g. lithium, anticonvulsants, atypical antipsychotics, antidepressants and conventional antipsychotics)
  • Other factors which may affect results were matched and adjusted i.e. drugs affecting DM, psychiatric comorbidities (alcohol and SA, personality disorder, anxiety disorder, impulse-control behaviour) and medical comorbidites (Hypertension, obesity, arthritis, cerebral vascular disease, COPD, dyslipidemia and coronary heart disease.)

6 Important questions addressed in this article:

1. Does antipsychotic induce DM in Bipolar Affective disorder (BAD) patients?
  1. The risk of developing DM was greatest among clozapine users (Exposure Hazard Ratio = 6.9), followed by zeldox (HR=4.6), olanzapine (HR=4.0), risperidone (HR= 3.5) and quetiapine (HR=2.3), conventional (HR=1.5) with adjusted model for age, sex, duration of bipolar follow-up, use of medication and concomitant drugs. This is not adjusted for psychiatric and medical comorbidites.
  2. When compared of atypical with conventional antipsychotics, the risk of DM was greatest among clozapine (HR=7.0) > olanzapine (HR=3.2)>risperidone (HR=3.4) > quetiapine (HR=1.8) > conventional with referral of HR =1.0, with controlling covariates of age, sex, duration of follow up, use of lithium, anticonvulsants, antidepressants or concomitant drugs, psychiatric and medical co-morbidities.
  3. Both patients receiving conventional and atypical antipsychotic for BAD have an increased risk of DM after controlling for personal risk factors and concomitant drug use.
2. Can DM be due to use of antipsychotic itself or underlying BAD?
  1. It is unclear how much DM in the study population might be due to the use of antipsychotics, as those with BAD would have poorer overall physical health, less healthy lifestyle, poorer access to health care services.
  2. Literature indicated clozapine and olanzapine are more likely to be associated with DM (indicated by Diabetic ketoacidosis and atherogenic lipid profile) than other atypical agents. Possible mechanism via impairment of insulin resistance, which may occur because of a weight gain, a change in body fat distribution, by a direct effect on insulin-sensitive target tissues.
3. How does antipsychotic affect DM in BAD compared with schizophrenia?
  1. Compared with published studies of patients with schizophrenia, the findings in BAD are similar or comparable. E.g. patients with schizophrenia had risk of DM associated with clozapine (HR 7.4-8.4) > olanzapine (HR 1.2-5.8) and risperidone (HR = 1.1-2.2).
  2. The results indicating the risk of developing DM is statistically significant for BAD taking clozapine, olanzapine, risperidone and quetiapine after controlling for comorbities, personal risk factors and concomitant drug use.
  3. Interestingly, the hazard ratio associated with ziprasidone was large (HR=4.6) without controlling for co-morbidities; then it became smaller (HR 1.7). This indicated that co-morbidities are critical covariates for assessing the risk of drug-induced diabetes.
4. What are the other factors / co-morbidities apart from antipsychotic use would affect risk of developing DM?
  1. The risk of DM is also associated with Hypertension (HR= 2.7) > dyslipidemia (HR = 2.7) > coronary heart disease (HR 2.6) > obesity (HR= 2.2) > cerebrovascular disease (HR= 1.5).
  2. Some antipsychotics like olanzapine, clozapine and risperidone are associated with weight gain, hyperlipidemia and hypertriglyceridemia, which are independent risk factors for heart disease.
  3. It is likely that incident DM was associated with metabolic syndrome, as indicated by higher HRs for obesity, HT, CVD, CHD and dyslipidemia.
  4. From this study, patient with impulse-control disorder or anxiety disorder had higher risk for diabetes. It is postulated that they have less healthy lifestyles, less medication compliance or poorer access to health care services.
5. What are the limitations of this study?
  1. This is a retrospective review which does not have direct information on the severity of bipolar disorder, socioeconomic class, lipid profiles, fasting glucose or BMI related to weight gain. Other confounding factors such as ethnicity and positive family history of metabolic disease were not adjusted.
  2. It did not include all atypical antipsychotics such as amisulpiride and aripripazole.
  3. It is not clear that different medications prescribed before the study period might be partially limited to the increased risk of diabetes i.e. clinician might have prescribed one drug over the other based on the clinical mood state. This is a compensatory attempt to reduce this confounding bias by adjusting for known concomitant drugs and co morbidities.
  4. In addition, it is possible to underestimate the prevalence of DM due to limited time window and other mental services not billed or enrolled in this managed care organization.
6. What are the clinical implications?
  1. This study provides useful information for disease management strategies in terms of selection of psychotropics and consideration of relevant co-morbidities for patients with bipolar disorder.
  2. Atypical antipsychotics provide great benefit to a wide variety of people with psychiatric disorders but with adverse effects related to increased risk of metabolic disease such as obesity, diabetes and dyslipidemia.
  3. Atypical antipsychotic like clozapine, olanzapine, risperidone and quetiapine are consistently associated with a clinically important increased risk of diabetes in bipolar patients. Metabolic complications are a major issue for patients receiving antipsychotic therapy.
  4. The choice of atypical antipsychotic should consider the risk-benefit co morbid conditions, thus the propensity of an antipsychotic to induce diabetes is a critical considerations.
Resources Centre Literature Review Risk of DM associated with atypical antipsychotic use among patients with Bipolar Affective Disorder (BAD)