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2437 Am J Health-Syst PharmVol 60 Dec 1, 2003

FORMULARY REVIEW Aripiprazole


F ORMUL ARY
REVI EW
Aripiprazole
ELIZABETH WINANS
ELIZABETH WINANS, PHARM.D., BCPP, is Clinical Associate Profes-
sor, Departments of Pharmacy Practice and Psychiatry, University of
Illinois at Chicago.
Address correspondence to Mary Ellen Bonk, Pharm.D., Universi-
ty HealthSystem Consortium, 2001 Spring Road, Suite 700, Oak
Brook, IL 60523-1890 (Bonk@uhc.edu).
The University HealthSystem Consortium acknowledges Danesh
Alam, M.D., Gara L. Coffey, Pharm.D., Sondra May, Pharm.D., and
Gerald A. Subar, Pharm.D., for their review of this monograph.
Abstract: The pharmacology, pharmacoki-
netics, clinical efficacy, adverse effects,
drug interactions, and dosage and adminis-
tration of aripiprazole are discussed.
Aripiprazole is a third-generation anti-
psychotic agent indicated for use in the
treatment of schizophrenia. Unlike other
antipsychotics, aripiprazole demonstrates
mixed D
2
and serotonin (5-HT
1A
) receptor
agonistantagonist activity that is hypothe-
sized to improve schizophrenias positive
and negative symptoms; the drug has been
referred to as a dopamineserotonin stabi-
lizer. Aripiprazole is well absorbed, with
peak plasma concentrations occurring
within three to five hours after administra-
tion. The oral availability is 87%. The mean
elimination half-life is about 75 hours for
aripiprazole and 94 hours for its active me-
tabolite. In controlled, randomized, multi-
center trials, aripiprazole has demonstrated
efficacy in the treatment of schizophrenia
comparable to that of haloperidol and su-
S
chizophrenia is a major mental
illness that affects between 0.5%
and 1% of the population.
1
Typi-
cally, symptoms begin during the lat-
er teenage years to the mid-twenties,
and men have an earlier onset than
women. The symptoms are catego-
rized as either positive (excess or dis-
tortion of normal function) or nega-
tive (diminution or loss of normal
function).
2
Characteristic symptoms
include (1) delusions, (2) hallucina-
tions, (3) disorganized speech, (4)
grossly disorganized or catatonic be-
havior, and (5) negative symptoms
(anhedonia, lack of motivation,
speech deprivation). To meet the di-
agnostic criteria for schizophrenia,
two or more of these five symptoms
must be present for a significant
amount of time over a one-month
period
1
and must also be present for
at least six months. In addition, these
symptoms are associated with
marked social or occupational dis-
turbances. Once a diagnosis has been
made, it is further classified into the
following subtypes: paranoid, disor-
ganized, catatonic, undifferentiated,
and residual. The diagnosis of a specif-
ic subtype is based on the most current
clinical presentation. Further, since
perior to placebo. In a single clinical trial,
aripiprazole was superior to placebo in
the treatment of acute mania. The most
frequent adverse effects are headache,
anxiety, insomnia, nausea, vomiting, and
lightheadedness. Because aripiprazole is a
substrate of both cytochrome P-450 isoen-
zymes 3A4 and 2D6, there is a potential for
other drugs to affect its metabolism. The
recommended starting dosage is 10 or 15
mg daily, preferably administered with
meals.
Aripiprazole offers an alternative to
second-generation antipsychotic agents in
the treatment of schizophrenia.
Index terms: Absorption; Antipsychotic
agents; Aripiprazole; Blood levels; Dosage;
Drug administration; Drug interactions;
Drugs, availability; Excretion; Half life;
Mechanism of action; Metabolism; Pharma-
cokinetics; Schizophrenia; Toxicity
Am J Health-Syst Pharm. 2003; 60:2437-45
symptom prominence may change
over time, the specific schizophrenia
subtype may change as well.
Traditionally, patients with
schizophrenia are treated with anti-
psychotics on a long-term basis. Ac-
cording to the Mount Sinai Confer-
ence consensus treatment guidelines
for schizophrenia, patients experi-
encing their first psychotic episode
should be treated for 12 to 24
months.
3
For those with multiple ep-
isodes, lifetime antipsychotic
treatment may be necessary. Positive
symptoms such as hallucinations,
delusions, and disorganized language
or behavior are possibly related to a
hyperdopaminergic activity within
Originally published as a drug monograph in
April 2003 by the University HealthSystem
Consortium. Reprinted with permission.
Copyright 2003, University HealthSystem
Consortium. All rights reserved.
2438 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
the mesolimbic system. Conversely,
negative symptoms are believed to
derive from a hypodopaminergic state
in the prefrontal and frontal cortex of
the brain. Conventional antipsychot-
ics work by antagonism of dopamine
2
(D
2
) receptors throughout the brain.
D
2
receptor blockade in the mesolim-
bic area reduces dopamine, thus im-
proving positive symptoms. Unfortu-
nately, D
2
receptor blockade in the
prefrontal cortex/cortex area further
decreases dopamine, resulting in no
benefit and, at times, a worsening of
negative symptoms.
4
This has been a
fundamental problem in the pharma-
cotherapy of schizophrenia.
