Augmentation of Clozapine with Aripiprazole in Severe Psychotic Bipolar and Schizoaffective Disorders: A Pilot Study

Abstract

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.

Pharmacological Approaches for Treatment-resistant Bipolar Disorder

“…Both found greater reduction in mania symptom ratings than with a placebo, without greater risk of adverse effects or of early discontinuation [ 29 , 30 ]. Three small, open trials added aripiprazole to other treatments in treatment resistant bipolar disorder (including in bipolar depression), and found some evidence for beneficial effects [ 31 , 32 ], including one that included subjects who had not responded well to a trial of clozapine [ 33 ]. Among adverse effects, aripiprazole has a substantial risk of inducing akathisia-like restlessness, which can interact badly in agitated or manic bipolar disorder patients [ 31 , 32 ].…”

Clozapine for treatment-resistant bipolar disorder: a systematic review

“…Although we excluded all of the case series and case reports in this comprehensive review, the literature search provided 13 case reports/series in which clozapine was used for TRBD ( Table 4). The 13 articles included five on mania (42,(70)(71)(72)(73), five on rapid cycling BD (15,(74)(75)(76)(77), and three on other TRBDs (29,78,79).…”

“…Two trials described the number and duration of hospitalizations, the number of psychotropic co-medications and the number of hospital visits for medical reasons and for intentional self-harm/overdose as significantly reduced during clozapine treatment (12,29,51,58). Another retrospective study comparing patients with schizophrenia and psychotic BD indicated that the latter had significantly higher response rates to clozapine (12).…”

“…In contrast to schizophrenia, definitions of treatment-resistant bipolar disorder (TRBD) vary greatly (17,(25)(26)(27). However, a failure to respond to at least two trials of dissimilar treatments, involving an adequate dose and duration, could serve as a conservative definition (28)(29)(30)(31).…”

Role of aripiprazole in treatment-resistant schizophrenia

“…Most of the open-label and case studies as well as case reports show positive effects of this combination on overall psychopathology53,93–95,99,101–104,109 and on negative symptoms 96,97,99,102,103. Several reports describe the possibility of dose reduction for clozapine in combination with aripiprazole, a strategy that might help so-called treatment-intolerant patients 93,98,101,102.…”