Risperidone Versus Clozapine in Treatment-Resistant Chronic Schizophrenia: A Randomized Double-Blind Study

University of Strasbourg, Strasburg, Alsace, France
American Journal of Psychiatry (Impact Factor: 12.3). 05/1998; 155(4):499-504. DOI: 10.1176/ajp.155.4.499
Source: PubMed


The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients.
In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales.
Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness.
Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

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    • "Resistance to pharmacotherapy in schizophrenia patients is a common and important clinical problem. Definitions of treatment resistance can differ significantly: in the kind of ineffective antipsychotics (APs), duration of treatment, psychopathological symptoms and the psycho-social functioning of the patient (Brenner et al., 1990; Bondolfi et al., 1998; Peuskens, 1999). According to NICE (National Institute for Health and Clinical Excellence) treatmentresistant schizophrenia has been defined as failure of improvement of the target symptoms despite an adequate trial of medication for 6–8 weeks with adequate dosing of at least two groups of APs (NICE, 2003). "
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    ABSTRACT: An analysis of literature shows that there is still little evidence concerning the efficacy of electroconvulsive therapy (ECT) combined with antipsychotic therapy in a group of treatment-resistant schizophrenia patients. More precisely, its influence on cognitive functions is still equivocal. The aim of this study was to assess the influence of ECT combined with antipsychotic therapy on working memory, attention, and executive functions in a group of treatment-refractory schizophrenia patients. Twenty-seven patients completed the study: 14 men and 13 women, aged 21 to 55 years (mean age, 32.8 years), diagnosed with treatment-resistant schizophrenia. Each patient underwent a course of ECT sessions and was treated with antipsychotic medications. Before the ECT and within 3 days after the last ECT session, the participants were assessed with the following neuropsychological tests: Trail Making Test (TMT) and Wisconsin Cart Sorting Test (WCST). There were no significant differences in the TMT and WCST results after combined ECT and antipsychotic therapy in treatment-refractory schizophrenia patients. According to the results of the neuropsychological tests, there was no decline in attention, executive functions, or working memory. The current study shows no significant difference in attention, working memory, or executive functions after treatment with a combination of electroconvulsive and antipsychotic therapy. This suggests that combined electroconvulsive therapy may not have a negative influence on the neuropsychological functioning of patients with treatment resistant schizophrenia.
    No preview · Article · Feb 2015 · Journal of Nervous & Mental Disease
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    • "Treatment resistance to neuroleptic agents is more frequent in male than female, patients with poorer premorbid functioning, and earlier age of onset (Meltzer, 1997). After the robust evidence of the superiority in efficacy of clozapine over other antipsychotics (Kane et al., 1988; Wahlbeck et al., 1999; Chakos et al., 2001; Iqbal et al., 2003), there was a recent trend to move to broader definitions of treatment resistance so that more patients are offered treatment with clozapine (Bondolfi et al., 1998; Pantelis and Lambert, 2003; The British Psychological Society and The Royal College of Psychiatrists, 2010). In fact, clozapine appears to have a positive effect even in symptoms traditionally considered resistant, such as negative symptoms and cognitive disturbances, particularly in domains of attention, verbal fluency and executive functions (Meltzer and McGurk, 1999). "
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    ABSTRACT: Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better understanding of its biological underlying processes could improve treatment. The aim of this study was to compare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patients and healthy controls (HC). Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ individuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface modelling (implemented in freesurfer package) to identify group differences in cortical thickness. Statistical significant differences were identified using Monte-Carlo simulation method with a corrected p-cluster<0.01. Results: Patients in the TR-SCZ group showed a widespread reduction in cortical thickness in frontal, parietal, temporal and occipital regions bilaterally. NR-SCZ group had reduced cortex in two regions (left superior frontal cortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorsolateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group. Conclusions: The reduction in cortical thickness in DLPFC indicates a more severe form of the disease or a specific finding for this group. Alterations in this region should be explored as a putative marker for treatment resistance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is diagnosed, are needed to clarify these hypotheses.
    Full-text · Article · May 2013 · Schizophrenia Research
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    • "This open-label, non-randomised study involved 30 outpatients with treatment-resistant schizophrenia: 14 males and 16 females aged at least 18 years. The diagnosis of schizophrenia was based on the DSM-IV TR criteria (American Psychiatric Association, 2000), and treatment resistance was defined as a failure to respond or the presence of intolerance to at least two neuroleptic agents belonging to two different chemical classes given at appropriate doses (equivalent to at least 500 mg/day of chlorpromazine) for at least 4 weeks each within the previous 5 years (Bondolfi et al. 1998). The study included patients requiring a change in their current antipsychotic therapy for any reason (e.g. "
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    ABSTRACT: It is still common to encounter a partial or no response to antipsychotic treatment in clinical practice, but only individual case reports are currently available concerning the efficacy of long-acting risperidone (RLAI) in treatment-resistant schizophrenia. The relationship between RSP and 9-OH-RSP plasma levels, and clinical response or tolerability has not yet been thoroughly assessed. This open-label, non-randomised study involved 30 outpatients with treatment-resistant schizophrenia, who were prescribed RLAI for 6 months, and clinically evaluated using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression-Improvement Scale (CGI-I), and the Simpson and Angus Scale for Extrapyramidal Side Effects (EPSE). Plasma RSP and 9-OH-RSP levels were determined at steady-state, and the metabolic ratio (MR) was calculated as plasma 9-OH-RSP/RSP levels. At the end of the study, 60% of the patients responded to RLAI (a >or=20% reduction in the PANSS score). Linear regression analysis showed a significant positive relationship between the RSP dose and active moiety (RSP + 9-OH-RSP) (r = 0.4; p = 0.02). There was a significant positive relationship between active moiety and EPSE scores (r = 0.6; p = 0.00). The BPRS responders had a significantly higher mean MR than the non-responders (3.41 +/- 1.87 SD vs 1.60 +/- 0.98 SD) (p = 0.00). Therapeutic drug monitoring seems to be useful in optimising the dose of RLAI, especially in the case of tolerability problems. MR might be a better index of clinical response to RLAI than the value of the active moiety, although this needs to be confirmed by further data.
    Full-text · Article · Jul 2010 · Psychopharmacology
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