Mechanism of Action of Schizophrenia for More Targeted Treatment
Schizophrenia remains an enigma that has fascinated the foremost minds of psychiatry and neuroscience for more than a hundred years. At stake is more than just the crucial welfare of the millions afflicted, for schizophrenia research may represent the key to an understanding of the mechanisms by which the brain filters, prioritizes and processes the relentless current of information available from the richness of its internal, social and natural environments.
It is likely that an imbalance in the complex, interrelated chemical reactions of the brain involving the neurotransmitters dopamine and glutamate (and possibly others) plays a role in schizophrenia. Neurotransmitters are substances that allow brain cells to communicate with one another. Basic knowledge about brain chemistry and its link to schizophrenia is expanding rapidly and is a promising area of research.
Some researchers believe schizophrenia is a single disorder, whereas others believe it is a syndrome (a collection of symptoms) based on numerous underlying disorders. Subtypes of schizophrenia have been proposed in an effort to classify people into more distinct groups. However, among individuals, the subtype may change over time.
Mood changes occur both as symptoms of schizophrenia and as reactions to its devastating effects; for example, depression after a schizophrenic episode (post-psychotic depression) is common and often severe, and it is during this time that a person suffering from schizophrenia is most likely to commit suicide.
Schizophrenic apathy and an incapacity for pleasure can also be mistaken for depression. The most common form of substance abuse in people with schizophrenia is an addiction to nicotine. People with schizophrenia are addicted to nicotine at three times the rate of the general population (75–90 percent vs. 25–30 percent).
Unfortunately, it is difficult to predict the effectiveness of a specific drug in any given individual with schizophrenia.The selection of particular antipsychotic medications for particular patients with schizophrenia is more art than science. A new study published most recently in the issue of Biological Psychiatry suggested that variants in a specific gene, RGS4, predict the effectiveness of different antipsychotic treatments. Our results also indicate that the predictive power of the RGS4 genetic variants differed between patients of self-reported African and European ancestry, and thus emphasize the importance of including multiple ethnic groups in a study.
Although there are many drugs approved to treat schizophrenia, including the commonly prescribed "atypical antipsychotics," a high degree of dissatisfaction remains among physicians and patients. The recent CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, conducted by the National Institute of Mental Health and reported in The New England Journal of Medicine, evaluated several antipsychotic medications and revealed that 74% of patients taking antipsychotics discontinued treatment within 18 months, primarily because of insufficient efficacy and tolerability issues. Each medication has a specific mechanism of action, and many are meant to target a certain symptom or group of symptoms.
It is also suggested that there may be a convergence of dopamine and serotonin inputs on to limbic lobe neurons and a competition between these two fiber systems can result in excessive dopamine inputs to GABA cells. Blockade of the DA receptors on these cells by antipsychotic medications would tend to release these GABA cells to provide more effective inhibition of other neurons that project to many other regions of the brain.
Recent developments in schizophrenia research have shed considerable light on the putative mechanism of action of antipsychotic medications. These investigations have also produced unexpected insights into the function of the normal brain and even the vagaries of personality. Scientists leaped to the conclusion that excessive amounts of dopamine in the brain must be the cause of schizophrenia. Thus began a nearly 30-year adventure in which clinical investigators attempted to prove this dopamine hypothesis.
The field of schizophrenia research has come alive with many exciting new potential approaches to treatment. From the introduction of chlorpromazine to the current day, all treatments approved by the U.S. Food and Drug Administration have had, at their core, a single treatment mechanism, the blockade of the dopamine D2 receptor. The introduction of clozapine in the 1980's suggested a potential that other brain targets might complement the blockade of dopamine D2 receptors to treat symptoms that failed to respond to the "typical" antipsychotics. We are now entering an age where new treatments are being rationally developed within the context of translational neuroscience, i.e., the steps whereby basic molecular neuroscience leads to fundamental new mechanisms that can be tested in animal and human laboratory-based research that, in turn, leads to tests of new medications in our clinics. The January 1st issue of Biological Psychiatry includes encouraging new research related to three new treatment approaches.
In the first study, indicate that a novel drug tested which is effective in an animal model of schizophrenia. Joseph H. Neale, Ph.D., lead author on this project, comments, "While treating patients with receptor agonists can be highly effective therapy, drugs that increase the action of the transmitter that activates the same receptor have traditionally been very effective with fewer side effects than chronic agonist treatment.
In the second article; accumulating evidence suggests that -7 nicotinic receptors, a subtype of nicotinic receptors, are a most attractive target for novel therapeutic drugs of neuropsychiatric diseases including schizophrenia and Alzheimer's disease. Behavioral abnormalities in animals after repeated administration of the NMDA receptor antagonist phencyclidine (PCP) have been used an animal model of schizophrenia.
NMDA receptors are a type of receptor for the excitatory neurotransmitter glutamate and were known to play a prominent role in cognitive processing. It therefore made sense that the behavioral disturbances induced by PCP might be due to its interaction with NMDA-associated PCP receptors.
