Antipsychotics and Diabetes Ryan Suemoto, PharmD, CDE Naval Medical Center San Diego

Objectives Describe the cardiovascular risk of mental health disorders and diabetes Describe the metabolic side effects of atypical antipsychotic medications Review the ADA/APA/AACE/NAASO Consensus on Antipsychotic Drugs and Obesity and Diabetes

Antipsychotic Agents First Generation Chlorpromazine (Thorazine) Perphenazine (Trilafon) Trifluoperazine (Stelazine) Thiothixene (Navane) Haloperidol (Haldol) Fluphenazine (Prolixin) Extrapyramidal side effects Tardive Dyskinesia Second Generation (AKA - Atypicals) Clozapine (Clozaril) - 1989 Risperidone (Risperdal) - 1993 Olanzapine (Zyprexa) - 1996 Quetiapine (Seroquel) - 1997 Ziprasidone (Geodon) - 2001 Aripiprazole (Abilify) - 2002 Metabolic side effects Advantages: Tx Negative symptoms Improves mood Prevents relapse Here is a table of the current available antipsyhotics. They are broken down into generation which most of you may be familiar with. Because the EPS and tardive dyskinesia, second generation antipsychotics, also known as atypical antipsychotics, were a blessing. Not only b/c they didn’t cause EPS or TD, but they also helped treat negative symptoms, improve mood and cognition and prevented relapses. However, since their development (esp Clozapine) we have metabolic side effects

Schizophrenia and Diabetes Limited epidemiological data increased prevalence of obesity, impaired glucose tolerance, and type 2 diabetes in people with psychiatric illness Schizophrenics, independent of treatment two-fold increased risk of diabetes mellitus compared to the general population. Epidemiological data is limited because there are few prospective trails. Data from most studies suggest that the prevalence of both diabetes and obesity among individuals with schizophrenia and affective disorders is 1.5–2.0 times higher than in the general population. Many characteristics of people with schizophrenia, such as sedentary behavior, may contribute to the apparently higher prevalence of metabolic abnormalities. However, none of these studies controlled for all of the major diabetes risk factors. For example, BMI and family history of diabetes were rarely determined, nor were the control populations appropriately matched for these and other variables. Thus, it is unclear whether psychiatric conditions per se, independent of other known diabetes risk factors, account for the increased prevalence.

Schizophrenia and CVD More than two thirds die of CVD Compared with 50% in the general population More prevalent cause of death than suicide It has been reported that more than two thirds of patients with schizophrenia will die of coronary heart disease, compared with 50% of the general population. CVD is thus a much more prevalent cause of death than suicide. Hennekens CH et al. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005 Dec;150(6):1115-21.

Schizophrenia and Metabolic Syndrome Higher prevalence abdominal obesity elevated TGs high blood pressure 2 to 3 times more likely to meet metabolic syndrome criteria than general population Patients with schizophrenia have a higher prevalence of abdominal obesity, elevated TGs and high blood pressure, all of which are components of metabolic syndrome. In the US, patients with schizophrenia are 2 to 3 times more likely to meet metabolic syndrome criteria than the general population…a finding see in other countries such as Finland and Canada.

Diabetes and Antipsychotics Drug surveillance and retrospective analyses association between specific SGAs and both diabetes and obesity UK Case-control study SGA and FGA to be 4.7 and 1.7 times greater to develop diabetes compared to non-users respectively Evidence for weight gain and abnormalities of glucose and lipid metabolism in patients taking SGAs is in part derived from case-control studies, pharmacovigilance (e.g., through MedWatch), and database reviews. Many of these studies suffer from their retrospective nature, heterogeneity of methodology, selection or ascertainment bias, and absence of appropriate or well-characterized control subjects. Comparison studies among SGAs are also limited by relatively short periods of study, by failure to control for a possible treatment sequence bias in "switchover" studies, and by not always using clinically equivalent dosages of the medications. High rates of smoking and physical inactivity may also contribute to the excess mortality. Therefore, if SGA therapy further increases the risk for obesity and type 2 diabetes, this should be of major clinical concern. Although there are significant shortcomings in many of the studies examining the relationships between the SGAs and obesity or diabetes, clear-cut trends can be identified. Kornegay CJ, Vasilakis-Scarmozza C, Jick H, et al. Incident Diabetes Associated with Antipsychotic Use in the United Kingdom General Practice Research Database. J Clin Psychiatry 2002;63:758-62.

