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ANTI-PSYCHOTIC DRUGS: Can They Cause Type 2?

Posted on: Thursday, 2 December 2004, 03:00 CST

Paul E. Keck, Jr., MD, is studying the effects of four drugs often prescribed for schizophrenia and bipolar disorder to see if taking them increases the risk of type 2.

PAUL E. KECK, JR., MD

Occupation

Professor of Psychiatry, Pharmacology, and Neuroscience, The University of Cincinnati College of Medicine

Professional Focus

Psychiatry, pharmacology, type 2 diabetes

Outside Interests

Golf, tennis, skiing, fly-fishing, rooting for his son's lacrosse team

Research Funding

ADA Clinical Research Award

One of the hottest topics in diabetes research today is whether certain drugs prescribed for mental disorders such as schizophrenia and bipolar disorder can cause type 2 diabetes. It's an area of research rife with statistical pitfalls, however, because both schizophrenia and bipolar disorder may increase the risk of type 2 themselves. People with these illnesses often neglect their health and may become overweight or obese, which ups the risk of developing type 2.

Paul E. Keck, Jr., MD, professor of Psychiatry, Pharmacology, and Neuroscience at the University of Cincinnati College of Medicine, is set to unravel the mystery piece by painstaking piece, however. Keck is using funds from an American Diabetes Association Clinical Research Award to sort out the risks of the disorders and the drugs often prescribed to treat them.

Background

Before getting to the nitty-gritty of treatment for schizophrenia and bipolar disorder, first it's necessary to understand what they are.

People with schizophrenia are unable to tell what's real from what isn't. At the onset of the disorder, their thinking may be disorganized, and they may speak incoherently. As the disorder progresses, they may experience "psychosis," in which they hear voices or experience hallucinations and delusions. For instance, they may believe that the government is after them. Alternately, they may believe they are Jesus, or the president. If you've ever seen A Beautiful Mind, a movie based on the life of Nobel Prizewinning mathematician John Nash, who has the disorder, you have an idea of what schizophrenia is.

Bipolar disorder is different. It is often known as "manicdepressive" illness. People with bipolar disorder suffer unusual shifts in mood, from euphoria or irritability to depression. The disorder moves in cycles and the swings are severe.

During the manic part of the cycle, someone with bipolar disorder may have racing thoughts, increased sex drive, and poor judgment about his or her own limitations. He or she may spend money wildly, abuse drugs, and take an excessive number of risks.

During the depressive part of the cycle, the same person may experience all the symptoms of regular clinical depression, including loss of interest in things he or she used to enjoy, changes in appetite or sleep patterns, feelings of hopelessness or pessimism, and suicidal thoughts.

Now for the drugs in question. Keek's team is studying the effects of four drugs: aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal). All of these drugs are used to quell abnormal amounts of excitement in the brain, as is seen in people with schizophrenia and people in the manic stage of a manic-depressive cycle.

Confounding And Compounding

Keek's goal is to determine if and how the drugs affect type 2 risk, and separate that from how the disorders themselves affect type 2 risk. To do this, he and his team will study newly admitted patients at the psychiatric care unit at the University of Cincinnati Hospital who have never been treated before.

The team will measure each patient's insulin sensitivity by using a frequently sampled intravenous glucose tolerance test in a method developed by David D'Alessio, MD, codirector of the hospital's General Clinical Research Center. The test involves frequent blood tests over several hours to measure how much insulin the pancreas puts out in response to glucose infused intravenously and then how tissues take up glucose in response to insulin infused intravenously.

The research team will then recruit 100 patients with regular, healthy glucose tolerance to participate in the study, 25 on each drug. The recruitment methods were designed based on earlier research in collaboration with Stephen Strakowski, MD, and Susan McElroy, MD, and give special consideration to the nature of the patients' disorders.

The result of his study may influence, treatment guidelines for mental illness, says Keck, here with wife. Sue, and dogs Maddy (left) and Finn (right).

Informed consent is very important, says Keck, and the team has several safeguards in place to make sure the patients understand what the study will involve. The researchers will explain the study to the patients, and the patients will fill out a nine-question questionnaire and give their consent in writing. An independent psychiatrist with no affiliation with the study will assess each patient, as well.

Once the patients become study participants, they will undergo two more frequently sampled intravenous glucose tolerance tests, one six weeks after starting treatment for their disorder, and one four months into treatment.

At the end of the study, the researchers will compare the results of each glucose tolerance test and see if there are any differences in insulin release from the pancreas and insulin sensitivity in the body.

It sounds simple enough. If the participants' insulin release and sensitivity are fine before taking the drugs, but change after starting treatment, it must be the drugs, right?

Not necessarily.

Keck offers several reasons why insulin release and sensitivity may change in people with these disorders who take the drugs:

First, physical inactivity, binge eating, and smoking are all common among people with mental illness. Physical inactivity and binge eating can lead to weight gain, which is a risk factor for type 2. Smoking is also a risk factor for type 2.

Second, in times of psychosis (in schizophrenia) or mania, there may be an imbalance of stress hormones like cortisol, which affects how the body uses glucose.

Both the behaviors and the psychosis may continue for a few weeks after starting treatment because the drugs in question take a few weeks to kick in.

Third, once the drugs begin to take effect, they may increase the appetites of the study participants, which may cause weight gain and obesity. "All four drugs have different degrees of impact on weight gain," says Keck. "Olanzapine has the most impact, risperidone and quetiapine are in the middle, and aripiprazole has the least."

Fourth, the drugs may somehow interfere directly with insulin release by the pancreas or insulin sensitivity in the cells.

The team's job, then, is to review the test results while accounting for the potential impact each drug has on weight, whether participants actually gain weight (and why-in other words, is the weight gain caused by the drug or by a failure to respond to treatment?), and what each participant's other risk factors are for diabetes, including age, ethnicity, and family history.

Keck says it's going to involve a lot of statistical juggling and analysis, but it will be worth it.

"From this study, we hope to find evidence that will tell us just how much we need to worry about the drugs. This could affect treatment guidelines for mental illness, the choice of drugs, or how often you should check blood glucose after starting treatment to make sure the drugs aren't affecting blood glucose," he says.

"Just as diabetes is a public health problem, so are these disorders. There's an intersection between two big problems that affect a lot of people, perhaps as many as 10 million people in the United States. We think this is one of the better designed studies to address this problem, and we think it will benefit people with these illnesses."

To sponsor an ADA research project at the Research Foundation's Pinnacle Society level of $ 10,000 or more, call EIIy Brtva, MPH, managing director of Individual Giving, at (703) 253-4377, or e- mail her at ebrtva@diabetes.org.

Copyright American Diabetes Association Dec 2004

Source: Diabetes Forecast

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