Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Aripiprazole once-monthly long-acting injectable

for the treatment of schizophrenia

Steven G Potkin & Adrian Preda

To cite this article: Steven G Potkin & Adrian Preda (2016) Aripiprazole once-monthly long-
acting injectable for the treatment of schizophrenia, Expert Opinion on Pharmacotherapy, 17:3,
395-407

To link to this article: http://dx.doi.org/10.1517/14656566.2015.1114100

Published online: 11 Feb 2016.

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 EXPERT OPINION ON PHARMACOTHERAPY, 2016
VOL. 17, NO. 3, 395–407
http://dx.doi.org/10.1517/14656566.2015.1114100

DRUG EVALUATION

Aripiprazole once-monthly long-acting injectable for the treatment of

schizophrenia
Steven G Potkina and Adrian Preda b

a
Psychiatry and Human Behavior, Robert R. Sprague Chair in Brain Imaging, UC Irvine, Irvine, CA 92617, USA; bHeath Sciences Clinical
Professor of Psychiatry, UC Irvine School of Medicine, Orange, CA 92868, USA

ABSTRACT ARTICLE HISTORY

Introduction: Patient non-adherence increases the risk for relapse and the long-term care of Received 13 August 2015
schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring Accepted 26 October 2015
adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM Published online
12 January 2016
LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is
the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of KEYWORDS
schizophrenia. aripiprazole; atypical
Areas covered: This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM antipsychotic; LAI; long-
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LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 – 46.5 days, acting injectable; quality of
allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week life; schizophrenia
double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a
52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events
(≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to
discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is
tolerated by >90% of patients. Injection does not require additional training of health personnel
or post-injection observation.
Expert opinion: AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.

1. Introduction families, can jeopardize relationships and disrupts psy-

chosocial development, employment or education.
1.1 Schizophrenia
Relapses can be demoralizing to the patient and
Schizophrenia is a chronic and disabling illness asso- increase the stigma of mental illness as well as the
ciated with significant functional impairment. financial costs.[10] Increasing evidence suggests that
Functional impairment in schizophrenia has been cor- relapse duration may accelerate brain volume loss.[11]
related with several clinical factors including positive Although relapses can occur as part of the natural
and negative symptoms [1] and cognitive deficits,[1] course of schizophrenia,[9] a growing body of evidence
and other factors such as nonadherence to antipsycho- suggests that medication nonadherence increases the
tics,[2] reduced subjective well-being [3] and poor qual- risk for future episodes.[7,12] Of note, even short inter-
ity of life,[4] and rates of relapse.[5] ruptions in the course of antipsychotic treatment might
Despite the many available treatment options, most increase the risk for relapse.[13]
patients with schizophrenia continue to experience Meta-analyzes demonstrate that antipsychotic treat-
multiple relapses. High relapse rates in response to ments clearly prevent relapse and rehospitalization in
treatment after the first episode [6] are typical, with patients with schizophrenia.[14] A main cause of
~80% of patients having multiple relapses during the relapse is dose reduction either by patients’ nonadher-
first 5 years of treatment.[6,7] ence or by prescribers’ initiation. To this point, Wang
There are many reasons to prevent relapse in schizo- et al. [15] demonstrated statistically significantly more
phrenia. With each relapse, recovery can become relapses in patients who had their starting dose of
slower and less complete; regaining previous level of risperidone (4 – 8 mg/d) decreased by 50% after
function is often more difficult and illness may become 26 weeks of treatment. An even greater relapse rate
more resistant to treatment.[6,8,9] Further, relapse was seen in those with a 50% dose reduction after
causes considerable distress for patients and their 4 weeks. This result is not surprising given the clinical

CONTACT Steven G Potkin sgpotkin@uci.edu

© 2016 Taylor & Francis
 396 S. G. POTKIN AND A. PREDA

(n = 99) or placebo (n = 103). As early as week 1 all

Box 1. Drug summary active arms were significantly different from placebo on
Drug name Aripiprazole once-monthly (AOM long-acting positive and negative syndrome scale (PANSS) total
injectable)
Phase 1–4
scores (p < 0.01). No differences on PANSS total scores
Indication Acute and maintenance schizophrenia were observed between active treatment arms.[23] In a
Pharmacology Partial agonism at D2 and 5HT1A; similar 4-week RCT study of acutely exacerbated hospi-
antagonism at 5HT2A
Route of Intramuscular (gluteal or deltoid) talized patients randomized to oral aripiprazole 15 mg,
administration oral aripiprazole 30 mg, haloperidol 10 mg or placebo,
Chemical 7-[4-[4-(2,3dichlorophenyl)-1-piperazinyl]
structure butoxy]-3,4 dihydrocarbostyril monohydrate equal efficacy between all treatment arms was demon-
Pivotal trials Acute and maintenance Phase III [37] strated compared with placebo.[24] In a 6-week RCT in
acutely exacerbated schizophrenia patients randomized
to oral aripiprazole 10 mg (n = 106), oral aripiprazole
experience with patients who frequently miss doses. 15 mg (n = 106), oral aripiprazole 20 mg (n = 100) and
There may be more benefits other than relapse pre- placebo (n = 108), all doses of aripiprazole were signifi-
vention in patients who continue on their antipsycho- cantly different from placebo on PANSS total scores at
tics, perhaps to a greater extent if they remain on week 1 (15 and 20 mg), week 3 (10 mg) and over the
atypical antipsychotics. In a double-blind 196-week course of the study.[25]
In a randomized clinical 5-day trial focused on the
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study comparing ziprasidone with haloperidol, subjects

