Martin Zdanowicz, PharmD

Patients with schizophrenia and other disorders who take atypical antipsychotics should be monitored for an increased risk for diabetes.

Reducing the Risk for Metabolic Disorders Begins with Choosing the Right Treatment

	Patients taking antipsychotic agents, and particularly those with schizophrenia, are at risk for developing more detrimental conditions that can lead to increased susceptibility to cardiovascular disease and hyperlipidemia. Since 2002, coinciding with the addition of the newer generation of atypical antipsychotic drugs, patients have also been prone to an increase in weight gain and the subsequent metabolic effects leading to a predilection to type 2 diabetes. 

	According to the National Institute of Mental Health, in 2008, 2.4 million people in the United States were living with schizophrenia.

 Schizophrenia is a mental disorder characterized by positive symptoms like delusions, hallucinations, and disorganization of thought, and negative symptoms such as flat affect, avolition, alogia, anhedonia, and social inattention.

 In addition to the mental complications of the disorder, studies have shown that patients with schizophrenia are 2 to 3 times more likely to develop type 2 diabetes.

	There is not a clear understanding why schizophrenic patients are at an increased risk for developing type 2 diabetes. Schizophrenic patients have a number of risk factors for type 2 diabetes, including family history, increased body mass index (BMI), sedentary lifestyle associated with the disorder, and the use of atypical antipsychotic medications.

 In 2004, the FDA required that a warning be placed in the package inserts of all atypical antipsychotics addressing the increased risk of hyperglycemia and diabetes.

 There are many studies that show, however, that the risk of diabetes is greater with certain atypical antipsychotics, such as olanzapine (Zyprexa) and clozapine (Clozaril), whereas ziprasidone (Geodon) and aripiprazole (Abilify) are associated with the lowest risk.

Possible Mechanisms of Antipsychotic-induced Diabetes

	There are many proposed mechanisms to explain atypical antipsychotic-induced diabetes. One potential mechanism involves the weight gain associated with these medications. A study conducted in 2006 showed that 78.8% of patients taking antipsychotic medications experienced a weight gain greater than 7% compared with baseline.

	Possible explanations for the weight gain associated with atypical antipsychotics include the antagonism of hypothalamic histaminergic H1 receptors, serotonergic 5-HT2C receptors, and/or adrenergic alpha 2 receptors. The antagonism of H1 receptors is thought by some to be the best predictor of antipsychotic-induced weight gain. Olanzapine ans clozapine have the highest affinity for H1 receptors and are associated with the greatest weight gain; ziprasidone and aripiprazole have the lowest affinity for H1 receptors.

	Some patients develop diabetes without concomitant changes in BMI, however; therefore, there must be other possibilities aside from the weight gain. One possible mechanism involves alterations in pancreatic beta-cells, specifically antagonism of pancreatic adrenergic alpha 2 receptors, 5-HT1 alpha receptors, and/ or muscarinic M3 receptors. When these receptors are blocked, the beta-cells in the pancreas lose the ability to respond to changes in blood glucose levels. Another possibility involves alterations in glucose transporters on hepatic and skeletal muscle tissue. When these transporters are inhibited, glucose cannot get to target tissue and high levels of glucose remain in the blood.

 This is not a complete list of possible mechanisms; there is much more work to be done to fully explain why atypical antipsychotic medications induce type 2 diabetes.

	In response to the FDA warning concerning atypical antipsychotics and the risk of type 2 diabetes, the American Diabetes Association and the American Psychiatry Association introduced monitoring guidelines for patients taking antipsychotic medication in 2004.

 When initiating treatment with an antipsychotic, it is important to obtain a baseline weight/ BMI, blood pressure, and fasting triglycerides, and check for family history of type 2 diabetes. Weight/BMI should be monitored at every visit; fasting blood glucose and fasting lipids should be checked at week 12 and then annually.

	If there is a rise in triglycerides or weight gain, a switch to another agent, such as ziprasidone or aripiprazole, should be considered, and the patient should continue to be monitored. If a patient has dyslipidemia, pre-diabetes, or diabetes prior to initiating antipsychotic medication, it is recommended to avoid high-risk medications such as olanzapine and clozapine and to watch for signs and symptoms of diabetic ketoacidosis/hyperglycemic hyperosmolar syndrome.

	Another factor that should be considered when it comes to monitoring patients on atypical antipsychotics is age. A recent study showed that younger patients had a greater risk of developing diabetes compared with older patients. Based on the results of this study, younger patients should be considered to be at high risk for developing diabetes. Therefore, it is extremely important to monitor these patients more closely for any changes in endocrine function. Also, atypical antipsychotics such as ziprasidone and aripiprazole, which do not seem to pose a high risk of diabetes, should be strongly considered when initiating drug therapy.

	Once the decision has been made to initiate an atypical antipsychotic, there are several strategies that can be employed to try to prevent the development of type 2 diabetes. Diabetes prevention should begin with the careful selection of an atypical antipsychotic; it is recommended to use the lower-risk agents ziprasidone or aripiprazole. Patients should also be encouraged to exercise at least 30 minutes a day 7 days a week and follow a diet like the American Heart Association “Step 2” diet (Table 13 ). There are also pharmacologic options for preventing type 2 diabetes; recent studies have shown that metformin can be added to a patient’s drug regimen to not only prevent metabolic changes, but also to treat atypical antipsychotic—induced type 2 diabetes.

	Patients with schizophrenia are at increased risk of developing metabolic disorders like type 2 diabetes. This is due to a number of factors, including the treatment of schizophrenia with atypical antipsychotics. There are several potential mechanisms behind antipsychotic-induced diabetes, including the weight gain associated with these medications, the effects on pancreatic receptors and/or glucose transporters, or some other cause not yet discovered. Most likely, it is a combination of these effects. Of the atypical antipsychotics, clozapine and olanzapine are associated with the highest incidence of metabolic dysfunction, whereas ziprasidone and aripiprazole are considered to be the least risky.

	Due to the long-term complications associated with type 2 diabetes, patients should also be encouraged to follow a healthy diet and to exercise regularly. It is also imperative that patients taking atypical antipsychotics be monitored frequently for any endocrine changes. If laboratory results reveal hyperglycemia or type 2 diabetes, one should consider switching to an antipsychotic less likely to cause metabolic disturbances.

Dr. Berg is a pharmacist at CVS pharmacy in Savannah, Georgia. Dr. Stajich and Dr. Zdanowicz are professors at South University School of Pharmacy in Savannah, Georgia. 

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Martin Zdanowicz, PharmD

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