The present 16-week double-blind, randomized, placebo-controlled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms (Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale "Negative" (P = 0.006, mean change [SD] in active group vs placebo, -2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and "General Psychopathology" (P = 0.009, mean change [SD] in active group vs placebo, -5.3 [3.8] vs -0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P < 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs -0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within-group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002). Ziprasidone added to clozapine was effective on negative and cognitive symptoms, although it may be proposed as a helpful treatment in schizophrenia, mainly for those patients who partially respond to clozapine monotherapy.
<b>INTRODUCTION: </b>A substantial number of patients with treatment-resistant schizophrenia respond only partially to clozapine. Therefore, it has been common practice to use augmentation strategies to maximize clozapine's effect. But the efficacy of this strategy remains poorly established. We have conducted a randomized double-blind placebo controlled clinical trial in patients with schizophrenia currently receiving clozapine with partial response, and tested the efficacy of pimozide augmentation on positive and negative symptoms and also on neurocognitive measures.<b>METHODS: </b>Thirty-two outpatients enrolled in the clinical trial and 28 completed. Patients with adequate blood levels of clozapine were randomized to pimozide vs placebo and participated in the trial for 12 weeks receiving monthly assessments for Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS), and weekly assessments for electrocardiogram (EKG), and side effects. Neurocognitive tests measuring verbal fluency, working memory, motor and attention/executive function were obtained at study entry and end of the trial.<b>RESULTS: </b>We found no significant effect of pimozide on BPRS total, psychosis and depression subscale items, SANS scores or QTc interval. Neurocognitive measures did not show significant improvement either.<b>DISCUSSION: </b>In this well controlled clinical trial of patients with treatment-resistant schizophrenia currently receiving clozapine, pimozide augmentation was not an effective strategy to maximize the benefit for better control of positive and negative symptoms or improving neurocognitive function.
Clozapine augmentation with antipsychotic drugs is widely used despite sparse evidence supporting this strategy. Sertindole is a nonsedating atypical antipsychotic drug with low affinity for cholinergic receptors, which makes it potentially suitable for augmentation of clozapine. The study design was a 12-week, double-blind, randomized, placebo-controlled study including patients with International Statistical Classification of Diseases, 10th Revision schizophrenia (F20.0-F20.3) and treated with clozapine for at least 6 months who had not achieved sufficient response. Patients were randomized 1:1 to either sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske Undersøgelser, World Health Organization Quality of Life Brief, Drug Attitude Inventory, fasting glucose, lipids, and electrocardiogram. Clozapine augmentation with sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude Inventory. No increased adverse effects compared with placebo were found. Four patients randomized to sertindole experienced a significant worsening of psychosis, and 2 of them required psychiatric admission. Metabolic parameters were unchanged during the study, but augmentation of clozapine with sertindole was associated with a 12-millisecond (SD, 20-millisecond) QTc prolongation compared with 0 millisecond (SD, 20 milliseconds) in the placebo group (P < 0.03). Augmentation with sertindole showed no benefits compared with placebo. Psychiatrists should be aware that augmentation might not add any benefits for the patients and in some cases worsen psychosis.
The simultaneous prescription of two or more antipsychotic drugs in combination is a common treatment strategy for those patients who have demonstrated a suboptimal response to clozapine; nevertheless, evidence suggesting potential advantages of combination treatment with clozapine plus one antipsychotic in terms of efficacy and tolerability are still sparse. The present 24-week double-blind, randomized, placebo-controlled trial of adjunctive aripiprazole to clozapine therapy in schizophrenia was aimed to explore the efficacy of aripiprazole add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 15 mg/day of aripiprazole or a placebo. A final sample of thirty-one patients completed the study. The results obtained indicate that aripiprazole added to stable clozapine treatment showed a beneficial effect on the positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenia patients. Regarding executive cognitive functions, aripiprazole augmentation of clozapine had no significant effects. The findings provide evidence that aripiprazole augmentation of clozapine treatment is well-tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy; further double-blind, placebo-controlled trials in a larger number of patients are required to evaluate the therapeutic potential of aripiprazole augmentation of clozapine.
Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.