who remained on ziprasidone for >40 weeks had a reduction of agitation in acutely ill schizophrenia
much higher remission rate, functional recovery and (n = 459) or schizoaffective patients (n = 134), olanza-
better quality of life than those treated with haloper- pine 20 mg was compared with aripiprazole 15 mg on
idol.[16,17] day 1 that could be increased to aripiprazole 30 mg on
Patients treated with long-acting injectable (LAI) day 2. On the primary efficacy PANSS-Excitatory
typical antipsychotics remain on the medication for a Component, as well as the brief psychiatric rating
significantly longer time than patients treated with the scale-Positive, equal efficacy was demonstrated,
same typical antipsychotics in their oral formulations. although more benzodiazepine use was reported in
[18] Further, patients treated with atypical antipsycho- the aripiprazole group (41.2 vs 31.0% at visit 5). When
tics appear to be more adherent when prescribed LAI benzodiazepine use was co-varied, equal efficacy
formulations compared with the same medication as an between treatments remained.[26]
oral formulation.[19] Second-generation long-acting In a 26-week-long, open-label, naturalistic study of
antipsychotic treatment may prevent and possibly patients requiring a switch in antipsychotic medica-
reverse the loss of frontal lobe intracortical myelination tion because present antipsychotic was not well tol-
in chronic schizophrenia [20] that is associated with erated and/or clinical symptoms were not well
functional deterioration and treatment resistance. controlled, aripiprazole was compared with other
Oral aripiprazole for the treatment of schizophrenia standard of care (SOC) atypical antipsychotics.
has been available for more than a decade. An Patients on aripiprazole had a greater improvement
extended formulation of aripiprazole, Abilify Maintena® in quality of life compared with SOC [27] alternatives
aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM and was preferred by 58.8% of patients compared
LAI), was approved by the FDA in February 2013 [21] with 35.2% of patients who switched to an SOC
and the European Commission in November 2013.[22] atypical antipsychotic.[27]
AOM LAI represents the first dopamine D2 partial ago- Intramuscular (i.m.) aripiprazole solution has also
nist available in a long-acting formulation for the treat- demonstrated short-term efficacy for agitation asso-
ment of schizophrenia. We will review the relevant data ciated with both schizophrenia and bipolar disorder.
for AOM LAI efficacy and tolerability in schizophrenia. [28,29] In the following sections, we review the data
Questions have been raised about the efficacy of on long-acting aripiprazole suspension, which is a dif-
partial D2 agonists. Therefore, the efficacy data for oral ferent formulation of aripiprazole than i.m. aripiprazole
aripiprazole will be briefly reviewed. In a Phase III aripi- although consisting of the same molecule, aripiprazole.
prazole randomized controlled trial (RCT) study, acutely In conclusion, the above data of oral aripiprazole or
exacerbated hospitalized patients with schizophrenia or short-term i.m. aripiprazole solution clearly demon-
schizoaffective disorder were randomly assigned to strate that this partial D2 agonist has equal efficacy to
4 weeks of oral aripiprazole 20 mg (n = 101), oral established D2 antagonist antipsychotics for the treat-
aripiprazole 30 mg (n = 101), risperidone 6 mg ment of schizophrenia.
 EXPERT OPINION ON PHARMACOTHERAPY 397

1.2 Competitor compounds direct comparison between olanzapine LAI and others
SG LAIs is not available.
Many clinicians believe that second-generation antipsy-
Aripiprazole LAI (aripiprazole lauroxil, Aristada®) is a
chotics (SGA) LAIs are superior to first-generation depot
pro drug of aripiprazole. Following i.m. injection, it is
medications (e.g., haloperidol decanoate and fluphena-
metabolized to form N-hydroxymethyl-aripiprazole,
zine decanoate) in tolerability and possibly efficacy;
which is subsequently hydrolyzed to aripiprazole. The
however, the evidence supporting this opinion is lack-
efficacy was established in a 12-week RCT in which
ing.[30] First-generation depot medications enjoyed
accurately exacerbated patients with schizophrenia
widespread use in the 1990s but were partially sup-
were admitted to an inpatient unit and then rando-
planted by the advent of SGA oral medications that
mized to receive i.m. injections of aripiprazole lauroxil
offered less risk of side effects such as Parkinson’s
441 mg, aripiprazole lauroxil 882 mg or placebo.
symptoms, akathisia and tardive dyskinesia. With the
Patients received 15 mg of oral aripiprazole for
introduction of SGA LAIs, the appropriate use of LAIs
21 days to establish tolerability and to achieve early
is being reconsidered. In addition to AOM LAI, there are
therapeutic exposure from the combined release of
three other second-generation atypical long-acting
aripiprazole lauroxil and oral aripiprazole. Significant
antipsychotics (SGA LAIs) (Table 1).
improvement was observed in both lauroxil groups as
Risperidone LAI (Risperdal Consta®) was the first
early as day 8, which continued throughout the 85-day
SGA available as an LAI. It is given every 2 weeks
treatment period. The 441 mg dose of aripiprazole
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and requires oral supplementation for ~3 weeks until

lauroxil contains 300 mg of aripiprazole.[33] Three
a steady state is reached. Risperidone is converted to
weeks of oral aripiprazole coverage is required. Kinetic
9-hydroxyrisperidone (a.k.a. paliperidone) and is con-
and pharmacological differences and approved indica-
sidered a pro-drug by many. Risperidone LAI use
tions between Abilify Maintena and aripiprazole lauroxil
includes the following limitations: delayed time to
have not been determined. The 441 mg dose can be
therapeutic plasma levels, which are usually achieved
given as a monthly deltoid or gluteal injection. The 662
3 – 5 weeks after first injection and delayed time to a
and 882 mg doses are gluteal. The 882 mg dose can be
significant clinical effect, which is usually seen after
given monthly or every six weeks (Table 1).
the third injection. As a result, the patients should
continue to take oral risperidone for at least 3 weeks
following the first risperidone LAI injection.[31] There 2. Introduction of the compound
is also a dose change limitation as it is recommended
2.1 Therapeutic indications
to give at least three injections of a particular dose
before increasing dosage. AOM LAI is an atypical antipsychotic indicated for the
Paliperidone (a.k.a., 9-hydroxyrisperidone) palmitate treatment of schizophrenia in the US based on RCTs
LAI (Invega Sustenna®) is administered every 4 weeks. in patients with acute relapses of schizophrenia and
Oral coverage with risperidone or paliperidone is not maintenance treatment for the prevention of relapse
needed to achieve therapeutic blood levels as a two- (Box 1).
dose initiation injection strategy is used (234 mg on day
1 followed by 156 mg on day 8 and then monthly doses
of 78 – 234 mg). An every-three-month injection 2.2 Qualitative and quantitative composition
(Invega Trinza™) has recently been approved for AOM LAI is available in two types of kits: prefilled
patients who have been stabilized on Invega dual-chamber syringes containing either 300 or
Sustenna® for at least 4 months.[32] 400 mg, or single-use vials of 300 or 400 mg. The
Olanzapine LAI (Zypreda Relprevv®) is administered single-use vials are needed for <300 mg injections.
every 4 weeks; however, its use is limited because of AOM LAI is a suspension of sterile lyophilized powder
the rare development of postinjection syndrome (i.e., reconstituted with sterile water and administered as
confusion, delirium, profound sedation and possible an i.m. injection.
coma), thus requiring observation for 3 h post injection
and specially trained staff and registered facility with
ready access to emergency services. Further, oral olan- 2.3 Administration
zapine compares unfavorably with the other SGAs with AOM can be administered to acutely exacerbated schizo-
regard to metabolic adverse effects including weight phrenia patients once tolerability has been established by
gain, risk for diabetes and dyslipidemia; however, a history or oral challenge for patients not previously
 398 S. G. POTKIN AND A. PREDA

Table 1. Comparison of FDA-approved LAIs.

