Objective: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. Method: 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. Results: 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. Conclusions: 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.; Indications:40 patients with treatment-refractory schizophrenia or schizoaffective psychosis.; Patients:40 in- and outpatients. Leponex/RIS group n=20 (19 males, 1 female; mean age, 40.8 ± 6.9 years), Leponex/placebo (PL) group n=20 (16 males, 4 females; mean age, 39.9 ± 10.8 years). Duration of follow-up: 16 weeks.; TypeofStudy:Evaluation of the efficacy and safety of Leponex augmented with risperidone (RIS) in patients with schizophrenia refractory to Leponex monotherapy. Randomized, double-blind, placebo-controlled clinical study for risperidone, open study for Leponex.; DosageDuration:At baseline, mean monotherapy doses were 528.8 and 402.5 mg daily in the Leponex/RIS and Leponex/PL groups, respectively; 2 patients had received doses as high as 900 mg daily. Duration: 30-584 weeks (mean 396.9) as monotherapy and 12 weeks in combination with RIS.; Results:The initial Leponex dose was significantly higher and the initial SANS score somewhat lower, although not reaching significance, in the Leponex/RIS group than the Leponex/PL group. All patients completed 12 weeks of treatment in their randomly assigned group. Mean doses of RIS were 4.1 ± 1.4 mg daily at week 6 and 4.43 ± 1.5 mg daily at week 12. Only 8 patients received the maximum 6 mg daily dose of RIS and 2 of these experienced acute akathisia that required a dose reduction. By the end of the 12-week treatment period, a treatment response (20% or greater reduction in BPRS total score) was achieved by 7(35%) of the 20 patients in the Leponex/RIS group and by 2 (10%) of the 20 patients in the Leponex/PL group (p<0.01). The BPRS total scores decreased significantly from baseline to week 12 in both treatment groups (main effect for time: F=7.8, df=2, 76, p<0.0001), with a significant group-by-time interaction reflecting a greater score reduction with Leponex/RIS treatment (F=3.73, df=2, 76, p<0.04). Score reductions from baseline to week 6 were similar in the two groups but were greater with Leponex/RIS treatment from week 6 to week 12. To determine whether the initial baseline differences contributed to the between-group difference, an analysis of covariance was performed using the baseline BPRS total score as the covariate. With the effects of the baseline differences removed (main covariate between patients effect: F=258.8, df=1, 37, p<0.0001), the main effect of time was no longer significant (F=0.338, df= 2, 74, p>0.05). However, the between-group difference at endpoint remained significant. Scores on the BPRS positive symptom subscale decreased significantly from baseline to week 12 in both groups (main effect for time: F=8.3, df=2, 76, p<0.001), but the group-by-time interaction reflected a significantly greater score reduction with Leponex/RIS treatment than with Leponex/PL. Negative symptoms (SANS scores) decreased significantly from baseline to week 12 with Leponex/RIS treatment (main effect for time: F=4.46, df=2, 76, p<0.04), and the between-group difference was significant. In general, double-blind augmentation treatment was well tolerated. Both treatment groups had mean initial Simpson-Angus Rating Scale scores below 1.0, indicating minimal severity of movement disorders. The Simpson-Angus Rating Scale scores were lower with Leponex/RIS treatment throughout the trial, although they increased to approach those of Leponex/PL treatment by week 12. The frequency of other adverse events did not differ between groups. Plasma Leponex levels did not increase significantly during augmentation treatment, and no changes were observed in white blood cell counts. Absolute neutrophil counts were comparable in the two groups at baseline but were significantly higher with Leponex/RIS treatment at both treatment time points.; AdverseEffects:Unspecified number of patients experienced movement disorders, neutrophilia, weight gain, agranulocytosis, and seizures.; AuthorsConclusions: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.; FreeText:Mean disease duration was about 20 years in both groups. Patients had not responded to ≥2 and in some cases ≥6 different antipsychotic drugs. Nine patients had not responded to RIS. All patients had failed to show an adequate clinical response to an adequate trial of Leponex (≥3 months of ≥600 mg daily orally or a plasma level of ≥350 ng/ml). A 4-week baseline evaluation and Leponex run-in phase was followed by 12 weeks of placebo- controlled augmentation with RIS. To initiate the baseline observation period, all patients had to have remained on a stable dose of Leponex for at least 4 weeks. After the run-in period, patients were randomly assigned in a 1:1 ratio to augmentation with RIS or matching PL. RIS was started at 1 mg daily, with planned increases to 1 or 2 mg daily on day 4, to 2 to 3 mg daily on day 8, to 4 mg daily on day 21, and to 6 mg daily on day 22. At each weekly clinic visit, the treating psychiatrist could instruct the research fellow to either continue to increase the current dose of blinded study medication. Biweekly evaluations included the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Scale for the Assessment of Negative Symptoms (SANS). Movement disorders were assessed at 2-week intervals with the Simpson-Angus Rating Scale. A full biochemistry test panel, urinalysis, and hematologic studies were obtained before randomization and at the end of the study. Weekly safety and tolerability evaluations included white blood cell counts, temperature, blood pressure, heart rate, and respiration as well as subjective symptoms.
