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Home , Antipsychotic, Aripiprazole

– a new class of ? Graylands Hospital Bulletin 2003 Vol. 11 No. 4 November ISSN 1323-1251

! Aripiprazole (Abilify) is the latest antipsychotic to be registered in Australia for the treatment and maintenance therapy of . It is the first in a new emerging class of atypical known as the “ system stabilisers”. ! Whether the novel mode of action of aripiprazole will translate into significant clinical advantages is not yet apparent. Available data do not suggest any superiority over existing agents with regard to efficacy in schizophrenia. ! Safety and tolerability data however suggest that aripiprazole may have some advantages when compared with other atypical antipsychotics. Unlike some of these agents, research indicates it does not cause , excessive or cardiac rhythm disturbance, nor is it associated with glucose or lipid changes. ! If these initial observations are confirmed with widespread, long-term clinical use, aripiprazole could be a very promising addition to the range of antipsychotics currently available. ! More research is needed to determine its efficacy and safety in refractory schizophrenia and special populations such as the elderly and children. ! It is not yet available on the Pharmaceutical Benefits Scheme (PBS) or included on Graylands Hospital Formulary. ! Price details are currently unavailable. However, the manufacturers indicate that it will likely be priced between and at recommended daily doses. What is novel about aripiprazole’s lead to improved tolerability. It can be mode of action? compared to a “thermostat”, reducing Similarly to existing antipsychotics, neurotransmission in situations where dopamine activity is aripiprazole acts at dopamine D2 receptors in the limbic system, but as a high (psychoses) and enhancing partial rather than an neurotransmission in situations where antagonist (1). A will dopamine activity is low (negative / displace dopamine at receptors, as cognitive symptoms). It also would an antagonist, but instead of simultaneously maintains a balance in completely blocking the receptor and other important areas of dopaminergic preventing all activity, it behaves like a neurotransmission such as those that weaker version of dopamine itself. regulate motor function and . This does not result in any weaker This should translate theoretically in action as an antipsychotic, but should clinical practice to a low incidence of

Graylands Hospital Drug Bulletin 2003 Vol 11 No.4 1 (EPS) and Common Side Effects (4) prolactin elevation. Headache Nausea Aripiprazole combines this dopamine Vomiting stabilising action with partial agonism Agitation Light-headedness at 5HT1A (theoretically decreased Anxiety anxiety, depressive symptoms, However, unlike some of the atypical improvement in negative symptoms) agents, research indicates it is and similarly to other atypical associated with minimal prolactin, antipsychotics, antagonism at 5HT2A lipid, or glucose changes, significant receptors (theoretically decreased EPS, weight gain or QTc prolongation (4,5). improvement in negative symptoms) (2) If these initial observations are . confirmed following extensive use in What is the pharmacokinetic profile general clinical practice, aripiprazole of aripiprazole? could be a very valuable addition to the Aripiprazole is well absorbed, the peak range of antipsychotics currently plasma concentration occurring within available. 3-5hrs of dosing (3). The only dose-related side effect was It is extensively metabolised by the found to be sedation (most prominent via CYP450 3A4 & 2D6 to form at 30mg), the incidence of which an active metabolite (dehydro- seems to decrease with time. aripiprazole). Clearance is primarily Does aripiprazole interact hepatic. significantly with other ? Once-daily dosing is possible due to its Potent CYP3A4/2D6 inhibitors eg. long elimination half-life (75 and ketoconazole, , , 100hrs for aripiprazole and active may reduce aripiprazole clearance. metabolite, respectively). The dose of aripiprazole should be Steady-state concentration is reached reduced or started at 10mg. Less within two weeks of dosing. For this potent inhibitors of these enzymes that reason, dosage adjustments should be may also theoretically interact with made not less than two weeks apart in aripiprazole, include , order to fully assess patient response. and erythromycin. Potent CYP3A4 inducers eg. Are there any unusual precautions may lead to increased associated with the use of aripiprazole clearance. The dose of aripiprazole? aripiprazole may have to be increased. No. Aripiprazole carries the usual Other inducers of this enzyme that may standard warnings found on theoretically interact with aripiprazole manufacturer’s product information for include phenytoin and dexamethasone. antipsychotics. NB. Dose adjustments may be As to be expected, there is currently necessary following withdrawal of the insufficient data at present to above interacting . recommend its use in or lactation. No interaction was found with , , warfarin or omeprazole (3). How does aripiprazole’s side-effect How much evidence is available to profile differ to existing atypical support its use in clinical practice? antipsychotics? Short-term efficacy Similarly to existing atypicals, There are five (4 & 6 week) - aripiprazole has a low propensity for (4) controlled trials in over 1500 inpatients extrapyramidal symptoms (EPS) . with acute relapse of schizophrenia or

