Glutamate Modulators

The glutamate hypofunction hypothesis of schizophrenia has already been discussed. In rodents, NMDA antagonists increase locomotor activity and enhance amphetamine-induced DA release. However, 5HT2A antagonists are more effective than D2 antagonists in blocking this increase in locomotor activity, suggesting a possible mode of action of drugs that are both 5HT2A and D2 antagonists, e.g., clozapine and risperidone. This suggests that dysregulation of DA function associated with schizophrenia might be secondary to NMDA hypofunction. Thus the balance between D2 antagonism and NMDA receptor modulation may be pivotal for the improvement of both positive and negative symptoms in schizophrenia. Drugs that directly activate NMDA receptors, therefore, might be useful in treating patients with schizophrenia. Such agents, however, have been shown to excessively increase neuronal excitability, to cause seizures, and to be neurotoxic. Recently, many pharmacologically more subtle strategies involving activation of glutamate receptors have been suggested.

Glycine is an obligatory positive allosteric modulator of the NDMA receptor activity. Glycine site agonists and partial agonists (glycine, D-serine 6, D-cycloserine) and the glycine transporter (GlyT) inhibitor sarcosine 64, are effective in treating some of the symptoms, particularly negative symptoms and cognitive impairment, of schizophrenia when used adjunctively with existing antipsychotic drugs.67 Of these agents, D-serine appears to be the most promising based on pharmaceutical characteristics and clinical outcomes. When combined with drugs like risperidone and olanzapine, D-serine improves positive and negative symptoms in treatment-resistant patients in some but not all studies. However, the efficacy of this compound appears to attenuate with repeated use, and it is not useful in patients who are receiving clozapine. Agonists of glutamate metabotropic receptors are also being explored as a potential treatment for schizophrenia.68 Metabotropic glutamate receptors are G protein-coupled receptors (GPCRs) that have been classified into eight discrete subtypes. The group II mGluRs are often located presynaptically and typically modulate glutamate release. Reduction in glutamate release by group II agonists can block the behavioral activation caused by PCP and amphetamine in rats. Early stage group II mGluR ligands include LY 404039 65, LY 354740 8, and MGS 0039 66. Both orthotopic and allosteric modulators have been shown to have antipsychotic-like activity in animals but allosteric modulators appear not to suffer from rapid tachyphylaxis and, therefore, could have utility as a novel approach as a maintenance therapy for patients with schizophrenia. In addition, the group I mGluR, mGluR5, has been implicated as a potential novel target for schizophrenia. Both pharmacological blockade and genetic ablation of mGluR5 have been found to decrease prepulse inhibition in rodent studies, and CDPPB 67, a selective positive allosteric modulator of mGluR5, reverses the psychotomimetic effects of amphetamine in rat models.69 Since mGluR5 is linked to potentiation of NMDA receptor currents in a number of brain regions, it has been suggested that a selective activator of this receptor may be an effective drug for restoration of cognitive function.

Another class of agents that has been shown, at least in vitro, to allosterically enhance AMPA receptor activity is the ampakines. One of these agents, CX-516 68, was studied in combination with clozapine in a small clinical study and was shown to improve some symptoms associated with schizophrenia. As a sole agent, CX-516 does not appear to be effective in improving positive symptoms or cognition in patients with schizophrenia. Another ampakine, ORG 24448/ CX-619, is being tested as an adjunctive therapy as part of the NIMH effort to facilitate the development of medications to enhance cognition in patients with schizophrenia.

Blood Pressure Health

Blood Pressure Health

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