AOM LAI Abilify Paliperidone palmitate LAI Olanzapine LAI Risperidone LAI
Maintena® Invega Sustenna® Zyprexa Relprevv® Risperdal Consta® Abilify Lauroxil Aristada®
Indications SZ SZ, SA SZ SZ SZ
adjunct BP-D
Clinical studies Acute and Acute and maintenance Acute and Acute (SZ) and SZ
maintenance maintenance maintenance (BP-D)
Target dose 400 mg every 4 78 – 234 mg every 4 weeks 150 – 300 mg 25 – 50 mg every 2 441 or 662 mg every 4 weeks
weeks after loading dose every 2 weeks or weeks 882 mg every 4 or 6 weeks
405 mg every 4
weeks
Administrative Once/month Once/month Once or twice/ Twice/month 441 or 662 mg every/month
frequency/month month 882 mg every month/6
weeks
Loading dose −
Volume + − (−)
882 mg in 3.2 ml
Needle gauge + − (−)
Reconstitution (–) + − −
Storage −− −
Oral supplementation – − −
Injection-site pain − −
Metabolic adverse events (−) − (−)
Weight gain (−) − (−)
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CYP450 CYP2D6 CYP2D6 (minor) CYP1A2, CYP2D6 CYP2D6 CYP2D6

CYP3A4 CYP3A4 (minor) CYP3A4 (minor) CYP3A4
Prolactin ++ − (−) −− ++
Sexual adverse events − −−
QTc* −− − −
EPS − −
Akathisia − − − −
Sedation −
*Woosley, RL and Romero, KA, www.Crediblemeds.org, QT drugs List, Accessed 07-16-2015, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755.
Prescriber information does not have a QTc caution for AOM.
Blanks indicate neutral. +: Indicate advantages; + +: Noteworthy advantage; –: Disadvantages; − −: Noteworthy disadvantage; (−): Mild disadvantages; AOM:
Aripiprazole 400 mg once-monthly; BP-D: Bipolar depression; EPS: Extrapyradimal symptoms; LAI: Long-acting injectable; SZ: Schizophrenia; SA:
Schizoaffective disorder.

treated with oral aripiprazole as well as to stabilized out-

patients. The recommended starting and maintenance
AOM dose is 400 mg. Titration is not required.
Continuing treatment with 10 – 20 mg oral aripiprazole
Figure 1. Chemical structure of aripiprazole.
or another oral antipsychotic for 14 day after the first
injection is recommended to maintain therapeutic aripi-
prazole levels during the initiation of therapy, although 4. Pharmacodynamics
Cmax is reached in 5 days for deltoid and 7 days for gluteal
administration. In the case of adverse effects at the Aripiprazole is a partial agonist at the dopamine D2 and
400 mg dosage, decreasing the dose to 300 mg once serotonin 5-HT1A receptors, and an antagonist of 5-
monthly should be considered. More than 90% of patients HT2A receptors. The relationship of AOM LAI’s efficacy
in clinical trials who were treated with 400 mg did not to affinity to other receptors has not been clearly estab-
require dose adjustment and remained on that dose.[34] lished. Aripiprazole’s affinity in vitro is high for D2 and
D3 dopamine and 5-HT1A and 5-HT2A serotonin recep-
tors (highest for D2), moderate for dopamine D4, sero-
tonin 5-HT2C and 5-HT7, α1 adrenergic, and histamine
3. Chemistry
H1 receptors and the serotonin reuptake site and not
AOM LAI contains aripiprazole in its monohydrate poly- appreciable for muscarinic cholinergic receptors. AOM
morphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3- LAI activity is due to aripiprazole and, to a lesser extent,
dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocar- its main metabolite, dehydro-aripiprazole, which has
bostyril monohydrate, with a molecular mass of 466.40. affinities for D2 receptors similar to aripiprazole and
Its empirical formula is C23H27Cl2N3O2•H2O, whose che- represents ~29% of the parent drug exposure in plasma
mical structure is shown in Figure 1 [35]. (prescriber information, AKA PI).
 EXPERT OPINION ON PHARMACOTHERAPY 399

5. Pharmacokinetics and metabolism concern is the rare occurrence of anaphylactic reaction.

AOM LAI’s recommended starting and maintenance dose
5.1 Absorption of AOM
(if tolerated) is 400 mg per month. Titration is not
Owing to low solubility of aripiprazole particles, aripi- required. If there are adverse reactions at 400 mg or
prazole absorption into the systemic circulation is slow concomitant medications affect the metabolism of aripi-
and prolonged following i.m. injection. After multiple i. prazole, the dose can be decreased to 300 mg once
m. doses, the plasma concentration of aripiprazole monthly or lower. In the RCT, >90% of patients remained
gradually increases to a maximum plasma concentra- on 400 mg once monthly.
tion at a median tmax of 4 days for the deltoid muscle Concomitant with the first injection, it is recom-
and 5 – 7 days for the gluteal muscle. For single-dose mended that treatment with oral antipsychotics, not
administration of AOM LAI, the extent of absorption limited to aripiprazole, be continued for 14 consecu-
(AUC) was similar for both the deltoid and gluteal tive days to ensure therapeutic aripiprazole concen-
injection sites, but the rate of absorption (Cmax) was trations whereas AOM LAI therapy is initiated.[39]
higher following administration to the deltoid muscle. Some patients do not require a full 14 days of oral
The mean aripiprazole elimination half-life is 29.9 days overlap, although longer oral overlap may be optimal
for 300 mg and 46.5 days for 400 mg. Steady-state for some patients who may have excessive histaminic
concentrations are achieved by the fourth injection or cholinergic blockade from previous antipsychotic
for both doses and both sites of administration.[22] treatment or symptoms consistent with dopamine
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receptor hypersensitive.[39,40] The European

approval is more limited, with an indication of AOM
5.2 Distribution LAI for patients stabilized on oral aripiprazole and
Based on intravenous administration studies, aripipra- receiving 14 days concomitant oral aripiprazole with
zole is widely distributed throughout the body with an the first injection.
apparent volume of distribution of 4.9 l/kg, consistent
with extensive extravascular distribution. At therapeutic 6.1 Dose reductions
concentrations, aripiprazole and dehydro-aripiprazole
are >99% bound to serum proteins, primarily to For patients who are poor CYP2D6 metabolizers who
albumin. are also receiving a CYP3A4 inhibitor for ≥14 days, a
dose reduction of 200 mg is indicated. For patients
taking a strong CYP2D6 or CYP3A4 inhibitors, dose
5.3 Biotransformation reduction from 400 to 300 mg, or from 300 to
200 mg, is recommended. For patients with both 2D6
Aripiprazole is extensively metabolized by the liver pri-
and 3A4 inhibition, a two-step reduction is indicated
marily by three biotransformation pathways: dehydro-
(i.e., 400 to 200 mg or 300 to 160 mg). Patients taking
genation, hydroxylation and N-dealkylation. Based on in
CYP3A4 inducers should avoid use of aripiprazole.
vitro data, dehydrogenation and hydroxylation are com-
pleted through CYP3A4 and CYP2D6 enzymes, whereas
N-dealkylation is catalyzed by CYP3A4 (EPAR [36]). 7. Clinical efficacy
Aripiprazole is not a substrate of CYP1A1, CYP1A2,
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 7.1 Study 1: ASPIRE US [41]
CYP2E1 enzymes and does not undergo direct glucur- This RCT study’s objective was to evaluate the efficacy
onidation (PI).[37] and safety of AOM maintenance therapy for the treat-
ment of schizophrenia. The study had four parts: open-
label conversion to oral aripiprazole (4 – 6 weeks),
6. Safety and tolerability
open-label stabilization on oral aripiprazole (10 –
Tolerability with oral aripiprazole needs to be established 30 mg; 4 – 12 weeks), single-blind stabilization on
before starting AOM LAI. The prescribing information (PI) AOM 400 mg (12 – 36 weeks) and double-blind 2:1
recommends 2 weeks to establish tolerability. However, randomization to AOM 400 mg (n = 269) or placebo
in a 12-week RCT,[38] acute tolerability was established (n = 134) (up to 52 weeks). The participants were out-
in 3 days with 10 mg/d for patients not previously patients between the ages of 18 and 60 who required
treated with oral aripiprazole. None of the 195 patients chronic antipsychotic treatment for schizophrenia. The
without previous exposure to aripiprazole showed intol- primary outcome was time to impeding relapse during
erability during the 3-day oral challenge. The main the time AOM that was randomly withdrawn (Phase
 400 S. G. POTKIN AND A. PREDA