In general, antipsychotics are
classified as either conventional
(first-generation agents) or atypical
(second-generation agents). First-
generation agents are further classi-
fied as either high- or low-potency
agents based on their binding affinity
to D
2
receptors. Low-potency con-
ventional agents strongly antagonize
muscarinic,
1
-adrenergic, and his-
tamine receptors, leading to anti-
cholinergic side effects, orthostatic
hypotension, and sedation, respec-
tively. Further, low-potency agents
are associated with increased central
nervous system depression. High-
potency agents are associated with
increased extrapyramidal symptoms
(EPSs) secondary to their high bind-
ing affinity to dopamine receptors
but demonstrate less histamine
blockade, fewer anticholinergic ef-
fects, and less
1
-adrenergic block-
ade. Second-generation or atypical
agents differ from conventional an-
tipsychotics in that they are associat-
ed with fewer EPSs and possess sero-
tonin
2
(5-HT
2
) blockade in addition
to D
2
blockade.
5,6
Product description
Aripiprazole (Abilify, Bristol-
Myers Squibb Company, Princeton,
NJ, and Otsuka American Pharma-
ceutical Inc., Rockville, MD), an oral
psychotropic, is a quinolinone deriv-
ative with a molecular weight of
448.38 (Figure 1).
Unlike other antipsychotics, ari-
piprazole demonstrates mixed D
2
and serotonin (5-HT
1A
) receptor
agonistantagonist activity that is
hypothesized to improve positive
and negative symptoms of schizo-
phrenia. On the basis of these unique
antipsychotic pharmacologic prop-
erties, aripiprazole has been referred
to as a third-generation antipsychot-
ic and a dopamineserotonin system
stabilizer. The drug was approved by
the Food and Drug Administration
(FDA) on November 15, 2002, for
the treatment of schizophrenia.
Pharmacology
The second-generation antipsy-
choticsrisperidone, olanzapine,
quetiapine, and ziprasidonewere
introduced in the United States in
the 1990s. These agents were devel-
oped in response to the inadequacies
of the first-generation agents, includ-
ing minimal or no efficacy in a num-
ber of patients with schizophrenia,
lack of improvement in cognitive
The Formulary Review section contains
monographs provided to AJHP by the Clini-
cal Knowledge Service, Drug Monograph
Group, of the University HealthSystem Con-
sortium (UHC), Oak Brook, IL. The mono-
graphs are written by drug information spe-
cialists and pharmacotherapists from UHC
member institutions and VHA institutions,
undergo peer review by UHC and VHA phar-
macists and physicians, and appear here some
months after initial distribution. They have
been edited by AJHP and contain new ab-
stracts. For more information, see the initial
installment in the December 1, 1997, issue or
call Karl A. Matuszewski, M.S., Pharm.D.,
or Mary Ellen Bonk, Pharm.D., at UHC
(630-954-1700).
functioning, a high incidence of
tardive dyskinesia and other EPSs, and
a lack of efficacy in the treatment of
negative symptoms.
7
Pharmacologic
differences associated with second-
generation as compared with first-
generation agents include low D
2
to D
1
receptor occupancy, a high affinity for
D
4
receptors, a high ratio of 5-HT
2
to
D
2
receptor blockade, and a selectivity
for D
2
receptors in the mesolimbic sys-
tem.
7
Thus, differences in dopaminer-
gic activity, as well as greater 5-HT
2
blockade, provide the atypicals with a
unique approach to the treatment of
psychotic symptoms.
Aripiprazole, a third-generation
antipsychotic agent, possesses a
unique mechanism of action. It acts
as a partial agonist at D
2
receptors,
while second-generation antipsy-
chotics are antagonists at the D
2
re-
ceptors.
8
As a partial agonist, ari-
piprazole acts as a D
2
antagonist in
the presence of high levels of endoge-
nous dopamine, and, conversely,
when minimal endogenous dopa-
mine is present, the drug has D
2
re-
ceptor agonist activity. Aripiprazole
has also demonstrated partial agonist
activity at the 5-HT
1A
receptor,
9
as
well as antagonistic action at the
5-HT
2A
receptor.
10
It has been postu-
lated that partial agonist activity at
the 5-HT
1A
receptor may contribute
to improvement in anxiety, depres-
sion, negative symptoms, and fewer
EPSs.
9
To illustrate the concept of a
partial agonist, Inoue et al.
11
investi-
gated aripiprazoles effect on sponta-
neous prolactin release from isolated
anterior pituitary slices in male rats.
With the addition of talipexole, a D
2
agonist, spontaneous prolactin re-
lease was decreased. The addition of
haloperidol, a potent D
2
antagonist,
produced an eightfold increase in
Figure 1. Chemical structure of aripiprazole.
Cl
N
H
I
N NCH
2
CH
2
CH
2
CH
2
O
Cl
O
2439 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
prolactin release. By contrast, ari-
piprazole increased spontaneous
prolactin release twofold. These re-
sults are consistent with aripipra-
zoles partial D
2
agonistantagonist
properties. Clinically, partial agonist
activity at the D
2
receptors may result
in fewer prolactin-related adverse
events, such as galactorrhea and
amenorrhea.
Bioavailability and
pharmacokinetics
Aripiprazole is well absorbed, with
peak plasma concentrations occurring
within three to five hours after admin-
istration.
12
Its oral bioavailability is
87%. High-fat meals delay the time to
maximum concentration (t
max
) by
three hours, although they do not af-
fect the maximum concentration or
the area under the curve (AUC).
Aripiprazole is metabolized via
three major hepatic routes: dehydro-
genation, hydroxylation, and N-
dealkylation.
