Clinical Institute of Neuroscience, University of Barcelona, Spain
Neurobiologie de lAnxiété et de la Depression, Faculté de Médecine, Nantes, France
Bristol-Myers Squibb Co., Wallingford, Connecticut, USA
Bristol-Myers Squibb Co., Wallingford, Connecticut, USA
Bristol-Myers Squibb Co., Plainsboro, New Jersey, USA
Bristol-Myers Squibb Co., Lawrenceville, Princeton, New Jersey, USA
Otsuka America Pharmaceutical Inc., Princeton, New Jersey, USA
Bristol-Myers Squibb Co., Lawrenceville, Princeton, New Jersey, USA
Bristol-Myers Squibb Co., Braine lAlleud, Belgium
Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan
on behalf of the Aripiprazole Study Group
Correspondence: 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{at}clinic.ub.es
Declaration of interest This study was sponsored by Bristol-Myers Squibb Company, Princeton, New Jersey, USA, and Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan.
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ABSTRACT |
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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 ( 50% 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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INTRODUCTION |
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METHOD |
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Exclusion criteria were the presence of rapid-cycling bipolar I disorder; duration of the current manic episode of more than 4 weeks; proven substance misuse; patient considered unresponsive to antipsychotics; patient at significant risk of suicide; recent treatment with a long-acting antipsychotic, lithium or divalproate; use of psychotropic medications (other than benzodiazepines) within 1 day of randomisation; fluoxetine treatment in the past 4 weeks; and previous enrolment in an aripiprazole clinical study.
Written informed consent was obtained from the patient or a legally acceptable representative. The study protocol, procedures and consent statement were approved by the institutional review boards of all participating sites.
Study design
In this 12-week, multicentre, double-blind comparative trial, patients were
randomised to receive either aripiprazole or haloperidol, using a fixed
randomisation schedule allocating patients between the two treatment arms in a
1:1 ratio.
Phase 1 (weeks 13)
Following a wash-out period of 13 days, patients fulfilling the
entry criteria were randomised to receive aripiprazole 15 mg per day or
haloperidol 10 mg per day. At the end of week 1 or 2, patients showing a poor
response to therapy, measured using the Clinical Global Impression
(Spearing et al,
1997) and defined as a Clinical Global ImpressionBipolar
Disorder (CGIBP) Improvement (mania) score of 3 or above, could have
their daily dosage increased to aripiprazole 30 mg or haloperidol 15 mg.
Patients intolerant of the higher dosage could return to the initial lower
dosage. Patients unable to tolerate 15 mg aripiprazole or 10 mg haloperidol
discontinued the trial.
At the end of this 3-week period, patients with a CGIBP Severity (mania) score of 4 or more (moderately ill or worse) or a MontgomeryÅsberg Depression Rating Scale (MADRS; MontgomeryÅsberg, 1979) score of 18 or more discontinued the trial.
Phase 2 (weeks 412)
Patients remaining in the study throughout weeks 412 continued with
the treatment and dose regimen prescribed in week 3. The dosage of study
medication could be decreased from 30 mg to 15 mg per day for aripiprazole and
from 15 mg to 10 mg per day for haloperidol if necessary for tolerability, but
not increased. If this lower dosage was not tolerated, the patient was
withdrawn from the study.
Patients were also withdrawn if there was a lack of maintained effect (originally observed at week 3), or intolerance as indicated by any of the following: increase in CGIBP Severity (mania) score from previous assessment, confirmed on two consecutive visits; hospitalisation for manic or depressive symptoms; need for additional or increased doses of psychotropic medications; MADRS score of 18 or more; or need for concomitant medication for symptomatic treatment of side-effects.
Efficacy assessments
The primary efficacy outcome was an effectiveness measure of response.
Responders were defined as patients who remained in therapy at week 12 and had
a 50% or greater improvement from baseline in YMRS total score. Assessments
(YMRS, CGIBP and MADRS) were made at baseline, days 4, 7, 10 and 14,
then weekly until week 6 and every 2 weeks during weeks 612. Secondary
efficacy measures included the response rate at week 3 (i.e. remaining in
treatment with a 50% or greater improvement in YMRS total score from baseline)
and time to discontinuation for any reason.