IV). The study had two built-in planned interim analyzes. compared with AOM 50 mg at all time points (Figure 3).
At the first planned interim analysis at 64 events, statis- Further, AOM 400 mg was superior to oral aripiprazole
tical significance was observed and the study was 10 – 30 mg at several time points including end point
stopped. Time to relapse was increased in the AOM (Figure 3).
group with a hazard ratio of 5.03 favoring AOM The two ASPIRE studies clearly demonstrated main-
(Figure 2); actual rates of relapse were also lower in the tenance efficacy for (impending) relapse prevention;
AOM group (10 vs 39.6%). Secondary analyzes using however, they do not address whether AOM is an
PANSS total scores demonstrated a drop from baseline effective and safe treatment for acute schizophrenia
of 65 (Phase II) to 55 (Phase III). In Phase IV, placebo- patients.
treated patients returned to their PANSS baseline. It is of The next question of clinical relevance is, is AOM an
interest that dropouts due to lack of efficacy with aripi- effective treatment for acutely ill patients?
prazole were very low (11 out of 710 patients in Phase II
and 13 out of 576 in Phase III), consistent with robust
efficacy for both oral aripiprazole and AOM (Figure 2). 7.3 Study 3: AOM in the acute treatment of
schizophrenia [38]
This double-blind RCT efficacy study compared AOM
7.2 Study 2: ASPIRE EU [43]
400 mg monthly versus placebo over a 12-week course
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This study was similar to ASPIRE US. Stability criteria for of treatment for schizophrenia patients experiencing an
progression between study phases required a PANSS acute psychotic episode. Acute psychosis was defined
score of ≤80 and ≤4 on conceptual disorganization, by a PANSS total score of ≥80 and >4 on conceptual
suspiciousness, hallucinatory behavior and unusual disorganization, hallucinatory behavior, suspiciousness
thought content. The comparison groups were AOM and unusual thought content at screening and baseline.
400 mg (n = 265), oral aripiprazole 10 – 30 mg Mean PANSS score on screening was 103/104 (AOM/
(n = 266) and a very low dose control of AOM 50 mg placebo) with a mean CGI-S of 5.2, indicating a mark-
(n = 131). The percentages of patients reaching relapse edly ill severity. Patients with a first episode of schizo-
criteria at week 26 were 7, 8 and 22%, respectively, phrenia or substance abuse were excluded. The average
demonstrating superiority of both AOM 400 mg and age was 42/43 years for AOM/placebo, with most sub-
oral aripiprazole 10 – 30 mg compared with AOM jects being males (77%/81%) and of African-American
50 mg. In the secondary end point analysis, changes descent (65.5%/65.7%). Only 6.5/6.4% of the patients
in PANSS and clinical global impression - severity (CGI had taken oral aripiprazole before entering the study;
-S) scores were statistically superior for AOM 400 mg those without previous aripiprazole exposure received

Figure 2. Time from randomization to impending relapse during double-blind treatment. Agency EM. Abilify Maintena (aripipra-
zole). Reproduced from publicly available data [42].
 EXPERT OPINION ON PHARMACOTHERAPY 401

Adjusted mean change in PANSS total scores

3

1
AOM 50
0 AOM 400
Oral 10–30
–1

–2

–3
8 Weeks 16 Weeks 24 Weeks 32 Weeks 38 Weeks
Weeks of treatment

Figure 3. Adjusted mean change of PANSS total score in Phase III (efficacy sample, last-observation-carried-forward). Data from [43].
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10 mg/d open label for 3 days to establish tolerability The next clinically relevant question is whether the
before the 7-day washout that all patients completed predicted decrease in relapse rates, as demonstrated in
(note the PI recommends up to 2 weeks of oral expo- the ASPIRE studies, translates to decreased hospital
sure to establish tolerability). No patient experienced an costs in the community.
acute allergic reaction in this study. All patients were
hospitalized for the first two weeks or longer if
required. Concomitant oral aripiprazole of 10 – 20 mg/ 7.4 Study 4: Mirror Image study [44]
d (mean: 12.8 mg/d) was administered to patients ran- The Mirror Image study was an open-label study where
domized on AOM LAI for 2 weeks but not to patients schizophrenia patients were switched from oral antipsy-
randomized to placebo. The primary efficacy outcome chotic medications (SOC) to AOM. The number of retro-
measure from baseline to week 10 (the predefined end spective psychiatric hospitalizations while patients were
point) demonstrated significantly greater improvement treated with SOC oral antipsychotics was compared with
on total PANSS score compared with placebo. The key the number of hospitalizations after AOM 400 mg initia-
secondary measure, change from baseline in CGI-S, was tion. The number of psychiatric hospitalizations was
also significant. A total of 64% of the AOM LAI subjects assessed at 3 and 6 months before AOM treatment and
and 49% of the placebo group completed the 10 weeks compared with 3 and 6 months post-AOM treatment. The
of treatment. The most common reason for disconti- number of psychiatric hospitalizations was significantly
nuation was withdrawal of consent for AOM LAI lower following AOM treatment, with retrospective versus
patients (19%) and lack of efficacy in the placebo prospective rates of 27.1 versus 2.7% (p < 0.0001) for
group (29%). There were significantly greater least months 4 – 6 and 38.1 vs 8.8% for months 1 – 6. In a
square mean (LSM) changes favoring the AOM group post hoc analysis, the savings in psychiatric hospital costs
compared with placebo: for total PANSS score changes were also significant ($13,388 pre-AOM vs $5645 post-
specifically −15.1 (95% CI: −19.4 to −10.8; p < 0.0001) AOM), a savings clearly exceeding medication costs.
and CGI-S improvement specifically −0.8 (95% CI: −1.1 Mirror Image studies are limited in that they do not
to −0.6; p < 0.0001). include a parallel active control group and are subject to
In conclusion, in patients with an acute exacerbation cohort effects such as admission and insurance policy and
requiring hospitalization, AOM LAI 400 mg was effective availability of treatment; at the same time, a mirror design
compared with placebo, as evidenced by significant mitigates other unknown confounders (e.g., heterogene-
changes in symptom severity (PANSS total and CGI-S) ity in course of illness) and reduces between groups
and greater rates of study completion. variability, as the same group of subjects is compared in
The above three studies indicate that AOM 400 mg is a pre- and postintervention design.
effective for relapse prevention in both stabilized schi- Although the evidence presented indicates that
zophrenia outpatients and in the treatment of acutely AOM is an effective and safe choice for acute treatment
exacerbated schizophrenia inpatients. of schizophrenia as well as schizophrenia maintenance,
 402 S. G. POTKIN AND A. PREDA