In the third investigation; shown that a recently discovered brain receptor for serotonin (5-HT7) might be of importance for understanding certain aspects of schizophrenia.Their study focused on sensory input processing, which is often impaired in schizophrenia, and finds that blockade of this particular serotonin receptor in mice alleviates this impairment and this receptor as a treatment target may lead to more specific and better medications for disorders such as schizophrenia."
It was known that ketamine initially impairs the inhibitory circuitry in the brain's cortex and hippocampus by blocking the NMDA receptor, a molecule on the cell surface that controls the activity of neurons. But the UCSD researchers at their another study discovered that, as a result of blocking the receptor, ketamine also substantially increased the activity of NADPH oxidase, causing further disruption of neuronal signaling.
NADPH oxidase is normally found in white blood cells circulating outside the brain, where it helps kill bacterial and fungal infections by producing superoxide, a compound that can cause substantial damage to cells.
Ketamine causes a 'disinhibition' of brain circuitry, taking the brakes off the system and causing overexcitation of the brain in response to a stimulus. "This overexcitation activates NADPH oxidase, which then produces superoxide - resulting in detrimental changes in key synaptic proteins and profoundly affecting nervous system function; they found.
"Our findings suggest that compounds that inhibit NADPH oxidase in the brain, without totally blocking its protective function of killing bacteria, could provide future therapies for schizophrenia or other diseases in humans that exhibit similar changes in neural circuitry," concluded at that study.
LY2140023 is an antipsychotic agent that is a metabotropic glutamate 2/3 receptor agonist. This agent has a new mechanism of action that is efficacious in treating schizophrenia and potentially other neuropsychiatric conditions; according to a another new study. A novel antipsychotic with this new mechanism of action that is effective and is also with a favorable safety and tolerability profile is much desired.
Schizophrenia may occur, in part, because of a problem in an intermittent on/off switch for a gene involved in making a key chemical messenger in the brain, scientists have found in a study of human brain tissue. The researchers found that the gene is turned on at increasingly high rates during normal development of the prefrontal cortex, the part of the brain involved in higher functions like thinking and decision-making — but that this normal increase may not occur in people with schizophrenia.
The study was funded by the National Institutes of Health's National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development.
The gene, GAD1, makes an enzyme essential for production of the chemical messenger, called GABA. The more the gene is turned on, the more GABA synthesis can occur, under normal circumstances. GABA helps regulate the flow of electrical traffic that enables brain cells to communicate with each other. It is among the major neurotransmitters in the brain.
Abnormalities in brain development and in GABA synthesis are known to play a role in schizophrenia, but the underlying molecular mechanisms are unknown. In this study, scientists discovered that defects in specific epigenetic actions — biochemical reactions that regulate gene activity, such as turning genes on and off so that they can make substances like the GAD1 enzyme — are involved. Results of the research were published in the issue of the Journal of Neuroscience, by Schahram Akbarian, MD, PhD, Hsien-Sung Huang, PhD student, and colleagues at the University of Massachusetts Medical School and Baylor College of Medicine.
"This discovery opens a new area for exploration of schizophrenia," said NIMH Director Thomas R. Insel, MD. "Studies have yielded very strong evidence that schizophrenia involves a decrease in the enzymes, like GAD1, that help make the neurotransmitter GABA. Now we're starting to identify the mechanisms involved, and our discoveries are pointing to potential new targets for medications."
Another enzyme, Mll1, may play a role in the epigenetic actions. For genes to be turned on, temporary structural changes in certain proteins — histones — must take place to expose the genes' blueprints in DNA. The researchers found evidence that, in schizophrenia, changes in Mll1 activity may interfere with this process in histones whose alterations enable the GAD1 blueprint to be exposed.
The researchers also showed, in mice, that antipsychotic medications like clozapine appear to correct this epigenetic flaw. This raises the possibility of developing new medications aimed at correcting defects in the mechanisms involved. Finding more precise molecular targets for development of new schizophrenia medications is a key effort, because it can lead to more effective treatments with fewer side effects. Clozapine and other current antipsychotic medications are effective for many patients, but not all, and they can cause side effects severe enough that some people choose to stop treatment.
The researchers also found that people with three different variations of the GAD1 gene — variations previously associated with schizophrenia — also were more likely to have indicators of a malfunction in brain development. Among them were indicators of altered epigenetic actions related to GABA synthesis.
"We've known that schizophrenia is a developmental disease, and that something happens in the maturation of the prefrontal cortex during this vulnerable period of life. Now we're beginning to find out what it is, and that sets the stage for better ways of preventing and treating it," Akbarian said.
"Once we identify people as being high risk, we have a very good chance of knowing whether or not they're likely to develop a serious mental disorder like schizophrenia and that, if they do, it will happen fairly quickly. That's such a critical window of opportunity for getting them the help they need"; said researcher of NIMH.
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