Cause of problem-solving deficit in schizophrenia found?

New research has traced elevated levels of a specific compound in the brain to problem-solving deficits in patients with schizophrenia.
The finding suggests that drugs used to suppress the compound, called kynurenic acid, might be an important supplement to antipsychotic medicines, as these adjuncts could be used to treat the disorder's most resistant symptoms – cognitive impairments.
Though schizophrenia is commonly characterized by hallucinations and delusions, patients also have problems with what is known as cognitive flexibility or executive decision-making. Many patients can set a goal and plan one way to achieve it, but cannot adjust their thinking if circumstances force them to consider alternative strategies.
"We've got this core cluster of symptoms that is the Achilles heel for these individuals, and we're not really doing a good job of treating them," said John P. Bruno, professor of psychology, psychiatry and neuroscience at Ohio State University and principal investigator of the research.
Bruno and colleagues have combined advanced animal modeling of schizophrenia-related chemical changes in the brain with the observation that the production of too much kynurenic acid is linked to troubled thinking that affects the research animals' behavior.
The compound is present in all human brains and has some useful functions. But in excessive amounts, the researchers found, kynurenic acid interferes with other chemical processes that govern the ability to pay attention and think strategically under changing conditions.
"If we try to make predictions about how disabled patients with schizophrenia will be and how likely are they to be integrated into the social fabric, it's the severity of the cognitive deficits that are most predictive," Bruno said. "Antipsychotics are particularly good at what we call positive symptoms, but these same drugs are very poor at treating the cognitive deficits.
"There are a lot of therapeutic strategies for dealing with schizophrenia, but one which has not been explored, and which we think has a great deal of promise, has to do with regulating production of kynurenic acid," Bruno said.
He described the research Tuesday (11/18) at the Society for Neuroscience meeting in Washington, D.C.
Bruno and colleagues tested kynurenic acid's effects on cognitive abilities in rats. Seven rats were given a compound that stimulated excess production of the molecule in their brains, while a control group of rats received no such stimulation. All of the rats were subjected to a test gauging their ability to make what is called an extra-dimensional set shift, requiring them to change response strategies based on changing contingencies – in this case, in a quest to find food.
Only 28 percent of the rats with elevated kynurenic acid were able to solve problems to receive a food reward, compared to 100 percent of the control animals. Before the intervention, all of the animals were equally able to find the food under changing circumstances.
The kynurenic acid essentially exacerbates a phenomenon already observed in patients with schizophrenia – the fact that two neurotransmitters in their brains are not as active as they need to be to allow for normal problem-solving capabilities.
These two neurotransmitters critical to normal cognition are acetylcholine and glutamate. Their activity is partially regulated by what are called alpha-7 receptors, a class of proteins involved in the brain's chemical communication system. In the case of schizophrenia, these neurotransmitters are already at abnormally low levels, most likely because of genetic mutations.
Excess levels of kynurenic acid inhibit the work of the alpha-7 receptors, meaning they suppress the release of these neurotransmitters even more.
"So we've already got problems with these neurotransmitters, and then to make matters worse, we've got all this extra kynurenic acid antagonizing the alpha-7 receptors, which just throws gasoline onto the fire," Bruno said. "If we can design drugs that are able to inhibit the enzymes that are responsible for overproducing kynurenic acid, we may improve cognitive performance in these patients."
Antipsychotic agents used to control hallucinations and delusions act on different neurotransmitters. Agents targeting kynurenic acid production could be part of a medication cocktail that could restore additional neurochemistry responsible for cognition, Bruno said.
Bruno's research group is able to precisely gauge the effects of the compound on neurotransmitters in the brain because of the animal model used for the research. Schizophrenia was once considered too complex a disorder to model in an animal brain, but Bruno and colleagues have developed a rat model to focus on specific cognitive deficits traced to the part of the brain known as the prefrontal cortex.
An element of the modeling is the painless use of microelectrodes in the animals' brains to measure neurotransmitter levels before and after introduction of the agent that elevates kyurenic acid. The real-time measurements allow the scientists to prove the causal relationship between the elevated compound and the reduced presence of the neurotransmitters.
"No one is claiming that we're producing rats with schizophrenia. What we can do is model the neural side pathologies and see if those pathologies lead to behavioral impairments that look like what see on the clinical side. When we get both of those to line up as we have in this model, we have a valid model to ask questions about developing novel therapeutics," Bruno said. "This has allowed us to move from molecules to neurotransmitters to cognitive behavior all in one fell swoop. These findings set the foundation for several years of research that we hope will have some very big implications."