it is not clear how AOM compares with similar interven- anhedonia, purposeful activity, empathy and emotional
tions, such as other second-generation atypical LAI. interaction) was significantly improved with AOM LAI
When it comes to LAIs, the question facing clinicians compared with PP. The preplanned assessment of
is, how do the different SGA LAIs compare in patients younger patients (age ≤35) showed the largest
with schizophrenia? Unfortunately, there are few such between-treatment difference of 10.7 points on the
studies. Most comparisons of SGA LAIs are with oral QLS (Figure 4). This is considerably larger than the −5
SGAs. The following head-to-head comparison of AOM point noninferiority margin and is double the minimal
400 mg with paliperidone palmitate (PP) once-monthly clinically important difference [47] of 5.3. Key secondary
is the exception. end point CGI-S LSM change from baseline to week 28
also showed significant improvements after AOM LAI
compared with the PP treatment and was greater in
7.5 Study 5: the Qualify study [45]
the ≤35-year-old subjects (Figure 4).
The goal of this Phase IIIb, multicenter, 28-week, rando- Tolerability was better for AOM LAI than PP on the
mized, open-label, rater-blinded, parallel group study Investigator’s Assessment Questionnaire.[48] The inci-
was to compare the effectiveness and tolerability of dence of all-cause discontinuation was numerically
AOM 400 mg (n = 148), with PP (n = 147) at a dose of lower for AOM LAI (29.7%) compared with PP
50 – 150 mg in the EU/Canada equivalent to 78 – (36.7%). In the LAI treatment continuation phase,
234 mg/month in the US for the treatment of schizo- the treatment-emergent adverse events (TEAEs)
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phrenia. The primary outcome measure was the increased weight, insomnia and psychotic disorder
Heinrichs–Carpenter Quality of Life Scale (QLS) [46] as were more frequent in PP-treated patients. Mean
QLS may best fit the clinician’s and patient’s long-term weight gain was 0.2 ± 5.9 kg (n = 100) for AOM LAI
treatment aims. Improving the quality of social interac- and 1.4 ± 6.6 kg for PP (n = 83). At the end of the
tions and negative symptoms may be more important study, 39% of patients judged as not being ready for
than decreasing psychotic symptom severity in schizo- compensated work at the beginning of the study
phrenia. The QLS is a widely used health-related scale were subsequently rated as having the capacity for
focused on intrapsychic, social and negative symptoms. work on the Work Readiness Questionnaire [49] on
It has been used to measure functioning in schizophre- AOM compared with 17% on PP. This odds ratio of
nia, including response to psychopharmacological 2.3 in functional capacity is consistent with the
treatment.[4,40] greater improvement in intrapsychic symptoms, CGI
AOM LAI and PP doses were initiated according to and other secondary measures.
FDA-approval guidelines (AOM 400 mg could be In conclusion, this head-to-head study showed sig-
reduced to 300 mg for tolerability; PP was initiated nificantly greater improvement in QLS and other sec-
with the standard loading dose and then flexible dosing ondary measures for AOM LAI compared with PP using
of 78 – 234 mg/month for 20 weeks). clinically relevant dosing schedules. Although the QLS
Stable adult patients needing a change from present and Investigator’s Assessment Questionnaire ratings
treatment due to inadequate response, poor tolerability were obtained by a blinded investigator, the other
or lack of adherence and who, in the investigator’s secondary measures were not, raising the question of
judgment, would benefit from LAI treatment were bias. However, the entire data set (both blinded and
included, provided they had a CGI-S score of 3 – 5 unblinded) is consistent with superiority of AOM LAI
inclusive and had been on oral antipsychotic treatment over PP in this population, for example, unblinded
for 3 months before the screening visit. Intolerance to Work Readiness Questionnaire rating were consistent
or previous lack of efficacy with oral aripiprazole, risper- with blinded QLS work ratings as were unblinded CGI-
idone or paliperidone, or previous treatment with LAIs S ratings with blinded QLS ratings.
within 6 months before screening were exclusionary.
The study was designed as a noninferiority trial (mar-
7.6 Summary of side effects
gin −5 points on the QLS score) and if noninferiority was
met, superiority was subsequently tested. Superiority In the AOM LAI European Registration trial, the most
was achieved. Improvement on QLS total scores from common TEAE with AOM 400 mg during the rando-
baseline to week 28 for AOM 400 versus PP was signifi- mized-withdrawal phase were insomnia, akathisia,
cant (LSM change (±SE): AOM 400 mg: 7.47 ± 1.53, PP: headache and weight changes (weight increases: 9.1%;
2.80 ± 1.62); LSM treatment difference was 4.67 (95% CI: weight decreases: 9.8%). These events occurred at simi-
0.32–9.02, p = 0.036). The intrapsychic foundation QLS lar rates in the oral aripiprazole group with the excep-
domain (sense of purpose, motivation, curiosity, tion of akathisia, which occurred at a lower rate in the
 EXPERT OPINION ON PHARMACOTHERAPY 403
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Figure 4. Effects of AOM 400 and PP treatment on QLS total scores (A) and CGI-S scores (B) for subjects ≤35 years of age. LSM changes
from baseline were analyzed using a mixed model for repeated measures. *p < 0.05, **p < 0.01 indicate significant differences between
treatments (AOM 400 vs PP). Error bars indicate the standard error of the LSM. Reproduced with permission from [45]. AOM 400:
Aripiprazole 400 mg once-monthly; LSM: Least squares mean; PP: Paliperidone palmitate; QLS: Quality of Life Scale.

oral aripiprazole group. Most adverse effects reported to include maintenance in schizophrenia based on effi-
in the randomized-withdrawal phase were mild or mod- cacy demonstrated in a drug discontinuation trial. In
erate in severity.[43] In the US registration trial, AOM 2013, Abilify Maintena (AOM LAI) was approved for the
LAI (n = 269) was well tolerated overall. TEAEs (occur- treatment of schizophrenia based on efficacy demon-
ring in ≥5% of patients) included increased weight (26/ strated in a randomized-withdrawal design (e.g., the
269, 9.7%), akathisia (15/269, 5.6%), headache (16/269, ASPIRE studies). In 2014, the US label was revised to
5.9%), tremor (16/269, 5.9%), anxiety (16/269, 5.9%) and include efficacy for the treatment of acutely exacerbated
insomnia (27/269, 10.0%).[41] AEs were generally inpatients with schizophrenia. AOM LAI has been evalu-
greater in the acute relapse study than in the nonacute ated for safety in 2188 schizophrenia patients.
patient study (e.g., weight increased 16.8% with AOM
vs 7.0% with placebo and akathisia 11.4% for AOM vs
3.5% for placebo). In the head-to-head comparison
9. Conclusion
study, TEAE >5% were low: insomnia 2.5% for AOM
and 5.5% for PP; weight gain 10.1% for AOM and The Phase III data are consistent in demonstrating effi-
15.6% for PP.[45] cacy for AOM for the treatment of acute exacerbations
of schizophrenia as well as for the prevention of
relapse. The effect sizes are clinically relevant and
meaningful to patients and caregivers as well as pre-
8. Regulatory affairs
scribers. The good tolerability of AOM is consistent with
In 2002, oral aripiprazole was approved for the treatment that of oral aripiprazole, with a favorable weight gain
of schizophrenia based on efficacy demonstrated in and metabolic profile. Despite the good tolerability,
short-term inpatient trials. In 2003, the label was revised weight and metabolics should be monitored for
 404 S. G. POTKIN AND A. PREDA