The large numbers of partial clozapine responders represent a major therapeutic challenge. Unfortunately, there are no clear data to support how best to treat these patients. This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine. A total of 69 inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind, placebo-controlled, randomized clinical trial. Of them, 33 participants were randomized to risperidone and 36 were randomized to placebo. There was no significant group difference in the predefined response criteria. There were modest group differences for Brief Psychiatric Rating Scale (BPRS) positive symptoms, which were significant in the completer analysis (F=5.70; df=1, 70.3; p=0.02; ES=0.27) but not the intent-to-treat (ITT) analyses (F=3.01; df=1, 77.5; p=0.09; ES=0.19). A similar pattern was found for the BPRS total score, with the completer analysis showing a significant improvement in the risperidone group (F=5.21; df=1, 64.9; p=0.03; ES=0.27), whereas the ITT analysis was not significant (F=3.52; df=1, 71.3; p=0.06; ES=0.22). In addition, there was a small, but significant, group difference for negative symptoms, as measured by the SANS total score, which favored the risperidone group (F=5.67; df=1, 78.7; p=0.02; ES=0.24). There were no significant group differences on safety measures, including neuropsychological test and extrapyramidal symptom scores. A significant elevation of prolactin in the risperidone group was observed. The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients. The study results are discussed in the context of previous double-blind studies of adjunctive risperidone. (clinicaltrials.gov, trial number: NCT00056498).
AIM: To evaluate the efficacy and safety of the augmentation of clozapine with aripiprazole in patients with treatment-resistant schizoaffective and psychotic bipolar disorders in a retrospective manner. Pharmacodynamic and pharmacokinetic interactions between the two drugs were also investigated.
PATIENTS: Three men and 4 women (median age 36 and 40 years, respectively) who had mean scores at BPRS and CGI-Severity of 59.1+/-12.0 and 5.4+/-0.5, respectively, were treated with clozapine (mean dose 292.9+/-220.7 mg/day). Patients received an adjunctive treatment with aripiprazole (mean dose 6.8 +/- 3.7 mg/day). Clozapine, norclozapine and aripiprazole plasma levels were measured by means of a high performance liquid chromatograpy with UV detection.
RESULTS: Total scores at BPRS decreased significantly (from 59.1+/-12.0 to 51.1+/-15.6, p=0.007) after aripirazole augmentation. In particular, the factors "thought disorder" (from 10.4+/-4.4 to 9.0+/-4.5, p=.047) and "anergia" (from 10.0+/-2.7 to 8.0+/-2.4, p=.018) significantly improved. Concomitant administration of aripiprazole and clozapine did not result in an increase in side effects over the period of treatment. Dose-normalized plasma levels of both clozapine and norclozapine and the clozapine/norclozapine metabolic ratio in all patients did not vary as well.
CONCLUSION: The augmentation of clozapine with aripirazole was safe and effective in severe psychotic schizoaffective and bipolar disorders which failed to respond to atypical antipsychotics. A possible pharmacokinetic interaction between clozapine and aripiprazole does not account for the improved clinical benefit obtained after aripiprazole augmentation.
Journal»The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
INTRODUCTION: Combination of antipsychotic substances is a therapeutic option increasingly applied in patients with schizophrenia, who do not respond to antipsychotic monotherapy. Recently, various reports on combination of clozapine with aripiprazole in adults have been published. As there is not yet data on adolescent patients, we aimed to study the above-mentioned augmentation strategy in this population.
METHODS: We included 15 patients with schizophrenia from a child and adolescent psychiatric department (8 male; mean age 19.3 [SD+/-1.2, range 17.2-21.2] years). Patients had been under clozapine treatment, followed by aripiprazole augmentation. Retrospectively, patients' medical records were reviewed, using a rating scale in analogy to the Clinical Global Impressions (CGI) scale.
RESULTS: Mean observation time was 11.1 [SD+/-9.7] months. Mean CGI-Severity scores improved significantly (p=0.003, d=0.76) from 5.3 (baseline) to 4.5 (endpoint; last observation carried forward (LOCF)). CGI-Improvement scores decreased from 3.7 (after 1 month) to 3.3 (endpoint; LOCF) (p=0.212, d=0.45).
CONCLUSIONS: In adolescents with schizophrenia, aripiprazole augmentation of clozapine treatment might be an effective therapeutic strategy. Prospective studies for this age group are required to obtain more specific clinical data on clinical effectiveness.
The present 16-week double-blind, randomized, placebo-controlled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms (Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale "Negative" (P = 0.006, mean change [SD] in active group vs placebo, -2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and "General Psychopathology" (P = 0.009, mean change [SD] in active group vs placebo, -5.3 [3.8] vs -0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P < 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs -0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within-group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002). Ziprasidone added to clozapine was effective on negative and cognitive symptoms, although it may be proposed as a helpful treatment in schizophrenia, mainly for those patients who partially respond to clozapine monotherapy.