12
In vitro data suggest
that aripiprazole is extensively me-
tabolized via the hepatic cytochrome
(CYP) P-450 3A4 and CYP2D6
isoenzyme pathways. Its major me-
tabolite, dehydro-aripiprazole, has
demonstrated similar affinities for D
2
receptors and represents approxi-
mately 40% of aripiprazoles AUC in
the plasma.
13
The mean elimination
half-life (t

) is approximately 75 and
94 hours for aripiprazole and its ac-
tive metabolite, respectively.
12
Ari-
piprazole and dehydro-aripiprazole
are more than 99% bound to serum
proteins, primarily albumin.
Mallikaarjun et al.
14
reported the re-
sults from two randomized, placebo-
controlled, double-blind studies that
evaluated the safety, tolerability, and
pharmacokinetic parameters of ari-
piprazole in normal healthy men. In
the first study, subjects were random-
ized to receive placebo (n = 3) or one
of four aripiprazole doses (5, 10, 15, or
20 mg daily). Six patients were as-
signed to each aripiprazole treatment
group. In the second study, patients
received either placebo or aripiprazole
titrated from 10 mg daily for days 1
and 2, to 20 mg daily for days 3 and 4,
and then to 30 mg daily for days 5 to
14. Under steady-state conditions, on
day 14, the mean peak plasma concen-
tration of aripiprazole (C
max
) ranged
from 77 to 302 g/L, with a corre-
sponding t
max
of 3 and 5 hours, respec-
tively. The terminal t

ranged from 48
to 68 hours across all groups. Linear
regression analysis of the C
max
and
AUC versus dose demonstrated a lin-
ear pharmacokinetic profile for doses
between 5 and 30 mg/day. There were
no serious adverse events or deaths.
However, one subject withdrew on
day 1 because of nausea and postural
hypotension. As a whole, nausea, pos-
tural dizziness, and somnolence were
the most common adverse events and
accounted for 46.9% of all such events.
Their severity and frequency did not
correlate with increasing concentra-
tions of aripiprazole.
Indications
Aripiprazole is indicated for the
treatment of schizophrenia, with effi-
cacy established through trials lasting
four to six weeks.
12
In 2003, a supple-
mental new drug application for the
long-term treatment of schizophre-
nia was submitted to FDA.
15
In addition, aripiprazole is under
investigation for the treatment of
acute mania associated with bipolar
disorder and Alzheimers disease.
15,16
Clinical efficacy
The efficacy of aripiprazole for
the treatment of schizophrenia has
been evaluated in several placebo-
controlled, randomized, multicenter
trials. Of these trials, three have in-
cluded an active control of either ha-
loperidol
17,18
or risperidone.
19
The
drug has also been evaluated in sub-
jects experiencing a mixed or manic
episode of bipolar I disorder.
16
Other
than the published trial conducted
by Kane et al.,
17
all studies have been
reported in abstract or poster form.
Schizophrenia. Two long-term,
multicenter, randomized, double-
blind trials evaluating the safety and
efficacy of aripiprazole compared
with haloperidol were prospectively
combined for analysis
18
and will be
collectively reported as one trial. In
this 52-week trial, 1294 subjects were
randomized to either 30 mg of ari-
piprazole daily (n = 861) or 10 mg of
haloperidol daily (n = 433). Investi-
gators were allowed a one-time dos-
age reduction to 20 mg/day of ari-
piprazole or 7 mg/day of haloperidol.
All subjects were suffering from an
acute relapse of schizophrenia. The
primary efficacy measures were the
Positive and Negative Syndrome
Scale (PANSS) and Montgomery As-
bury Depression Rating Scale
(MADRS). The PANSS measures in-
clude positive and negative subscales,
as well as the total score. On this
scale, the individual symptom severity
score ranges from 1 (symptom-
absent) to 7 (symptom-severe). The
Clinical Global Impression (CGI) scale
comprises two 7-point scales: the Se-
verity of Illness (CGI-S) and Global
Improvement (CGI-I) scales. A score
of 1 represents not ill on the CGI-S
and a degree of change of very much
improved on the CGI-I, while a score
of 7 represents an extreme severity
of illness on the CGI-S and very
much worse on the CGI-I.
Baseline demographics with re-
spect to age, mean age at first epi-
sode, number of past hospitaliza-
tions, onset of recent relapse, weight,
and mean PANSS scores were similar
between groups. Failure to maintain
a response was defined as a CGI score
of 6 or an adverse event of worsen-
ing schizophrenia and a score of 5
on at least one of the following
PANSS items: delusions, conceptual
disorganization, hallucinations, or
suspiciousness. Of the 861 subjects
randomized to aripiprazole, 853
were analyzed for efficacy and 859
for safety. Similarly, of the 433 pa-
tients randomized to haloperidol,
430 were analyzed for efficacy and
431 for safety. The percentage of sub-
jects discontinuing the study was
2440 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
57% for the aripiprazole group and
70% for the haloperidol group.
Discontinuation secondary to
symptom worsening was slightly
higher in the aripiprazole group
(17%) versus the haloperidol group
(13%). A larger percentage of sub-
jects in the haloperidol group dis-
continued secondary to adverse
events. A 20% improvement in
PANSS scores was achieved in 72%
and 69% (p = 0.362) of the aripipra-
zole and haloperidol subjects, respec-
tively. The weekly mean change from
baseline on the total PANSS scores
was similar between groups, reaching
an approximate decrease of 21 and
23 points for haloperidol and ari-
piprazole, respectively. Further, 52%
of the aripiprazole group and 44% of
the haloperidol group achieved a
30% improvement on the PANSS
measurement (p = 0.003), with sig-
nificant differences favoring ari-
piprazole seen as early as week 12
(p 0.05) and continuing through
week 52 (p 0.01). Using Kaplan-
Meier estimates, the percentage of
subjects maintaining a response of
30% improvement on the PANSS at
week 52 was 85% for the aripiprazole
group and 79% for the haloperidol
group (risk ratio, 0.7; p = 0.098). At
weeks 8, 26, and 52, the percentage of
subjects receiving treatment and still
responding was significantly greater
in the aripiprazole group versus the
haloperidol group. This study also
used the MADRS to address depres-
sive symptoms. At week 8, aripipra-
zole produced significant decreases
in MADRS scores compared with ha-
loperidol (p < 0.05).
