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Effectiveness of aripiprazole v. Haloperidol in acute bipolar mania: Double-blind, randomised, comparative 12-week trial

  • Eduard Vieta (a1), Michel Bourin (a2), Raymond Sanchez (a3), Ronald Marcus (a3), Elyse Stock (a4), Robert McQuade (a5), William Carson (a6), Neveen Abou-Gharbia (a5), Rene Swanink (a7) and Taro Iwamoto (a8)...

Abstract

Background

Despite several treatment options, adherence to therapy is poor in patients with bipolar disorder.

Aims

A double-blind, controlled comparison of aripiprazole and haloperidol in patients with bipolar I disorder experiencing acute manic or mixed episodes.

Method

Patients (n=347) were randomised to receive aripiprazole or haloperidol in this 12-week, multicentre study. The primary outcome measure was the number of patients in response (550% improvement from baseline in Young Mania Rating Scale score) and receiving therapy at week 12.

Results

At week 12, significantly more patients taking aripiprazole (49. 7%) were in response and receiving therapy compared with those taking haloperidol (28. 4%; P<0. 001). Continuation rates differed markedly between treatments (week 12: aripiprazole, 50. 9%; haloperidol, 29. 1%). Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (62. 7% v. 24. 0%).

Conclusions

Aripiprazole showed superior levels of response and tolerability to haloperidol in the treatment of an acute manic episode for up to 12 weeks.

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Copyright

Corresponding author

Dr Eduard Vieta, Director of Research, Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona 08036, Spain. Tel: +34 93 227 5401/5494; e-mail: evieta@clinic.ub.es

Footnotes

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Declaration of interest

This study was sponsored by Bristol-Myers Squibb Company Princeton, New Jersey USA, and Otsuka Pharmaceutical Co. Ltd, Tokyo Japan.

Footnotes

References

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Effectiveness of aripiprazole v. Haloperidol in acute bipolar mania: Double-blind, randomised, comparative 12-week trial

  • Eduard Vieta (a1), Michel Bourin (a2), Raymond Sanchez (a3), Ronald Marcus (a3), Elyse Stock (a4), Robert McQuade (a5), William Carson (a6), Neveen Abou-Gharbia (a5), Rene Swanink (a7) and Taro Iwamoto (a8)...
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eLetters

The importance of appropriate administration of atypical antipsychotics for maximum effectiveness

Eduard Vieta, Director of the Bipolar Disorders Program
18 January 2006

Sir,

We thank you for raising these important issues for discussion (Electronic letter: Aripiprazole – potential for worsening psychosis and agitation – caution for use in mania? P Gangopadhyay). The case studies cited in your letter suggest the emergence of some psychotic symptoms following aripiprazole treatment; however, in these cases, aripiprazole was added to existing antipsychotic therapy, either to haloperidol, atypicals or to both. This is not consistent with the prescribing regimen outlined in the Summary of Product Characteristics (SPC) for aripiprazole,which recommends monotherapy starting at 10 mg/day or 15 mg/day (Abilify, 2005). Clinical studies to date have evaluated aripiprazole as monotherapy, both in schizophrenia and in bipolar mania. Thus, the safety and efficacy of aripiprazole in combination regimens has not been clearly established and caution is advised when it is used in combination with other centrally acting agents (Abilify, 2005).

Rapid switching to aripiprazole from an agent that has antagonist activity at dopamine receptors may lead to rebound phenomena, resulting from increased intrinsic stimulation of receptors. Thus, switching from D2antagonistic agents should be carried out cautiously, with a slow taperingof previous drug administration over several weeks and increased dosing ofaripiprazole over 1 or 2 weeks. As with other antipsychotic agents, when switching to aripiprazole from a sedating antipsychotic, patients should be monitored for rebound signs of activation, such as insomnia (Travis et al, 2005). In the pooled analysis of short-term studies (Marder et al, 2003), the incidence of akathisia was 6.8% with placebo, 10.0% with aripiprazole, and 18.0% with haloperidol. Insomnia occurred in a similar proportion of patients in each group (placebo, 18.6%; aripiprazole, 24.1%;haloperidol, 24.0%).

In clinical studies with aripiprazole, over 6,000 patients with schizophrenia received aripiprazole. In a pooled analysis of almost 1,000 patients treated with aripiprazole during short term trials, psychosis as a serious adverse event did not occur more often with aripiprazole than with haloperidol or placebo (aripiprazole, 1.1% (n = 10); haloperidol, 1.5% (n = 3); placebo, 1.5% (n = 6)) and led to discontinuation in a lowerproportion of aripiprazole-treated than in placebo-treated patients (aripiprazole, 3.6%; haloperidol, 1.5%; placebo, 6.1%) (Marder et al, 2003).

