Horrobin, D.F.; Glen, A.I.M.; Cantrill, R.C.
Clozapine : elevation of membrane unsaturated lipid levels as a new mechanism of action
Biol Psychiatry (World Congress of Biological Psychiatry, Nice, June 1997) 1997; 42(1 Supp1): 161S.


The mechanism of action of clozapine remains uncertain. New antipsychiatric drugs developed on the basis of the receptor-blocking profile of clozapine behave more like haloperidol without side effects than like clozapine itself. We have explored other possible mechanisms. Some schizophrenics, especially those with the deficit syndrome, have low levels of the highly unsaturated lipids, arachidonic acid (AA) and docosahexaeonic acid (DHA) in red cell membranes. Such low levels are likely to modify the function of receptors associated with membranes. We therefore measured red cell AA and DHA in eight schizophrenic individuals before starting clozapine and after 8-16 weeks on the drug. In every individual AA and DHA levels rose substantially (p < 0.01 for both). There are several possible mechanisms for this effect. One is an antioxidant action. In red cells subjected to hydrogen peroxide which destroys AA and DHA by oxidation, clozapine protected the AA and DHA in a dose-related manner. We conclude that maintenance of normal membrane lipid composition may be an important action of clozapine.

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