The incidence of the most com-
mon adverse events, including in-
somnia, anxiety, headache, agitation,
and somnolence, was similar be-
tween treatment groups, although
the incidence of akathisia and
pseudoparkinsonian symptoms was
significantly higher with haloperidol
than with aripiprazole (25% versus
12%, p < 0.001). Similarly, any EPS-
related event was reported by ap-
proximately 10% of the aripiprazole
subjects versus 32% of the haloperi-
dol subjects. At the study endpoint,
subjects in the aripiprazole group
demonstrated improvement from
baseline on the following movement
rating scales: the Simpson-Angus
Scale (SAS), the Barnes Akathisia
Rating Scale (BARS), and the Abnor-
mal Involuntary Movements (AIMS)
rating scale. Those in the haloperidol
group demonstrated a worsening of
movement-related adverse effects on
all scales. Overall, weight gain in both
groups was minimal (1 kg), but in
those subjects with a body mass in-
dex of less than 23 kg/m
2
, aripipra-
zole was associated with a significant
weight gain compared with haloperi-
dol (approximately 2.5 kg versus 1.5
kg, p < 0.05). Finally, there was no
significant change from baseline in
the QTc interval for either group.
Another long-term trial compar-
ing aripiprazole with placebo for the
prevention of relapse in 310 patients
with chronic, stable schizophrenia
was conducted by Carson et al.
20
Subjects were randomized to receive
either 15 mg/day of aripiprazole (n =
155) or placebo (n = 155) for 26
weeks. The investigators defined
stable as no significant improve-
ment or worsening of symptoms
during the previous three months. In
this study, the primary outcome
measure was the time to relapse, de-
fined as a CGI improvement score of
5 (minimally worse) or a PANSS
score of moderately severe on the
hostility or uncooperative items for
two consecutive days or a 20% in-
crease in total PANSS score. Using
Kaplan-Meier estimates, the proba-
bility of not experiencing a relapse
before week 26 was 39% in the place-
bo group and 63% in the aripiprazole
group. In the aripiprazole group, the
total PANSS scores improved signifi-
cantly (p < 0.05) versus placebo.
However, the mean change from
baseline at endpoint was approxi-
mately 5 points, which is of modest
clinical significance. Significantly
fewer subjects who were randomized
to aripiprazole experienced a relapse
or discontinuation secondary to lack
of efficacy or an adverse event. In
general, aripiprazole was well tolerat-
ed, with adverse events comparable
to those seen in the placebo group.
Further, subjects in both groups dis-
continued therapy because of ad-
verse events at similar rates (ari-
piprazole, 11%; haloperidol, 8%).
Kane et al.
17
evaluated aripipra-
zole and haloperidol versus placebo
in a four-week, double-blind, ran-
domized study of 502 hospitalized
patients suffering from an acute re-
lapse of schizophrenia or other
schizoaffective disorders. All subjects
underwent a five-day washout period
within one week of screening. At the
end of the washout phase, 414 sub-
jects were randomized to one of four
treatment groups: aripiprazole 15
mg/day, aripiprazole 30 mg/day, ha-
loperidol 10 mg/day, or placebo.
Study drug doses were fixed
throughout the four-week treatment
period. All psychotropic agents were
prohibited during the washout and
double-blind treatment, except for
lorazepam for anxiety or insomnia.
The SAS, BARS, and AIMS scales
were used to assess EPSs at baseline
and then weekly throughout the
study, and benztropine was allowed
for treatment of EPS.
The primary efficacy measure was
the mean change from baseline at
week 4 on the PANSS total and posi-
tive symptom subscales and CGI-S
scores. Additional efficacy variables
included mean change from baseline
on the PANSS negative subscale,
PANSS-derived Brief Psychiatric
Rating Scale (BPRS), and mean CGI-
I score. Efficacy data were collected at
screening, at the end of the washout
period (baseline), and on days 7, 14,
21, and 28. Baseline demographics
were similar among the four treat-
ment groups. At week 4, a total of 248
patients (60%) completed the trial.
The most common reasons for dis-
continuation were withdrawal of con-
2441 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
sent (17%), adverse events (11%), and
insufficient response (10%).
Both dosage groups of aripipra-
zole and haloperidol produced sig-
nificant improvements compared
with placebo on the PANSS total
score, PANSS positive subscale score,
CGI-S and CGI-I scores, and BPRS
core score. For the PANSS negative
subscale, aripiprazole (15 mg) and
haloperidol demonstrated significant
improvement (p = 0.006 and p =
0.043, respectively), compared with
placebo. Response, defined a priori,
was either a CGI-I score of 1 or 2 or a
30% decrease from baseline on the
PANSS total score. The aripiprazole
groups receiving 15 and 30 mg pro-
duced significantly higher percent-
ages of responders than the group
receiving placebo (p = 0.002 and p =
0.050, respectively). Alternatively,
the response rate for haloperidol did
not differ significantly from that for
placebo (p = 0.089). The onset of re-
sponse was similar among all active
treatment groups and was evident by
week 2 of the study. In general, side
effects were mild to moderate. Wors-
ening of psychosis was the most
common adverse event resulting in
discontinuation. The most common
treatment-emergent adverse effects
(5%) were headache, anxiety, in-
somnia, nausea, vomiting, akathisia,
somnolence, orthostatic hypoten-
sion, hypertonia, and blurred vision.