Safety and tolerability assessments
Adverse event reports were gathered throughout the study and evaluated by
investigators for severity and likely relationship to study medication.
Extrapyramidal symptoms were evaluated using the SimpsonAngus Scale
(SAS; Simpson & Angus,
1970), the Barnes Akathisia Scale (BAS;
Barnes, 1989) and the Abnormal
Involuntary Movement Scale (AIMS; National
Institute of Mental Health, 1975), administered at baseline and at
weeks 1 (except for AIMS), 2, 3, 6 and 12.
Patients vital signs were measured at screening and each assessment visit during the study. Electrocardiograms, serum prolactin concentrations, routine laboratory tests, body weight measurements and physical examinations were performed at screening and at weeks 3, 8 (except physical examinations) and 12.
Concomitant medications
The following medications were prohibited during the study: antipsychotic
agents, mood stabilisers/anti-epileptics, lithium, benzodiazepines (except
lorazepam 4 mg per day or oxazepam 60 mg per day during days 14, and
lorazepam 2 mg per day or oxazepam 30 mg per day during days 510),
antidepressants and all other psychotropic drugs. Anticholinergic agents were
not permitted for symptomatic or prophylactic treatment of extrapyramidal
symptoms during the study, because of their potential to mask differences in
treatment tolerability between the two agents.
Statistical methods
The primary outcome measure (number of patients on treatment and in
response at week 12) was evaluated by the CochranMantelHaenszel
test (unstratified) using the safety sample (patients randomised to treatment
and who took at least one dose of study medication). Patients who discontinued
the study during the 12-week phase and patients without a 50% or greater
improvement in YMRS total score at week 12 were considered to be
non-responders. Response rates at week 3 were also evaluated using the
CochranMantelHaenszel test. Change from baseline measures were
evaluated by analysis of covariance (ANCOVA) with treatment as main effect and
baseline value as covariate. All efficacy analyses were performed on the last
observation carried forward (LOCF) and observed cases data-sets. Time to
discontinuation was evaluated using the log rank test.
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RESULTS |
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Patient disposition
Overall, 229 randomised patients (66.0%) completed the first 3 weeks of
treatment: 134 (76.6%) of the 175 patients receiving aripiprazole and 95
(55.2%) of the 172 patients receiving haloperidol (P < 0.001)
a difference of 21.3% (95% CI 11.430.9). At the end of the
second phase, 89 (50.9%) and 50 (29.1%) patients had completed 12 weeks of
aripiprazole or haloperidol treatment, respectively (P < 0.001;
difference 21.8%, 95% CI 11.431.7).
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Treatment with aripiprazole and haloperidol was associated with marked mean reductions in CGIBP Severity (mania) scores (Fig. 4). Over the 12-week study, aripiprazole and haloperidol reduced CGIBP Severity (mania) scores by 2.58 and 2.27 points, respectively (LOCF analysis; P=0.095). Mean decreases in CGIBP Severity (mania) scores were also similar in the two groups using observed cases analysis (aripiprazole -3.71, haloperidol -3.55). Other efficacy measures showed similar changes in the aripiprazole and haloperidol groups with both LOCF and observed cases analyses (Table 2).
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At week 3 of the first phase, 50.9% of aripiprazole-treated patients responded to treatment compared with 42.6% of haloperidol-treated patients (P=0.126; RR=1.19, 95% CI 0.951.50) (see Fig. 2). An initial rapid reduction in YMRS was noted in the first 3 weeks of therapy (aripiprazole -15.7, haloperidol -15.7; LOCF), with responses sustained and improving over subsequent weeks of treatment. Marked reductions in CGIBP Severity scores for mania (aripiprazole -2.0, haloperidol -1.9; LOCF) and overall bipolar illness (aripiprazole -1.6, haloperidol -1.4; LOCF) were also observed at week 3 with both treatments, whereas CGIBP depression scores showed minimal change from baseline in either group (aripiprazole 0.0, haloperidol 0.1; LOCF). The proportion of patients in remission (YMRS total score < 12) was 35% with aripiprazole and 31% with haloperidol treatment at week 3. Differences between the groups were not statistically significant for any of these assessments.
