Critical Apprasal of Newly Approved Drugs Used To Treat Schizophrenia

10.1586/ECP.12.70 61 ISSN 1751-2433 2013 Expert Reviews Ltd www.expert-reviews.
com
Review
Schizophrenia is a serious, chronic psychiatric
disorder with a lifetime prevalence of approx-
imately 1% worldwide and major adverse con-
sequences [1]. These include profound impair-
ments in cognition, social functioning and
work capacity [24], and increased risk of early
mortality owing to poor physical health and sui-
cide [57]. Although there is currently no cure
for schizophrenia, many of its most distressing
clinical signs and symptoms can be managed
with the long-term use of antipsychotic medica-
tion in conjunction with effective psychosocial
interventions [8].
Antipsychotic drug treatment has remained
the centerpiece of both acute and long-term
management of schizophrenia for the last sev-
eral decades. Goals of pharmacotherapy with
anti psychotic drugs include amelioration of
severe psychotic symptoms (such as hallucina-
tions, delusions, disorganized behaviors and
aggression/ hostility) during acute-phase treat-
ment; prevention of acute symptom exacerba-
tions and reduction of nonpsychotic signs and
symptoms of schizophrenia (e.g., negative or
decit signs and symptoms, depression, and
so on) during maintenance-phase treatment;
and to improve quality of life and psychosocial
functioning as the overarching goal [9].
Antipsychotic drugs are broadly classied into
two groups: typical and atypical [10]. Typical and
atypical antipsychotic drugs approved for clinical
use in the USA share a common mechanism of
action blockade of central dopamine D
2
neuro-
receptors [10] with the one exception being ari-
piprazole, an atypical antipsychotic and partial
D
2
agonist [11]. Both typical and atypical antipsy-
chotics are effective for reducing symptoms and
preventing relapse in adults with schizophrenia
[12,13]. In this respect, differences in efcacy
between antipsychotics is thought to be modest,
with the exception of superior effectiveness of the
atypical antipsychotic, clozapine, for treatment-
resistant schizophrenia [14,15]. Atypical antipsy-
chotics are distinguished clinically from typical
antipsychotics by lower propensity for causing
antidopaminergic side effects (including extrapy-
ramidal symptoms [EPS] and prolactin elevation)
and lower long-term risk of tardive dyskinesia at
William V Bobo
Department of Psychiatry, Vanderbilt
University School of Medicine,
Nashville, TN, USA
Tel.: +1 615 327 7049
Fax: +1 615 322 1578
william.v.bobo@vanderbilt.edu
This article reviews the pharmacological prole and published efcacy and tolerability/safety
data of iloperidone, asenapine and lurasidone, the most recent atypical antipsychotics to
be approved in the USA for the treatment of schizophrenia. All three agents are similar in
terms of overall efcacy and low propensity for clinically signicant weight gain or adverse
changes in glycemic or lipid prole. However, these agents differ from one another in terms
of formulations, pharmacokinetics, and dosing and nonmetabolic adverse effect prole. For
each drug, comparative and real-world effectiveness studies are lacking, as are effectiveness
and safety data in elderly, young and pregnant/nursing patients. As such, the exact place
of iloperidone, asenapine and lurasidone within the broader antipsychotic armamentarium is
currently difcult to establish.
KEYWORDS: antipsychotic asenapine iloperidone lurasidone schizoaffective disorder schizophrenia
Asenapine, iloperidone
and lurasidone: critical
appraisal of the most recently
approved pharmacotherapies
for schizophrenia in adults
Expert Rev. Clin. Pharmacol. 6(1), 6191 (2013)
Expert Review of Clinical Pharmacology
2013 Expert Reviews Ltd
10.1586/ECP.12.70
1751-2433
1751-2441
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Expert Rev. Clin. Pharmacol. 6(1), (2013) 62
Review
clinically relevant doses [10]. Nearly all atypical antipsychotics are
potent antagonists at serotonin 5-HT
2A
neuroreceptors, a property
not shared by the typical neuroleptics [16].
Currently, ten atypical antipsychotic drugs are approved and
marketed in the USA for the treatment of schizophrenia in adults.
Of these, the most recently approved are iloperidone (Fanapt
TM
,
Vanda Pharmaceuticals, MD, USA; approved in May 2009),
asenapine (Saphris
TM
, Schering-Plough, Kenilworth, NJ, USA;
approved in August 2009) and lurasidone (Latuda
TM
, Sunovion
Pharmaceuticals, Inc., Marlborough, MA, USA; approved in
October 2010). After a several year hiatus, these agents arrived
on the market in relatively short order, with relatively limited
availability outside of the USA. For example, of the three, only
asenapine has regulatory approval by the EMA and in the UK
for treating manic or mixed episodes associated with bipolar I
disorder, although the EMA is considering an application for
marketing authorization for iloperidone. As such, the role of ilo-
peridone, asenapine and lurasidone for treating patients with
schizophrenia, as well as important differences between each
agent, may be unknown to many clinicians. This paper provides
a review of the pharmacological properties of these three atypical
antipsychotic drugs, discussed in order of approval in the USA,
and the results of available published acute- and maintenance-
phase studies in adults with schizophrenia. Added commentary
on the place of asenapine, iloperidone and lurasidone among the
other pharmacotherapeutic options for schizophrenia treatment,
is also included.
Pharmacological prole
Pharmacodynamics
Iloperidone exhibits high afnity for dopamine D
2
and D
3
, and
serotonin 5-HT
2A
receptors, where they act as antagonists (TABLE 1)
[1719], a pattern consistent with its atypical antipsychotic prole;
however, the functional signicance of iloperidones antagonist
activity at dopamine D
3
receptors is unknown. Iloperidone binds
with moderate afnity to dopamine D
4
, serotonin 5-HT
6
and
5-HT
7
, and noradrenergic
1
receptors; and with low afnity
to dopamine D
1
, serotonin 5-HT
1A
and histamine H
1
receptors
[17,18]. Iloperidone has no signicant binding activity at muscarinic
cholinergic M
1
receptors [18]. Iloperidone functions as an anta-
gonist at noradrenergic
1
receptors, which predicts its orthostatic
hypotensive effects [17,18].
Asenapine, like most other atypical antipsychotics, is also a
potent antagonist at dopamine D
2
and serotonin 5-HT
2A
recep-
tors (TABLE 1) [17,20]. Asenapine also binds potently to serotonin
5-HT
1A
, 5-HT
2C
, 5-HT
6
, 5-HT
7
, histamine H
1
and noradrenergic
1
receptors, but has negligible afnity for muscarinic M
1
recep-
tors [17,20,201]. With the exception of muscarinic M
1
receptors,
asenapine behaves as a potent antagonist at each of these sites [21].
There is evidence that asenapine acts as a partial agonist at 5-HT
1A

