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Letter   |    
Worsened Agitation and Confusion in Schizophrenia Subsequent to High-Dose Aripiprazole
Jan Thone
The Journal of Neuropsychiatry and Clinical Neurosciences 2007;19:481-482.

SIR: Aripiprazole is a novel atypical antipsychotic drug with a unique pharmacological profile.1 Partial agonism of dopamine D2, serotonin 5-HT1A and antagonism of serotonin 5-HT2A receptors seemed to be the basis of its therapeutical effect.1 In clinical studies aripiprazole has shown to be effective in the treatment of schizophrenia and bipolar disorders in a dose range of 10—30 mg/day.1 Among all other antipsychotic drugs, aripiprazole is considered to have the least adverse effects.1

Recently Duggal et al. published a case report that high-dose aripiprazole treatment improved symptoms in treatment resistant schizophrenia.2 We report on a schizophrenic patient whose symptoms worsened after a high-dose treatment attempt with aripiprazole.

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Case Report

"Mr. L," a 31-year old patient, with a 14 years history of schizophrenia, was admitted to the hospital with a renewed schizophrenia exacerbation (DSM-IV criteria). He particularly manifested agitation and confusion besides insomnia, paranoid delusions and erratic and absentminded thoughts.

Lastly he had received aripirazole 20 mg/day without entering a stable phase. In order to improve mild ongoing psychotic symptoms the dose of aripiprazole was raised stepwise to 60 mg/day following a case report by Duggal et al.2 As a consequence of raising aripiprazole dose Mr. L.’s status worsened and hospitalization became necessary. At the time of hospitalization his medication regimen included aripiprazole 60 mg/day. Measurement of serum drug level confirmed an elevated level of 385 ng/ml. Since Mr. L. had initially rejected a reduction of aripiprazole, olanzapine 15 mg/day was added. After 4 weeks of aripiprazole-olanzapine combination no melioration of the situation was reached. Subsequently administered aripiprazole was reduced to 15 mg/day whereas olanzapine treatment (15 mg/day) was continued. Reduction of aripiprazole was accompanied by clear improvement of symptoms during the next 7 days.

Currently, 12 weeks later, our patient is treated with aripiprazole 15 mg/day and olanzapine 10 mg/day and is free of agitation, confusion and other psychotic symptoms.

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Comment

Temporal relationship between raising daily aripiprazole dose, symptomatic worsening and improvement with reduction of aripiprazole argues against a natural course of schizophrenia and supports the idea that emergence of symptomatic worsening in the case described is due to high-dose aripiprazole medication.

Worsened agitation and psychotic symptoms with aripiprazole is not a new phenomenon.3 However, here we depict a case in which the worsening of symptoms appear as a result of increasing aripiprazole dose above the recommended dose of 15 to 30 mg/day. A possible explanation could be that aripiprazole’s agonist effects may enhance dopaminergic neurotransmission, resulting in intensification of psychosis. However, treatment with aripiprazole 30 mg/day induces a dopamine D2 and D3 receptor occupancy of almost 95%.4 Therefore we query that observed effects are induced by an increased dopamine D2 and D3 receptor activation. We favor, that worsening symptoms in particular agitation and confusion has been related to an exaggerated serotonin 5HT1A receptor activation.

Clinicans should notice that high-dose aripiprazole may be associated with worsening psychotic symptoms due to its unique receptor profile. However, in treatment resistant schizophrenia some patients may benefit from an aripiprazole-olanzapine combination.

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Fleischhacker WW: Aripiprazole. Expert Opin on Pharmacotherapy 2005; 6:2091—2101
 
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Duggal HS, and Mendhekar DN: High-dose aripiprazole in treatment-resistant schizophrenia. J Clin. Psychiatry 2006; 67:674—675
 
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Ramaswamy S, Vijay D, William M. et al: Aripiprazole possibly worsens psychosis. Int. Clin. Psychopharmacol 2004; 19:45—48
 
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Yokoi F, Gründner G, Biziere K, et al: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C] raclopide. Neuropsychopharmacology 2002; 27:248—259
 
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References

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Fleischhacker WW: Aripiprazole. Expert Opin on Pharmacotherapy 2005; 6:2091—2101
 
.
Duggal HS, and Mendhekar DN: High-dose aripiprazole in treatment-resistant schizophrenia. J Clin. Psychiatry 2006; 67:674—675
 
.
Ramaswamy S, Vijay D, William M. et al: Aripiprazole possibly worsens psychosis. Int. Clin. Psychopharmacol 2004; 19:45—48
 
.
Yokoi F, Gründner G, Biziere K, et al: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C] raclopide. Neuropsychopharmacology 2002; 27:248—259
 
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