Long-Term Efficacy and Tolerability of Clozapine Combined with Ziprasidone or Risperidone

Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, University of Heidelberg, Mannheim, Germany.
Pharmacopsychiatry (Impact Factor: 1.85). 08/2010; 43(6):216-20. DOI: 10.1055/s-0030-1254089
Source: PubMed


Treatment resistance in schizophrenia often leads to add-on of atypical antipsychotics to clozapine.
In a randomized trial, we recently obtained evidence for comparable efficacy and differential side effects of clozapine in combination with ziprasidone (CZ, N=12) versus risperidone (CR, N=12). Here, we present the open-label, long-term evaluations of these patients after 26 and 52 weeks.
Sustained improvements of psychopathology as assessed by PANSS (positive and negative syndrome scale), SANS (scale for the assessment of negative symptoms), and HAMD (Hamilton depression scale) were documented in both subsamples being treated according to protocol, while dropouts reduced the study sample after 26 (CZ: reduced by -4; CR: -2) and 52 weeks (CZ: -0; CR: -5). We observed a slight increase of akathisia in the CZ group whereas general clozapine-associated side effects improved.
The combinations of clozapine with ziprasidone or risperidone exhibit long-term efficacy, but the level of evidence is limited. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary.

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Available from: Mathias Zink, Nov 14, 2014
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    • "An additional two studies compared ziprasidone and risperidone as augmentation strategies. Both agents were shown to have comparable clinical efficacy but, different side effects (Zink et al., 2009; Kuwilsky et al., 2010). Patients with risperidone were more prone to hyperprolactinemia, extrapyramidal symptoms, and weight gain. "
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    ABSTRACT: A significant proportion of patients with schizophrenia that receive clozapine remain desensitized with only a partial response. In this group of patients, the outcomes regarding the addition of various psychotropics in combination with clozapine treatment for augmentation are controversial. In this review, literature regarding the efficacy and safety of adjunctive agents in clozapine resistant schizophrenic patients is examined. Augmentation agents added to clozapine in treatment resistant schizophrenic patients consist of antipsychotics, antidepressants, mood stabilizers, other agents (eg. omega-3 fatty acids and glutamatergic agents), and electroconvulsive therapy (ECT) are highlighted in this review. The number of controlled studies evaluating augmentation of clozapine in schizophrenia patients is highest for risperidone and lamotrigine add-on treatments. However, the results of recent meta-analyses studies do not support any benefit of either agent combined with clozapine treatment. Some evidence regarding the success of clozapine augmentation with amisulpride, aripiprazole, mirtazapine, omega-3 fatty acids, and ECT have been obtained and ultimately needs further clinical investigation. Current findings from relevant clinical investigations have determined that these studies have limitations consisting of small sample size, variable definitions of clozapine resistance, heterogeneity of outcome measures, and methodological designs. In addition, sufficient evidence does not yet exist regarding the success of various adjunctive treatments for clozapine resistant patients.
    Full-text · Article · Jan 2014
    • "Also ziprasidone has been successfully added to clozapine in numerous case reports and open trials. A head-to-head comparison of ziprasidone or risperidone combined with clozapine revealed similar immediate and long-term efficacy on treatment-resistant schizophrenic symptoms at a diverging range of side effects regarding serum prolactin, extrapyramidal symptoms, and QTc-prolongation (Kuwilsky et al., 2010[16]; Zink et al., 2009[35]). "
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    ABSTRACT: Treatment-resistant symptoms complicate the clinical course of schizophrenia, and a large proportion of patients do not reach functional recovery. In consequence, polypharmacy is frequently used in treatment-refractory cases, addressing psychotic positive, negative and cognitive symptoms, treatment-emergent side effects caused by antipsychotics and comorbid depressive or obsessive-compulsive symptoms. To a large extent, such strategies are not covered by pharmacological guidelines which strongly suggest antipsychotic monotherapy. Add-on strategies comprise combinations of several antipsychotic agents and augmentations with mood stabilizers; moreover, antidepressants and experimental substances are applied. Based on the accumulated evidence of clinical trials and meta-analyses, combinations of clozapine with certain second-generation antipsychotic agents and the augmentation of antipsychotics with antidepressants seem recommendable, while the augmentation with mood stabilizers cannot be considered superior to placebo. Forthcoming investigations will have to focus on innovative pharmacological agents, the clinical spectrum of cognitive deficits and the implementation of cognitive behavioral therapy.
    No preview · Article · Mar 2012
    • "Anyway, clinical features of studies included in the meta-analysis were not heterogeneous. Two studies compared risperidone and ziprasidone as augmentation strategies (Kuwilsky et al., 2010; Zink et al., 2009). Both agents showed comparable clinical efficacy but different side effect profiles: patients during treatment with risperidone were more prone to hyperprolactinemia, extrapyramidal symptoms and weight gain. "
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    ABSTRACT: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy. Objectives: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis. A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5). 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.
    No preview · Article · Sep 2011 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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