Addition of Aripiprazole to the Clozapine May Be Useful in Reducing Anxiety in Treatment-Resistant Schizophrenia
There exist many case reports and studies on the antipsychotic augmentation by aripirazole in partial responders to clozapine, the most seem to be finding a slight difference in the PANSS and CGI scores after the aripirazole addition. The results of our report are compatible with those of other studies but, we have found a considerable antianxiety action in both of the cases. The 5HT1A agonism of aripirazole could be hypothesized as mechanism contributing to this effect.
In this paper, we report on 2 cases in which augmentation with aripiprazole had a beneficial impact on anxiety.
2. Case Presentation
2.1. Case Report 1
Ms. A, a 40-year-old woman diagnosed with a residual schizophrenia  was admitted following an exacerbation of psychotic symptoms with a predominance of anxiety despite 700 mg/d of clozapine for two years. The clinical scores and the trough plasma concentrations of clozapine and norclozapine at admission were CGI : 5; total PANSS: 123; positive: 17/49; negative: 18/49; excited component: 12/35; general: 39/112; Hamilton-anxiety: 14/56; clozapine: 896 ng/mL; norclozapine: 551 ng/mL, respectively (clozapine therapeutic range: 350–600 ng/mL [15–17]). Because of the risks of seizures, the dose was reduced to 500 mg/d, and aripiprazole (10 mg/d) was added. Clozapine and norclozapine plasma concentrations measured after 10 days were decreased according to the reduction of the dose (615 ng/mL and 478 ng/mL, resp.). The aripiprazole plasma concentration after 10 days was 282 ng/mL. Following a clinical reduction of the anxiety, the patient was discharged from the hospital three weeks after the addition of aripiprazole.
A followup over 6 months did not reveal any change in the CGI and PANSS scores (at 6 months: CGI : 5; total PANSS: 125; positive: 18/49; negative: 23/49; excited component 10/35; general: 38/112). On the other hand, the Hamilton-anxiety score diminished progressively to 12, 7, and 8 after one, three, and 6 months, respectively. Clozapine and norclozapine plasma levels were stable over this period (at the sixth month: 608 ng/mL, 443 ng/mL, and 75 kg, resp.), and the comedications (clorazepate 20 mg/d, valsartane 40 mg/d, zopiclone 7,5 mg/d, and tamsulosine 0.4 mg/d) were not modified. No reports are describing an impact on anxiety by the antihypertensive comedication by valsartane (an angiotensin II receptor antagonist) and tamsulosine (peripheral 1-antagonist). There is no significant pharmacokinetic or pharmacodynamic interactions of that comedication and the antipsychotic/anxiolytic treatments.
2.2. Case Report 2
Mr. L, a 48-year-old man with a diagnosis of residual schizophrenia  treated for many years with clozapine 500 mg/d was admitted because of the worsening of his anxiety. The clinical scores and the trough plasma concentrations of clozapine and norclozapine were: CGI : 4; total PANSS: 88; positive: 20/49; negative 25/49; excited component: 9/35; general 40/112. Hamilton-anxiety: 24/56; clozapine: 594 ng/mL; norclozapine: 470 ng/mL, respectively. Aripiprazole 10 mg/d was added to clozapine (dose unchanged) and lorazepam (1 mg/d) was discontinued. The patient was discharged three weeks after the aripiprazole addition.
A followup over 3 months did not reveal any change in the CGI and PANSS scores (at 3 months: CGI : 4; total PANSS: 73; positive: 20/49; negative: 25/49; excited component: 7/35; general: 40/112), while the Hamilton-anxiety score diminished progressively to 19 and 15 after one and three months, respectively. The clozapine and norclozapine plasma concentrations at three months were 431 ng/mL and 343 ng/mL, respectively.
In the present paper the augmentation did not result in a reduction of psychotic symptoms despite a treatment period of 3 to 6 months, which is in agreement with previous reports [5, 10–13]. Because a therapeutic window has been demonstrated for clozapine [17, 18], it is important to mention that therapeutic blood levels of clozapine were maintained during the whole observation period. An important reduction of anxiety was clinically observed in both cases, with a marked improvement of psychosocial functioning observed, which allowed a change of residential institution of both cases, three and six months after the discharge from the hospital, for a residential stay in more open environment with less psychosocial accompanying measures.
