Clozapine Augmented With Risperidone in the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial

Department of Psychiatry, Drexel University, Filadelfia, Pennsylvania, United States
American Journal of Psychiatry (Impact Factor: 12.3). 02/2005; 162(1):130-6. DOI: 10.1176/appi.ajp.162.1.130
Source: PubMed


The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.
In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale.
From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment.
In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.

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Available from: Richard C Josiassen
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    • "APP may increase the risk of adverse effects and the cost of treatment [3] [9], which may negatively impact QOL, but such assumptions were not demonstrated in this study. Possibly, the improved efficacy of APP compared to AMP [6] [7] [8] [37] partly offset the negative effects of severe adverse effects and the high treatment cost on QOL. Moreover, it is possible that SF-12 is not sensitive to detect more subtle changes of QOL. "
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    ABSTRACT: Objective: In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians, but their prescribing patterns have not been studied. This study examined the frequency as well as demographic and clinical correlates of antipsychotic polypharmacy (APP) and its impact on quality of life (QOL) in patients with schizophrenia treated in primary care in China. Method: A total of 623 community-dwelling patients from 18 randomly selected primary care services were interviewed. Patients' socio-demographic and clinical characteristics, including number of hospitalizations, antipsychotic drug-induced side effects, and QOL were recorded using a standardized protocol and data collection procedure. Results: The rate of APP prescription was 31% (193/623). Of the patients on APP, 89.6% received 2 antipsychotics, 10.4% received 3 or more antipsychotics. Clozapine (35.6%) was the most commonly prescribed second generation antipsychotic (SGA), while perphenazine (17.8%) was the most commonly prescribed first generation antipsychotic (FGA). Multiple logistic regression analyses revealed that patients on APP were more likely to receive SGAs and anticholinergics, had fewer hospitalizations, younger age of onset, and higher doses of antipsychotics. There were no significant differences between the two groups in any of the QOL domains. Conclusions: Approximately a third of Chinese patients with schizophrenia in primary care receive APP. Further examination of the rationale and appropriateness of APP and its alternatives is warranted.
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    • "A vizsgálatok egymásnak ellentmondó eredményekre jutottak. Egyes randomizált kontrollált vizsgálatokban (Freudenreich et al., 2007; Josiassen et al., 2005) előnyösebbnek találták a clozapinhoz adott risperidon hatását a clozapin+placebónál, más vizsgálatokban azonban (Anil Yagcioglu et al., 2005; Honer et al., 2006) nem tudtak különbséget kimutatni ugyanezen két terápia között. A vizsgálatokból készült metaanalízisben (Correll et al., 2009) a clozapint tartalmazó kombinált kezelések a hatékonyság hiányának a vizsgálatokban használt definíciói alapján szignifikánsan hatékonyabbnak mutatkoztak, mint a clozapint nem tartalmazó kombinációk. "
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    ABSTRACT: Main indication for antipsychotic medication is the treatment of schizophrenia and other psychotic disorders. Influential protocols in the treatment of schizophrenia recommend the use of antipsychotics in monotherapy. In case of therapy resistance, combination of antipsychotics is a feasible option. Applying antipsychotics in combination is common in clinical practice, although existing efficacy and safety data concerning antipsychotic combinations are scarce. Authors, after reviewing existing scientific data, make attempt to give recommendations for combined antipsychotic therapy in everyday clinical practice.
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    • "A number of small, open trials published in the last century were followed by double blind RCTs, which were inconclusive. While Freudenreich et al. (2007) and Josiassen et al. (2005) found advantages when adding risperidone to clozapine over a placebo control group in double blind RCTs (n=40 and n=24, respectively), these positive results could not be confirmed by another RCT (n=30) by Anil Yagcioglu et al. (2005) and Akdede et al. (2006). In the largest sample evaluated so far, Honer et al. (2006) compared the efficacy of clozapine combined with risperidone to clozapine plus placebo in 68 patients with schizophrenia who had previously failed to respond to clozapine monotherapy in an 8 wk double blind RCT. "
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    ABSTRACT: Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens.
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