receptors [22]. Interestingly, weight gain with asenapine during
short- and long-term clinical studies has been modest despite its
potent serotonin 5-HT
2C
and histamine H
1
receptor antagonist
prole (reviewed below) [23,24]. In addition, clinical studies of
asenapine document a low incidence of orthostatic hypotension
and dizziness despite asenapines potent antagonist effects at
noradrenergic
1
receptors [25].
Lurasidone also binds with high afnity to dopamine D
2
and
serotonin 5-HT
2A
receptors, and to 5-HT
7
receptors (TABLE 1) [26].
As shown in TABLE 1, lurasidone binds with marginally higher
afnity to D
2
than 5-HT
2A
receptors. Lurasidone has moderate
binding afnity for serotonin 5-HT
1A
receptors; weak afnity for
noradrenergic
1
and
2c
, and serotonin 5-HT
2C
receptors; and
no signicant binding activity at histamine H
1
or muscarinic M
1

receptors [26]. Lurasidone acts as an antagonist at D
2
and serotonin
5-HT
2A
and 5-HT
7
receptors, and a partial agonist at serotonin
5-HT
1A
receptors [26].
Pharmacokinetics & metabolism
Iloperidone is formulated as solid tablets for oral administra-
tion, the available milligram strengths are listed in TABLE 2 [202].
Iloperidone is well absorbed from the GI tract and peak plasma
concentrations are reached within 24 hours [202]. Administration
with food has no signicant effect on the area under the curve, t
max

