Clozapine – Mechanism of Action and Non D2 Receptor Actions

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Clozapine has a mechanism of action that is unique to other second generation antipsychotics. (SGAs)


Clozapine mechanism of action

  • Clozapine is a dopamine and serotonin antagonist (5HT2A) with a few unique differences compared to other SGAs.
  • Clozapine has a high dissociation constant for D2, which is even higher than that of dopamine itself.
  • Clozapine has much higher antagonistic activity on cortical and limbic dopamine D4 than D2 receptors.
  • It also antagonizes 5HT2 serotonergic receptor subtypes (5HT2A & 5HT2C) and adrenergic (α1), histamine (H1), and muscarinic receptors (M1).
  • Clozapine is considered a potent inverse agonist at the 5-HT2AR similar to pimavanserin which is a atypical antipsychotic with predominant 5-HT2A antagonist or inverse agonist effects which has received FDA approval in 2016 for hallucinations and delusions associated with Parkinson’s disease. [Stępnicki et al, 2018]
  • Clozapine has 5HT1A partial agonist activity which increases DA in PFC which is thought to have a beneficial effect in terms of reducing negative and cognitive symptoms.
  • The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy rates is unique to Clozapine and may explain its lower propensity for Extrapyramidal side effects.
  • Clozapine is hypothesised to have some anti-inflammatory properties as demonstrated in rats exposed to an inflammatory challenge, with response measured through activated microglia. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. [Ribeiro B et al.,2013 ]
  • Clozapine and its two major metabolites, clozapine-N-oxide (CNO) and N-desmethylclozapine (NDC) exhibit neuroprotective and anti-inflammatory properties. [Regen F et al., 2020]
  • Endogenous retinoid acid (RA) signalling is involved in the pathophysiology of schizophrenia. Patients with schizophrenia have lower levels of all-trans RA; at-RA (The biologically most active metabolite of vitamin A). Clozapine and its metabolites potently inhibit RA catabolism thus increasing levels of at-RA. [Regen F et al., 2020]
  • Clozapine is also postulated to increase the GABAergic neuroactive steroid (NS) allopregnanolone which has anxiolytic and antidepressant properties.[Marx C et al., 2006]; [Zorumski C et al., 2013]


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