Schizophrenia Daily News Blog

Clozapine Effectiveness Explained?

Clozapine (Clozaril) is frequently noted by schizophrenia researchers to be the "Gold Standard" (the best possible drug) for treatment of schizophrenia, in terms of effectiveness - but it unfortunately has occasional side effect of causing one to two percent of patients to develop a condition called agranulocytosis, in which the white blood cell count drops dramatically. The patient becomes extremely vulnerable to infections and unable to fight them off. This condition is dangerous and potentially fatal.

This week there is news that suggests that researchers are beginning to understand exactly why Clozapine is so effective.

In a recent study conducted by Dr. Javitt and others, at New York University, it was noted that Clozapine inhibits "System A glycine transport", which may account for its enhanced activity in schizophrenia patients. This increased understanding could lead to more effective drugs, or potential additive treatments to existing drug treatment plans. Dr. Javitt is one of the leading researchers in the area of Glycine and how this amino acid seems to reduce the negative symptoms of schizophrenia. Following is more coverage of this new study, that was done in rats, but may be relevant to humans also, because in many important ways rat brains are similar to human brains:

System A glycine transport antagonism may underlie clozapine efficacy

    "Clozapine is an atypical antipsychotic with particular efficacy in schizophrenia, possibly related to potentiation of brain N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission," psychiatrists in the United States explained. "NMDARs are regulated in vivo by glycine, which is regulated in turn by glycine transporters."

    In this recently-published research report, D.C. Javitt and coauthors at New York University examined the "transport processes regulating glycine uptake into rat brain synaptosomes," and the "effects of clozapine on synaptosomal glycine transport."

    "Clozapine inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response (0.5-1 microg/mL)," test results revealed. "By contrast, other antipsychotics studied were ineffective."

These research discoveries indicated "first that System A transporters, or a subset thereof, may play a critical role in regulation of synaptic glycine levels and by extension of NMDA receptor regulation, and second that System A antagonism may contribute to the differential clinical efficacy of clozapine compared with other typical or atypical antipsychotics," the researchers concluded.

Source: Molecular Psychiatry - Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action. Mol Psychiatr, 2005;10(3):276-286).