Olanzapine and clozapine

Cholestatic hepatitis has been reported with risperidone, and liver function test abnormalities (mostly transient) have been reported with olanzapine and clozapine. 

Risperidone, 9-OH-risperidone, olanzapine, and clozapine maintained a higher potency for occupying 5-HT 2 than D2 receptors. 

In 1996, Pilowsky and coworkers (111) found that olanzapine-treated patients showed significantly lower occupancy of striatal D 2 receptors compared with neuroleptic-treated patients. In support of the clinical trial data, PET studies have shown that 5-HT 2 and D2 receptor occupancies with olanzapine and clozapine are comparable, and that olanzapine should have a low propensity to evoke acute EPS (112). 

Varying degrees with all antipsychotics except olanzapine and clozapine. Most marked with sulpiride... 

Recall that one of the key drug-metabolizing enzymes is the cytochrome P450 (CYP450) enzyme called 1A2. Two atypical antipsychotic drugs are substrates of 1A2, namely olanzapine and clozapine. That means that when they are given con-... 

On the other hand, when an inducer of 1A2 is given concomitantly with either of the two antipsychotic substrates of 1A2, the level of the antipsychotic may fall. This happens when a patient begins to smoke, because smoking induces 1A2, and this would cause levels of olanzapine and clozapine to fall (Fig. 11—45). Theoretically this might cause patients stabilized on an antipsychotic dose to relapse if the levels fell too low. Also, cigarette smokers may require higher doses of these atypical antipsychotics than nonsmokers. 

FIGURE 11-44. Clozapine and olanzapine are substrates for cytochrome P450 1A2 (CYP450 1A2). When these drugs are given with an inhibitor of this enzyme, such as the antidepressant fluvoxamine, plasma levels of olanzapine and clozapine can rise. 

FIGURE 11—48. Several antidepressants are inhibitors of CYP450 2D6 and could theoretically raise the levels of 2D6 substrates such as risperidone, olanzapine, and clozapine. However, this is not usually clinically significant. 

Hyperlipidemia associated with antipsychotic drugs has been reviewed (SEDA-29, 64). Haloperidol and the atypical antipsychotic drugs ziprasidone, risperidone, and aripiprazole would be associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine would be associated with higher risks. However, severe clozapine-induced hypercholesterolemia and hypertriglyceridemia has been reported in a patient taking clozapine (55). 

Cyt 2D6 metabolizes haloperidol, risperidone, thioridazine, sertindole, olanzapine and clozapine common substrates - fluoxetine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, propranolol, metoprolol, timolol, codeine, encainide, flecanide. Common inhibitors - paroxetine, sertraline, fluoxetine. 

As well as their effects on the brain, neuroleptics commonly produce other potentially lethal effects. They are all toxic to the heart, inducing conduction defects and arrhythmias. Olanzapine and clozapine also interfere with normal metabolism, causing what is known as metabolic syndrome. This syndrome has only recently been described and is defined as the occurrence of obesity, diabetes, hypertension and dyslipidaemia6 (Shirzadi Ghaemi 2006). The underlying cause of the syndrome is thought to be resistance to insulin. All these effects... 

The benefits of the atypical neuroleptic drugs in patients with bipolar disorder and the possibility that risperidone, quetiapine, olanzapine, and clozapine cause... 

Fluvoxamine increases clozapine plasma concentrations (SEDA-27, 58). and the differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine have been studied in healthy volunteers (256). Fluvoxamine significantly reduced the N-des-methylclozapine to clozapine ratio, implying reduced metabolism of clozapine. 

Bar KJ, Hager F, Sauer H. Olanzapine and clozapine induced stuttering. Pharmacopsychiatry 2004 37 131-4. 

Olanzapine and clozapine have been compared in a double-blind study by Lilly Research Laboratories for 18 weeks in 220 patients with schizophrenia conclusions were based on the one-sided lower 95% confidence limit of the treatment effect observed from the primary efficacy... 

Plasma concentrations of olanzapine and clozapine are lower in smokers than in non-smokers, mainly because of induction of CYP1A2. Two patients who smoked tobacco... 

The future of psychopharmacotherapy may include creative dietary or other pharmacological manipulations of the CYP enzyme system to achieve a positive treatment response. Recently, it was demonstrated that levels of cyclosporine (an expensive immunosuppressive agent) were dramatically increased in patients who were concomitantly administered grapefruit juice (Hollander et al. 1995). In other studies, paroxetine and fluoxetine were used to raise desipramine levels in superextensive me-tabolizers who were nonresponsive to standard doses (Kraus et al. 1996). Also, the authors used fluvoxamine to augment olanzapine and clozapine concentrations when a lack of response was obtained at standard or upper-level doses. Because per-pill costs of many of today s newer-generation psychoactive compounds often prove prohibitive, use of dietary and pharmacological CYP inhibitors could have significant pharmacoeconomic implications. 

Wang C-Y, Zhang Z-J, Li W-B, Zhai Y-M, Cai Z-J, Weng Y-Z, Zhu R-H, Zhao J-P, Zhou H-H. The differential effects of steady-state fluvoxamine ontiie pharmacokinetics of olanzapine and clozapine in healthy volunteers. J Clin Pharmacol (2004) 44,785-92. 

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