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Patients experiencing a switch to depression were defined post hoc
as those whose CGIBP depression sub-scale scores worsened by 2
points (CGIBP depression scores were available for 337 of the
participants). Of 173 patients treated with aripiprazole, 19 (11.0%) switched
to depression; of 164 on haloperidol, 29 (17.7%) switched to depression
(RR=1.61, 95% CI 0.942.76; P=0.079).
Safety
Adverse events
The most frequently reported adverse events during the study are shown in
Table 3. The most frequent
adverse events leading to discontinuation ( 10% in at least one of the
two treatment arms) were extrapyramidal symptoms (haloperidol, n=32
(18.9%); aripiprazole, n=5 (2.9%)), and akathisia (haloperidol,
n=24 (14.2%); aripiprazole, n=9 (5.1%)). Overall, 18
patients had a serious adverse event during the study or within 30 days of
discontinuation (aripiprazole, n=6; haloperidol, n=12). In
general these were related to the underlying diagnosis. One patient in the
haloperidol group discontinued treatment because of liver damage considered
possibly related to study medication.
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Patient discontinuations
Overall, 208 patients (59.9%) discontinued treatment during the 12-week
study: haloperidol, n=122 (70.9%); aripiprazole, n=86
(49.1%). During the study, time to discontinuation for any reason was
significantly greater for patients receiving aripiprazole than those receiving
haloperidol (P < 0.001) (Fig.
6). The hazard ratio for discontinuation of haloperidol over
aripiprazole was 1.96 (95% CI 1.482.59). In addition, 13 patients
(aripiprazole, n=5; haloperidol, n=8) who completed the
first 3 weeks of treatment did not enter the second phase of the study (weeks
412).
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In weeks 13 of the study, 118 patients (34.0%) discontinued treatment: haloperidol, n=77 (44.8%); aripiprazole, n=41 (23.4%). The most common reason for discontinuation was experiencing adverse events (20.2%), which showed a marked difference in incidence between the groups (aripiprazole, 9.7%; haloperidol, 30.8%). Other reasons for discontinuation included patient withdrawal of consent (6.1%) and lack of efficacy (5.2%). In weeks 412 of the study, 77 patients (22.2%) discontinued treatment: haloperidol, n=37 (21.5%); aripiprazole, n=40 (22.9%). The most common reason for discontinuation was experiencing adverse events (overall, 11.5%; aripiprazole, 8.6%; haloperidol, 14.5%). Other reasons for discontinuation were similar in incidence to those in weeks 13.
Extrapyramidal adverse events
The incidence of extrapyramidal adverse events in the haloperidol group
(62.7%) was more than double that in the aripiprazole group (24.0%).
Extrapyramidal syndrome and akathisia were the most frequently reported of
these adverse events, and were much more frequent with haloperidol than with
aripiprazole (see Table 3). The
SAS, BAS and AIMS scores all showed minimal changes from baseline to end-point
with aripiprazole. Significantly greater mean increases (i.e. worsening) in
scores were observed with haloperidol compared with aripiprazole (P
0.002) (Fig. 6). Rating
scale scores at week 3 also showed minimal mean changes from baseline with
aripiprazole treatment, and larger mean increases with haloperidol treatment
(SAS: aripiprazole 0.65, haloperidol 4.85; BAS: aripiprazole 0.15, haloperidol
0.57; AIMS: aripiprazole 0.04, haloperidol 0.50; observed cases analysis).
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When stratified by mean body mass index (BMI) at baseline, patients with a relative high baseline BMI (> 27 kg/m2) lost weight during aripiprazole treatment (-0.86 kg), compared with an increase in weight with haloperidol treatment (0.41 kg). Patients with the lowest baseline BMI (< 23 kg/m2) showed increases in weight with both aripiprazole (+1.38 kg) and haloperidol (+0.64 kg) treatment (observed cases analyses).
Serum prolactin levels
Serum prolactin levels showed a mean decrease from baseline in the
aripiprazole group (-13.4 ng/ml, -284.1 mU/l), and a mean increase in the
haloperidol group (7.7 ng/ml, -163.2 mU/l) at week 12; this difference was
statistically significant (P < 0.001). Similar changes in
prolactin levels were observed at week 3 (aripiprazole -12.5 ng/ml (-265
mU/l), haloperidol 15.5 ng/ml (328.6 mU/l); observed cases analysis). In the
haloperidol group, 57.1% of patients experienced serum prolactin levels above
the upper limit of normal compared with 14.1% in the aripiprazole group.
