Clozapine is a medicine which is used in schizophrenia. Clozapine is used to treat schizophrenia. Clozapine is given to people when their previous treatments for schizophrenia have not been successful or when those treatments have caused bad side-effects. Clozapine is also used in people who have Parkinson's disease who suffer with psychosis and in whom other treatment has not been successful. Clozapine was developed by Sandoz in 1961, and trials took place in 1972, when it was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany, and Finland in 1975. Early testing was performed in the United States around the same time.In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.In 2005 FDA approved criteria to allow reduced blood monitoring frequency. Clozapine is classified as an atypical antipsychotic drug because its profile of binding to serotonergic as well as dopamine receptors. Clozapine is also a partial agonist at the 5-HT1A receptor, putatively improving depression, anxiety, and the negative cognitive symptoms. A direct interaction of clozapine with the GABAB receptor has been shown.GABAB receptor deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models. Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
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