Graylands Hospital Drug Bulletin 2003 Vol 11 No.4 2 (6-9). Two Acute bipolar trials are fully published (6,7), the Aripiprazole is not yet licensed for this remainder being currently available use. However, like other only in abstract or poster (meta- antipsychotics, it may also be useful in analysis) format. Some improvements managing an acute manic episode. in symptoms were noted at week one with aripiprazole (8). One published, placebo-controlled In general, aripiprazole (15-30 mg) study in approximately 250 patients is was more effective than placebo with available. Twice as many patients in regard to positive and negative the aripiprazole group as in the placebo symptom improvement (except one group responded to treatment (40% vs. study, where 30mg aripiprazole was 19%). Superior response rates with aripiprazole were evident by day 4 not found to be superior to placebo in (13) the treatment of negative symptoms(7)). (mean dose 27.9mg) . The overall response in aripiprazole- No trials are available in the elderly, treated patients was similar to that seen children or in first episode or treatment in patients receiving (10 resistant schizophrenia as yet. mg/day) or risperidone (6 mg/day). What equivalence does aripiprazole Long- term efficacy have to ? There are two trials (one fully This parameter is of controversial (10) published ) investigating value for atypical antipsychotics. maintenance and relapse prevention in However, a recent article stated 7.5mg chronic schizophrenia. aripiprazole was equal to 100mg A 26-week trial found aripiprazole chlorpromazine (using the 2mg haloperidol equals 100mg 15mg to be more effective than (14) placebo in preventing relapse in chlorpromazine convention) . stabilized patients with chronic What are the dosage schizophrenia. Reported adverse event recommendations? rates were similar for each group (10). The recommended starting and A 52-week trial showed aripiprazole to maintenance dose is 15mg once daily, be more effective than haloperidol for with or without food. Morning dosing the long-term maintenance treatment of may be more appropriate, as it is not schizophrenia. Significantly more sedating at recommended doses and patients had responded AND remained insomnia is a possible side effect. on treatment at endpoint (31% vs. 20% Adjust the dose if necessary after two respectively). Study discontinuation weeks. The range 15-30mg was found rates for both drugs were high but not to be effective in clinical trials but the statistically different from each other manufacturer states there is no (57% & 70% for aripiprazole and evidence to support improved efficacy haloperidol respectively). Aripiprazole with doses higher than 15mg/day. No was superior in terms of negative dosage adjustment is required in the symptom improvement (11). elderly, hepatic or renal impairment or according to smoking status. Neurocognitive effects A 26-week open-label study versus Due to aripiprazole’s lack of olanzapine in chronic, stable properties, it may be appropriate in the schizophrenia or schizoaffective initial stages of therapy to use a disorder suggested that aripiprazole or sedative may be superior in improving certain antipsychotic to help control symptoms neurocognitive deficits, especially of a very disturbed or aggressive memory dysfunction (12). patient.

