The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models.[1] The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.[2]
Like dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, glutamate antagonists, such as PCP and ketamine, mimic some positive and negative symptoms with less brain harm.
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Schizophrenia that is unmanagable by lifestyle changes (like reducing stress or stopping drug habits) is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms (things which should not be there, such as hallucinations or a paranoid delusion).
Unfortunately, the typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, they may not adequately reduce negative symptoms.
Ketamine and PCP were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). PCP however is less representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia.[3] No drug has been found to induce schizophrenic symptoms completely, nor has been able to mimic developmental abnormalities.
An early clinical trial by Eli Lilly of the drug LY2140023 has shown potential for treating schizophrenia without the weight gain and other side-effects associated with conventional anti-psychotics.[4][5][6] This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).[7]
Studies of glycine (and related co-agonists at the NMDA receptor) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.[8]
A research done on mice in early 2009 has shown that when the neuregulin-1\ErbB post-synaptic receptor genes are deleted, the dendritic spines of glutamate neurons initially grow, but break down during later development. It was found that symptomic similarities to the disease matched schizophrenia upon expression.(symptoms such as disturbed social function, inability to adapt to predictable future stressors)[9][10] This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.