Schizophrenia
From Science Online
Contents |
Introduction: Statistics and Symptoms of Schizophrenia
Schizophrenia is a chronic disease that affects the brain. Schizophrenia affects men and women equally, but normally symptoms are seen earlier in men. The first symptom of schizophrenia is a drastic change in behavior. Symptoms of psychosis or hallucinations may follow. People with schizophrenia may experience symptoms of hallucinations. These include visual hallucinations such as seeing things that are not actually present, auditory hallucinations such as hearing voices in their head, tactile hallucinations such as feeling as if something is touching your skin that is not actually present, olfactory hallucinations or smelling things that other people cannot smell, and gustatory hallucinations or tasting things that are not there. Other symptoms include delusions such as believing that people are reading their minds, controlling their thoughts, or planning to harm them. These debilitating symptoms sometimes cause people with schizophrenia to become withdrawn from society and fear interactions with others. Unfortunately, many people with schizophrenia find it very difficult to cope with these symptoms and approximately 10% of schizophrenic people commit suicide. Schizophrenia affects 51 million people all over the world and 2.2 million people in the United States. Twice as many people suffer from schizophrenia as compared to Alzheimer’s and six times as many people suffer from schizophrenia as compared with insulin dependent diabetes.
Myths and Misconceptions about Schizophrenia
Many movies depict people with schizophrenia as especially violent. However, the onset of schizophrenia does not increase a person’s potential to be harmful to others. A schizophrenic person is no more likely to become violent after being diagnosed with schizophrenia than they were before being diagnosed. Another misconception about people who suffer with schizophrenia is that they have a split personality. Schizophrenics have only one personality. Schizo is a Greek word meaning "split" but means a split from society, not a split personality. People that suffer from schizophrenia are not developmentally delayed and do not have a lower than average inteligence level.
(Schizophrenia.com)
(Schizophrenia Fellowhip)
Structure of hKAT-II
Article on Crystal Structure of Human Kynurenine Aminotransferase
There are over 30 Alpha helices and approximately 4 Beta sheets in this structure
hKAT-II is a catalyst that aids in the conversion of knunrenine to kynurenic acid. Abnormal levels of kynurenic acid are believed to possibly be the cause of some neurological diseases such as schizophrenia. (See below)
Etiology: Biochemistry of Schizophrenia
There are two primary hypotheses surrounding the cause of schizophrenia. The first is the Dopamine Hypothesis of Schizophrenia in which a possible over abundance of dopamine is the cause for a hyperactive dopaminergic signal transduction. The second hypothesis is the Glutamate Hypothesis of Schizophrenia. This hypothesis suggests that the N-methyl-D-aspartate (NMDA) receptor does not function as it should. A relatively new hypothesis that links the two hypotheses above is called the Kynurenic Acid Hypothesis of Schizophrenia.
The Dopamine Hypothesis suggests that an overstimulation of dopamine receptors is the cause for Schizophrenia. Dopamine is a hormone and neurotransmitter that is produced in several areas of the brain. Dopamine has the ability to activate five different types of receptors. The most relevant in terms of schizophrenia and the Dopamine Hypothesis is the D2 receptor or the antipsychotic receptor. There are two possible circumstances in which a schizophrenic patient may be subjected to high levels of dopamine. The first is the there is an overproduction of dopamine that leads to more dopamine binding to the D2 receptor. The second is that there are more D2 receptors in the brain which would allow more dopamine to bind to these receptors. Support for this theory comes from the effects that drugs like amphetamine and cocaine have on dopamine production and the symptoms they induce. These drugs increase dopamine production and users can experience psychosis after large doses or extended use. This is very similar to schizophrenic patients who would have also been subjected to high levels of dopamine for long periods of time. Furthermore, a group of drugs called phenothiazines that prevent dopamine binding to the D2 receptor have successfully been used to reduce positive psychotic symptoms.
The Glutamate Hypothesis suggests that the N-methyl-D-aspartate (NMDA) receptor is unable to properly function. NMDA is a type of ionotropic receptor for glutamate. These receptors are involved in channeling sodium or calcium into neurons and potassium out. Calcium is needed for synaptic plasticity which is the synapse’s ability between two neurons to communicate and is involved in learning and memory. NMDA is a special ionotropic receptor because it is “doubly gated” by both voltage and ligand. NMDA is only activated when glutamate binds to the receptor at the same time as a depolarizing shift in the membrane potential occurs. This theory was first proposed by Kim Kornhauber and colleagues in 1980 and quickly came under fire due to a lack of knowledge at the time surrounding the glutamate system. More recently, evidence has surfaced that validates the theory. Non-Schizophrenic individuals who were given phencyclidine (PCP) or ketamine (both NMDA receptor antagonists) displayed schizophrenic like symptoms. Furthermore, when schizophrenic patients were given the antagonists their symptoms were amplified. Two ideas have been proposed that may account for the compromised NMDA receptors. The first is that the NMDA channel kinetics have been modified in some way. The second is that the proteins that link NMDA receptors to signal transduction pathways have been modified in some way.
Proposed in 2007, the Kynurenic Acid Hypothesis of Schizophrenia fuses the above two hypothesis. It suggests that kynurenic acid neutralizes glutamate and acts at the glycine-site of the N-methyl-D-aspartate (NMDA) receptor. Similar to phencyclidine (PCP) and ketamine, elevated levels of kynurenic acid increased the rate at which midbrain dopamine neurons fire. This suggests that kynurenic acid can be responsible for symptoms that Schizophrenics display. Furthermore, kynurenic acid levels are higher in schizophrenic patients compared to control subjects. The protein kynurenine aminotransferase II (hKAT-II, displayed above) catalyzes the conversion of kynurenine to kynurenic acid (KYNA). Normal levels of KYNA act as antiexcitotoxins and anticonvulsants. KYNA acts at three receptors. The first is the previously mentioned antagonist at the glycine site of the NMDA receptor. The second is as an antagonist of alpha7 nicotinic receptor which increases the permeability of calcium which was earlier discussed as a necessity for normal neuron function. The third is as a ligand at the GPR35 receptor which is a G protein receptor involved in gastrointestinal function. This Kynurenic Acid Hypothesis is still new and more research will undoubtedly be conducted, but it is promising in its ability to fuses the two other leading hypotheses.
Chemical Structure of L-Glutamate
Chemical Structure of Kynurenic Acid
(Schizophrenia Research Forum)
Treatment
Currently, the best treatment for schizophrenic patients is combination of antidepressants, antianxiety, and antipsychotic medications. There are two types of antipsychotic drugs available to treat schizophrenia. The first types of medications are the traditional antipsychotic drugs and have been around since the 1950’s. They help to ameliorate the "positive symptoms" of schizophrenia. Positive symptoms are symptoms experienced due to heightened sensory function such as delusions and paranoia. Traditional antipsychotic drugs include chlorpromazine, fluphenazine, and haloperidol. These drugs block dopamine receptors. The negative side effects of these drugs include dry mouth, dizziness, and blurred vision, trouble with muscle control, fidgeting, tremors, feet shuffling, facial tics, lip licking, panting, muscle cramps, and grimacing. The second types of medication available to treat schizophrenia are the newer antipsychotic drugs which have been available since the 1990's. These drugs include Seroquel, Zyprexa, Risperdal, and Clozaril. These new drugs can treat both the positive and negative symptoms of schizophrenia by binding to both the dopamine and serotonin receptors. Negative symptoms include withdraw from society, flat facial expressions, and a loss of energy and apathy. There is currently no cure for schizophrenia but new medications are providing new hope for people suffering from schizophrenia.
