Inpharma 1454 - 11 Sep 2004

Aripiprazole advantageous in bipolar disorder– Ngaire Polwart –

Aripiprazole [Abilify], a partial dopamine and serotonin receptor agonist, is an effective and well toleratedtreatment for acute mania in patients with bipolar disorder, according to several studies presented at the XXIVthCollegium Internationale Neuropsychopharmacologicum (CINP) Congress [Paris, France; June 2004]. Two ofthese studies showed that aripiprazole produced significantly greater responses than either placebo orhaloperidol. Furthermore, aripiprazole demonstrated superior tolerability to haloperidol; this favourabletolerability profile was confirmed in a pooled analysis of placebo-controlled trials. Another pooled analysisindicated that the benefits of aripiprazole were seen in different subgroups of patients with bipolar disorder,including those with manic or mixed episodes, rapid-cycling bipolar disorder, and with or without psychoticsymptoms. Another placebo-controlled study presented at the meeting showed that aripiprazole also prolongedthe time to the relapse of symptoms in patients with bipolar disorder who had previously experienced a manic ormixed episode.

Simpson-Angus Scale (SAS) and Abnormal InvoluntaryEffective in acute mania . . .Movement Scale (AIMS) did not differ significantlySignificantly greater improvements in key outcomebetween aripiprazole and placebo. Patients in bothmeasures of acute mania were observed in patients withtreatment groups experienced slight increases inbipolar disorder who received aripiprazole, comparedbodyweight (0.53kg for aripiprazole and 0.18kg forwith those who received placebo or haloperidol, in twoplacebo); however, the difference between the tworandomised, double-blind studies.groups was not statistically significant. Four adverseThe first of these studies involved 272 patients withevents (dyspepsia, constipation, akathisia and painacute mania or mixed episodes who requiredextremity) had an incidence of ≥ 10% and occurredhospitalisation.1 Patients received aripiprazoletwice as frequently in aripiprazole recipients, compared30 mg/day or placebo, for 3 weeks. Patients receivingwith placebo-treated patients; however, these eventsaripiprazole had an option to decrease their dosage towere generally of mild-to-moderate intensity.15 mg/day for tolerability reasons; however, the

Compared with haloperidol, aripiprazole wasmajority of patients (85%) continued to receive theassociated with significantly lower increases from30 mg/day dosage.baseline in EPS rating scale scores (SAS, AIMS andThe primary efficacy endpoint was the mean changeBarnes Akathisia scales). Thus, the incidence of EPS wasin the Young Mania Rating Scale (YMRS) from baseline tolower with aripiprazole, compared with haloperidol (9%week 3. Significantly greater changes in the YMRS scorevs 36% of patients). Reductions in serum prolactin levelswere observed with aripiprazole, compared withfrom baseline were observed in aripiprazole recipients,placebo (–12.5 vs –7.2). Significant improvements inwhereas haloperidol was associated with increases inYMRS scores were noted in aripiprazole recipients asprolactin.early as day 4 of treatment, and continued for the

duration of the study. Furthermore, a significantly Pooled analysis supports tolerabilitygreater response rate (defined as a reduction in YMRS findingsscore of ≥ 50%) was observed among aripiprazole, A pooled analysis of safety and tolerability data fromcompared with placebo, recipients (53% vs 32%; studies involving patients with bipolar disorderp < 0.01). Aripiprazole was also superior to placebo confirmed the favourable tolerability profile ofwith respect to other outcome measures, including aripiprazole.3 A total of 977 patients who had beenimprovements in Clinical Global Impressions - Bipolar treated with aripiprazole (n = 568) or placebo in four(CGI-BP) Severity of Illness (mania) score (p < 0.01), randomised, double-blind, 3-week studies wereCGI-BP change in preceding phase (mania) score included in this analysis.(p = 0.001), and the mean change in the hostility score The most frequent adverse events (≥ 15% of patients)on the Positive and Negative Syndrome Scale (p < 0.01). reported by patients receiving aripiprazole included

headache, nausea, dyspepsia and akathisia. The majority. . . and superior to haloperidolof these adverse events were mild-to-moderate inIn the second study, 347 patients (inpatients andseverity and transient in nature. There were nooutpatients) with acute mania or mixed bipolar episodessignificant differences between aripiprazole and placeboreceived aripiprazole 15 mg/day (with an option toin terms of changes in bodyweight, elevations in serumincrease to 30 mg/day) or haloperidol 10 mg/day (withprolactin levels and absolute changes in QTc intervals.an option to increase the dosage to 15 mg/day), forAripiprazole was not associated with dose-dependent12 weeks.2 Average daily doses at the end of week 3 anddifferences in EPS. The proportions of patientsweek 12 were 22.6 mg/day and 21.6 mg/day,discontinuing treatment due to adverse events wererespectively, for aripiprazole, and 11.6 mg/day andsimilar for aripiprazole and placebo (11% and 10%,11.1 mg/day for haloperidol.respectively).The proportion of responders (patients with a ≥ 50%

improvement in YMRS total score and remaining on Effective across different subgroupstreatment) was significantly greater with aripiprazole, The benefits of aripiprazole have been observedcompared with haloperidol (50% vs 28%; p < 0.001). across different subgroups of patients with bipolar

disorder, including those with disease states that haveFavourable tolerability profiletraditionally been considered difficult to treat, such asAripiprazole was generally well tolerated in patientsrapid-cycling bipolar disorder and bipolar disorder withwith acute mania. Changes from baseline inpsychotic features. In a pooled analysis of data from twoextrapyramidal symptoms (EPS), according to the

