May 11, 2005

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).


Thanks for adding another proposed working mechanism of Clozapine to the list.

We should realize that protein-uptake from food plays an important role.
There GLYCINE has to compete with other proteins.
We should study the effects of different protein diets on schizophrenia. E.g. meat versus fish versus dairy vegetarian versus veganist diets.

This does fit in with your April special report:

Glycine Therapy - A New Direction for Schizophrenia Treatment?


"Special Consideration - Glycine Interaction with Clozapine

Oddly enough, some of the same studies above reported an exacerbation of negative symptoms in patients treated with d-cycloserine who were already taking clozapine. D-cycloserine is the only partial glycine-modulatory site agonist - d-serine and glycine are both full agonists. Interestingly, the full agonists did not show any effects (beneficial or detrimental ) in subjects taking clozapine. Coyle [2004] suggests that because clozapine somehow acts to alter the glycine modulatory site on NMDA receptors to allow full occupancy, full agonists such as glycin and d-serine do not provide any additional benefit. Moreover, a partial agonist like d-cycloserine, in the presence of already fully-occupied glycine-modulatory sites (due to clozapine action), would only serve to displace some of these occupied sites, thus explaining the worsening of negative symptoms."

from URL:


Posted by: freeZotic at May 17, 2005 10:11 AM

i realy wonder the drop of blood counts is realy a truth as compared to other sideffects like its effect on heart and recent memory.But it is the only atypical with significant resistance to relapse even when the patients are subjected to other environmental factors.

Posted by: captain johann at June 4, 2005 06:14 AM

From my experience clozapine
enhances my quality and duration of sleep.
I have taken it most of the last 10 years,
and meanwhile i feel like addicted to it
because trying to drop it does not work, especially
i do not sleep well and long enough.

Posted by: nicolas at November 13, 2005 09:12 AM

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