outliers. The range of positive outcomes as measured confirmation study of AOM versus PP would be desir-
by PANSS, CGI, QLS and Work Readiness Questionnaire able but is unlikely to be conducted given the resources
is consistent with wide-range efficacy of LAI in required. Although some would recommend waiting for
schizophrenia. such confirmation, our recommendation is to use the
available data for guidance.
At present, LAIs tend to be offered late in the course
10. Expert opinion
of illness and usually to those with the most severe
The prevention of relapse is a main goal for the treat- symptoms and least treatment and rehabilitation
ment of schizophrenia. Relapse is frequently associated resources. It is time to reconsider our treatment recom-
with progressive deterioration in illness course and mendations. LAIs remove the uncertainty about possi-
emergence of treatment resistance. In some patients, ble nonadherence; a patient who shows up for an LAI
relapses are accompanied by loss of brain tissue and and receives it is 100% compliant. With oral medica-
frontal lobe myelination. Relapses usually result in tions, the clinician is forced to guess about patient
patient demoralization, decreased quality of life, func- compliance. With LAIs, the guesswork is removed and
tional impairment and increased stigma. In addition to the appointment can be better spent focusing on other
these human and social costs, relapse is associated with issues rather than compliance.
loss of productivity and higher treatment-associated The use of LAIs varies markedly from country to
costs. Consequently, schizophrenia is one of the main country with 30 – 50% use in Austria, the UK, East
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causes of worldwide adult disability. Rates of remission Asia, Turkey and Portugal, but only 10% in Italy and
are increased and patient quality of life is improved the US. Ethnographic studies [51,52] of prescriber and
with treatment adherence to antipsychotic drugs. patient interactions highlighted barriers to prescribing
Poor medication adherence is a critical factor in LAIs. Clinicians tended to offer LAIs with hesitation,
relapse. Medication nonadherence is common, as high- reluctance and lack of enthusiasm, focusing on the
lighted by a nationwide Finnish study of all first-hospi- injection itself as an imposition rather than on specific
talized schizophrenia patients (n = 2588) in which benefits provided by LAI use. Clinicians felt that LAIs
54.3% did not collect antipsychotic prescriptions or may be viewed as a loss of autonomy despite little
discontinued their initial treatment within 30 days of evidence in patient interviews. Advantages of LAIs,
discharge.[50] Studies comparing LAIs with the same including convenience and privacy, were often not
oral antipsychotic medications have often failed to mentioned.
detect an advantage of LAIs in the context of good There is little published data on optimal switching
patient adherence in a research setting. However, in a strategies to AOM from oral or depot antipsychotic
recent study of first-episode patients treated in a rich medications. If patients have not been exposed to
psychosocial research environment, there was a sixfold oral aripiprazole, some oral exposure is required. The
decrease in risk of relapse between risperidone LAI PI recommends up to 2 weeks to establish tolerability;
compared with oral risperidone.[12] In more naturalistic however, the rare but dangerous anaphylaxis reaction
nonresearch settings, where compliance is less com- can be assessed following a single dose of oral aripi-
plete, the advantages of LAIs are typically observed. prazole. In the Kane et al. 12-week acute study,[38]
The Qualify study [45] suggests that treatment with 3 days of tolerability testing were satisfactory. This
AOM 400 may have greater efficacy and fewer side article demonstrates that AOM 400 is effective as a
effects than PP LAI in measurements of quality of life, treatment in acutely exacerbated hospitalized patients
CGI, readiness to work and tolerability (less AEs and less with schizophrenia. Although full tolerability assess-
sexual side effects). The response in the Qualify study ment may require several weeks, anaphylaxis can be
was greatest for subjects ≤35 years old.[45] These stu- determined in a day. Potkin et al. [39] demonstrated
dies [12,45] together highlight the benefits of early that many oral antipsychotics can provide antipsycho-
intervention with atypical LAIs in general. The demon- tic coverage while therapeutic aripiprazole blood con-
strated advantages of AOM over PP in the Qualify study, centrations following AOM injection are being
if confirmed, would point towards the value of inter- obtained. Our experience is that the same principle
vening with AOM in the early stages of schizophrenia applies to overlap with LAIs. For example, switching
when functionality remains largely preserved and may from depot haloperidol or fluphenazine can be accom-
be most benefitted by pharmacological intervention. It plished by administering the AOM injection 1 week
is likely that such an intervention may change the long- before what would be the next scheduled haloperidol
term outlook of schizophrenia and return more patients or fluphenazine injection. Similarly, 1 week before the
to a productive life as they live with schizophrenia. A next scheduled Consta or Sustenna injection is also a
 EXPERT OPINION ON PHARMACOTHERAPY 405

favorable time for the first AOM injection. One should ORCID
be mindful that in switching from antipsychotics with Adrian Preda http://orcid.org/0000-0003-3373-2438
strong cholinergic and histaminic antagonism (e.g.,
olanzapine) to AOM can result in cholinergic and his-
taminic rebound. If recognized, short-term use of
diphenhydramine can decrease these rebound-related Bibliography
side effects. Papers of special note have been highlighted as either of
Schizophrenia patients are particularly sensitive to interest (•) or of considerable interest (••) to readers.
strong expressed emotion and criticism. The ques- 1. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia,
tioning by caretakers of whether oral medication “just the facts” 4. Clinical features and conceptualization.
was taken is frequently a daily, stressful event for Schizophr Res. 2009;110(1–3):1–23.
2. Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting
both patient and caretaker. LAIs reduce this negative
injectable vs oral antipsychotics for relapse prevention in
interaction from daily to monthly. LAIs also remove schizophrenia: a meta-analysis of randomized trials.
the need for the patient not living with family to Schizophr Bull. 2014;40(1):192–213.
remember to take daily oral medications. LAIs also 3. Lambert M, Schimmelmann BG, Schacht A, et al.
can provide greater privacy, for example, from room- Differential 3-year effects of first- versus second-genera-
tion antipsychotics on subjective well-being in schizo-
mates questioning what the patient’s medications are
phrenia using marginal structural models. J Clin
for. The effectiveness of LAIs in general and that the
Downloaded by [Gazi University] at 13:13 16 February 2016

