Mechanism of Action
Clozapine is classified as an atypical antipsychotic drug because its profile of binding to serotonergic as well as dopamine receptors; its effects on various dopamine mediated behaviors also differ from those exhibited by more typical antipsychotics. In particular, clozapine interferes to a lower extent with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, but it does not induce catalepsy nor inhibit apomorphine-induced stereotypy in animal models as is seen with 'conventional' neuroleptics. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom from extrapyramidal side effects together with strong anticholinergic activity.
Several metabolites of clozapine exhibit binding profiles similar to the original molecule. N-Desmethylclozapine may contribute significantly to the atypical effects of treatment by acting as an agonist and/or partial agonist at D2, D3, δ-opioid, M1, M2, M3, M4, M5 receptors, and an antagonist/inverse agonist at 5-HT2A and 5-HT2C receptors.
Clozapine is also a partial agonist at the 5-HT1A receptor, putatively improving depression, anxiety, and the negative cognitive symptoms.
Clozapine also is a strong antagonist at different subtypes of adrenergic, cholinergic and histaminergic receptors, the last two being predominantly responsible for its side effect profile.
A direct interaction of clozapine with the GABAB receptor has been shown. GABAB receptor deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
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