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

  • Allan H. Young (a1), Dan A. Oren (a2), Adam Lowy (a3), Robert D. McQuade (a4), Ronald N. Marcus (a2), William H. Carson (a4), Nina H. Spiller (a2), Anne F. Torbeyns (a5) and Raymond Sanchez (a4)...

Abstract

Background

Well-tolerated and effective therapies for bipolar mania are required.

Aims

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.

Method

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.

Results

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%).

Conclusions

Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

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Copyright

Corresponding author

Allan H. Young, LEEF Chair and Co-Director, Institute of Mental Health, Department of Psychiatry, University of British Columbia, Suite 430–5950 University Boulevard, Vancouver, BC V6T 1Z3, Canada. Email: allanyoun@gmail.com

Footnotes

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Declaration of interest

This study was supported by Bristol-Myers Squibb (Princeton, New Jersey) and Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan). A.H.Y received speaker fees from numerous pharmaceutical companies, including Bristol-Myers Squibb, for lecturing on this topic. A.L. received speaker fees from Eli Lilly, AstraZeneca and Pfizer. R.D.McQ., R.S. and W.H.C. are employees of Otsuka Pharmaceutical Development & Commercialization Inc. D.A.O., R.N.M., N.H.S. and A.F.T. are employees of Bristol-Myers Squibb.

Footnotes

References

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21 Vieta, E, Bourin, M, Sanchez, R, Marcus, R, Stock, E, McQuade, R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania. Doubleblind, randomised, comparative 12-week trial. Br J Psychiatry 2005; 187: 235–42.
22 Keck, PE, Orsulak, PJ, Cutler, AJ, Sanchez, R, Torbeyns, A, Marcus, RN, et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord 2008; Oct 2: Epub ahead of print.
23 Tohen, M, Goldberg, JF, Gonzalez-Pinto Arrillaga, AM, Azorin, JM, Vieta, E, Hardy-Bayle, MC, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003; 60: 1218–26.
24 Bowden, CL, Grunze, H, Mullen, J, Brecher, M, Paulsson, B, Jones, M, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005; 66: 111–21.
25 McIntyre, RS, Brecher, M, Paulsson, B, Huizar, K, Mullen, J. Quetiapine or haloperidol as monotherapy for bipolar mania – a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol 2005; 15: 573–85.
26 Smulevich, AB, Khanna, S, Eerdekens, M, Karcher, K, Kramer, M, Grossman, F. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. Eur Neuropsychopharmacol 2005; 15: 7584.
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Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study

  • Allan H. Young (a1), Dan A. Oren (a2), Adam Lowy (a3), Robert D. McQuade (a4), Ronald N. Marcus (a2), William H. Carson (a4), Nina H. Spiller (a2), Anne F. Torbeyns (a5) and Raymond Sanchez (a4)...
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eLetters

ethics of a placebo controlled trial in acute mania

Rajesh Jacob, Consultant Psychiatrist
10 February 2009

This study is quite similar to a previous trial of Risperidone in acute mania compared with a placebo which raised serious ethical concerns and which was published in this journal a few years back.(Khanna., et al 2005)It is ethically questionable to use a placebo controlled arm when there are clinically effective treatments available to treat the condition (WMA,2008).It is is quite strange that acutely unwell manic patients requiring hospitalisation had given valid written informed consent to participate in the study.There is no mention of mental capacity assessment in these patients before they gave consent.Considering some of the centres where these studies are conducted, sometimes consent is obtained from family members or relatives when patients are too unwell to give consent.The authors have failed to state this point as well in their article.These points need to be taken into account before any placebo controlled trials are carried out in conditions where there are proven effective treatments available.

ReferencesWMA (2008) Ethical Principles for Medical Research Involving Human Subjects

Khanna S, Vieta E, Lyons B, Grossman F, Eerdekens M, Kramer M. Risperidone in the treatment of acute mania. Br J Psychiatry 2005; 187: 229-234.
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Aripiprazole Vs haloperidol in acute mania.

Kamini Vasudev, Specialist Registrar, Adult Psychiatry
10 February 2009

We read with keen interest the study by Young et al (1), which evaluates the efficacy and safety of a relatively newer antipsychotic agent in acute mania. We would like to make a few comments.

First, we are intrigued to note that haloperidol was chosen as a comparator in this study when previously, a similar methodologically robust study has been performed comparing Aripiprazole with haloperidol inacute mania (2). That study however did not have a placebo arm.

Haloperidol has been conventionally used as an active control when examining the efficacy of atypical antipsychotics in the treatment of acute mania in patients with bipolar disorder. This is because extensive data is available to confirm its usage in this condition. However, in the present time clinical use of haloperidol is limited because of its relatively higher rates of extrapyramidal side-effects contributing to poor tolerability, particularly in bipolar patients. Sufficient evidence is now available to confirm efficacy of other more widely used and better tolerated agents than haloperidol in acute mania. The current evidence based guidelines on bipolar disorder (3), recommend use of atypical antipsychotic agents and valproate as one of the first line agents for treating acute mania. Therefore, would it have been more clinically relevant to compare the efficacy and safety of Aripiprazole with one of these newer agents?

