Sep. 17, 2003 Whether the long-term use of the newer schizophrenia drugs damages or improves a patient's cognitive ability is the focus of a cooperative study by the University of Georgia and the Medical College of Georgia.
Many of the older antipsychotics used to quell delusions and hallucinations - the hallmark of schizophrenia - also impair the ability to think, learn and remember, says Dr. Alvin V. Terry Jr., pharmacist and pharmacologist at UGA and MCG.
"Cognitive dysfunction has become a hot issue in schizophrenia research," says Dr. Terry, principal investigator on a $1.1 million National Institute of Mental Health grant to compare the cognitive effects of typical antipsychotics and their newer counterparts called atypicals.
Ironically, memory problems can result from the disease itself and the drugs can compound that problem, so that cognitive symptoms often are the most debilitating and difficult to treat, says Dr. Sahebarao P. Mahadik, neuroscientist at MCG and the Department of Veterans Affairs Medical Center in Augusta.
Schizophrenia affects 1 percent of people worldwide and is diagnosed at the mean age of 20. That early onset coupled with the disruptive behavior that can result from a lack of treatment means many of these patients are on medication lifelong.
Drs. Mahadik and Jennifer L. Waller, MCG biostatistician, are co-investigators on the study to help determine whether the atypical antipsychotics also contribute to cognition problems over the life of these patients.
"The traditional side effects always quoted for the older (typical) antipsychotic drugs are parkinsonian-type movement disorders," says Dr. Terry. In fact, that debilitating side effect is a primary reason that, outside of hospital walls, many patients refuse to take their medication, he says.
"It has always been a big dilemma," Dr. Mahadik says. "If you keep patients institutionalized, it costs a tremendous amount of money. If you give them drugs and get them to the point where they can leave the hospital, they commonly stop taking their medications because they make them feel bad. Then they go back to experiencing hallucinations and it just gets worse and worse," he says of the horrific cycle the atypical drugs were designed to help break.
The newer drugs, although much more expensive than their older counterparts, cause fewer problems with movement disorders; clinical evidence suggests they may also cause fewer cognitive problems, the researchers say.
UGA and MCG researchers are doing laboratory experiments to objectively measure the impact of two of the older drugs, haloperidol and chlorpromazine, and three of the atypicals, olanzapine, risperidone and clozapine.
In this new study, they are giving the different antipsychotics daily to healthy rats at levels that mimic what patients receive for 180 days, or about one-fifth of the rodent's lifespan, to measure the long-term impact of these drugs.
They will study memory function and eventually analyze brain chemistry, looking at how form and function have been impacted by the drugs. "One important issue is to determine how these drugs affect brain plasticity, the growth of cells, how cells communicate and such," Dr. Mahadik says. The researchers have evidence from previous work, including two similar studies of shorter duration - for 45 and 90 days - that document the deleterious effects of haloperidol on cell structure and signaling. Pathological changes in the postmortem brain of schizophrenics also have been reported in the medical literature.
"The key question relates to how much of the change is a result of the patient's illness and how much is a result of the drug," Dr. Mahadik says. "Our animal system allows us to precisely delineate how the drugs affect brain cell morphology and structure."
Their previous studies yielded no hard evidence that the newer drugs cause these types of changes, but Dr. Terry said one reason for increasing the duration to 180 days was some "tantalizing" evidence indicating that at the 90-day point some adverse changes might be in the making.
"At least from a pharmacologic standpoint, these drugs given chronically - as they are to patients - have not been adequately studied," Dr. Terry says. "Nearly all of the pharmacology that was originally described was based on acute studies in animals. You give them a dose of haloperidol, you study receptors in their brain, you see that they block dopamine receptors so they don't have as many psychotic outbursts. Patients are quiet, docile and more easily managed … but their cognition becomes impaired, and it's worse than it would have been without treatment. What we are in the process of doing is evaluating these atypical drugs to see if they really are better from a cognitive perspective in the long term."
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