It has been suggested that in anxiety disorders, the adjunction of atypical antipsychotics to the current SSRI and/or benzodiazepine treatment could, through the modulation of the dopaminergic system, be beneficial but the data are not conclusive [19, 20].
The agonist action of aripiprazole on the 5HT1A receptors could eventually contribute to the antianxiety action that we have observed .
However, considering the present observations could be due to external factors or to the natural evolution of the illness, a randomized controlled study is required to evaluate the efficacy of the clozapine-aripiprazole combination in cases of treatment-resistant schizophrenia with predominance of anxiety. Moreover, the anxiety observed in Case 1 could have been in part attributable to psychotoxic effects due to the high plasma concentration at the begining of the followup .
The authors attest that their research is not sponsored by any pharmaceutical companies, biomedical device manufacturers, or other corporation whose products or services may be related to the subject matter of the article and that they have no a financial relationship with this kind of commercial organizations.
P. Conus received an unrestricted educational grant for an investigator initiated trial from Bristol-Myers Squibb, and supports for attending conferences and/or giving speeches from Bristol-Myers Squibb, Janssen-Cilag, Eli Lily and Astra Zeneca. C. B. Eap received non-restricted educational grants for investigator initiated trials from Janssen-Cilag and Bristol-Myers Squibb. He received honoraria for conferences or teaching CME courses from Astra Zeneca, Bristol-Myers Squibb, Eli Lily, Essex Chemie, Glaxo-Smith Kline, Janssen-Cilag, Lundbeck, Novo Nordisk, and Organon.
J. Kane, G. Honigfeld, J. Singer, and H. Meltzer, “Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine,” Archives of General Psychiatry, vol. 45, no. 9, pp. 789–796, 1988.View at: Google Scholar
A. Cipriani, M. Boso, and C. Barbui, “Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD006324, 2009.View at: Google Scholar
J. A. Lieberman, A. Z. Safferman, S. Pollack et al., “Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome,” American Journal of Psychiatry, vol. 151, no. 12, pp. 1744–1752, 1994.View at: Google Scholar
C. I. Mitsonis, N. P. Dimopoulos, P. A. Mitropoulos et al., “Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: an open-label pilot study,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 31, no. 2, pp. 373–377, 2007.View at: Publisher Site | Google Scholar
A. E. Anil Yagcioglu, B. B. Kivircik Akdede, T. I. Turgut et al., “A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety,” The Journal of clinical psychiatry, vol. 66, no. 1, pp. 63–72, 2005.View at: Google Scholar
G. Remington, “Augmenting clozapine response in treatment-resistant schizophrenia,” in Therapy-Resistant Schizophrenia, H. Elkis and H. Y. Meltzer, Eds., vol. 26 of Advances in Biological Psychiatry, pp. 129–151, Karger, Basel, Switzerland, 2010.View at: Google Scholar
J. S. Chang, Y. M. Ahn, H. J. Park et al., “Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial,” Journal of Clinical Psychiatry, vol. 69, no. 5, pp. 720–731, 2008.View at: Google Scholar
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR, American Psychiatric Publishing, 4th edition, 2000.
W. Guy et al., ECDEU Assessment Manual for Psychopharmacology, U.S. Department of Helath, Education, and Welfare, Rockville, Md, USA, 1976.
S. R. Kay, L. A. Opler, and A. Fiszbein, Positive and Negative Syndrome Scale-Manual, Multi-Health Systems, New York, NY, USA, 1992.
P. J. Perry, D. D. Miller, S. V. Arndt, and R. J. Cadoret, “Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients,” American Journal of Psychiatry, vol. 148, no. 2, pp. 231–235, 1991.View at: Google Scholar
K. Gao, D. Muzina, P. Gajwani, and J. R. Calabrese, “Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review,” Journal of Clinical Psychiatry, vol. 67, no. 9, pp. 1327–1340, 2006.View at: Google Scholar
S. Pallanti, L. Quercioli, and A. Pazzagli, “Social anxiety and premorbid personality disorders in paranoid schizophrenic patients treated with clozapine,” CNS Spectrums, vol. 5, no. 9, pp. 29–43, 2000.View at: Google Scholar