or C
max
[27]. Steady-state concentration is reached within 34 days
of initial dosing [202]. Iloperidone is ~95% protein bound, and is
extensively metabolized in the liver via CYP2D6 and CYP3A4
[28]. The mean elimination half-life of iloperidone is 18 hours
for CYP2D6 extensive metabolizers, and 33 hours for slow
metabolizers [202]. One of iloperidones two primary metabolites
(P88-8991) has a receptor binding prole similar to that of the
parent compound, while the other (P95-12113) does not appear
to cross the bloodbrain barrier to a signicant degree [29].
Asenapine is formulated as a rapidly dissolving tablet for sub-
lingual or buccal administration (TABLE 2) [203]. Thus, the primary
site of drug absorption is the oral mucosa, which results in a bio-
availability of approximately 35%. Swallowing the tablet reduces
bioavailability to <2%. Asenapine is rapidly absorbed, and reaches
peak plasma concentration within 0.51.5 hours [203]. However,
drinking liquids within 10 minutes of sublingual administra-
tion of asenapine can signicantly reduce its bioavailability; thus,
avoidance of eating or drinking within 10 minutes of asenapine
administration is recommended [203]. Steady-state concentrations
are reached within 3 days if administered twice daily (b.i.d.).
Asenapine is highly (95%) protein bound, undergoes direct glu-
curonidation by UGT1A4 and is metabolized in the liver by the
CYP1A2 isoenzyme (to a lesser degree by CYP3A4, followed by
CYP2D6) [30,203]. Asenapine is converted to several metabolites
[30], none of which are thought to contribute signicantly to its
overall pharma cological prole. The mean elimination half-life
of asenapine is 1339 hours. Severe hepatic impairment (Child
Pugh class C), but not mild to moderate impairment (ChildPugh
classes A or B, respectively), results in profound increases in asenap-
ine concentration, while no degree of renal impairment appears to
result in increased asenapine exposure [31]. As such, the product
label recommends against the use of asenapine for patients with
severe hepatic impairment, while no adjustment of dose appears
warranted based on renal function [203].
Lurasidone is formulated as a solid oral tablet and is rapidly
absorbed, reaching peak plasma concentration in 13 hours
Bobo
63
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[204]. The absorption of lurasidone is signicantly increased
when administered with food: area under the curve and C
max

are increased two- and three-fold, respectively, in the fed versus
fasting state [204]. Lurasidone is distributed widely throughout the
body, is highly (99.8%) protein bound and extensively metabo-
lized in the liver via the CYP3A4 isoenzyme [204]. Lurasidone has
three pharmacologically active metabolites, one of which (ID-
14283) has a pharmacodynamic prole similar to that of the par-
ent compound [32]. The mean elimination half-life of lurasidone
is 18 hours, but may be expected to be higher after achieving
steady-state concentrations [33].
Drug interactions & dosing
The recommended starting doses, dose titration schedules and
usual clinical dose ranges are presented in TABLE 2.
Iloperidone
Even though the clinically effective dose range of iloperidone for
treating adults with schizophrenia is 612 mg b.i.d., the recom-
mended starting dose is low (1 mg b.i.d.) and titration is required
in order to lower orthostatic hypotension risk [202]. As specied in
the product labeling, adequate symptom control may be slightly
delayed compared with agents that do not require titration to
Table 1. Binding activity of iloperidone, asenapine and lurasidone at selected neuropharmacological
targets.
Target Binding activity K
i
(nM)
,
Iloperidone Ref. Asenapine Ref. Lurasidone Ref.
Dopamine receptors
D
1
216.0 [19] 2.9 [201]
D
2
3.3 [17] 2.0 [17] 1.7 [26]
D
3
7.1 [19] 46.2 [201]
D
4
25.0 [19] 1.8 [201] 0.3 [24]
D
5
319.0 [19] 22.7 [201]
Serotonin receptors
5-HT
1A
33.0 [17] 15.0 [17] 6.8 [26]
5-HT
2A
0.2 [17] 0.8 [17] 2.0 [26]
5-HT
2C
14.0 [17] 0.3 [17]
5-HT
6
63.1 [18] 1.4 [201]
5-HT
7
112.0 [18] 0.9 [201] 0.5 [26]
Norepinephrine receptors
1
0.3 [17] 1.1 [17] 47.9 [26]
2
3.0 [17] 16.1 [17] 40.7
[26]
Histamine receptors
H
1
12.3 [17] 9.3 [17] >1000 [26]
Muscarinic (cholinergic) receptors
M
1
>1000 [18] 24.3 [201] >1000
#
[26]
M
2
>1000 [18] 79.1 [201]
M
3
>1000 [18] 38.7 [201]
M
4
>1000 [18] >1000 [201]
M
5
>1000 [18] 9.5 [201]
Monoamine transporters
Dopamine transporter >1000 [18] >1000 [201]
Norepinephrine transporter >1000 [18] >1000 [201]
Serotonin transporter >1000 [201]
All values are K