Most cases of nausea and vomiting
resolved within the first week of
treatment. The overall incidence of
EPSs was comparable between the
placebo (21%) and the aripiprazole
15-mg (18%) and 30-mg (21%)
groups. The 30-mg group was associ-
ated with a slight but not statistically
significant increase (0.2) in SAS
scores. On the BARS, the 15-mg dose
was associated with a slight increase
of 0.1 unit, which again was not sta-
tistically significant. Within the halo-
peridol group, 37% reported at least
one EPS-related adverse effect. Halo-
peridol was associated with a signifi-
cant worsening of scores on the SAS
(1.1, p < 0.001) and BARS (0.3, p <
0.05) compared with placebo, while
aripiprazole when compared with
placebo was not.
Across all treatment groups, the
mean change in body weight did not
differ from that seen with placebo.
With respect to increases from
baseline in serum prolactin levels,
haloperidol produced significantly
greater increases than placebo (p <
0.001). Aripiprazole at both doses
was associated with a slight but not
statistically significant decrease in
prolactin levels and was comparable
to placebo. In all groups, changes
from baseline in QTc intervals were
not statistically significant.
Yeung et al.
19
assessed the efficacy
and safety of aripiprazole versus ris-
peridone in patients with schizo-
phrenia or schizoaffective disorder.
This four-week, multicenter, double-
blind, placebo-controlled trial in-
volved 404 subjects who were experi-
encing an acute exacerbation of
symptoms. Subjects were random-
ized to receive placebo (n = 103),
aripiprazole 20 mg/day (n = 101),
aripiprazole 30 mg/day (n = 101), or
risperidone 6 mg/day (n = 99). Sub-
jects randomized to risperidone were
titrated to 6 mg/day over days 1 to 3.
The primary outcome measures were
the PANSS and CGI scales. At week
4, all three active treatment arms
demonstrated significant improve-
ment on the PANSS total, negative
subscale, and PANSS-derived BPRS
scores over placebo (p 0.05). Fur-
ther, significant improvement was
seen as early as week 1 for all active
treatment groups. Discontinuation
because of adverse events or lack of
efficacy was similar among all three
active treatments and less than the
rate for placebo. All treatment
groups demonstrated a slight de-
crease in mean SAS scores. When
akathisia was assessed, all treatment
groups demonstrated a slight in-
crease in scores (approximately 0.18
for treatment and 0.11 for placebo).
The mean weight change from base-
line was approximately 1.2 kg for the
aripiprazole 20-mg dose, 0.7 kg for
the 30-mg dose, 1.5 kg for risperi-
done, and 0.25 kg for placebo.
Mean serum prolactin levels in-
creased fivefold for risperidone over
placebo, but aripiprazole showed
no change in prolactin levels. Ari-
piprazole demonstrated changes in
QTc prolongation that were similar
to those seen with placebo, while
risperidone was associated with a
twofold increase in QTc intervals.
Acute mania. Aripiprazole was
compared with placebo in a three-
week multicenter, double-blind, ran-
domized study of 262 subjects expe-
riencing a mixed or mania episode of
bipolar I disorder.
16
The drug was
initiated at 30 mg with an option to
decrease to 15 mg if patients could
not tolerate the higher dose. The pri-
mary efficacy measure was the
change from baseline on the Young
Mania Rating Scale (YMRS); second-
ary measures included CGI-Bipolar
(CGI-BP) scores (for mania, depres-
sion, and overall bipolar illness) and
the CGI-S. Lorazepam was allowed
through day 10 on a fixed, tapered,
milligram-per-day basis. Baseline
subject demographics between the
two groups were similar.
Treatment was completed by 54
(42%) and 28 (21%) subjects in the
aripiprazole and placebo groups, re-
spectively. A total of 10% of those in
the aripiprazole and 12% of those in
the placebo groups discontinued
treatment secondary to lack of effica-
cy. The percentage of discontinua-
tions appears low, since subjects not
doing well clinically were eligible to
enter into open-label treatment.
Other reasons for discontinuation
included adverse events, withdrawal
of consent, loss to follow-up, subjects
deemed unreliable, and other known
causes. The mean dose of aripipra-
zole at endpoint was 27.9 mg/day,
with 86% of the subjects remaining
on 30 mg/day of aripiprazole
throughout the study. On day 21,
YMRS changes from baseline were
2442 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
significantly greater in the aripipra-
zole group than in the placebo group
(8.15 versus 3.35, p = 0.002, re-
spectively). In addition, aripiprazole
was statistically superior to placebo
(p < 0.005) beginning on day 4 and
throughout the study endpoint.
CGI-BP scores for aripiprazole were
statistically superior to those for pla-
cebo from day 4 through day 21.
Mean changes in CGI-BP scores were
1.0 versus 0.39 (p = 0.001) for the
aripiprazole and placebo groups, re-
spectively. Finally, the overall response
rate, defined as a decrease of 50% in
the YMRS total score at week 3, was
significantly greater for the aripipra-
zole group than for the placebo group
(40% versus 19%, p = 0.001).