The efficacy of aripiprazole in patients with bipolar mania is well established. Two 3-week studies have shown that aripiprazole is efficacious and well-tolerated compared with placebo in bipolar mania, with superiority to placebo observed as early as day 4 in both studies (Keck et al, 2003; Sachs et al, in press). In addition, aripiprazole has been shown to be superior to placebo at preventing relapse in patients with a recent manic or mixed episode who had been stabilized on aripiprazole for at least 6 weeks prior to randomization (Keck et al, In press).

In the current study (Vieta et al, 2005), a significantly greater number of aripiprazole-treated patients than haloperidol-treated patients remained on treatment and achieved a clinical response, thus, adding to the body of evidence demonstrating the effectiveness of aripiprazole in treating bipolar mania. In a recent report on pooled data from two placebo-controlled studies (Sachs et al, 2005), agitated manic patients had significant improvements with aripiprazole over placebo.

Eduard Vieta Director of Research, Clinical Institute of Neuroscience, Hospital Clinic,University of Barcelona, IDIBAPS, Barcelona 08036, Spain.Tel: +34 93 227 5401/5494; email: evieta@clinic.ub.es

ReferencesAbilify (2005) Abilify package insert. Princeton, NJ: Bristol-Myers Squibb, Co.Keck, P. E., Calabrese, J. R., Mcquade, R. D., et al (In press) A Placebo-Controlled 26-Week Trial of Aripiprazole in Recently Manic Patients With Bipolar I Disorder. J Clin Psychiatry.Keck, P. E., Jr., Marcus, R., Tourkodimitris, S., et al (2003) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry, 160, 1651-1658.Marder, S. R., McQuade, R. D., Stock, E., et al (2003) Aripiprazole in thetreatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res, 61, 123-136.Sachs, G., Sanchez, R., Marcus, R., et al (in press) Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol.Sachs, G., Pultz, J., Pikalov, A., et al (2005) Antimanic response to aripiprazole with high versus low agitation. Neuropsychopharmacol. 30, (Suppl 1), S236.Travis, M. J., Burns, T., Dursun, S., et al (2005) Aripiprazole in schizophrenia: consensus guidelines. Int J Clin Pract, 59, 485–495.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.
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Aripiprazole- potential for worsening psychosis and agitation- caution for use in mania?

Partha Gangopadhyay, Senior House Officer
30 November 2005

Aripiprazole acts as a dopamine agonist in hypodopaminergic states and as a dopamine antagonist in hyperdopaminergic states (Stahl 2001a,b). There have been a series of reports of worsening psychosis (Ramaswamy et al, 2004), worsening paranoia and agitation (Reactions Weekly, 2004), worsening of schizoaffective disorder (Reeves et al, 2004) and worsened agitation (Dequardo, 2004) associated with the use of aripiprazole. The mechanisms by which aripiprazole might contribute to worsening in psychosis in certain circumstances can be discussed with reference to its mode of action.

The partial dopamine agonist action of aripiprazole on presynaptic receptors could reduce dopamine, which would be beneficial in schizophrenia, whilst the action on postsynaptic receptors (when there is post synaptic receptor up regulation) may lead to stimulation, thus exacerbating psychosis (Ramaswamy et al, 2004). Prior use of atypical antipsychotics such as risperidone, olanzapine and quetiapine could lead to post synaptic D2 receptor upregualtion (Silvestri et al, 2000) resulting in aripiprazole acting as a partial agonist at post synaptic receptors causing a worsening in psychosis.

It has also been postulated that a rapid switch to aripiprazole may require the dopamine system some time to “reset” itself and thus in the short term may increase dopamine (Ramaswamy et al, 2004) potentially worsening psychosis. Another possibility is that the combined use of aripiprazole with other antispsychotics may lead to agonistic action at serotonin 5HT1A receptor due to additive effects. This in turn could lead to increased serotonin levels resulting in worsening symptoms.

The role of agitation as a side effect of aripiprazole needs to be considered. Aripiprazole has been shown to produce akathisia and insomnia (Marder et al, 2003), and the combination of these in a background of worsening psychosis could be linked to aggression. It can also be speculated that aripiprazole with its partial agonist action might lead toa hyperdopaminergic state in key brain circuits that regulate emotion and violence in the prefrontal cortex and limbic system structures (Davidson et al, 2000).