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Gingko biloba does nothing for memory, researchers say

One of the most widely used herbal supplements for improving memory and cognition has no impact on the development of dementia or Alzheimer's disease, according to new results from a $30 million, multi-center study.
The Ginkgo biloba for the Evaluation of Memory (GEM) Study was the largest clinical trial ever to evaluate the effects of the dietary supplement ginkgo biloba (ginkgo) on the occurrence of dementia. The study tested the effectiveness of 120 milligrams (mg) of ginkgo twice daily versus placebo in lowering the incidence of dementia and Alzheimer's in normal, elderly people and those with mild cognitive impairment.
Results from the study show that 240 mg of ginkgo daily has no effect on the onset of dementia or development of Alzheimer's. The study appears in this week's issue of the Journal of the American Medical Association.
Many people today use ginkgo leaf extracts hoping to improve memory, to treat or help prevent Alzheimer's and other types of dementia, to decrease intermittent claudication (leg pain caused by narrowing arteries) and to treat sexual dysfunction, multiple sclerosis, tinnitus, and other health conditions. In Europe and the United States, ginkgo supplements are among the best-selling herbal medications and it consistently ranks as a top medicine prescribed in France and Germany.
"Alzheimer's disease is a devastating disease affecting large numbers of older adults," said Gregory Burke, M.D., M.Sc., the lead investigator for the Wake Forest University Baptist Medical Center clinical site. "Our best strategy is to prevent dementia before it begins."
The study was conducted primarily to determine if ginkgo would decrease the incidence of all types of dementia and, more specifically, reduce the incidence of Alzheimer's. The study also aimed to evaluate ginkgo for its effects on overall cognitive decline, functional disability, incidence of cardiovascular disease and stroke, and total mortality.
The results were disappointing and surprising, said Burke and Jeff Williamson, M.D., M.H.S., principal investigator for the GEM Study Clinical Coordinating Center at Wake Forest Baptist.
"In addition to its widespread use based on the belief that it helps memory function," Williamson said, "Ginkgo biloba had enough promising circumstantial evidence from laboratory and animal studies and enough safety information to warrant a full-scale test in humans."
Dementia is a form of brain disease that can seriously affect a person's ability to carry out daily activities. It is caused by many conditions, some of which are reversible. Alzheimer's is one of the most common forms of dementia in older people, affecting nearly 4.5 million Americans, according to the National Institute on Aging. It is an incurable disease with a slow progression beginning with mild memory loss and ending with severe brain damage and death.
The GEM Study was conducted at four clinical sites: Wake Forest Baptist, the University of Pittsburgh, Johns Hopkins University, and the University of California-Davis.
Investigators followed a total of 3,069 participants age 75 or older, who had either normal cognition or mild cognitive impairment. Participants were randomized to receive twice-daily doses of either 120 mg of ginkgo extract or placebo. The dose of ginkgo was selected based on prior clinical study results that found 120 mg twice daily to be the most effective dose. The gingko product used in the study was supplied by Schwabe Pharmaceuticals and is sold in the United States as Ginkgold MaxTM, under the Nature's Way label.
Patients were followed for an average of about six years, with a maximum of just over seven years. During the study, 523 participants were diagnosed with dementia, 246 in the placebo group and 277 in the ginkgo group, leading researchers to declare that ginkgo showed no overall effect for reducing all types of dementia or Alzheimer's.
"It is very unlikely that ginkgo biloba is effective at any dose over a five-year period and in anyone over 75 years old," Williamson said. "It is also ineffective in people with signs of early memory loss. What is not known yet is whether the effect of ginkgo biloba might require taking the drug for many, many years, say 15 years, before there is even a sign of memory loss."
For the millions of people spending their money on over-the-counter ginkgo for the perceived promise of protection from dementia and Alzheimer's, Williamson suggests they spend their money elsewhere, while remaining mentally and physically active.
And though ginkgo failed to perform as hoped, Williamson explained that the trial was valuable in many ways to the scientific community. The study experience itself demonstrates the feasibility of conducting large dementia prevention trials in older adults, the researchers said.
"One of the most important findings from this study is that we can recruit and follow adequate numbers of volunteers for this purpose, even in the rapidly growing population of people over age 75," he said. "This will be critical for the most cost-effective use of scarce Medicare dollars in the future.
"Secondly, we are already learning a lot of new information from the GEMS volunteers about how dementia develops and how not all memory change is a sign of impending dementia," Williamson added.
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