From the Guidelines
Clozapine (Clozaril) is an atypical antipsychotic medication that works by blocking multiple neurotransmitter receptors in the brain, particularly dopamine D2 and serotonin 5-HT2A receptors, with a unique binding profile that distinguishes it from other antipsychotics. It was FDA approved in 1989 for treatment-resistant schizophrenia and for reducing suicidal behavior in schizophrenia patients. Clozapine is classified as a dibenzodiazepine-derived atypical (second-generation) antipsychotic. Regarding CYP450 interactions, clozapine is primarily metabolized by CYP1A2, with additional metabolism by CYP3A4 and CYP2D6, making it susceptible to drug interactions with inhibitors or inducers of these enzymes, as noted in studies such as 1. For example, cigarette smoking (which induces CYP1A2) can lower clozapine levels, while fluvoxamine (a CYP1A2 inhibitor) can significantly increase clozapine concentrations. The most common side effects include:
- Sedation
- Hypersalivation
- Constipation
- Weight gain
- Orthostatic hypotension However, its most serious adverse effect is agranulocytosis (severe reduction in white blood cells), which necessitates regular blood monitoring through the clozapine REMS program, as highlighted in 1. Given the potential for serious side effects, the use of clozapine should be carefully considered and monitored, particularly in patients with a history of blood disorders or those taking medications that may interact with clozapine, as discussed in 1. Additionally, patients should be closely monitored for signs of agranulocytosis, and the medication should be discontinued immediately if symptoms occur, as emphasized in 1. Overall, while clozapine can be an effective treatment for treatment-resistant schizophrenia, its use requires careful consideration of the potential risks and benefits, as well as close monitoring for side effects, as noted in 1.
From the FDA Drug Label
The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] 1, 4 diazepine Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePTTM Study (≥10% in the Clozapine or olanzapine group) Adverse Reactions Clozapine N=479 % Reporting Salivary hypersecretion 48 Somnolence 46 Weight increased 31
- How it works: The mechanism of action of clozapine is unknown, but it is proposed to be mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors.
- FDA approved: Not explicitly stated in the provided text.
- Classification: Clozapine is an atypical antipsychotic drug, a tricyclic dibenzodiazepine derivative.
- CYP450 Interactions: Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.
- Most common side effects:
From the Research
How Clozapine Works
- Clozapine is a dibenzazepine compound that has a distinct pharmacologic profile, with a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity 3.
- It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors 3.
- Clozapine's unique pharmacological profile is thought to contribute to its effectiveness in treating a range of neuropsychiatric disorders, including treatment-resistant schizophrenia and schizoaffective disorder 4.
FDA Approval and Classification
- Clozapine is an atypical antipsychotic drug that was approved by the FDA for the treatment of schizophrenia 5.
- It is classified as a dibenazepine class of antipsychotic drugs, which is distinct from typical antipsychotic drugs such as haloperidol and chlorpromazine 5.
CYP450 Interactions
- There is no direct information on CYP450 interactions in the provided studies, however, it is known that clozapine is metabolized by the liver and may interact with other medications that affect the CYP450 enzyme system.