The mechanism of action of Clozapine, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D<sub>2</sub>) and serotonin type 2 (5HT<sub>2</sub>) receptor antagonism. Atypical antipsychotic drugs such as clozapine have been proposed to block the 5HT2 and D2 receptors at therapeutic doses as evidenced by blockage in accelerating levels of growth hormone and cortisol secretion. The antipsychotic activity of clozapine is assumed to be the cause of D2 blockade while interacting with other receptors as well. With regards to mode of action in blocking dopaminergic receptors, clozapine exhibits higher affinity for D4 compared to the D2 receptor subtype. In addition, D1 antagonistic activity of clozapine enhances dopaminergic activity by increased extracellular brain dopamine concentrations specifically in the prefrontal cortex which is believed to explain its efficacy against negative symptoms generally observed in schizophrenia when using other drugs. Interestingly, clozapine has not been able to block arousal behavior which is the case when using other dopamine agonists after prolonged treatment.
Interaction of clozapine with the immune system has also been found important when using this drug. Neutrophil apoptosis otherwise known as agranulocytosis was detected after administration of clopazine alone and bioactived clozapine to nitrenium ion at supratherapeutic and therapeutic levels, respectively. At supratherapeutic concentrations, clozapine can be toxic due to the drug itself or its stable metabolite products. At therapeutic levels however, the chemically reactive nitrenium ion is believed to bound to cellular protein, deplete intracellular GSH, and lead to final polymorphonuclear (PMN) and mononuclear leukocyte cytotoxicity in vitro. Agranulocytosis induced by bioactived clozapine can be inhibited by using antioxidants and genistein. PMN apoptosis is believed to be achieved by decelerating the life span of circulating cells after clozapine administration.
Clozapine has also shown to interact with GABA receptors. Clozapine is able to induce release of glutamate and D-serine and decrease expression of glutamate transporters in astrocytic cell cultures with no neurons.