SGAs: Diabetes More frequent with the SGAs than the FGAs risk greatest for clozapine and olanzapine Hyperglycemia can be seen within a few weeks of initiating drug treatment Hyperglycemia may resolve after the medication is discontinued Recurrent hyperglycemia after re-challenge Diabetes is more frequently associated with SGAs versus FGAs. With the greatest incidence seen with clozapine and olanzapine. Blood sugars can increase within weeks of starting these agents and may resolve after discontinuing the medication. Recurrent hyperglycemia occurs after re-challanging with the same agent

SGAs: Weight Gain Rapid increase in body weight in the first few months of therapy May not reach a plateau even after 1 year Limited data suggest that most of the weight gained is fat canine model indicates increase total visceral fat mass and intrahepatic lipid content

SGAs: Dyslipidemia Changes in serum lipids correlate with changes in body weight Clozapine and olanzapine greatest weight gain greatest increases in TC, LDL, and TGs and with decreased HDL cholesterol It’s hard to say that dyslipidemia is a direct cause of atypical antipsychotics OR is it a cause of weight gain. There is a correlation with serum lipid changes and changes in body weight. Clozapine and olanzapine, which cause the greatest weight gain, also cause the greatest increases in TC, LDL, and TGs.

2004: Second Generation Antipsychotics (SGAs) FDA mandates changes in labeling Warnings for hyperglycemia and diabetes Affects all atypical antipsychotics Consensus Development Conference on Antipsychotic Drugs & Obesity & Diabetes Aripiprazole and ziprasidone Little/no weight gain Little/no diabetes Little/no dyslipidemia In 2004, the FDA mandated changes in labeling warning patients and healthcare professional for hyperglycemia and diabetes. This affected all atypical antipsychotics, even aripiprazole and ziprasidone. Also in 2004, the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity had a consensus development conference on antipsychotic agents, obesity and diabetes. This consensus concluded that of the atypical antipsychotics, aripiprazole and ziprasidone have little association with weight gain, diabetes or dyslipidemia Diabetes Care 2004; 27:596-601.

*More frequent assessments may be warranted based on clinical status ADA/APA/AACE/NAASO Consensus on Antipsychotic Drugs and Obesity and Diabetes: Monitoring Protocol Base 4 wks 8 wks 12 wk Qtrly 12 mos. 5 yrs. Personal/family Hx X Weight (BMI) Waist circumference Blood pressure Fasting glucose Fasting lipid profile *More frequent assessments may be warranted based on clinical status Diabetes Care. 27:596-601, 2004

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Multi-center, NIMH-sponsored 18 months “Real World” setting Concomitant medications, medical illnesses, substance use disorders allowed Effectiveness (Phase 1) Published in NEJM 2005 Since 2004…the CATIE trial was published in 2005. CATIE was an 18 month, multi-centered trial, sponsored by the National Institute of Mental Health. They chose minimal exclusion criteria to reflect a real world setting. They included patients previously on antipsychotic agents, any comorbid illness and also allowed substance use disorders.

Medications in CATIE First Generation Fluphenazine (Prolixin) Second Generation (AKA - Atypicals) Clozapine (Clozaril) Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Phase 1 (double blind, random treatment): Olanzapine, quetiapine, risperidone, ziprasidone, or perphenazine. Clozapine was not chosen as a first-line drug in this study because it has already been shown to possess superior efficacy compared with typical antipsychotic medications; however, it was included in later phases of the trial. Phase 2 involved the cohort who discontinued their assigned medication and agreed to try another antipsychotic -- one of the second-generation antipsychotics that had not yet been given to the individual during phase 1 of CATIE Aripiprazole was not added until phase 3, because it was not FDA approved yet when phase 1 started.

CATIE Summary 74% discontinuation rate for all drugs Consistent with practice and clinical trials Weight and metabolic side effects Clozapine and olanzapine > quetiapine and risperidone Ziprasidone least weight and metabolic effects There was a 74% discontinuation rate for the drugs. This is a finding that we see in clinical practice and other trials. Clozapine and olanzapine had more weight gain and metabolic side effects then quetiapine and risperidone. Patients treated with olanzapine gained an average of 2 pounds per month, and a larger percent of olanzapine-treated patients gained 7% or more of their baseline body weight than those treated with the other agents (30% vs 7% to 16% in the other groups, P < .001). Olanzapine treatment also had the greatest increase in glycosylated hemoglobin (HbA1C), total cholesterol, and triglycerides when compared with any of the other study drugs. Ziprasidone had the least weight gain and metabolic effects.

CATIE Summary Perphenazine less costly than other medications not significantly or substantially less effective SGAs may be most effective in the refractory schizophrenia More patients discontinued perphenazine as a result of extrapyramidal side effects (EPS) than any of the other drugs (8% vs 2% to 4% for the other drugs, P = .002).

Summary Consideration of metabolic risks when starting SGAs Patient, family, and care giver education Baseline screening Regular monitoring Referral to specialized services, when appropriate

Questions?