Clozapine interactions

Therefore, we believe that this alone is not a sufficient definition for atypicality. We prefer to define atypical antipsychotics as those that are less prone to causing EPS because they work differently than the typical antipsychotics. This, of course, raises the question of just how these medications work. Using clozapine as the starting point to answer this question has proved difficult. Why The problem is that clozapine interacts with so many different types of nerve cell receptors that it becomes hard to tell which of these actions makes the difference. 

Michal P, Lysikova M, El-Fakahany EE, Tucek S. 1999. Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors. Eur J Pharmacol 376 119-125. 

Chong S-A, Remington G. Re Sertraline-clozapine interaction. CanJPsyclnatry (1998) 43, 856-7. 

Antonini M, Ghisellini P, Pastorino L, Paternolli C, Nicolini C (2003) Preliminary electrochemical characterisation of cytochrome P4501A2-clozapine interaction. lEE Proc Nanobiotechnol 150 31-34... 

Similar interactions as clozapine may need to increase the usual olanzapine dose when a patient begins to smoke, or decrease olanzapine dose if smoking is stopped or nicotine replacement is used instead of smoking. 

These differences may become particularly germane if co-prescribing with some antipsychotics is undertaken. For example, in certain individuals, combinations of clozapine with benzodiazepines may lead to unexpected adverse events, including delirium and augmented respiratory depression (Jackson, Markowitz Brewer-ton, 1995 Grohmann et al, 1989). Presumably if there are additive or synergistic effects of ethnicity on clearance of one or both substances, adverse events may be enhanced. Similar interactions are theoretically possible with olanzapine, as adverse interactions have been described between olanzapine and benzodiazepines, at least in the elderly (Kryzhanovskaya etal, 2006). 

Eerslew KE, Hagardom AN, Harlan GC, McCormick WE. 1998. A fatal drug interaction between clozapine and fluoxetine. J Forensic Sci 43 1082. 

Drug interactions Diuretics" NSAIDs (e.g., ibuprofen)" Lamotrigine Clozapine" Contraceptives HIV protease inhibitors" ... 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Hypersensitivity to the drug or any other component of the product (cross-sensitivity between phenothiazines may occur) comatose or greatly depressed states caused by CNS depressants or from any other cause (phenothiazines, clozapine, loxapine, molindone, pimozide, haloperidol) coadministration with other drugs that prolong the QT interval and in patients with congenital long QT syndrome or history of cardiac arrhythmias (mesoridazine, thioridazine, pimozide, ziprasidone see Drug..Interactions). 

Drugs that may interact with clozapine include caffeine, SSRIs, benzodiazepines, risperidone, CYP1A2 induces/inhibitors, CYP3A4 inhibitors, phenobarbital, and ritonavir. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

Among the reports on overlapping or combining clozapine and risperidone, some pharmacokinetic interactions have been reported ( 100, 103,104 and 105). 

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