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Clozapine: Mechanisms of its Unique Efficacy and Unusual Constellation of Side Effects

Clozapine (Clozaril) is the gold standard for treatment-resistant schizophrenia.

Its unique efficacy can not be explained by blocking D2 dopamine receptors, which is the purported principal mechanism of action of most other antipsychotics.

No other medication causes severe anticholinergic (constipation) and cholinergic (salivation) side effects.

clozapine antimuscarinic and muscarinic

In the U.S., clozapine is underappreciated and under-prescribed.

Clozapine Efficacy

  • Large protective effect on mortality with schizophrenia, decreasing all-cause death by 44% (mortality rate ratio = 0.56) compared to other antipsychotics (Vermeulen et al, 2019)

  • Risk of tardive dyskinesia is near zero

  • In strictly defined treatment-resistant schizophrenia, the anticipated response rate to antipsychotics other than clozapine is < 5%, compared to ~ 50% for clozapine (Meyer & Stahl, 2020).  

  • High-dose olanzapine is a distant #2 at ~7% response

  • The likelihood of responding to clozapine drops by ~10% with every failed antipsychotic trial (John AP et al, 2018). 

  • There is a critical treatment window of 2.8 years of meeting criteria for treatment resistance after which effectiveness of clozapine drops from 82% to 31% (Yoshimura et al, 2017). 

  • ~10% of individuals with schizophrenia treated with clozapine for ~1 year may be “super-responders” or “awakeners” (Stahl, 2024). Such patients may be well enough to be employed, live independently, and sustain long-term relationships. 

  • Some authors advocate clozapine as a treatment of “first resort” for schizophrenia rather than reserving it for treatment-resistant cases (Opler & Laitman, 2017).

  • Uniquely effective in schizophrenia patients with psychogenic polydipsia or impulsive aggression

  • Rates of discontinuation of clozapine is markedly lower than any other antipsychotic (Vanasse et al, 2016). 

  • Only 5% of U.S. patients who would benefit from clozapine are prescribed it (Olfson et al, 2016).

Cholinergic Effects

90% of patients taking clozapine experience sialorrhea (hypersalivation) due to muscarinic effect.

cholingeric / muscarinic mnemonics acetylcholine Stahl

Anticholinergic Effects

Clozapine can cause severe constipation because it highly anticholinergic.

Anticholinergic mnemonics

Clozapine Mechanisms

Anticholinergic effects are due to clozapine (parent drug) and cholinergic effects are caused by the active metabolite, norclozapine.

mechanism of clozapine and norclozapine stahl

Clozapine and Norclozapine Ballicules

Although the principal mechanism of clozapine is not fully understood, we know it is not D2 antagonism. All of the green binding pegs on these ballicules may be contributory. NMDA receptor agonism may be the most important single mechanism.

clozapine mechanism of action

norclozapine mechanism of action

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