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

Alessandra Benedetti§, 1, *, Antonello Di Paolo^, 1, Marianna Lastella^, Francesco Casamassima§, Chiara Candiracci°, Antonella Litta§, Laura Ciofi^, Romano Danesi^, Lorenzo Lattanzi§, Mario Del Tacca, Giovanni Battista Cassano§
1 those Authors equally contributed to the study

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© Benedetti et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Via Roma 57, 56126 Pisa – Italy; Tel: +39-050-835411; Fax: +39-050-21581; E-mail:,
§ Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa
^ Department of Internal Medicine, University of Pisa
° Psychiatric Clinic, Polytechnic University of Marche, Ancona



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.


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.


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.


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.

Keywords: Psychotic bipolar disorder, schizoaffective disorder, clozapine, aripiprazole, augmentation, pharmacokinetic interactions.