GLUTAMATE, SCHIZOPHRENIA
& OTHER CNS DISORDERS
The understanding that glutamate dysfunction contributes to schizophrenia is supported by several lines of investigation. First, it has been observed that patients with schizophrenia exhibit blunted signaling in the prefrontal cortex (an area of the brain in which glutamate signaling plays a particularly important role) during the performance of cognitive tasks. Further, a correlation between reduced glutamate levels in the cerebrospinal fluid from patients with schizophrenia and the severity of positive symptoms (hallucinations, delusions and paranoia) has been detected by some investigators.
More specifically, data implicate deficient signaling through NMDA receptors (a specialized glutamate receptor) as a potential causative factor underlying the symptoms of schizophrenia. In this regard, patients with schizophrenia have been shown to exhibit elevated levels of the endogenous NMDA antagonists NAAG and kynurenic acid, which could result in diminished activity of NMDA receptors.
Lastly, noncompetitive NMDA receptor antagonists have been shown to create a psychotic state that is strikingly similar to schizophrenia. For example, phencyclidine (PCP) is capable of recreating a broad array of symptoms, including those categorized as positive symptoms, negative symptoms (loss or decrease in ability to speak and express emotion and social withdrawal) and cognitive symptoms (impairments in working memory, executive functioning and other cognitive functions) that have been linked with schizophrenia.
Collectively, these data implicate impaired cortical function, due at least in part to altered glutamate signaling, as a key event that contributes to schizophrenia. As a result, molecular mechanisms capable of regulating glutamate release represent novel and potentially promising treatment targets.
A number of targets related to the glutamate system have attracted significant attention for the potential treatment of schizophrenia, as well as other disease states. Agonism of the group 2/3 metabotropic glutamate receptors (mGluR’s) as well as the targeting of other mGluR’s is prominent in this regard and there is considerable interest in examining the therapeutic potential of group II mGluRs as a means of reducing glutamate neurotransmission. Efforts to enhance NMDA receptor stimulation, including increased activation of the glycine site of the NMDA receptor, represent another approach that has yielded positive data. A third approach is to target AMPA receptors and in this regard preclinical studies indicate that PCP-induced deficits in working memory can be blocked by an AMPA receptor antagonist.
While distinct, glutamate-based drug development efforts are individually addressing each of the above targets, none seem capable of addressing all of the key pathological changes that appear to be occurring. Promentis believes that its approach takes the fullest account of the glutamatergic system and the nature of glutamatergic dysfunction that has been observed in the context of schizophrenia. Within this framework, Promentis is aggressively embarking on an effort to redefine what is possible in the treatment of schizophrenia and other psychiatric disorders.