Second, the authors have not made any reference to an important issuerelated to safety of Aripiprazole. Serious adverse events were reported in19 (11.4%) patients in Aripiprazole group as compared to 5 (3%) patients in haloperidol group. We think that more than 1 in 10 patients developing a serious adverse event, leading to worsening in the psychiatric symptoms,is a clinically significant finding and merits further discussion. It is possible that this was related to the effects of Aripiprazole independently or due to the relatively rapid wash out period (2-14 days) from the previous psychotropic agent. Aripiprazole being a partial agonistat post-synaptic D2 receptors can worsen psychosis and agitation (4). Thiscan be worse if the changeover from a D2 antagonist antipsychotic (which causes post synaptic D2 receptor upregulation) is not gradual (4). Though 'recent treatment with long-acting antipsychotics' was one of the exclusion criteria cited in this study, would it be worth analysing the data on these 19 patients to examine the factors contributing to worsening?

Third, the names, doses and duration of concomitant anxiolytic medications used in the trial are not clear. The authors mention in the methodology that 'benzodiazepines were permitted, the dose was tapered from Clinically, agitation is a common side-effect of Aripiprazole and is reported as the commonest reason for its discontinuation (5). It would be useful to compare doses of rescue anxiolytic medications required in the three groups in this study. This is important as it is possible that the increased use of anxiolytics in Aripiprazole group led to decreased reporting of akathisia.

References

1.Young AH, Oren D A, Lowy A et al. (2009). Aripiprazole monotherapyin acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry; 194: 40-48.

2.Vieta, E., Bourin, M., Sanchez, R., et al (2005) Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry; 187, 235-242.

3.Goodwin, G.M. (2003) For the consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treatingbipolar disorder: recommendations from the British Association for Psychopharmacology. J of Psychopharmacology; 17 (2): 149-173.

4.Ramaswamy S, Vijay D, William M, Pirzada S, Fernandes P, FrederickP (2004). Aripiprazole possibly worsens psychosis. International Clinical Psychopharmacology; 19(1): 45-48.

5.Shajahan P, MacRae A, Bashir M, and Taylor M (2008). Who responds to aripiprazole in clinical practice? An observational study of combination versus monotherapy. J Psychopharmacol; 22(7): 778 - 783.
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Conflict of interest: None Declared

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Aripiprazole for mania

Lindsay Moran, Doctor
24 January 2009

We read with a mixture of interest, concern and scepticism the recentarticle by (Young et al., 2009) describing the results of a randomized control trial of Aripiprazole monotherapy in acute mania.

The World Medical Association declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects (WMA, 2008) has since 1964 been a benchmark for trialists around the world to adhere to. Trials in developing countries in the past using placebos as well as the FDAs decision to recently adopt the less rigorous Good Clinical Practice as an alternative has invited numerous criticisms (Lurie and Wolfe, 1997),(Lurie and Greco, 2005).

The authors of this study carefully selected a population of manic patients to be enrolled and presumably the study protocol was designed prior to FDA adopting these changes. Surely it would not have been difficult to find a standard comparator that is well established as a treatment option for this condition, instead of subjecting patients with serious enduring mental illnesses, most likely to deteriorate without appropriate treatment, to a placebo intervention. For patients allocated to the placebo arm, this was discontinued after an arbitrary 3 weeks. If the authors decided it was unethical to continue a placebo arm beyond 3 weeks, we wonder why this arbitrary cut off was chosen rather than say forexample 2 weeks.

Also it was interesting to note that patients not well enough to be discharged at the end of 3 weeks, who would essentially be regarded as treatment failures, were excluded from all further analyses thereby biasing results favourably towards the intervention arms. Excluding data for patients who were not well to be discharged at the end of 3 weeks seems like a disservice to those ill people who had given their informed consent to participate in the trial with a placebo arm. The authors conclude that the efficacy of aripiprazole is similar to haloperidol and that aripiprazole was better tolerated in terms of extrapyramidal side effects. However the aripiprazole arm had more serious adverse events which were statistically significant compared to haloperidol (see figure 1). With regards to the serious adverse events there could potentially beimportant clinical implications in prescribing of aripiprazole.

The eventual conclusion, unsurprisingly, is that there is no significant difference between aripiprazole and haloperidol. We wonder ifsuch a trial could have been conducted using a non-inferiority model, using the same comparators but excluding the placebo arm which appears totally unnecessary in this context. There is a need for more pragmatic clinical trials to be designed to mimic patients seen in the general population rather than carefully chosen ones seen in rigid randomized control trial settings (Lieberman and Stroup, 2003). We hope that future researchers will acknowledge that although demonstrating beneficial effects of a new intervention is easier against placebo, the larger interests of patient care should drive new methodologies forward and the noble interest behind the 1964 WMA declaration is upheld by individual researchers regardless of regulatory authorities reducing the threshold byabandoning the Helsinki declaration.

References

LIEBERMAN, J. A. & STROUP, T. S. (2003) Guest editors' introduction: what can large pragmatic clinical trials do for public mental health care? Schizophr Bull, 29, 1-6.

LURIE, P. & GRECO, D. B. (2005) US exceptionalism comes to research ethics. Lancet, 365, 1117-9.

LURIE, P. & WOLFE, S. M. (1997) Unethical trials of interventionsto reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med, 337, 853-6.

WMA (2008) Ethical Principles for Medical Research Involving Human Subjects.

YOUNG, A. H., OREN, D. A., LOWY, A., MCQUADE, R. D., MARCUS, R. N., CARSON, W. H., SPILLER, N. H., TORBEYNS, A. F. & SANCHEZ, R. (2009) Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry, 194, 40-8.
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