Blocked enzyme reverses schizophrenia-like symptoms
Researchers at MIT's Picower Institute for Learning and Memory have found that inhibiting a key brain enzyme in mice reversed schizophrenia-like symptoms. Click to read more
Schizophrenia May Be Linked To Immune System
All Things Considered, July 1, 2009 Three new genetic studies are providing some tantalizing hints about what causes schizophrenia.
The studies, published in the journal Nature, identify sections of our genetic code in which small changes can affect a person's risk for developing the disorder. Click to read more
Equipment gives glimpse into schizophrenia...
The Mental Health Association in North Carolina, Inc. used the virtual experience Mind Storm, which includes a headset and virtual screen, to give legislative building visitors and lawmakers a better understanding of the illness, Schizophrenia affects just over 1 percent of the U.S. population each year, according to the National Institute of Mental Health. Click to read more
Novel Treatment May Provide Relief for People with Schizophrenia
By Duke Medicine News and Communications
A compound that naturally occurs in the brain and other areas of the body may be a promising new treatment for the most severe and disruptive symptoms of schizophrenia, according to researchers from Durham Veterans Affairs Medical Center and Duke University Medical Center. Click to read more
Antipsychotic Drug Approved for Use in Addition to Antidepressants for Treating Depression
By Miranda Hitti WebMD Health News
Nov. 20, 2007 -- The FDA has approved the antipsychotic drug Abilify for treatment of depression when used along with antidepressants. Abilify isn't a new drug; it was first approved five years ago. But it's the first drug approved by the FDA as an addition to antidepressants for adults with major depressive disorder, according to Otsuka Pharmaceutical Co. and Bristol-Myers Squibb. Click to read more
Brain Compound Kynurenic Acid Like 'Gasoline Onto The Fire' Of Schizophrenia
Scientific Blogging, Science 2.0, www.scientificblogging.com, (c) 2008 ION Publications LLC.
New research has traced elevated levels of a specific compound in the brain called kynurenic acid to problem-solving deficits in patients with schizophrenia.
The finding suggests that drugs used to suppress the compound 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."
Gene Alterations Could Mean New Treatments for Schizophrenia
NeuroPsychiatry Reviews, June 2007, Vol. 8, No. 6
While studies have shown that several psychiatric disorders are associated with white matter defects, a new study suggests that those defects can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric diseases. The findings, published in the May 8 Proceedings of the National Academy of Sciences, may provide insight into new treatment options for patients with schizophrenia and bipolar disorder.
Using a mouse model, researchers led by Gabriel Corfas, PhD, Kristine Roy, PhD, and Joshua Murtie, PhD, of the Neurobiology Program at the Children’s Hospital in Boston, found that when Neuregulin 1 (NRG1), a growth factor, and erbB4, one of its receptors, are altered, it causes pathologic changes in the brain’s white matter. These changes also lead to alterations in biochemical signaling.
The researchers blocked NRG1-erbB signaling in oligodendrocytes in the mice. While this led to a proliferation of oligodendrocytes, the cells had fewer branches and formed a significantly thinner myelin sheath around nerve fibers, causing those fibers to conduct electrical impulses more slowly. The researchers also reported increased levels of functional dopamine receptors and transporters in the mice.
In addition, the mice whose NRG1-erbB signaling was blocked exhibited behavioral changes that appeared to be consistent with mental illness, including a lack of interest in their surroundings and social withdrawal—qualities thought to be a manifestation of “negative” schizophrenic symptoms. When exploring an open field, the transgenic mice were hypoactive, moving less quickly and stopping more often when compared to normal mice. And when the mice were subjected to a social interaction test in which an unfamiliar intruder male mouse was placed in the cages of both the transgenic and the normal mice, the transgenic mice were slower to investigate the intruder, compared to the normal mice. The transgenic mice also showed behaviors suggestive of anxiety, which is commonly seen in patients with schizophrenia and bipolar disorder, and an increased sensitivity to amphetamine, which is seen in many patients with schizophrenia.
The researchers said further investigation should be conducted on the possibility of modifying NRG1-erbB signaling with drugs as a way of treating or preventing schizophrenia. “We need to investigate whether the white matter defects emerge early, before psychotic symptoms are evident,” said Dr. Corfas. “If they do, that raises the possibility of early diagnosis and preventive treatment.”
The idea of schizophrenia arising from white matter defects may also help explain the timing of emergence. Recent evidence suggests that myelination of the prefrontal cortex occurs not only during infancy and childhood but also during late adolescence or early adulthood, when schizophrenia strikes.
“We now need to go back to patients with schizophrenia and see whether those with variants of the NRG1 and erbB4 genes have differences in their white matter,” said Dr. Corfas. “It may be that there are different kinds of schizophrenia, arising from alterations in the different genes, and that directed treatments could be developed from different forms.” The researchers plan to investigate other genes linked with schizophrenia, studying whether they interact with NRG1-erbB signaling and how they may alter brain function.
Suggested Reading:
Roy K, Murtie JC, El-Khodor BF, et al. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci U S A. 2007; ¬104:¬8131-8136.