i
(nM) based on Psychoactive Drug Screening Program certied data using human cloned receptors [201], human brain receptors [17] or other human
cloned receptor data [18,19,26], unless otherwise specied. Lower numbers indicate higher binding afnity.
Receptor binding prole data and references were accessed using the Psychoactive Drug Screening Program K
i
Database [201]. Data for asenapine and lurasidone
were identied using the designations ORG-5222 and SM 13496, respectively.
K
i
values for lurasidone binding at -2a and -2c adrenergic receptors as reported by Ishibashi et al. [26] were 40.7 and 10.8 nM, respectively.
#
Binding afnity for muscarinic cholinergic receptors, but not muscarinic receptor subtypes, was reported by Ishibashi et al. [26].
Recently approved antipsychotic drugs for schizophrenia
Review
Table 2. Clinical summary of iloperidone, asenapine and lurasidone for the treatment of schizophrenia
in adults.
Iloperidone Asenapine Lurasidone

Brand name Fanapt
Saphris
Latuda
Approved adult indications (USA) Schizophrenia Schizophrenia Schizophrenia

Bipolar I manic or mixed episodes
Formulations/dosage strengths Solid oral tablets (1, 2, 4, 6, 8,
10, 12 mg)
Rapidly dissolving tablets (5, 10 mg) Solid oral tablets (20, 40, 80,
120 mg)
Rapidly dissolving black cherry
avored tablets (5, 10 mg)
Recommended starting dose 1 mg b.i.d. 5 mg sublingually b.i.d.
40 mg once daily
,,#
with food
Recommended titration schedule Increase to 2, 4, 6, 8, and
12 mg b.i.d. on days 2, 3, 4, 5,
6 and 7 (respectively)

Recommended dose range 612 mg b.i.d. 510 mg b.i.d.
40160 mg/day
,#
with food
Maximum daily dose 24 mg per day 20 mg per day
160 mg/day
,#
with food
Metabolism Extensively metabolized:
CYP450 2D6 and 3A4
Direct glucuronidation: UGT1A4 Extensively metabolized:
CYP3A4
Metabolized (major): CYP1A2
Metabolized (minor): CYP3A4, 2D6
Potential PK Increase iloperidone exposure:
strong CYP450 2D6
and
3A4
inhibitors
Caution advised when
coadministering with drugs that are
both CYP1A2 substrates and
inhibitors
Coadministration with potent
CYP3A4 inhibitors
or
inducers
is contraindicated.
Caution advised when
coadministering with moderate
CYP3A4 inhibitors (daily dose
not to exceed 40 mg)
Effect of smoking No effect on drug
concentration thus far shown
No effect on drug concentration
thus far shown
No effect on drug concentration
thus far shown
Potential PD Caution when coadministering
with potent CYP450 2D6 and
3A4 inhibitors
Asenapine is a weak CYP450 2D6
inhibitor; thus, may increase
exposure to some CYP450 2D6
substrates
Caution required when
coadministering with moderate
CYP3A4 inhibitors (maximum
dose 40 mg/day)
Close monitoring advised
when coadministering with
potent noradrenergic
1