Electrocardiography
Electrocardiogram (ECG) analysis showed an on-treatment QTc
value of 450 ms or more and a 10% or greater increase from baseline for 4
patients (2.7%) in the haloperidol group and 5 patients (3.0%) in the
aripiprazole group, calculated using
Bazetts (1920) formula,
and no patient in either group using the Food and Drug Administration
(2000) Neuropharmacological
Division formula. There was no discontinuation owing to ECG abnormalities.
Vital signs and laboratory analyses
No clinically meaningful difference was detected in vital sign
measurements, laboratory abnormalities or cholesterol levels between the
aripiprazole and haloperidol treatment groups.
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DISCUSSION |
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Haloperidol was chosen as an active comparator in this study because of the extensive study of this drug as an effective treatment of the manic symptoms, including psychosis, of acute mania (Garfinkel et al, 1980). Several atypical antipsychotic studies examining treatment of acute mania in patients with bipolar disorder have used haloperidol as an active control (Segal et al, 1998; Tohen et al, 2003; McIntyre et al, 2005; Smulevich et al, 2005). In these studies, haloperidol-treated patients showed similar improvements in mania rating scale scores to those receiving atypical (olanzapine or risperidone) therapy (Segal et al, 1998; Tohen et al, 2003), and remission rates were similar at week 6 and week 12 with olanzapine and haloperidol in the comparison study (Tohen et al, 2003).
Treatment effectiveness
The primary outcome measure in our study showed that a significantly
greater number of aripiprazole-treated patients continued to respond to
treatment at week 12, as measured by a 50% or greater improvement in YMRS
total score from baseline and remaining in therapy, compared with patients
treated with haloperidol (49.7% v. 28.4%, P < 0.001).
This outcome measure is affected by both efficacy and tolerability, and was
chosen to reflect the combination of efficacy, safety and tolerability
required for a treatment to be effective in clinical practice.
Analysis of YMRS and CGI measures showed similar efficacy improvements with both aripiprazole and haloperidol treatment. Total YMRS scores showed marked improvements with both aripiprazole and haloperidol, which were sustained over the 12-week study. Both treatments provided rapid control of manic symptoms, with marked decreases in YMRS scores from baseline observed with aripiprazole and haloperidol at week 3. The improvements in YMRS scores seen with aripiprazole therapy in our study are comparable with those observed in 12-week comparison studies of haloperidol with olanzapine (Tohen et al, 2003), risperidone (Smulevich et al, 2005) and quetiapine (McIntyre et al, 2005). Reductions in YMRS scores with aripiprazole at week 3 were also similar to those observed with olanzapine in a 3-week comparison with divalproex (Tohen et al, 2002) and a 4-week, risperidone v. haloperidol study (Segal et al, 1998).
The similar improvements in efficacy scores observed with aripiprazole and haloperidol treatment in this study are consistent with findings from comparison studies with olanzapine (Tohen et al, 2003) and risperidone (Segal et al, 1998), which also showed similar improvements with haloperidol and atypical therapy. The difference between the efficacy and effectiveness results observed in our study highlights the impact that tolerability has on overall treatment effectiveness. The superior maintained response observed with aripiprazole at week 12 reflects the increased ability of patients to continue taking aripiprazole compared with haloperidol, which is a pragmatic outcome measure with high external validity.
Depressive symptoms
It has been suggested that the use of typical antipsychotic therapy might
worsen or induce depression in this patient population
(Vieta, 2003). In this study,
fewer patients receiving aripiprazole experienced a switch to depression
compared with those receiving haloperidol (11.0% v. 17.7%), although
this did not reach statistical significance. Similar findings have been
reported in studies with olanzapine and quetiapine (Brecher & Huizar,
2003; Tohen et al,
2003), suggesting that atypical antipsychotics may offer benefits
over typical agents in preventing or delaying the switch to depression in
patients with bipolar disorder.