Safety data (EPSs, serum prolac-
tin, and weight) were collected for all
subjects who received at least one
dose of double-blind medication us-
ing the last observations carried for-
ward. Pseudoparkinsonian symp-
toms were assessed using the SAS,
while akathisia was assessed with the
BARS. The SAS change from baseline
score was 0.01 for placebo versus
0.48 for aripiprazole. Similarly, the
change in BARS scores at endpoint
was 0.1 for placebo versus 0.33 for
aripiprazole. Both groups experi-
enced minimal weight loss: approxi-
mately 0.8 kg for placebo and 0.3 kg
for aripiprazole. Adverse events that
occurred at 5% and were twice
those seen with placebo included ac-
cidental injury (12%), nausea
(13%), somnolence (20%), and
akathisia (11%). The total discontin-
uation rate resulting from adverse
events was 11% for both groups. In
the aripiprazole group, 2% of sub-
jects discontinued therapy because
of akathisia and nausea and 1% be-
cause of tremor.
Adverse effects and toxicities
Treatment-emergent adverse
events occurring at an incidence of
5% and more frequently than pla-
cebo during short-term, placebo-
controlled trials are summarized in
Table 1. Data were collected on 926
subjects who received aripiprazole at
doses of 2 mg or more for up to six
weeks.
Overall, aripiprazole appears to be
well tolerated. Nausea and vomiting
seem to be problematic with initial
therapy. However, administration
with a meal may help reduce these
bothersome side effects. Further, the
incidence of nausea, vomiting, and
dyspepsia is greatly reduced after one
week of therapy.
A meta-analysis of the safety and
tolerability of aripiprazole in patients
with schizophrenia (n = 1648) was
completed by Stock et al.
21
Data from
five double-blind, placebo-controlled
trials lasting four to six weeks were
pooled: Four of the trials used halo-
peridol (5 to 20 mg/day) as active
controls and one used risperidone (6
mg/day). Four studies used fixed
aripiprazole doses ranging from 2 to
30 mg/day, while another used as-
cending daily doses of aripiprazole 5
to 30 mg. Baseline demographics
were similar for all five studies. The
incidence of EPSs was similar with
aripiprazole (21.1%) and placebo
(19.4%) but significantly greater in
the haloperidol group (43.5%) com-
pared with placebo (p < 0.001). Base-
line SAS scale scores for those ran-
domized to aripiprazole did not
change significantly, although pa-
tients randomized to haloperidol had
significant increases of approximate-
ly 1.2 (p < 0.01) compared with pla-
cebo. A significant change of 0.4
point from baseline was seen on the
BARS in the haloperidol group and
0.1 point for all aripiprazole groups
compared with placebo (p < 0.01 and
p < 0.05, respectively). No linear
dose relationship between aripipra-
zole and the development of akathis-
ia was apparent. In fact, 15 mg/day,
as opposed to 30 mg/day, produced
the greatest incidence of akathisia.
Weight gain associated with short-
term treatment at all doses (10 to 30
mg/day) of aripiprazole produced a
mean increase of 0.68 kg compared
with baseline (p < 0.001). Likewise,
compared with placebo, risperidone
produced a significant increase of ap-
proximately 1.4 kg from baseline (p
< 0.001). Weight gain associated
with haloperidol did not differ signif-
icantly from placebo.
An open-label, 26-week trial (n =
255) comparing aripiprazole with
olanzapine assessed changes in
weight and cholesterol.
22
At the study
endpoint, subjects treated with olan-
zapine gained significantly more
weight (3.6 kg), while those on ari-
piprazole lost 0.9 kg (p < 0.05). Fur-
ther, when data across three body-
mass-index groups were analyzed,
aripiprazole resulted in weight loss in
all three groups, while olanzapine
was associated with weight gain in all
groups. Further, median changes
from baseline were reported for
cholesterol. At weeks 4, 8, and 26,
aripiprazole was associated with a
decrease in median change from
baseline for cholesterol (197 to 187
mg/dL). Conversely, olanzapine was
associated with statistically signifi-
cant (p < 0.001) increases (202 to 210
mg/dL), although these results are of
marginal clinical significance.
First-generation antipsychotics
and risperidone are known to cause
prolactin elevations. Hyperpro-
lactinemia-related side effects such as
sexual dysfunction and dysmenorrhea
can be very problematic for patients.
Pooled data demonstrated that ari-
Rash
Asthenia
Constipation
Akathisia
Somnolence
Lightheadedness
Vomiting
Nausea
Insomnia
Anxiety
Headache
Table 1.
Adverse Events Occurring in 5%
of Patients
12
Adverse
Event
Frequency
(%)
6
7
10
10
11
11
12
14
24
25
32
2443 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
piprazole is not associated with an in-
crease in serum prolactin.
23
In fact, the
drug was associated with a small de-
crease in prolactin levels compared
with baseline. However, haloperidol
and risperidone demonstrated signifi-
cant elevations in prolactin of 120%
and 60% (p < 0.01), respectively.
A separate meta-analysis of the
cardiac safety of aripiprazole was
presented by Stock et al.
