Clozapine-olanzapine: a potentially dangerous switch. A report of two cases.

BACKGROUND: Withdrawal symptoms associated with switch between two typical antipsychotics are generally rare and mild. In contrast, switching from clozapine to risperidone can be lead to severe withdrawal symptoms. Different pathophysiologic aetiologies have been suggested for explaining these severe symptoms, including cholinergic supersensitivity and rebound. Theoretically, the switch from clozapine to olanzapine should not lead to any problems because those two agents have the same affinity in vitro for muscarinic receptors. OBJECTIVE: This study reports two cases of switches from clozapine to olanzapine, in refractory schizophrenic patients, which were associated with severe withdrawal symptoms. RESULTS: After the switch, the two patients developed diaphoresis, hypersialorrhea, bronchial obstruction, agitation, anxiety and enuresis. The symptoms were treated with anticholinergic medication and by an increase in dose of olanzapine to 20 mg/day. For one of the patients this treatment led to normalization of secretion. For the other patient, a superinfection leading to a bilateral pneumopathy which required emergency hospitalization in a general hospital was observed. CONCLUSION: The symptomatology and the response to treatment lead to the hypothesis of a muscarinic from abrupt weaning. The withdrawal symptoms disappeared rapidly with an increase in olanzapine dosage and with anticholinergic started at the beginning of the switch. We recommend slow clozapine weaning over 3 weeks or more with concurrent anticholinergic treatment.

Comparative oxidation of loxapine and clozapine by human neutrophils.

The clozapine-induced agranulocytosis could be due to the formation of a reactive intermediate formed in polymorphonuclear neutrophils and granulocyte precursors with the myeloperoxidase-hydrogen peroxide system. On the contrary, no case of agranulocytosis has been described for loxapine, an other neuroleptic drug with a very close structural analogy. We have compared the clozapine and loxapine interaction with the oxidative burst and particularly with this enzymatic complex. On the one hand, the assay of the oxidative species demonstrated a different impact for the two neuroleptics. The 50% inhibitory concentration was 92 microM for hydrogen peroxide and 40 microM for hypochlorous acid for loxapine. The loxapine target is located before the myeloperoxidase-hydrogen peroxide system in the oxidative stream, whereas clozapine diverts the chlorination pathway of the enzyme. On the other hand, the in vitro metabolism of drugs by the myeloperoxidase-hydrogen peroxide system has been investigated by mass spectrometry. Loxapine remains inert but clozapine undergoes the oxidation. The glutathione or ascorbate addition in the medium leads to a removal of the oxidation. Glutathione is able to trap the toxic intermediate and could avoid its formation.