Aripiprazole was associated with significant improvements in depressive symptoms over the course of the study. Significantly more patients demonstrated a 50% or greater decrease in MADRS total score from baseline with aripiprazole than with haloperidol at week 3 and week 12. Reductions in MADRS total scores from baseline occurred rapidly after the start of aripiprazole therapy, with significant differences from haloperidol observed at week 3, although statistical significance was not maintained at week 12.
Treatment adherence
Full adherence to treatment is associated with improved long-term patient
outcome (Tsai et al,
2001); higher recovery rates and shorter time to recovery
(Keck et al, 1998);
and reduced hospitalisation rates, days in hospital and treatment costs
(Svarstad et al,
2001). Treatment discontinuation is often the result of
unacceptable side-effects associated with therapy
(Sachs & Rush, 2003).
Treatment safety and tolerability are, therefore, key factors in patient
outcome. In this study, the time to discontinuation for any reason was
significantly greater for patients receiving aripiprazole than for those
treated with haloperidol (P < 0.001). Hazard ratio calculations
suggest that patients given haloperidol were almost twice as likely to
discontinue therapy as those given aripiprazole (P < 0.001),
adverse events being the most frequent reason for discontinuation.
Adverse events
Extrapyramidal syndrome, akathisia and tremor are common in patients
receiving typical antipsychotic agents. In this study, patients taking
haloperidol reported a four-fold increased incidence of extrapyramidal
symptoms compared with patients taking aripiprazole (36% v. 9%).
Although anticholinergic therapy was not allowed in this study, a greater
percentage of patients taking haloperidol received concomitant medications for
treatment of extrapyramidal symptoms. Despite this prohibition, the rate of
such symptoms with haloperidol was comparable with rates reported for lower
doses of haloperidol in other 12-week acute mania trials which allowed
concomitant anticholinergic use (Tohen
et al, 2003; McIntyre
et al, 2005;
Smulevich et al,
2005).
The reduced potential for extrapyramidal symptoms observed with aripiprazole is consistent with effects seen in previously published trials in schizophrenia and acute mania (Kasper et al, 2003; Keck et al, 2003; Marder et al, 2003; Pigott et al, 2003). This, and the lack of hyperprolactinaemia observed with aripiprazole in this study, may be explained by this drugs unique mode of action as a dopamine D2 partial agonist (Lieberman, 2004); these agonists act as functional antagonists in areas of high dopamine concentrations but not in areas of normal dopamine levels, such as the nigrostriatal and tubero-infundibular pathways, thus reducing symptoms without producing movement disorders or elevated prolactin levels. In regions of low dopamine concentration, a D2 partial agonist will show functional agonist activity.
Minimal mean changes in body weight were observed with both aripiprazole and haloperidol over the 12-week study. Lack of weight gain is an important treatment consideration, given the adverse effects of weight gain on treatment adherence and its implications for long-term patient health. Weight gain and obesity are established risk factors for cardiovascular disease and diabetes, and are associated with dyslipidaemia (National Institutes of Health, 1998). Clinical experience with other atypical antipsychotics has shown that the likelihood of weight gain differs markedly between different agents (American Diabetes Association et al, 2004). In addition, among the atypical antipsychotics, some have been attributed with an increased risk of diabetes (American Diabetes Association et al, 2004).
Study limitations
The findings of this study should, however, be considered in the light of
the following limitations. The overall study completion rates could limit the
generalisability of the results. The lack of anticholinergic medication use
specified by the study protocol and the limited dose range permitted for
haloperidol could have affected the results through a possible impact on the
ability of patients to tolerate haloperidol. It may also limit the extent to
which the haloperidol findings can be generalised to clinical practice.
However, extrapyramidal symptom rates with haloperidol were similar to those
reported in other 12-week studies that evaluated lower doses of haloperidol
and permitted the use of anticholinergic medications to manage these symptoms
(Tohen et al, 2003;
McIntyre et al, 2005;
Smulevich et al,
2005). The use of an atypical antipsychotic as a comparator in
future studies would be expected to overcome the tolerability limitations
associated with haloperidol, and reflect the increasingly widespread use of
atypicals for the treatment of mania
(Vieta, 2003).
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication June 9, 2004. Revision received November 11, 2004. Accepted for publication November 20, 2004.
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