Letters to the Editor
Aripirazole–Olanzapine
Combination for Treatment of Schizophrenia
Dear Editor:
Recent literature is equivocal about antipsychotic combination in schizophrenia (1). However, the advent of the new antipsychotic aripiprazole, which has a mechanism of action different from other atypical antipsychotics, rekindles interest in this field. I describe a patient with schizophrenia showing partial response to olanzapine alone, but showing a marked improvement in symptoms (particularly the negative symptoms) on augmentation with aripiprazole. The possible mechanism of aripiprazole’s efficacy in negative symptoms is discussed.
Case Report
Mrs A, a 47-year-old woman with a long-standing history of schizophrenia, was admitted with a psychotic exacerbation precipitated by discontinuation of medicines. On mental status examination, she had marked psychomotor retardation, poverty of speech, flat affect, persecutory and referential delusions, loosening of association, and poor insight and judgment. She scored 122 on the Positive and Negative Symptom Scale (PANSS) with predominant negative symptoms (negative score 46, positive score 25). The patient was restarted on her previous antipsychotic; namely, olanzapine titrated to 20 mg daily, with further increase precluded by increased sedation. Despite 6 weeks on this dosage of olanzapine, there was modest improvement in positive symptoms but none at all in negative symptoms. In view of her partial response to olanzapine, aripiprazole was added at 15 mg daily as an augmenting agent. Within 2 weeks of this addition, the patient began to show improvement in her symptomatology. Her PANSS score dropped to 54 (a drop of 56%) after 6 weeks of olanzapine and aripiprazole combined. The positive, negative, and general psychopathology score decreased by 50%, 69%, and 45%, respectively. The patient was discharged on this combination and continues to maintain her improvement 2 months after discharge, at the same dosage of the 2 drugs. The notable improvement in negative symptoms deserves further attention; possible mechanisms are discussed below.
Olanzapine has a D2 receptor occupancy of 71% to 80% in the usual clinical dosage range of 10 to 20 mg daily, with the occupancy rising with dosage increase (2). Aripiprazole also shows a dose- dependent D2 receptor occupancy above 85% at dosages of 10 to 30 mg daily (3). With both olanzapine and aripiprazole having a high D2 receptor occupancy, one may question the rationale of combining these drugs. However, even at D2 occupancy values above 90%, extrapyramidal symptoms (EPS) are not observed with aripirazole (3). This may be attributed to aripiprazole’s being a partial agonist at the D2 autoreceptor. It would be interesting to explore how this mechanism may contribute toward improvement in negative symptoms.
Negative symptoms of schizophrenia have been hypothesized to result from a decrease in tonic dopamine transmission (4). Further, D2 autoreceptors tonically inhibit dopaminergic neurons (5). Stimulation of these receptors, as is the case with aripiprazole, induces their desensitization, leading to increased dopamine release (4). This novel mechanism may underlie aripiprazole’s low propensity to cause EPS and may also contribute toward its possible efficacy in negative symptoms. The previous generation of atypical antipsychotics, including clozapine, relies mainly on 5-HT2A antagonism for their greater efficacy in negative symptoms (6). Though aripiprazole also has a 5-HT2A antagonistic action, its role as a dopamine autoreceptor agonist may provide additional benefits for countering negative symptoms. Indeed, the study by Kane and colleagues showed that 15 mg daily, but not 30 mg daily, of aripiprazole produced a significantly greater improvement in PANSS negative subscale score, compared with placebo (7). There is some evidence to suggest that dopamine autoreceptor agonists do improve negative symptoms in schizophrenia patients with predominant negative symptoms (8). As aripiprazole acts as a dopamine agonist in the presence of significant receptor reserve for dopamine (which may be secondary to receptor upregulation following a hypodopaminergic state) (9), it can be speculated that schizophrenia patients with residual negative symptoms who are on potent D2 antagonists may benefit from the addition of small doses of aripiprazole. Further studies of aripiprazole at lower and higher dosages in primary negative symptoms are encouraged.
References
1. Freudenreich O, Goff DC. Antipsychotic combination in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30.
2. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155:921–8.
3. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, and others. 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] raclopride. Neuropsychopharmacology 2002;27:248–59.
4. Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999;46:40–55.
5. Millan MJ, Gobert A, Newman-Tancredi A, Lejuene F, Cussac D, Rivet JM, and others. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptor, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293:1048–62.
6. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(Suppl 2):106S–15S.
7. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito G, Zimbroff DL, and others. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
8. Wetzel H, Hillert A, Grunder G, Benkert O. Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms. Am J Psychiatry 1994; 151:1499–2.
Harpreet S Duggal, MD, DPM
Pittsburgh, US
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