24
This anal-
ysis includes both short- and
long-term data with comparisons to
haloperidol (up to 10 mg/day), ris-
peridone (up to 6 mg/day), and olan-
zapine (dose not reported). In the
short-term studies, mean QTc
change from baseline was similar for
aripiprazole and placebo, regardless
of the patients age. In fact, there
were small decreases in QTc intervals
noted for all aripiprazole dosages
(mean change, 4.4 msec). QTc
changes associated with haloperidol
and risperidone were 1.04 and 2.15
msec, respectively. At the study end-
point, 4.3% of aripiprazole subjects
exhibited a 30-msec increase in QTc,
similar to that for placebo patients
(5.5%), compared with 7.8% and
10.5% of haloperidol and risperi-
done subjects, respectively. Long-
term, 52-week data demonstrated
that compared with haloperidol,
aripiprazole was associated with a
significant decrease in mean change
in QTc from baseline (7.4 msec ver-
sus 4.0 msec, p < 0.05, respectively).
In a 26-week, open-label comparator
study of olanzapine, aripiprazole
demonstrated a significantly greater
decrease in mean change in QTc
from baseline than olanzapine (4.61
msec versus 1.35 msec, p < 0.05).
Thus, both long- and short-term
data suggest that aripiprazole is not
associated with QTc prolongation.
The incidence of tardive dyskine-
sia associated with aripiprazole is not
known. Postmarketing data and clin-
ical experience will assist clinicians in
determining this risk. Until such data
are available, all patients should be
monitored at least annually for the
development of abnormal involun-
tary movements.
12
Two possible cases of neuroleptic
malignant syndrome that occurred
in patients being treated with ari-
piprazole were reported in the pre-
marketing worldwide clinical data-
base. While the diagnostic evaluation
of patients with this syndrome is
complicated, exclusion of serious
medical illnesses should be consid-
ered before arriving at a diagnosis of
this syndrome.
12
Drug interactions
Because aripiprazole is a substrate
of both the CYP3A4 and CYP2D6
isoenzyme pathways, there is a poten-
tial for other drugs to affect its metab-
olism.
12
Agents that are known to in-
duce the CYP3A4 isoenzyme (such as
carbamazepine and phenytoin) may
induce aripiprazole metabolism, re-
sulting in lowered blood levels.
25
Con-
versely, inhibitors of the CYP3A4
isoenzyme (such as nefazodone and
ketoconazole) or the CYP2D6 isoen-
zyme (such as quinidine, fluoxetine,
and paroxetine) may inhibit aripipra-
zole metabolism and cause increased
blood levels. Aripiprazole is unlikely to
cause clinically significant changes in
the metabolism of other drugs metab-
olized through the CYP3A4 (e.g.,
dextromethorphan), CYP2C9 (e.g.,
warfarin), or CYP2C19 (e.g., ome-
prazole) isoenzymes. Further, ari-
piprazole has not been shown to alter
CYP1A2- and CYP3A4-mediated
metabolism.
12
Citrome et al.
13
evaluated the phar-
macokinetic profile and safety of ari-
piprazole in the presence of the mood
stabilizers lithium and divalproex
sodium. In this study, 12 subjects
received lithium and 10 received dival-
proex in conjunction with aripiprazole
in an open-label manner. Subjects
received aripiprazole (30 mg/day) for
the first 14 days, and a mood stabilizer
was added on days 15 to 36. The lithi-
um dose was titrated to achieve a se-
rum concentration of 1 to 1.4 meq/L.
The divalproex dose was titrated to
achieve a serum concentration be-
tween 50 and 125 mg/L. Clinical
symptomatology was assessed by the
PANSS, and cognitive function was as-
sessed by the Mini-Mental Status Ex-
amination (MMSE).
13
Coadministering lithium and
aripiprazole had no apparent effect
on the steady-state pharmacokinetic
parameters of aripiprazole or its ac-
tive metabolite.
13
There were small
increases in the C
max
and AUC of
aripiprazole, while clearance (CL)
decreased by 15%. Overall, there
were no consistent differences in
C
max
, AUC, and CL in subjects receiv-
ing aripiprazole monotherapy or
combination therapy.
When the drug was administered
with divalproex, moderate changes in
pharmacokinetic parameters were ob-
served. The AUC, C
max
, and minimal
concentrations of aripiprazole were
decreased by 24%, 26%, and 22%, re-
spectively. In addition, the t
max
and CL
increased by two hours and 33%, re-
spectively. There were similar effects
on the pharmacokinetic parameters of
the active metabolite.
Overall, the combination of ari-
piprazole with either lithium or di-
valproex appears to be safe and well
tolerated. In the lithium group, ad-
verse events were mild to moderate
in severity and resolved when thera-
py was discontinued. However, there
was one serious adverse event of a
confusional state, an event judged to
be lithium-induced encephalopathy.
In the divalproex group, four sub-
jects withdrew: two withdrew con-
sent and two discontinued therapy
because of adverse events (i.e., in-
guinal hernia and hostile behavior).
Again, adverse events were mild to
moderate and generally resolved one
day after therapy was discontinued.
When the drug was used in combina-
tion with lithium and divalproex,
there was no evidence of clinical de-
terioration, impaired cognition, or
increase in EPSs. With respect to lab-
oratory parameters, there were no
significant changes observed with
2444 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
either combination. Finally, ob-
served changes in aripiprazoles
pharmacokinetic profile secondary
to lithium are minimal, and they are
moderate for divalproex. Despite
these moderate pharmacokinetic
changes, they appear to be of little
clinical significance.
Dosage and administration
The recommended starting dose
of aripiprazole is 10 or 15 mg daily,
preferably administered with meals.
Aripiprazole has been shown to be
effective at dosages up to 30 mg/
day
12
; however, doses higher than 10 to
15 mg/day have not been shown to be
more effective.
26
Dosage increases
should be made no earlier than two
weeks after therapy begins; this is the
time needed to achieve a steady state.
