A recent Consensus Statement formulated by four major medical associations encouraged physicians to screen and monitor their patients on atypical antipsychotics for signs of rapid weight gain or other problems leading to obesity, diabetes and dyslipidemia. Yet, that same Consensus Statement has potentially evoked disagreements among pharmaceutical companies.
The Consensus Statement, published in the February issues of Diabetes Care and Journal of Clinical Psychiatry, was issued by an eight-person panel representing the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity. The panelists not only reviewed clinical studies examining the relationships between second-generation antipsychotics and diabetes, but they also heard presentations from experts in the fields of psychiatry, obesity and diabetes and from the U.S. Food and Drug Administration and pharmaceutical company representatives.
"Hopefully, [the Consensus Statement] provides a thoughtful summary of the use of these agents, their advantages and limitations, as well as practical guidelines for the use of these agents to avoid or minimize significant metabolic complications that can arise from their use," Eugene Barrett, M.D., panel chairperson, told Psychiatric Times. Barrett is a professor in the department of medicine at the University of Virginia.
Another member of the panel, John Davis, M.D., Gillman Professor of psychiatry at the University of Illinois at Chicago, told PT that the report is helpful in educating psychiatrists about obesity and type 2 diabetes prevention, and it should be viewed in a broader context than just second-generation antipsychotics and diabetes.
"Both obesity and type 2 diabetes are common, irrespective of medication, and other medications increase weight as well as SGAs [second-generation antipsychotics]," Davis said.
He added, "Most of our patients will be on most of these drugs at one time or another. We need to prevent type 2 diabetes and achieve the best symptoms reduction and improvement possible, but with the addition of assertive diet and exercise programs."
John Kane, M.D., chairperson of the department of psychiatry at Long Island Jewish Medical Center in New York and a member of the consensus panel, explained that many psychiatrists are aware of the issues surrounding antipsychotic drugs and the risk of diabetes, but are unsure of what to do.
Implementing the recommendations in the Consensus Statement will represent a shift in their practice, he said.
In the Consensus Statement, the panel noted that second-generation antipsychotics are generally better tolerated and more effective than the first-generation antipsychotics.
"Aside from clozapine [Clozaril], they have become the first-line agents for their indicated use and are increasingly being used off-label," the panel said.
Atypical antipsychotic usage extends from schizophrenia-spectrum disorders to bipolar disorder; dementia; psychotic depression; autism and developmental disorders; and, to a lesser degree, delirium; aggressive behavior; personality disorders; and posttraumatic stress disorder.
The consensus panel reported that second-generation antipsychotics have been associated with dramatic weight gain, diabetes (even acute metabolic decompensation, e.g., diabetic ketoacidosis [DKA]) and artherogenic lipid profiles (increased low density lipoprotein [LDL] cholesterol and triglyceride levels and decreased high density lipoprotein [HDL] cholesterol). Because of the close associations between obesity, diabetes and dyslipidemia, and cardiovascular disease (CVD), there is a heightened interest in the relationship between second-generation antipsychotics and the development of these major CVD risk factors.
The prevalence of both diabetes and obesity among individuals with schizophrenia and affective disorders is approximately 1.5 to two times higher than in the general population, the panel reported. What is unclear is how much the increased prevalence of obesity and diabetes relates to schizophrenia itself, and how much, if any, relates to pharmacologic treatments. The panel stated:
There is considerable evidence, particularly in patients with schizophrenia, that treatment with SGAs can cause a rapid increase in body weight in the first few months of therapy that may not reach a plateau even after 1 year of treatment. ... At 10 weeks of therapy, estimated average weight gain with drug treatment compared with placebo varies from ≈0.5 to 5.0 kg. Limited data suggest that in humans, most of the weight gained is fat.
Weight gain and changes in body composition may account for some of the suggested metabolic complications associated with second-generation antipsychotic therapy such as insulin resistance, metabolic syndrome, diabetes and dyslipidemia. With regard to development of obesity, diabetes and dyslipidemia, not all of the second-generation antipsychotics are equal, the panel said.
Clozapine and olanzapine (Zyprexa) are associated with the greatest weight gain and highest occurrence of diabetes and dyslipidemia, according to the panel:
Despite limitations in study design, the data consistently show an increased risk for diabetes in patients treated with clozapine or olanzapine compared with patients not receiving treatment with FGAs [first-generation antipsychotics] or with other SGAs. The risk in patients taking risperidone [Risperdal] and quetiapine [Seroquel] is less clear; some studies show an increased risk for diabetes, while others do not. The two most recently approved SGAs, aripiprazole [Abilify] and ziprasidone [Geodon], have relatively limited epidemiological data, but available clinical trial experience with these drugs has not shown an increased risk for diabetes.
With regard to serum lipids, the panel said that clozapine and olanzapine are associated with the greatest increases in total cholesterol, LDL cholesterol and triglycerides, and with decreased HDL cholesterol.
"Aripiprazole and ziprasidone ... do not seem to be associated with a worsening of serum lipids. Risperidone and quetiapine appear to have intermediate effects," the panel added.
Davis, who has a meta-analysis of the efficacy of second-generation antipsychotics on his Web site (Davis et al., 2003), said that the Consensus Statement provides good information about the risk of diabetes with second-generation antipsychotics, but there are other risks as well as diabetes.
"The present antipsychotics differ in both risks and benefits. I do not think they are a homogenous class. Some are more effective than others. Clozapine is the most effective but also the most risky. The first-generation antipsychotics cause EPS [extrapyramidal symptoms] but, more importantly, tardive dykinesia [TD]. Tardive dyskinesia has an incidence rate of 3% to 5% per year, so that after some years, the majority of patients are at risk. Serious TD can lead to death or be socially disfiguring," Davis told PT.
"The SGAs differ in side effects. Some cause a little EPS. Some cause more prolactin elevation than FGAs. Clozapine causes agranulocytosis, but death from this has been almost completely abolished with the clozapine monitoring system."
Davis added that he anticipates the Consensus Development Conference's conclusions may result in negative detailing on the part of some pharmaceutical companies.
"Negative detailing does spread information, so it is not without a redeeming feature, but it can be distorted information," he warned.
ADA, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity (2004), Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 27(2):596-601.
Davis JM, Chen N, Glick ID (2003), Web supplement. A meta-analysis of the efficacy of second-generation antipsychotics. Available at: www.psych.uic.edu/faculty/Meta_analysis.pdf. Accessed Feb. 17, 2004.
Weiden PJ, Simpson GM, Potkin SG, O'Sullivan RL (2003), Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry 64(5):580-588.