Psychopharmacol. 2011;31(2):226–230.
greatest benefits may be in the very early stages of 4. Karow A, Wittmann L, Schottle D, et al. The assessment of
illness are not usually pointed out in patient–physi- quality of life in clinical practice in patients with schizo-
cian interactions. It is time to reevaluate the way LAIs phrenia. Dialogues Clin Neurosci. 2014;16(2):185–195.
are prescribed, including discussions with patients 5. Almond S, Knapp M, Francois C, et al. Relapse in schizo-
phrenia: costs, clinical outcomes and quality of life. Br J
and their caregivers/family about the multiple advan-
Psychiatry. 2004;184:346–351.
tages and possible enhanced efficacy early in the 6. Emsley R, Chiliza B, Asmal L. The evidence for illness
course of illness. This change in our prescribing para- progression after relapse in schizophrenia. Schizophr
digm is overdue and will hopefully be reflected in Res. 2013;148(1–3):117–121.
revised treatment guidelines as it has the potential to • A summary of the consequences of relapse on course
of illness.
change the life of those with schizophrenia.
7. Robinson D, Woerner MG, Alvir JM, et al. Predictors of
relapse following response from a first episode of schizo-
phrenia or schizoaffective disorder. Arch Gen Psychiatry.
Declaration of interest
1999;56(3):241–247.
SG Potkin has received grant support, funding, honoraria, or 8. Kane JM. Treatment strategies to prevent relapse and
has been a paid consultant to the following companies, which encourage remission. J Clin Psychiatry. 2007;68(Suppl
have conducted scientific or medical research and/or mar- 14):27–30.
keted medications related to psychiatric and neurodegenera- 9. Wiersma D, Nienhuis FJ, Slooff CJ, et al. Natural course of
tive disorders: Alkermes, Amgen, Eli Lilly, FORUM schizophrenic disorders: a 15-year followup of a Dutch
Pharmaceuticals, Genentech, Janssen Pharmaceutical, incidence cohort. Schizophr Bull. 1998;24(1):75–85.
Lundbeck, Merck, Novartis, Otsuka, Sunovion, Roche, Takeda 10. Ascher-Svanum H, Zhu B, Faries DE, et al. The cost of
Pharmaceuticals International, Takeda Global Research and relapse and the predictors of relapse in the treatment of
Development and Toyama Pharmaceuticals. He has also schizophrenia. BMC Psychiatry. 2010;10:2.
received grant support, funding, or has been a consultant 11. Andreasen NC, Liu D, Ziebell S, et al. Relapse duration,
for the following funding agencies, universities and university treatment intensity, and brain tissue loss in schizophrenia:
affiliates, as well as professional organizations that conduct a prospective longitudinal MRI study. Am J Psychiatry.
medical or scientific research related to psychiatric and neu- 2013;170(6):609–615.
rodegenerative disorders: National Institute of Alcohol Abuse 12. Subotnik KL, Casaus LR, Ventura J, et al., et al. Long-
and Alcoholism (NIAAA), National Institute of Biomedical acting injectable risperidone for relapse prevention and
Imaging and Bioengineering (NIBIB), NIH/ National Center for control of breakthrough symptoms after a recent first
Research Resources, University of Southern California, episode of schizophrenia: a randomized clinical trial.
University of California San Francisco, University of California JAMA Psychiatry. 2015;72(8):822–829.
San Diego, Baylor College of Medicine, American Psychiatric •• In an optimal treatment setting, long-acting risper-
Association and Alzheimer’s Association. A Preda has received idone has clear clinical and biological advantages
honoraria or has been a paid consultant for Boehringer- over oral.
Ingelheim and Lundbeck. The authors have no other relevant 13. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and
affiliations or financial involvement with any organization or risk of rehospitalization among California Medicaid patients
entity with a financial interest in or financial conflict with the with schizophrenia. Psychiatr Serv. 2004;55(8):886–891.
subject matter or materials discussed in the manuscript apart 14. Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs
from those disclosed. versus placebo for relapse prevention in schizophrenia: a
 406 S. G. POTKIN AND A. PREDA

systematic review and meta-analysis. Lancet. 2012;379 standard of care: results from the STAR study. Eur
(9831):2063–2071. Psychiatry. 2008;23(5):336–343.
15. Wang CY, Xiang YT, Cai ZJ, et al. Risperidone mainte- 28. De Filippis S, Cuomo I, Lionetto L, et al. Intramuscular
nance treatment in schizophrenia: a randomized, con- aripiprazole in the acute management of psychomotor
trolled trial. Am J Psychiatry. 2010;167(6):676–685. agitation. Pharmacotherapy. 2013;33(6):603–614.
16. Potkin SG, Weiden PJ, Loebel AD, et al. Remission in 29. Sanford M, Scott LJ. Intramuscular aripiprazole: a review
schizophrenia: 196-week, double-blind treatment with of its use in the management of agitation in schizophre-
ziprasidone vs. haloperidol. Int J Neuropsychopharmacol. nia and bipolar I disorder. CNS Drugs. 2008;22(4):335–
2009;12(9):1233–1248. 352.
17. Stahl SM, Malla A, Newcomer JW, et al. A post hoc 30. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of
analysis of negative symptoms and psychosocial function paliperidone palmitate vs haloperidol decanoate for
in patients with schizophrenia: a 40-week randomized, maintenance treatment of schizophrenia: a randomized
double-blind study of ziprasidone versus haloperidol fol- clinical trial. JAMA. 2014;311(19):1978–1987.
lowed by a 3-year double-blind extension trial. J Clin 31. Medicine UNLo. Label: Risperdal consta- risperidone;
Psychopharmacol. 2010;30(4):425–430. 2015. Available from: http://dailymed.nlm.nih.gov/dai
18. Zhu B, Ascher-Svanum H, Shi L, et al. Time to disconti- lymed/drugInfo.cfm?setid=bb34ee82-d2c2-43b8-ba21-
nuation of depot and oral first-generation antipsychotics 2825c0954691.
in the usual care of schizophrenia. Psychiatr Serv. 32. Medicine UNLo. Label: Invega sustenna- paliperidone
2008;59(3):315–317. palmitate injection; 2015. Available from: http://dai
19. Beisteiner R, Hollinger P, Lindinger G, et al. Mental repre- lymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=
sentations of movements. Brain potentials associated with 1af14e42-951d-414d-8564-5d5fce138554.
Downloaded by [Gazi University] at 13:13 16 February 2016