Dosage adjustments are not routinely
indicated for patients with hepatic or
renal impairment, and there are no
recommendations for dosage adjust-
ments based on gender, race, or smok-
ing status. Data from single-dose (15-
mg) studies in patients 65 or older
demonstrated a 20% decrease in CL
compared with younger adults. How-
ever, after multiple doses, the pharma-
cokinetics of aripiprazole appeared
similar to those observed in young,
healthy subjects. Thus, no dosage ad-
justment is recommended for the eld-
erly. Safety and effectiveness in pediat-
ric and adolescent patients have not
been established. Aripiprazole is classi-
fied as pregnancy category C, and it is
recommended that women taking this
medication not breastfeed.
12
For patients who are taking ari-
piprazole in combination with agents
known to inhibit the CYP3A4 or
CYP2D6 isoenzymes, the dose of ari-
piprazole should be reduced to one
half of the usual dose. Similarly, for
patients taking CYP3A4 inducers such
as carbamazepine, the aripiprazole
dose should be doubled, with addi-
tional increases based on clinical eval-
uation.
12
Following the discontinua-
tion of an inhibitor or inducer, it will
be necessary to adjust the aripiprazole
dose accordingly to maintain clinical
stability.
Dosage forms
Aripiprazole is available in tablet
form in the following strengths: 10 g,
15 g, 20 g, and 30 mg.
12
The product
should be stored at 25 C (77 F).
Safety issues
To date, data on overdoses of arip-
iprazole are minimal.
12
In premarket-
ing studies involving more than 5500
patients, accidental or intentional
overdoses were identified in seven pa-
tients. Of two patients who ingested
180 mg, the largest amount identified,
one patient experienced somnolence
and vomiting. For all patients who
were assessed in the hospital, including
these two, there were no adverse
changes in vital signs, laboratory as-
sessments, or electrocardiogram pa-
rameters. An 18-month-old child acci-
dentally ingested 15 mg of aripiprazole
and 2 mg of lorazepam; the episode
was uneventful.
Occasionally, some medications,
both generic and brand, have similar-
sounding names, resulting in the po-
tential for product name confusion.
Table 2 lists various agents that sound
similar to aripiprazole and have the
potential for medication errors.
Economic issues
As an illness that affects approxi-
mately 0.5% to 1% of the population,
schizophrenia accounts for a dispro-
portionately large economic burden.
In 1990, costs related to schizophre-
nia were estimated to be $65 billion
per year
7
; the direct costs approached
$18.6 billion, and the indirect costs,
including lost productivity, totaled
$46.5 billion.
7
Although many as-
sume that medications comprise a
large percentage of the direct costs, in
fact, prescription medications ac-
counted for only 2.3% of direct costs,
or about $397 million.
27
While these
data are somewhat dated and do not
include all currently available second-
generation antipsychotics, the in-
creased price of these agents com-
pared with first-generation agents
may not significantly increase the
overall costs associated with schizo-
phrenia. Table 3 compares the costs
of the second-generation antipsy-
chotics, which may be used as first-
line treatment for schizophrenia.
Similar agents under
consideration
Aripiprazole is a novel antipsy-
chotic with a unique mechanism of
action. No other agents in this class
of drugs are under investigation.
Recommendations and critical
issues
In clinical trials, aripiprazole has
demonstrated efficacy comparable to
that of haloperidol and superior to
that of placebo. Generally, clinical
practice acknowledges the second-
generation antipsychotics as first-
line treatment for patients suffering
from schizophrenia; despite this, ha-
loperidol continues to be the gold
standard comparator in initial effica-
cy studies. Aripiprazole is well toler-
ated, with a low potential for EPSs,
cardiovascular effects, and weight
gain, so it can be used as a first-line
treatment option for patients with an
acute exacerbation of schizophrenia.
The low potential for adverse events
may help improve compliance in a
patient population where this is a
significant factor. For patients who
are overweight or have diabetes, ari-
piprazole would be preferable to
olanzapine and quetiapine. Aripipra-
zoles ability to act as a partial agonist
at the D
2
and 5-HT
1A
receptors has
led investigators to refer to it as a
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Table 2.
Sound-Alike Drugs That May
Be Confused with Aripiprazole
Drug
Available Dosage
Strength (mg)
20, 40
15, 30
10, 20, 40
20, 40
40
2445 Am J Health-Syst PharmVol 60 Dec 1, 2003
FORMULARY REVIEW Aripiprazole
dopamineserotonin stabilizer.
10
These pharmacologic actions make
aripiprazole unique. Despite these
pharmacologic differences, clinical
evidence suggests that aripiprazole
and haloperidol are equally effica-
cious. Studies comparing the efficacy
of aripiprazole with that of second-
generation antipsychotics such as ris-
peridone and olanzapine have not
been conducted. Its once-a-day dos-
ing may make it more acceptable to
patients than the twice-daily dosing
required for ziprasidone, quetiapine,
and risperidone.
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Aripiprazole (Abilify)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
Table 3.
Comparative Cost of Second-Generation Antipsychotic Medications
Drug Strength (mg)
10, 15
20, 30
2.5
5
7.5
10
15
20
25
100
200
300
0.25
0.5
1
2
3
4
20, 40, 60, 80
Average Wholesale
Price per Tablet
or Capsule ($)
28
10.14
14.34
5.36
6.34
7.26
9.63
14.45
19.25
1.60
2.90
5.48
7.22
2.96
3.07
3.17
5.10
6.17
8.13
4.47