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.
    • "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.
    03/2012; 10(1):20-32. DOI:10.4103/0973-1229.91588
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    • "Some studies demonstrate the efficacy of ziprasidone in treatment-resistant or treatment-intolerant patients with schizophrenia. Recently, one head-to-head trial comparing the combination of clozapine with risperidone (CR) versus clozapine with ziprasidone (CZ), differed with a marked prolactin increase in the CR group and a statistically significant QTc elongation in the CZ group46,47 Many other studies and anecdotal reports also report coadministration of ziprasidone with clozapine. In some cases, ziprasidone has been added to clozapine in attempts to reduce metabolic side effects as well as to optimize antipsychotic efficacy. "
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    ABSTRACT: Since schizophrenia is considered one of the top ten causes of disease-related disability in the world, the development of second-generation (atypical) antipsychotics (SGAs) has increased the hopes of psychiatrists. SGAs, however, cannot be considered a unique pharmacological class since each SGA has many complex pharmacologic actions, only some of which are shared with other SGAs. Even though manyantipsychotics have similar efficacy on average, prescribers may be able to achieve better than average results by considering differences in selecting a specific drug for a specific patient. Clinicians know that each patient is unique. In order to achieve best outcomes for the individual patient, the better therapy is the therapy tailored for the single patient. With this article, we provide information on a relatively new antipsychotic ziprasidone released in 2001 by Pfizer for the treatment of schizophrenia. Compared with other first line atypical antipsychotics ziprasidone has a unique profile due to potent interaction with serotonergic receptors and lesser action upon α1 adrenergic, H1 and M1 antagonist activities. This paper describes the development of ziprasidone, its unique properties and its metabolically-friendly profile including its receptor binding affinities, pharmacokinetics, CNS activity results of clinical efficacy and relevant clinical trials. Safety, efficacy and patient preference are also examined. The available literature on ziprasidone of the last five years is reviewed.
    02/2011; 3:1-16. DOI:10.4137/JCNSD.S4138
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