Inadequate response to clozapine poses a substantial problem in the pharmaco-therapy of refractory schizophrenia. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia.
Patients with DSM-IV schizophrenia who had a history of treatment failure or partial response to long-term clozapine treatment were recruited. A total of 62 patients with either a baseline Brief Psychiatric Rating Scale (BPRS) score of at least 35 or more than 2 Schedule for Assessment of Negative Symptoms (SANS) global rating item scores of at least 3 were randomly assigned to double-blind augmentation treatment with either aripiprazole (5-30 mg/day) or placebo over 8 weeks. The primary outcome measure was change in BPRS total score from baseline. The study was conducted between December 1, 2005, and December 10, 2006.
There was no significant difference in the primary outcome measure between the 2 groups. In secondary analyses, improvement was significantly greater with aripiprazole treatment than with placebo for negative symptoms assessed by both the BPRS negative symptom sub-scale and the SANS total score but not for positive symptoms. Prolactin and triglyceride levels were significantly lower in the aripiprazole group than in the placebo group. No significant differences between the 2 groups were observed in adverse effects, including extrapyramidal symptoms and serum glucose levels.
Although aripiprazole augmentation of clozapine did not lead to a significant improvement of total symptom severity in schizophrenia, a favorable change in the negative symptom domain was observed.
"In the case of resistance to clozapine, augmentation with second AP or lamotrigine is recommended in some guidelines . This strategy is based on the results of randomized studies demonstrating, among other things, that clozapine augmentation with aripiprazole, had a favorable impact on both the negative  and positive symptoms   and appeared to be safe. Consequently, one may hypothesize that adding aripiprazole to olanzapine or quetiapine might have a similar impact on the earliest stages of treatment. "
[Show abstract][Hide abstract] ABSTRACT: Background
The term antipsychotic polypharmacy (APP) refers to the concurrent use of two or more antipsychotic drugs in schizophrenia. The aim of this study was to investigate the range of APP in schizophrenic patients discharged from psychiatric units in Poland, and to determine its demographical and clinical correlates.
Data on the pharmacological treatment of 207 patients with a diagnosis of schizophrenia, discharged from six psychiatric hospitals from September–December 2011 were recorded by experienced psychiatrists. Clinical and demographical information was obtained on each patient. The severity of symptoms at admission, and their improvement during hospitalization were assessed using the Clinical Global Impression Scale.
At discharge, 52.7% of the patients were prescribed one, 42.5% two and 4.8% three antipsychotic drugs (AP). When two AP were applied, it was usually a combination of two second generation antipsychotics (SGA) (46%), or of both first generation antipsychotics (FGA) and SGA (48%). The SGA's olanzapine and risperidone were those most commonly prescribed. Patients treated with two or more AP had a higher number of previous hospitalizations than patients receiving antipsychotic monotherapy. Mood stabilizers were prescribed for nearly one third of the patients, while antidepressants and benzodiazepines were prescribed for fewer than 10%.
The prevalence of polypharmacy in Poland is similar to that reported in other countries. This may suggest that, in a substantial proportion of schizophrenic patients clinical response to the antipsychotic monotherapy is unsatisfactory. Further studies focusing on the efficacy and safety of strategies in the treatment of patients with schizophrenia not responding to antipsychotic monotherapy are necessary.
"Atypical antipsychotics, particularly olanzapine and risperidone, are more efficacious respect to haloperidol in the treatment of negative symptoms.9 In addition recent studies show as aripiprazole may improve negative dimension probably for its partial agonist activity at dopamine D2 receptors.4,10-12 In contrast, the use of antidepressants in augmentation to antipsychotics did not show a clear improvement of negative symptoms.13 "
[Show abstract][Hide abstract] ABSTRACT: Preliminary data indicate that predominant positive symptoms are predictive of subsequent treatment response, while negative and cognitive symptoms are associated with poor outcome. Purpose of the present study was to investigate the relation between the predominant clinical dimension, duration of illness and acute antipsychotic response in a sample of schizophrenic inpatients.
Fifty-one schizophrenic inpatients, receiving an antipsychotic mono-therapy, were dimensionally assessed at the admission in the Acute Psychiatric Unit of the University of Milan. Treatment response was selected as parameter of outcome and defined as a reduction >50% of baseline total The Positive and Negative Syndrome Scale (PANSS) score. Demographic and clinical variables between responders and non-responders were compared using one-way analysis of variance for continuous variables and χ(2) test for dichotomous ones. Binary logistic regression was performed to find if dimensional scores and duration of illness were associated with acute antipsychotic response.
A longer duration of illness was found in non-responders respect to responders (15.61 years vs. 8.28 years)(F=4.98, p=0.03). Higher scores on PANSS positive sub-scale (OR=1.3, p=0.03), lower scores on cognitive PANSS scores (OR=0.75, p=0.05) and shorter duration of illness (OR=0.93, p=0.04) were found to be predictive of acute antipsychotic response.
These preliminary results show that a long duration of illness as well as a more severe cognitive impairment is predictive of treatment non-response, indicating a worse outcome for chronic patients with predominant cognitive symptoms.
"To our knowledge, four RCT of aripiprazole in clozapine-refractory patients with schizophrenia have been published (see Table 1),105–108 three of which were double-blind and placebo-controlled,105,106,108 one comparing aripiprazole with haloperidol using blinded raters.107 These RCT together included a total of approximately 400 patients. "
[Show abstract][Hide abstract] ABSTRACT: About one third of patients with schizophrenia respond unsatisfactorily to antipsychotic treatment and are termed "treatment-resistant". Clozapine is still the gold standard in these cases. However, 40%-70% of patients do not improve sufficiently on clozapine either. In the search for more efficacious strategies for treatment-resistant schizophrenia, drugs with different pharmacological profiles seem to raise new hopes, but are they valid? The aim of this review was to evaluate the evidence for aripiprazole as a potential strategy in monotherapy or combination therapy for patients with treatment-resistant schizophrenia. The evidence for aripiprazole monotherapy and for the combination of aripiprazole with psychotropics other than clozapine is scant, and no recommendation can be made on the basis of the currently available data. More effort has been made in describing combinations of aripiprazole and clozapine. Most of the open-label and case studies as well as case reports have shown positive effects of this combination on overall psychopathology and to some extent on negative symptoms. Several reports describe the possibility of dose reduction for clozapine in combination with aripiprazole, a strategy that might help so-called "treatment-intolerant" patients. The findings of four randomized controlled trials with respect to changes in psychopathology seem less conclusive. The most commonly found beneficial effects are better metabolic outcomes and indicators of the possibility of reducing the clozapine dose. However, other side effects, such as akathisia, are repeatedly reported. Further, none of the studies report longer-term outcomes. In the absence of alternatives, polypharmacy is a common strategy in clinical practice. Combining aripiprazole with clozapine in clozapine-resistant or clozapine-intolerant patients seems to be worthy of further investigation from the pharmacological and clinical points of view.
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