Consensus Panel Urges Monitoring for Metabolic Effects of Atypical Antipsychotics

April 1, 2004

A new consensus statement has been issued regarding the high risk of diabetes and associated disorders with use of atypical antipsychotics. Several of the major pharmaceutical companies have responded negatively to this statement.

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.

Pharmaceutical Companies React

Already, the difference in risk profiles described in the Consensus Statement has evoked strong protests. Eli Lilly and Company, manufacturer of olanzapine, issued a statement on Jan. 26 saying it does not agree with several of the consensus panel's conclusions:

Eli Lilly and Company does not agree with a controversial conclusion of an opinion paper issued by an American Diabetes Association-sponsored panel, which states that second-generation antipsychotics (SGAs) differ in their diabetes risk profiles. Not only are these findings not supported by the total body of evidence available on the subject, they are in direct conflict with the U.S. Food and Drug Administration's (FDA) recent class labeling language which states, 'Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.' The FDA's class labeling decision called on the makers of all SGAs to include a warning on hyperglycemia and diabetes in their prescribing information.

Lilly said it did agree with the majority of the conclusions in the Consensus Statement, including the need to screen patients taking SGAs at baseline and follow them up for worsening of glucose control. However, Lilly expressed concern that "the inconsistency between FDA labeling and this consensus opinion conclusion may confuse patients and prescribers." Lilly remarked:

This could potentially lead to inappropriate discontinuation of certain medications and a lack of appropriate monitoring for all patients, which could have life-threatening consequences. ...The paper seems to minimize the considerable benefits that these medications provide to patients with debilitating and life-threatening mental illnesses like schizophrenia and bipolar disorder, which could outweigh metabolic risks, providing the paper with limited real-world applicability.

In September 2003 after an extensive review, the FDA asked manufacturers of atypical antipsychotic medications to add warning statements describing the increased risk of hyperglycemia and diabetes from taking these medications. The class labeling included the following language:

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with antipsychotics including [name of antipsychotic]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

The pharmaceutical companies--Lilly, Janssen and AstraZeneca Pharmaceuticals--have all modified their labeling to include the FDA's proposed diabetes warning for their agents (Zyprexa, Risperdal and Seroquel, respectively). Pfizer, however, is pursuing an exemption for Geodon.

In a supplement to its 2003 performance report, Pfizer said Geodon has been shown in clinical trials to be as effective as both Risperdal and Zyprexa in controlling positive and negative symptoms, with a lower incidence of EPS than Risperdal and significantly less weight gain and adverse changes in other metabolic indices (lipid levels, glucose control) than Zyprexa.

"A study published in the May 2003 issue of the Journal of Clinical Psychiatry [Weiden et al.] showed that Geodon significantly improved the symptoms of patients when switched from other anti-psychotics, including Zyprexa and Risperdal," Pfizer said. "In addition, Geodon was shown to reverse some of the negative effects these agents had on body weight and metabolic parameters."

Because of these findings, Pfizer told the FDA on Sept. 19, 2003:

Geodon has not been associated with an increased risk for diabetes. Evidence from clinical trials has consistently demonstrated that Geodon has a weight-neutral profile overall. Data also show that Geodon did not adversely affect patients' fasting insulin levels, the [homeostasis model assessment] insulin resistance index [HOMA-IR], total cholesterol and triglyceride levels, and blood-sugar levels. ... On November 24, Pfizer submitted a full response to the FDA's request for class labeling that contained a summary of relevant data and a proposal for Geodon labeling that did not include the class warning but instead focused on Geodon's metabolic advantages.

Andrew Bonfield, chief financial officer at Bristol-Myers Squibb (BMS), in a conference call with analysts on Jan. 29, said that both BMS and Otsuka Pharmaceutical are in discussion with the FDA about its requested label change for Abilify. With regard to the Consensus Statement, Bonfield said that BMS supports the ADA document and its recommendations.

Monitoring Patients

Given the potential for serious health risks, the consensus panel recommended that before physicians prescribe any antipsychotic medications, they first screen patients to determine their level of risk (Table).

The panel also recommended that nutrition and physical activity counseling be provided prior to initiation of second-generation antipsychotic treatment to patients who are overweight or obese. Patients with a high risk for weight gain, diabetes or dyslipidemias should be started on a second-generation antipsychotic associated with a lower likelihood of weight gain and glucose intolerance.

Patients, family members and caregivers, as well as health care professionals, the panel said, should be informed of the signs and symptoms of diabetes and especially those associated with acute decompensation, such as DKA.

For patients taking second-generation antipsychotics, the panel recommended that their weight be assessed at four, eight and 12 weeks after initiating therapy and quarterly thereafter. Any increase of 5% or more from baseline weight warrants consideration of changing to a different agent. Any change should involve cross-titration.

The panel also recommended that fasting glucose levels, lipid levels and blood pressure be assessed three months after the initiation of antipsychotic medications. After that assessment, blood pressure and plasma glucose values can be obtained annually or more frequently for patients at higher risk. In patients with normal lipid profiles, repeat testing should be performed at five-year intervals or more frequently if clinically indicated.

For patients with diabetes, the panel recommended referral to the ADA's diabetes self-management education program.

For patients with severe hyperglycemia, symptomatic hypoglycemia or glucose levels ≤60 mg/dL, even in the absence of symptoms, the panel recommended immediate consultation and care.

What Now?

As part of its recommendations, the consensus panel noted the many limitations with current studies of second-generation antipsychotics, such as lack of clinically equivalent dosages in comparisons of medications. More prospective, controlled trials are needed to evaluate how second-generation antipsychotics cause weight gain, dyslipidemia and diabetes and to identify patients at particular risk for these adverse events.

Kane noted that at his hospital, "We are going to implement the monitoring protocol" outlined in the Con-sensus Statement.

He added that Christoph Correll, M.D., in his department, is conducting a longitudinal study on a large number of adolescents receiving second-generation antipsychotics (see sidebar).

Kane added that exploring the relationship of second-generation antipsychotics and metabolic side effects is an iterative process because new data are always emerging.

The Consensus Statement also affected at least one panel member personally. Davis confided that he is not taking any psychotropic drugs but is overweight. After the Consensus Development Conference, he put himself on an exercise program and diet and has since lost 15 pounds.

References:

References 1. 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.
2. 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.
3. 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.