Incomplete or partial improvement of symptoms following treatment with clozapine is not infrequent in chronic schizophrenia. Commonly, patients are prescribed an additional antipsychotic medication, although there is little evidence from controlled studies of the efficacy of this practice. We performed a placebo controlled study of risperidone augmentation of partial response to clozapine in schizophrenia. Subjects were required to be treated with clozapine at a stable dose of 400 mg or more for at least 12 weeks prior to screening. Concurrent psychotropic medications were discontinued at least 2 weeks prior to study entry. At baseline (on clozapine), the total PANSS score was 97.1 (n=69), and following one week of placebo augmentation run-in the total PANSS score was 99.6. Subjects were randomized to continuation of clozapine+placebo, or to clozapine+risperidone 3.0 mg for 8 weeks. Clozapine doses were unchanged. The study completion rate was 94% (n=65). Using a last observation carried forward approach, the total PANSS score at the end of the double blind phase was 87.7- there were no statistically significant differences between the placebo- and the risperidone augmentation groups. According to a 20% decline in total PANSS score approach to categorize subjects as responders, the rates of response were 26% (n=9/35) in the placebo augmentation group, and 18% (6/34) in the risperidone augmentation group. Addition of the requirement of a CGI score of 3 or less to define treatment response resulted in a rate of 11% (4/35) in the placebo augmentation group, and 3% (1/34) in the risperidone augmentation group. Addition of risperidone to clozapine does not appear to offer significant advantages in reducing the symptoms of schizophrenia in patients with poor or incomplete response to clozapine alone. Supported by the Stanley Medical Research Institute.
BACKGROUND: Several open trials and case studies have reported beneficial effects following the addition of risperidone for partial responders to clozapine. The purpose of this study was to carry out a placebo-controlled, randomized, double-blind trial of the efficacy, safety, and tolerability of adjunctive treatment with risperidone in patients with schizophrenia partially responsive to clozapine. METHOD: In this 6-week double-blind study, 30 patients with DSM-IV schizophrenia who had partial response to clozapine despite being treated for a mean of 32 months were randomly assigned to risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale, the Clinical Global Impressions-Severity of Illness scale, the Global Assessment of Functioning scale, and the Quality of Life Scale. A variety of safety and tolerability measures were also obtained. Data were collected between November 2001 and July 2003. RESULTS: Significant improvement was noted in both groups on a variety of measures of psychopathology, but there was significantly greater improvement in the placebo-treated patients on the primary outcome measure, the PANSS positive symptom subscale. There were no significant differences between the treatment groups regarding extrapyramidal symptoms, weight gain, vital signs, serum clozapine levels, and QTc interval. The only side effect significantly more severe in risperidone-treated compared to placebo-treated patients was sedation. The patients treated with risperidone developed significant increases in plasma prolactin levels. CONCLUSION: Adjunctive risperidone treatment in schizophrenia patients partially responsive to clozapine does not significantly improve psychopathology or quality of life compared to placebo in a 6-week period. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
OBJECTIVE: Treatment options are very limited for individuals with schizophrenia resistant to clozapine. We tested the hypothesis that amisulpride augmentation would lead to an improvement in these patients. METHOD: This was an open non-randomized study. Thirty-three patients with sub-optimal response to clozapine were commenced on amisulpride in addition to clozapine. Clinical status was evaluated at baseline, 3 and 6 months using the Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Calgary Depression Scale, Calgary Anxiety Scale and various side effect rating scales. RESULTS: Twenty-eight subjects completed 6 months treatment on clozapine and amisulpride. There was a statistically significant improvement in the mean scores for PANSS, SANS and GAS at follow-up and no significant changes in side effect ratings. CONCLUSION: Co-administration of amisulpride, in a group of patients partially or non-responsive to clozapine, may lead to a substantial improvement in positive and negative symptoms, without worsening the side effect burden. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
BACKGROUND: The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved by atypical antipsychotics like clozapine and amisulpride. In patients whose symptomatology cannot be ameliorated by monotherapy, it might be necessary to combine two atypical antipsychotics. While clozapine interacts with a variety of neurotransmitter receptors, amisulpride predominantly binds with high affinity to D3/D2-dopamine receptors. Combination can be considered if a supplementary dopamine-receptor blockade is desired.
METHODS: We report on the therapy of 15 patients using a combination regimen of amisulpride and clozapine. Data were collected from patient records. The case reports document previous treatment attempts, describe the reason for the combination therapy, and determine its effect.
RESULTS: Major (six cases) or at least marked (eight cases) improvement of previously treatment-resistant positive and negative symptoms could be achieved by using a mean clozapine dose of 375 mg/day (serum level 0.38 mg/l) and an amisulpride dose of 527 mg/day. Additionally, by reducing the clozapine dose compared to monotherapy by 24 %, a significant reduction of side effects was observed.
CONCLUSIONS: The combination of amisulpride with clozapine considerably enriches the therapeutic arsenal in cases of severe schizophrenic psychoses. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.