Graylands Hospital Drug Bulletin 2003 Vol 11 No.4 3 What is a suitable regimen for References switching a patient from an existing 1. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, oral antipsychotic to aripiprazole? Kikuchi T, Yocca FD. Molinoff PB. Aripiprazole, a Novel Antipsychotic, is a High-Affinity Partial Agonist at Human Data collected by the manufacturer Dopamine D2 Receptors. J Pharmacol Exp Ther found the following three methods to 2002;302(1):381-389. (15) be equally safe and effective . 2. Keltner NL, Johnson V. Aripiprazole: A Third Generation of Antipsychotics Begins? Perspect Psychiatr Stop current antipsychotic one Care 2002;38(4):157-9. day, start aripiprazole the next 3. Abilify Product Information, July 2003. Start aripiprazole whilst 4. Marder SR, McQuade RD, Stock E, Kaplita S, Marcus simultaneously tapering down R, Safferman AZ, Saha A, Ali M, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and current antipsychotic over 2 tolerability in short-term, placebo-controlled trials. weeks* Schizophr Res 2003;61:123-136 Taper down existing 5. McQuade R, Jody D, Kujawa M et al. Long-term weight effects of aripiprazole vs olanzapine. POSTER: antipsychotic whilst at the same Presented at the 156th American Psychiatric Association time titrating aripiprazole Meeting; May 17-22,2003, San Francisco, California. upwards from 10mg (over period 6. Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, of 2 weeks) Stock E, Stringfellow J, Ingenito G, Marder SR. Aripiprazole, an antipsychotic with a novel mechanism of *Manufacturer suggests use of 2nd action and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen regimen as the risk of experiencing Psychiatry 2003;60:681-690. transient exacerbation of symptoms is 7. Kane JM, Carson WH, Saha AR, McQuade RD, reduced. Ingenito GG, Zimbroff DL, Ali MW. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schozphrenia and schizoaffective disorder. J Clin Presentation Psychiatry 2002;63:763-771. Available as 10mg, 15mg, 20mg and 8. Lieberman JA, Carson WH, Saha A, Stringfellow JC, 30mg tablets – all unscored. Archibald DG, Kujawa MJ, Iwamoto T. Meta-analysis of the efficacy of aripiprazole in schizophrenia. POSTER: Sponsor Presented at the 23rd Collegium Internationale Neuropsychopharmacologicum Congress Meeting; June Bristol-Myers Squibb 23-27 2002, Montreal, Canada. 9. . Data on file. ARIPIPRAZOLE 10. Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock Suitable for use in which patients? EG, Ingenito GG. Aripiprazole for the Prevention of Relapse in Stabilised Patients With Chronic ! As there is little experience of its Schizophrenia: A Placebo-Controlled 26-Week Study. J efficacy and safety to date, it Clin Psychiatry 2003;64:1048-1056. should not be used as a first line 11. Kujawa M, Saha A, Ingenito GG, Ali M, Luo X, antipsychotic. Archibald DG, Carson WH. Aripiprazole for long-term maintenance treatment of schizophrenia. POSTER: ! It would be useful for patients in Presented at the 23rd Collegium Internationale whom potential side effects such as Neuropsychopharmacologicum Congress Meeting; June 23-27 2002, Montreal, Canada. significant weight gain and 12.Cornblatt B, Kern RS, Carson WH. Neurocognitive lipid/glucose disturbances would effects of aripiprazole vs olanzapine in stable . be especially detrimental. POSTER: Presented at the 23rd Collegium Internationale Neuropsychopharmacologicum Congress Meeting; June ! There are no studies in treatment 23-27 2002, Montreal, Canada. resistant schizophrenia as yet. 13. Keck PE, Marcus R, Tourkodimitris S, Ali M, should still be used in Liebeskind A, Saha A, Ingenito G. A Placebo-controlled, Double-Blind Study of the Efficacy and Safety of preference to aripiprazole in this Aripiprazole in Patients with Acute Bipolar Mania. Am J instance. Psychiatry 2003;160:1651-1658. 14. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry Acknowledgement 2003;64:663-667. This article was written by Kate Smith and reviewed by members of the Pharmacy 15. Casey DE, Carson WH, Saha AR, Liebeskind A, Ali Department. Comments are welcome at the e- MW, Jody D, Ingenito GG on behalf of the Aripiprazole mail address: Study Group. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomised [email protected] study. 2003;166:391-399.

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