References –

Davidson RJ, Putnam KM, Larson CL (2000) Dysregulation in the neural circuitry of emotion regulation- possible prelude to violence. Science. 289:591-594.

Dequardo JR (2004) Worsened agitation with aripiprazole- adverse effect of dopamine partial agonism? Journal of Clinical Psychiatry. 65(1):132-133.

Marder SR, Mcquade RD, Stock E, Kaplita S, Safferman AZ et al (2003) Aripiprazole in the treatment of schizophrenia- safety and tolerability inshort-term, placebo-controlled trials. Schizophrenia Research. 61:123-126.

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

Reactions Weekly (2004) Aripiprazole: Exacerbation of paranoia and agitation: 2 case reports. 1: 6-6(1).

Reactions Weekly (2004) Aripiprazole: First report of excerbation of psychotic disorders: 4 case reports. 1: 6-7(2).

Reeves RR, Mack JE (2004) Worsening schizoaffective disorder with aripiprazole. American Journal of Psychiatry. 161:7.

Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ et al (2000) Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans - a clinical PET study. Psychopharmacology (Berlin). 152:174-180.

Stahl SM (2001 a) Dopamine system stabilizers, aripiprazole and the next generation of antipsychotics, part 1, “Goldlocks” actions at dopaminereceptors. Journal of Clinical Psychiatry. 62:841-842.

Stahl SM (2001 b) Dopamine system stabilizers, aripiprazole and the next generation of antipsychotics, part 2, illustrating their mechanism ofaction. Journal of Clinical Psychiatry. 62:923-924.
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Conflict of interest: None Declared

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Effectiveness and efficacy are not the same

Eduard Vieta, Director of the Bipolar Disorders Programme
18 November 2005

Sir,

We appreciate the points of Heres et al (in press) in their letter; however, there may be some misunderstanding regarding differences between efficacy versus effectiveness trials:

1.Although the withdrawal rate due to lack of efficacy with aripiprazole was higher than haloperidol (Vieta et al, 2005), a large number of haloperidol-treated patients discontinued early due to an adverse event and were no longer at risk to discontinue for lack of efficacy. Investigators could only attribute discontinuation to one reasonand discontinuation due to an adverse event took precedence over lack of efficacy.

Moreover, the withdrawal rate due to lack of efficacy for aripiprazole is comparable to other atypicals in 12-week mania studies (McIntyre et al, 2005; Tohen et al, 2003), so is not unusually high. The percentage of patients withdrawing for lack of efficacy with haloperidol in this study, however, is lower than previous studies (McIntyre et al, 2005; Tohen et al, 2003).

As this trial was designed as an effectiveness trial, the prespecified definition of response rate (primary outcome) was “YMRS reduction ³50% and continuation of therapy”. Therefore, the response ratesreported are neither LOCF nor OC, but represent response in the presence of therapy continuation, per the protocol. The exclusion of patients, who were not doing well at Week 3, for ethical reasons, did not affect the conclusions. Carrying forward the data from excluded patients (LOCF analysis) showed no difference in YMRS reduction between groups. Furthermore, there were no clinically relevant differences in secondary endpoints (OC or LOCF analysis), showing similar efficacy for the two treatments. The only between-treatment difference was clinical effectiveness, which incorporates efficacy and treatment continuation.

2.Interestingly, the rate of EPS-related adverse events with haloperidol in this study was similar to those reported with lower haloperidol doses in 12-week mania trials, where concomitant anticholinergic use was permitted (see table). The difference in discontinuation rate (aripiprazole, 49%; haloperidol, 71%) between the twogroups may reflect EPS-related events leading to discontinuation (e.g. extrapyramidal syndrome: aripiprazole, 3%; haloperidol, 19%). As the EPS rates are similar to other studies, this continuation difference is an important finding.

Although anticholinergics were prohibited, 9.6% of patients received medications for EPS (protocol deviations, biperiden, n=23; trihexyphenidyl, n=6; pridonal, n=2; tropatepine, n=2; procyclidine, n=1);the proportion was ~six-fold greater in the haloperidol group (17% vs. 3%).

Although significant mania improvement with antipsychotics occurs as early as Day 4, the full effect is usually not reached until 1–2 weeks (Keck et al, 2003; McIntyre et al, 2005). Benzodiazepines were permitted only during the initial 10-day period. After 10 days, benzodiazepine use was not allowed for any reason, including emergence of any side effects. As benzodiazepines may provide some relief from EPS, haloperidol-treated patients may have benefited in this regard.