Objective: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. Method: 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. Results: 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. Conclusions: 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.; Indications:40 patients with treatment-refractory schizophrenia or schizoaffective psychosis.; Patients:40 in- and outpatients. Leponex/RIS group n=20 (19 males, 1 female; mean age, 40.8 ± 6.9 years), Leponex/placebo (PL) group n=20 (16 males, 4 females; mean age, 39.9 ± 10.8 years). Duration of follow-up: 16 weeks.; TypeofStudy:Evaluation of the efficacy and safety of Leponex augmented with risperidone (RIS) in patients with schizophrenia refractory to Leponex monotherapy. Randomized, double-blind, placebo-controlled clinical study for risperidone, open study for Leponex.; DosageDuration:At baseline, mean monotherapy doses were 528.8 and 402.5 mg daily in the Leponex/RIS and Leponex/PL groups, respectively; 2 patients had received doses as high as 900 mg daily. Duration: 30-584 weeks (mean 396.9) as monotherapy and 12 weeks in combination with RIS.; Results:The initial Leponex dose was significantly higher and the initial SANS score somewhat lower, although not reaching significance, in the Leponex/RIS group than the Leponex/PL group. All patients completed 12 weeks of treatment in their randomly assigned group. Mean doses of RIS were 4.1 ± 1.4 mg daily at week 6 and 4.43 ± 1.5 mg daily at week 12. Only 8 patients received the maximum 6 mg daily dose of RIS and 2 of these experienced acute akathisia that required a dose reduction. By the end of the 12-week treatment period, a treatment response (20% or greater reduction in BPRS total score) was achieved by 7(35%) of the 20 patients in the Leponex/RIS group and by 2 (10%) of the 20 patients in the Leponex/PL group (p<0.01). The BPRS total scores decreased significantly from baseline to week 12 in both treatment groups (main effect for time: F=7.8, df=2, 76, p<0.0001), with a significant group-by-time interaction reflecting a greater score reduction with Leponex/RIS treatment (F=3.73, df=2, 76, p<0.04). Score reductions from baseline to week 6 were similar in the two groups but were greater with Leponex/RIS treatment from week 6 to week 12. To determine whether the initial baseline differences contributed to the between-group difference, an analysis of covariance was performed using the baseline BPRS total score as the covariate. With the effects of the baseline differences removed (main covariate between patients effect: F=258.8, df=1, 37, p<0.0001), the main effect of time was no longer significant (F=0.338, df= 2, 74, p>0.05). However, the between-group difference at endpoint remained significant. Scores on the BPRS positive symptom subscale decreased significantly from baseline to week 12 in both groups (main effect for time: F=8.3, df=2, 76, p<0.001), but the group-by-time interaction reflected a significantly greater score reduction with Leponex/RIS treatment than with Leponex/PL. Negative symptoms (SANS scores) decreased significantly from baseline to week 12 with Leponex/RIS treatment (main effect for time: F=4.46, df=2, 76, p<0.04), and the between-group difference was significant. In general, double-blind augmentation treatment was well tolerated. Both treatment groups had mean initial Simpson-Angus Rating Scale scores below 1.0, indicating minimal severity of movement disorders. The Simpson-Angus Rating Scale scores were lower with Leponex/RIS treatment throughout the trial, although they increased to approach those of Leponex/PL treatment by week 12. The frequency of other adverse events did not differ between groups. Plasma Leponex levels did not increase significantly during augmentation treatment, and no changes were observed in white blood cell counts. Absolute neutrophil counts were comparable in the two groups at baseline but were significantly higher with Leponex/RIS treatment at both treatment time points.; AdverseEffects:Unspecified number of patients experienced movement disorders, neutrophilia, weight gain, agranulocytosis, and seizures.; AuthorsConclusions: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.; FreeText:Mean disease duration was about 20 years in both groups. Patients had not responded to ≥2 and in some cases ≥6 different antipsychotic drugs. Nine patients had not responded to RIS. All patients had failed to show an adequate clinical response to an adequate trial of Leponex (≥3 months of ≥600 mg daily orally or a plasma level of ≥350 ng/ml). A 4-week baseline evaluation and Leponex run-in phase was followed by 12 weeks of placebo- controlled augmentation with RIS. To initiate the baseline observation period, all patients had to have remained on a stable dose of Leponex for at least 4 weeks. After the run-in period, patients were randomly assigned in a 1:1 ratio to augmentation with RIS or matching PL. RIS was started at 1 mg daily, with planned increases to 1 or 2 mg daily on day 4, to 2 to 3 mg daily on day 8, to 4 mg daily on day 21, and to 6 mg daily on day 22. At each weekly clinic visit, the treating psychiatrist could instruct the research fellow to either continue to increase the current dose of blinded study medication. Biweekly evaluations included the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Scale for the Assessment of Negative Symptoms (SANS). Movement disorders were assessed at 2-week intervals with the Simpson-Angus Rating Scale. A full biochemistry test panel, urinalysis, and hematologic studies were obtained before randomization and at the end of the study. Weekly safety and tolerability evaluations included white blood cell counts, temperature, blood pressure, heart rate, and respiration as well as subjective symptoms.