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Inpharma 11 Sep 2004 No. 14541173-8324/10/1454-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

Single Article

Aripiprazole advantageous in bipolar disorder – continued3-week, randomised double-blind placebo-controlled (15–30 mg/day) for 6–18 weeks. The stabilisationstudies, 516 patients were stratified according to criteria of a YMRS score of ≤ 10 and a Montgomery-episode characteristics (manic or mixed), disease Asberg Depression Rating Scale score of ≤ 13 for fourhistory (rapid cycling) and symptom severity.4 consecutive visits or 6 weeks were achieved in

The proportions of patients with manic or mixed 161 patients who were then randomised to double-blindepisodes were similar in the aripiprazole and placebo maintenance treatment with aripiprazole or placebo, forgroups (manic: 64% vs 62% of patients; mixed: 36% vs 26 weeks.38%). Similarly, the two treatment groups included Fewer aripiprazole-treated patients than placebosimilar proportions of patients with rapid-cycling bipolar recipients withdrew from the study (66% vs 50%). Thedisorder (20% for both aripiprazole and placebo groups) most common reason for discontinuation in the placeboand psychotic symptoms (17% for aripiprazole and 21% and aripiprazole groups was due to a lack of efficacyfor placebo). (43% and 24% of patients, respectively); lack of efficacy

Compared with placebo-treated patients, aripiprazole was defined as a patient requiring hospitalisation forrecipients experienced statistically significant manic or depressive symptoms, or requiring an additionimprovements from baseline in YMRS total scores, to or increase in their psychotropic medications otherregardless of episode type, disease history or severity than the study drug. Among patients who continued to[see table]. Patients with psychotic symptoms who were receive maintenance treatment, the time to relapse wastreated with aripiprazole also experienced significant longer with aripiprazole than with placebo (log rankimprovements in YMRS scores, compared with those p = 0.02). Furthermore, significantly fewer aripiprazole,receiving placebo (p < 0.001). compared with placebo, recipients experienced relapse

(25% vs 43%; p < 0.05). The relative risk (RR) for relapsewas significantly lower for aripiprazole than withChange from baseline in YMRSa scores in patientsplacebo (RR = 0.569; 95% CI 0.359, 0.902; p < 0.05).with bipolar disorder, according to episode type,1. Carson W, et al. Aripiprazole vs placebo for the treatment of acute mania indisease history and severity

patients with bipolar I disorder. International Journal ofPlacebo Aripiprazole Neuropsychopharmacology 7 (Suppl. 1): 332 (plus poster) abstr. P02.101, Jun

2004.Mean change in YMRS scores from baseline: 2. Sanchez R, et al. Aripiprazole vs. haloperidol for maintained treatment effect inacute mania. International Journal of Neuropsychopharmacology 7 (Suppl. 1):Total patients –6.9 –10.1 *243 (plus poster) abstr. P01.423, Jun 2004.Manic episode –6.5 –10.4 *

3. Blonde L, et al. Pooled randomized schizophrenia trials show greater log-termMixed episode –7.4 –9.7 ** diabetes risk with olanzapine than aripiprazole treatment. International Journal of

Neuropsychopharmacology 7 (Suppl. 1): 242 (plus poster) abstr. P01.420, JunRapid-cycling –5.5 –10.6 *2004.Severe symptoms –6.8 –11.6 * 4. Marcus R, et al. Efficacy of aripiprazole in sub-populations of bipolar disorderpatients with acute mania: a pooled analysis. International Journal of*p ≤ 0.001 vs placeboNeuropsychopharmacology 7 (Suppl. 1): 160-161 (plus poster) abstr. P01.103,

**p < 0.05 vs placebo Jun 2004.a Young Mania Rating Scale 5. McQuade R, et al. Aripiprazole for relapse prevention in bipolar disorder: a

26-week placebo-controlled study. International Journal ofNeuropsychopharmacology 7 (Suppl. 1): 161 (plus poster) abstr. P01.104, 22 Jun2004.Effective maintenance therapy 800969743

The time to relapse was significantly prolonged in » Editorial comment: Aripiprazole [Otsuka Pharmaceutical,patients with bipolar disorder who were stabilised onBristol-Myers Squibb] is awaiting approval for the treatment ofaripiprazole and continued taking aripiprazole for 26bipolar disorders in the US. It is already marketed for theweeks.5 Patients who had recently experienced a manic treatment of schizophrenia in the US, the EU, Puerto Rico and

or mixed episode underwent an initial stabilisation Mexico.phase in which they received open-label aripiprazole

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