Phencyclidine (PCP) and ketamine are NMDA receptor antagonists. They both can produce psychotomimetic effects and cognitive impairment in normal subjects and exacerbate these types of behavioral pathology in some patients with schizophrenia or other types of mental illness. Interestingly, ketamine is also a rapidly acting antidepressant, but PCP is not. Rapastinel is a tetrapeptide with some but not all ketamine like properties. It is also a rapidly acting antidepressant. We have previously demonstrated that an acute dose of rapastinel given 30 min before acquisition time (AT) rescues novel object recognition (NOR) in subchronic phencyclidine (scPCP)-treated mice. NOR is the rodent equivalent of human declarative memory. An acute dose of ketamine prevents NOR in wild type mice while rapastinel has no effect on NOR in wild type mice. Some treatments for schizophrenia such as atypical APDs,. e.g. lurasidone, risperidone, but not typical APDs, rescue rodent NOR in the scPCP model and also improve declarative memory in some patients with schizoprhenia. Interestingly, both lurasidone and risperidone are approved for and are widely used as adjunctive treatments for treatment resistant major depression. There is extensive evidence that ketamine antidepressant action is mediated by activation of mTOR pathway. There is some evidence that is also true for rapastinel. Much of this is based on the blockade of the antidepressant action of ketamine by rapamycin, an inhibitor of the mTOR pathway.
|Effective start/end date||9/1/16 → 11/22/19|
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