Although every trial design can be criticized, we think the results of our study accurately reflect the fact that manic patients are more likely to respond and stay on aripiprazole than on haloperidol over a 12-week period, which was the primary outcome of the study.

Eduard Vieta, MD, PhD,

Address of corresponding author: Dr Eduard Vieta. E-mail: evieta@clinic.ub.es. Phone: +34 93 227 5401/5494. Clinical Institute of Psychiatry and Psychology, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona 08036, Spain.

ReferencesHeres, S., Hamann, J. D., Kissling, W., et al (in press) Potential bias inantipsychotic drug trials [Letter]. Br J Psychiatry.Keck, P. E., Jr., Marcus, R., Tourkodimitris, S., et al (2003) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry, 160, 1651-1658.McIntyre, R. S., Brecher, M., Paulsson, B., et al (2005) Quetiapine or haloperidol as monotherapy for bipolar mania-a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol, 15, 573-585.Smulevich, A. B., Khanna, S., Eerdekens, M., et al (2005) 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, 15, 75-84.Tohen, M., Goldberg, J. F., Gonzalez-Pinto Arrillaga, A. M., et al (2003) A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry, 60, 1218-1226.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.
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Conflict of interest: None Declared

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Potential bias in antipsychotic drug trials

Stephan Heres, Psychiatrist
08 October 2005

Sir,

in a review on industry sponsored comparisons of atypical antipsychotics we identified a number of sources of bias potentially effecting the overall outcome of a trial (Heres et al, 2005). Following upon this publication we are committed to prospectively discuss bias in antipsychotic drug trials. In the report of Vieta et al. stating the conclusion “that aripiprazole offers superior effectiveness to haloperidolin the treatment of patients with acute mania for up to 12 weeks” we detected some potential sources of bias (Vieta et al, 2005).

1.We would like to ask the authors why the threefold higher rate of discontinuations due to lack of efficacy in the aripiprazole group, a highly statistically and clinically significant difference (Chi2=10.9; p<0.001) has not even be commented on. In the light of this we wonder whether the conclusion that aripiprazole is as effective as haloperidol can be deemed appropriate. Although statistically significantly more patients in the aripiprazole group responded to treatment, this was only the case in the observed cases (OC), not in the last observation carried forward (LOCF) analysis. As a matter of fact any analysis of data facing adrop-out rate as high as 60% is problematic regardless of the model applied. Still LOCF is currently more a standard than an OC analysis. Furthermore in a study design excluding all non-responders at week 3 from continuation although a considerable number of patients dropped out due toinefficacy in the aripiprazole group randomisation is clearly corrupted and the 12 weeks results are of questionable validity.

2.Certainly, the tolerability of aripiprazole was much better than that of haloperidol but is this really surprising given the high haloperidol dose used? This problem could have been avoided by the use of prophylactic (or at least prn) anticholinergic agents which has recently been shown to be very effective (Rosenheck et al, 2003). The authors arguethat this was not allowed in order to avoid masking of differences in tolerability. Accordingly it is then hard to understand why the use of benzodiazepines was allowed though effective in the treatment of side-effects likely to appear with aripiprazole such as akathisia and insomnia (Casey et al, 2003). Last not least as the focus of the study was effectiveness rather than efficacy acknowledged routine treatments such asthe use of antiparkinsonian drugs should be allowed.

Certainly without the pharmaceutical industry antipsychotic drug treatment would still be in the stone age and aripiprazole is definitely agreat contribution. However we must come back to more objective and balanced designing and reporting of antipsychotic drug trials.

Stephan Heres MD, Johannes Hamann MD, Werner Kissling MD and Stefan Leucht MD

address of corresponding author:Dr. Stephan Heres email: s.heres@lrz.tum.dephone: +49 89 4140-4227, fax -7339Klinik und Poliklinik fuer Psychiatrie und Psychotherapie der Technischen Universitaet Muenchen, Ismanigerstrasse 26, 81675 Muenchen, GermanyAddress of Dr. Hamann and Dr. Leucht is identical.Conflicts of interest: none

Reference List

1. Casey, D. E., Carson, W. H., Saha, A. R., et al (2003) Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl), 166, 391-399.

2. Heres, S, Davis, J, Maino, K, et al (2005) Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine and Quetiapine Beats Olanzapine Again.

An exploratory analysis of head-to-head studies on second-generation antipsychotics. Am.J.Psychiatry, in press.

3. Rosenheck, R., Perlick, D., Bingham, S., et al (2003) Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. JAMA, 290, 2693-2702.

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