A frequent treatment strategy for clozapine-resistant patients with schizophrenia is the use of specific augmentors that are suitable for adjunctive therapy. Clozapine is a polyvalent drug but it lacks high-potency dopamine receptor blockade (Kerwin & Osborne, 2000). Therefore, there has been interest in using as augmentors substituted benzamides with highly selective dopamine receptor blocking profiles (Kerwin, 2000). Augmentation strategies incorporating sulpiride are well documented. The authors of one study of sulpiride augmentation in 28 patients partially responsive to clozapine (Shiloh et al, 1997) noted a mean reduction of about 40–50% in various clinical response scores (Brief Psychiatric Rating Scale and Scale for the Assessment of Positive Symptoms).
Several groups have been interested in mimicking this study with amisulpride, a relative of sulpiride that is even more selective at the dopamine D2 receptor. A case series by Zink et al(2004) showed improvement in previously treatment-resistant symptoms following a combined treatment strategy of clozapine and amisulpride. In addition, our group performed an open trial of amisulpride augmentation in a long-term (52 weeks) study. Significant improvement was observed in half of the patients, with no additional side-effects. Moreover, this study monitored plasma levels to determine whether this was a pharmacokinetic interaction. Clozapine levels did not change throughout the duration of the trial, suggesting a pharmacodynamic interaction (Munro et al, 2004).
Augmentation with anti-epileptics
A glutamate hyperfunction hypothesis of schizophrenia has generated interest in the role of glutamate release inhibitors as clozapine augmentors. In a study of 26 treatment-resistant patients receiving lamotrigine (17) or topirimate (9) in addition to their existing antipsychotic treatment (a variety of antipsychotics), a significant improvement was observed when lamotrigine was added to risperidone, haloperidol, olanzapine or flupenthixol. However, no significant effect was observed in patients receiving topirimate augmentation in addition to clozapine, olanzapine, haloperidol or flupenthixol (Dursun & Deakin, 2001). The therapeutic effects of lamotrigine augmentation were also assessed in a rigorous randomised placebo-controlled cross-over study of 34 clozapine-resistant patients (Tiihonen et al, 2003). In this 14-week study, lamotrigine treatment significantly improved positive symptoms and general psychopathological symptoms, but had no effect on negative symptoms. The authors suggested that this was the first time a non-dopamine antagonist had proven efficacy in schizophrenia, giving further credence to the hyperglutamate neurotransmission hypothesis for the generation of positive symptoms in the disorder.
Management of clozapine-resistant schizophrenia
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