imagination of hand movements. Electroencephalogr Clin 33. Meltzer HY, Risinger R, Nasrallah HA, et al. A randomized,
Neurophysiol. 1995;96:183–193. double-blind, placebo-controlled trial of aripiprazole
20. Bartzokis G, Lu PH, Raven EP, et al. Impact on intracortical lauroxil in acute exacerbation of schizophrenia. J Clin
myelination trajectory of long acting injection versus oral Psychiatry. 2015;76(8):1085–1090.
risperidone in first-episode schizophrenia. Schizophr Res. 34. Raoufinia ABR, Eramo A, Nylander AG, et al. Initiation of
2012;140(1–3):122–128. aripiprazole once-monthly in patients with schizophrenia.
• Provides evidence that LAI risperidone compared Curr Med Res Opin. 2015;31(3):583–592.
with oral risperidone preserves brain myelination in 35. Medicine UNLo. Label: Abilify maintena- aripiprazole;
first-episode patients. 2014. Available from: http://dailymed.nlm.nih.gov/dai
21. Administration UFaD. ABILIFY MAINTENA KIT; 2013. lymed/drugInfo.cfm?setid=ee49f3b1-1650-47ff-9fb1-
Available from: http://www.accessdata.fda.gov/scripts/cder/ ea53fe0b92b6.
drugsatfda/index.cfm?fuseaction=Search.DrugDetails. 36. ABILIFY® (aripiprazole) Tablets [package insert]. Tokyo
22. Agency EM. Abilify Maintena (Aripiprazole); 2015. (Japan): Otsuka Pharmaceutical Co., Ltd.; 2014. Available
Available from: http://www.ema.europa.eu/ema/index. from: http://packageinserts.bms.com/pi/pi_abilify.pdf.
jsp?curl=pages/medicines/human/medicines/002755/ 37. ABILIFY MAINTENA® (aripiprazole) for extended-release
human_med_001711.jsp&mid=WC0b01ac058001d124. injectable suspension, for intramuscular use [package
23. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an anti- insert]. Tokyo (Japan): Otsuka Pharmaceuticals Co. Ltd.;
psychotic with a novel mechanism of action, and risperidone 2015. Available from: http://www.accessdata.fda.gov/
vs placebo in patients with schizophrenia and schizoaffec- drugsatfda_docs/label/2015/202971s006lbl.pdf.
tive disorder. Arch Gen Psychiatry. 2003;60(7):681–690. 38. Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole
•• The partial D2 agonist aripiprazole is equivalent to once-monthly in the acute treatment of schizophrenia: find-
risperidone in acute exacerbated schizophrenia. ings from a 12-week, randomized, double-blind, placebo-
24. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of controlled study. J Clin Psychiatry. 2014;75(11):1254–1260.
aripiprazole and haloperidol versus placebo in patients •• AOM 400 is effective as a treatment in acutely exa-
with schizophrenia and schizoaffective disorder. J Clin cerbated hospitalized patients with schizophrenia
Psychiatry. 2002;63(9):763–771. 39. Potkin SG, Raoufinia A, Mallikaarjun S, et al. Safety and
25. McEvoy JP, Daniel DG, Carson WH Jr., et al. A rando- tolerability of once monthly aripiprazole treatment initia-
mized, double-blind, placebo-controlled, study of the tion in adults with schizophrenia stabilized on selected
efficacy and safety of aripiprazole 10, 15 or 20 mg/day atypical oral antipsychotics other than aripiprazole. Curr
for the treatment of patients with acute exacerbations of Med Res Opin. 2013;29(10):1241–1251.
schizophrenia. J Psychiatr Res. 2007;41(11):895–905. 40. Jones PB, Barnes TR, Davies L, et al. Randomized con-
26. Kinon BJ, Stauffer VL, Kollack-Walker S, et al. Olanzapine trolled trial of the effect on Quality of Life of second- vs
versus aripiprazole for the treatment of agitation in acutely first-generation antipsychotic drugs in schizophrenia:
ill patients with schizophrenia. J Clin Psychopharmacol. Cost Utility of the Latest Antipsychotic Drugs in
2008;28(6):601–607. Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry.
• The partial D2 agonist aripiprazole was equivalent to 2006;63(10):1079–1087.
olanzapine in agitated acutely ill schizophrenia 41. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intra-
patients. muscular depot as maintenance treatment in patients
27. Taylor D, Hanssens L, Loze JY, et al. Preference of med- with schizophrenia: a 52-week, multicenter, randomized,
icine and patient-reported quality of life in community- double-blind, placebo-controlled study. J Clin Psychiatry.
treated schizophrenic patients receiving aripiprazole vs 2012;73(5):617–624.
 EXPERT OPINION ON PHARMACOTHERAPY 407

•• Provides evidence that AOM 400 is very effective in 47. Falissard B, Sapin C, Loze JY, et al. Defining the minimal
preventing relapse in stable schizophrenia patients. clinically important difference of the Heinrichs–Carpenter
42. Time from Randomization to Impending Relapse During Quality of Life Scale (QLS). Int J Methods Psychiatr Res.
Double-Blind Treatment. Agency EM. Abilify Maintena 2015. [Epub ahead of print].
(Aripiprazole); 2015. Available from: http://www.ema. 48. Tandon R, Devellis RF, Han J, et al. Validation of the
europa.eu/docs/en_GB/document_library/EPAR_-_Public_ Investigator’s Assessment Questionnaire, a new clinical
assessment_report/human/002755/WC500156105.pdf. tool for relative assessment of response to antipsycho-
43. Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole tics in patients with schizophrenia and schizoaffective
once-monthly for treatment of schizophrenia: double- disorder. Psychiatry Res. 2005;136(2–3):211–221.
blind, randomised, non-inferiority study. Br J Psychiatry. • Describes the Investigator’s Assessment
2014;205(2):135–144. Questionnaire, a clinical rating instrument measuring
44. Kane JM, Sanchez R, Zhao J, et al. Hospitalisation rates in efficacy, side effects and tolerability.
patients switched from oral anti-psychotics to aripiprazole 49. Potkin SG, Bugarski-Kirola D, Edgar CJ, et al.
once-monthly for the management of schizophrenia: final Psychometric evaluation of the Work Readiness
efficacy analysis. J Med Econ. 2015;18(2):145–154. Questionnaire in schizophrenia. CNS Spectr. 2014;1:1–8.
45. Naber D, Hansen K, Forray C, et al. Qualify: a rando- • A clinical tool that measures the capacity for compen-
mized head-to-head study of aripiprazole once-monthly sated work independent of job availability.
and paliperidone palmitate in the treatment of schizo- 50. Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort
phrenia. Schizophr Res. 2015; Epub ahead of print: pii: study of oral and depot antipsychotics after first hospi-
S0920-9964(15)00346-1 talization for schizophrenia. Am J Psychiatry. 2011;168
•• A randomized controlled trial head-to-head clinical (6):603–609.
Downloaded by [Gazi University] at 13:13 16 February 2016

study comparing AOM 400 with paliperidone palmi- 51. Potkin S, Bera R, Zubek D, et al. Patient and prescriber
tate demonstrating superiority of AOM for the perspectives on long-acting injectable (LAI) antipsycho-
improvement of quality of life and better tolerability. tics and analysis of in-office discussion regarding LAI
46. Heinrichs DW, Hanlon TE, Carpenter WT Jr. The Quality of treatment for schizophrenia. BMC Psychiatry.
Life Scale: an instrument for rating the schizophrenic 2013;13:261.
deficit syndrome. Schizophr Bull. 1984;10(3):388–398. 52. Weiden PJ, Roma RS, Velligan DI, et al. The challenge of
•• The widely used Quality of Life scale measures social offering long-acting antipsychotic therapies: a preliminary
interactions and functioning, negative symptoms and discourse analysis of psychiatrist recommendations for
role performance, and may more accurately reflect the injectable therapy to patients with schizophrenia. J Clin
clinician’s and patient’s long-term treatment goals. Psychiatry. 2015;76(6):684–690.
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