Aripiprazole for Mania

By Flavio Guzman, MD

Aripiprazole is approved for the treatment of manic episodes in type I bipolar disorder.

In this page you can find abstracts of review articles, guideline comments and controlled trials on the use of aripiprazole for the management of mania.

Review Articles

Aripiprazole: a review of its use in the management of mania in adults with bipolar I disorder.

Abstract:

Aripiprazole (Abilify®) is an atypical antipsychotic indicated for the treatment of mania associated with bipolar I disorder. It is unique in its class, as it is a partial agonist of dopamine D(2) and D(3), and serotonin 5-HT(1A) receptors and a modest antagonist of 5-HT(2A) receptors.

This article reviews the pharmacological properties, clinical efficacy and tolerability of oral aripiprazole in the management of mania associated with bipolar I disorder in adults. In well designed clinical trials in patients with recent manic or mixed episodes associated with bipolar I disorder, oral aripiprazole monotherapy or adjunctive therapy to lithium or valproate improved symptoms of mania following short-term (≤12 weeks) or maintenance (≤100 weeks) treatment. In addition, maintenance treatment with aripiprazole (as monotherapy or adjunctive therapy) prevented the recurrence of any mood episodes or manic episodes (but not depressive episodes) in patients who had previously been stabilized and maintained on aripiprazole.

Aripiprazole was generally well tolerated in these studies and was associated with a low risk of prolactin elevation, corrected QT interval prolongation and metabolic disturbances. Extrapyramidal symptoms occurred in up to 28% of aripiprazole recipients, but after longer-term treatment (≤100 weeks), symptom severity did not differ significantly from that in placebo recipients.

Aripiprazole treatment generally did not increase body weight to a clinically relevant extent; however, more patients receiving aripiprazole monotherapy than placebo had clinically significant body weight gain during 100 weeks’ treatment. Additionally, in a comparative trial, aripiprazole monotherapy was at least as effective as haloperidol monotherapy in terms of improving symptoms of mania, but had the advantage of a lower incidence of some adverse events, such as extrapyramidal symptom-related adverse events.

Further trials comparing aripiprazole with other agents, including atypical antipsychotics, would help to definitively position aripiprazole relative to these agents.

Current guidelines recommend aripiprazole as a first-line option (as monotherapy or adjunctive therapy) for the short-term treatment of mania associated with bipolar I disorder, and as a first-line (as monotherapy) or second-line (as adjunctive therapy) option for preventing the recurrence of mood episodes during longer-term therapy.

[Advances in the treatment of mania: aripiprazole].

Abstract:

Aripiprazole is a dopamine partial agonist antipsychotic drug that has just been approved in Europe for its use in the treatment of acute mania and for the prevention of manic episodes in bipolar disorder. Its efficacy in mania is superior to that of placebo, both as monotherapy and as adjunctive therapy, and comparable to that of haloperidol and lithium.

From the safety perspective it is remarkable that it is not highly sedative and does not impair the metabolic parameters.

The advantages of a non-sedative and metabolically neutral antimanic drug are particularly relevant in the long-term, due to their impact on cognition and quality of life. The experience on its use in routine clinical practice indicates that in order to avoid phenomena such as activation, abrupt worsening or akathisia, it is recommendable to start treatment with low doses and to increase them progressively, especially in those patients who are already receiving other drugs; moreover, it is advisable not to stop abruptly any ongoing treatment, unless there is an emergency, to transiently prescribe a concomitant benzodiazepine, and to maintain the dose that proved efficacious during the short term treatment during maintenance therapy.

Clinical Guidelines and Expert Opinion

By clicking the link below you can access the full text (PDF) of a review on treatment guidelines for acute bipolar mania:

Aripiprazole in patients with bipolar mania and beyond: an update of practical guidance.

Abstract:

Aripiprazole is an atypical antipsychotic with a pharmacological and clinical profile distinct from other atypical antipsychotics.A European multidisciplinary advisory panel of university-based experts in bipolar disorders convened in April 2010 to review new clinical guidelines for the management of mania and the role of aripiprazole in its treatment.

This report describes the consensus reached on how best to use aripiprazole in the treatment of mania.Current guidelines recommending aripiprazole for first-line treatment of mania have not generally translated to clinical practice. The panel agreed that clinicians may not feel sufficiently knowledgeable on how to use aripiprazole effectively in mania, and that the perception that aripiprazole is less sedating than other antipsychotics may hamper its use. There was consensus about the importance of ensuring that clinicians understood the distinction between antimanic efficacy and sedation. Most acutely manic patients may require night-time sedation, but continuous daytime sedation is not necessarily indicated and may interfere with long-term compliance.

If sedation is necessary, guidelines recommend the use of adjunctive benzodiazepines only for a short-time.Clinical practice guidelines widely recommend aripiprazole as a first-line treatment for mania. Although clinical trials may not represent all patient subpopulations, they show that aripiprazole is well tolerated and has a long-term stabilizing potential.

The successful use of aripiprazole rests on using the appropriate initial dose, titrating and adjusting the dose as needed and using appropriate concomitant medication to minimize any short-term adverse events. Low incidence of sedation makes aripiprazole a reasonable long-term treatment choice. If short-term sedation is required an adjunctive sedative agent can be added and removed when no longer needed.

Clinical considerations should influence treatment choice, and a better distinction between sedation and antimanic effects should be an educational target aimed to overcome potential barriers for using non-sedative antimanic agents such as aripiprazole.

Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance.

Abstract:

INTRODUCTION: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered.

AREAS COVERED: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder.

EXPERT OPINION: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole-valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients.

A UK panel consensus on the initiation of aripiprazole for the treatment of bipolar mania.

Abstract:

The objective of this consensus paper is to provide practical guidance on why and how aripiprazole, with its distinct pharmacological and side effect profile, should be used for treatment of acute bipolar mania.An advisory panel of UK healthcare professionals, with extensive experience of prescribing aripiprazole for acute bipolar mania, met to discuss its use in this setting.The panel agreed that aripiprazole is effective in treating bipolar mania when prescribed and dosed appropriately, in both the short and long term, as monotherapy or in combination with a mood stabilizer.

Unlike other atypical agents, aripiprazole has antimanic effects that are not associated with sedation, which is beneficial for patients, particularly in the long term. If rapid tranquillization is required when initiating aripiprazole in acutely disturbed patients, short-term coprescription of a benzodiazepine is recommended. Most side effects associated with aripiprazole occur within the first 1-3 weeks and are usually transient and easily treatable.

Aripiprazole poses low risk of metabolic side effects, sexual dysfunction, and anhedonia, which can facilitate treatment adherence and help improve clinical outcomes.Aripiprazole is an effective first-line treatment for acute bipolar mania with a favorable safety/tolerability profile.

Controlled Trials

Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-blind, randomized controlled trial.

Abstract:

Despite the fact that combination treatment for patients with acute bipolar is prevalent in clinical practice, the outcomes of adjunct treatment with aripiprazole and a mood stabilizer have rarely been reported. The aim of this single-blind, randomized, controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid (Ari+Val), compared with haloperidol plus valproic acid (Hal+Val), in acute manic patients.Treatment efficacy was prospectively assessed for 8 weeks in 42 patients with acute mania using the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale.

Emergent adverse events were assessed by the Drug-Induced Extrapyramidal Symptoms Scale and the Liverpool University Neuroleptic Side Effect Rating Scale.Both Ari+Val and Hal+Val produced a high rate of response (85.7% and 92.9%, respectively) and remission (82.1% and 85.7%, respectively) after the 8-week trial. Changes in the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale over the study period and time to remission and response were not significantly different between the 2 groups.

Patients treated with Ari+Val showed significantly fewer extrapyramidal adverse events than those treated with Hal+Val (t = -2.048, F = 40, P = 0.048). However, significant weight gain was more prevalent in the Ari+Val group than the Hal+Val group (t = 2.055, F = 40, P = 0.046).Our findings suggest that both combination strategies with Ari+Val and Hal+Val are beneficial for acute manic episode.

Although patients receiving Ari+Val showed fewer extrapyramidal symptoms than those taking Hal+Val, careful consideration of adverse events such as weight gain and sedation is warranted.

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol- controlled study

Abstract:

Well-tolerated and effective therapies for bipolar mania are required.To evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes.Patients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks.Mean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7). Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%).Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study.

Abstract:

To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania.Patients with acute bipolar I mania (DSM-IV-TR: YMRS > or =20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15-30 mg/day; n=155), placebo (n=165) or lithium (900-1500 mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12.

Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (-4.3 vs.-2.8; p=0.003), and up to Week 3 (-12.6 vs. -9.0; p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 (-12.0 vs. -9.0; p=0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (-14.5) and lithium (-12.7).

Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole (56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation; with lithium were nausea, headache, constipation, and tremor.Aripiprazole provided statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study.

Abstract:

The authors evaluated the efficacy and safety of adjunctive aripiprazole in bipolar I patients with mania partially nonresponsive to lithium/valproate monotherapy.This multicenter, randomized, placebo-controlled study included outpatients experiencing a manic or mixed episode (with or without psychotic features). Patients with partial nonresponse to lithium/valproate monotherapy (defined as a Young Mania Rating Scale total score >/=16 at the end of phases 1 and 2, with a decrease of </=25% between phases) with target serum concentrations of lithium (0.6-1.0 mmol/liter) or valproate (50-125 mug/ml) were randomly assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30 mg/day) or placebo (N=131) for 6 weeks.

Mean improvement from baseline in Young Mania Rating Scale total score at week 6 (primary endpoint) was significantly greater with aripiprazole (-13.3) than with placebo (-10.7). Significant improvements in Young Mania Rating Scale total score with aripiprazole versus placebo occurred from week 1 onward. In addition, the mean improvement in Clinical Global Impression Bipolar Version (CGI-BP) severity of illness (mania) score from baseline to week 6 was significantly greater with aripiprazole (-1.9) than with placebo (-1.6). Discontinuation rates due to adverse events were higher with aripiprazole than with placebo (9% versus 5%, respectively).

Akathisia was the most frequently reported extrapyramidal symptom-related adverse event and occurred significantly more frequently among those receiving aripiprazole (18.6%) than among those receiving placebo (5.4%). There were no significant differences between treatments in weight change from baseline to week 6 (+0.55 kg and +0.23 kg for aripiprazole and placebo, respectively; last observation carried forward).

Adjunctive aripiprazole therapy showed significant improvements in mania symptoms as early as week 1 and demonstrated a tolerability profile similar to that of monotherapy studies.

A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.

Abstract:

The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder.This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%.Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%).

For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups.

There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation.Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial.

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