receptor antagonists or
antihypertensive drugs with
anti-adrenergic properties
Coadministration with strong
CYP3A4 inhibitors is
contraindicated
Avoid coadministration with
other QT-prolonging drugs
Monthly cost
##
US$760.92 (all doses) US$753.06 (all doses) US$603.73 (40 and 80 mg/day)
US$965.88 (120 mg/day)
Reects information provided in the latest manufacturer label for each product, unless otherwise specied.
Information in the table reects dosage and administration for adults with schizophrenia (acute or maintenance phase treatment). Rapidly dissolving tablets are
suitable for sublingual or buccal administration. Eating and drinking should be avoided for at least 10 minutes after administration. Sublingual tablets should not be
chewed, crushed, divided or swallowed.
The starting dose of lurasidone is 20 mg daily for patients with moderate-to-severe hepatic failure; the maximum daily dose of lurasidone is 80 mg for patients with
moderate hepatic impairment, and 40 mg for severe hepatic impairment.
The starting dose of lurasidone is 20 mg daily (maximum dose 80 mg daily) when taken concomitantly with a moderate or potent CYP3A4 inhibitor (i.e., diltiazem,
and so on).
#
All doses of lurasidone should be taken with food (>350 calories).
Strong inhibitors of CYP2D6 include bupropion, cinacalcet, uoxetine, paroxetine, quinidine [205].
Strong inhibitors of CYP3A4 include indinavir, nelnavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir and telithromycin [205].
Inducers of CYP3A4, 5 and 7 include efavirenz, nevirapine, carbamazepine, glucocorticoids, modanil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone,
rifabutin, rifampin, St. Johns wort and troglitazone [205].
A comprehensive list of drugs for which substantial evidence exists of a QT-prolonging effect may be found online [206].
##
Reference for drug cost/month: Red Book Online. Micromedex Healthcare Series [207].
b.i.d.: Twice a day; PD: Pharmacodynamic drugdrug interaction; PK: Pharmacokinetic drugdrug interaction.
Bobo
65
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clinically effective doses [204]. Strong inhibitors of CYP2D6
(i.e., uoxetine, paroxetine, and so on) or CYP3A4 (i.e., keto-
conazole, clarithromycin, and so on) can signicantly delay the
metabolism and elimination of iloperidone, leading to elevated
iloperidone blood levels (TABLE 2) [202]. Thus, the total daily dose
of iloperidone will need to be reduced (by 50%, according to the
manufacturing label) if used in the presence of strong CYP2D6
and 3A4 inhibitors [202]. Coadministering iloperidone with other
QT-prolonging drugs should be avoided (TABLE 2) [202]. Iloperidone
is not recommended for use in patients with hepatic impairment.
Because renal impairment and smoking status are unlikely to
signicantly alter drug levels in absence of other pharmacokinetic
factors [28,202], dosage adjustment is not likely to be required.
Asenapine
The recommended starting dose for asenapine is 5 mg b.i.d.,
with an effective dose range of 510 mg b.i.d. [203]. As noted
above, asenapine is formulated for sublingual use. Thus, the tab-
lets should not be split to allow for single doses under 5 mg, nor
should they be crushed, chewed or swallowed. The risk of clini-
cally signicant drugdrug interactions involving asenapine has
not been extensively evaluated. Caution is advised when admin-
istering asenapine with CYP1A2 inhibitors (i.e., uvoxamine,
and so on), which may signicantly increase asenapine exposure
[203]. Asenapine is a weak CYP2D6 inhibitor, and may increase
exposure to drugs that are CYP2D6 substrates (such as parox-
etine). Thus, caution is also advised when combining asenapine
with other drugs that act as both substrates and inhibitors for
CYP2D6 (TABLE 2) [203]. Because asenapine acts as a potent nor-
adrenergic
1
receptor antagonist [17], blood pressure and ortho-
static symptom monitoring may be required when combining
asenapine with antihypertensive drugs, particularly those with
anti-adrenergic properties (TABLE 2). Asenapine is not recommended
for use in patients with severe hepatic impairment (ChildPugh
class C), while dosage adjustment is not required based solely on
level of renal impairment [31]. Smoking has not been shown to
si gnicantly alter asenapine exposure [34].
Lurasidone
The recommended starting dose of lurasidone is 40 mg daily,
and recent changes to product labeling reect an expanded effec-
tive dose range of 40160 mg daily [204]. All lurasidone doses
should be taken with food (>350 calories), as also reected in
the current product labeling [204]. Caution is recommended when
coadministering lurasidone with moderate CYP3A4 inhibitors,
with an upper dose limit of 40 mg/day (TABLE 2) [204]. Combining
lurasidone with potent CYP3A4 inducers (i.e., rifampin, and so
on) or inhibitors (i.e., diltiazepin, and so on) is contraindicated,
as these interactions can signicantly alter exposure to lurasi-
done (TABLE 2) [204]. The manufacturer has recommended against
prescribing lurasidone at doses above 40 mg daily in patients
with moderate or severe hepatic impairment, or with severe renal
impairment [204]. Because lurasidone is not a CYP1A2 substrate,
smoking is not expected to alter drug levels in absence of other
pharmacokinetic factors.
Clinical efcacy
Acute-phase treatment
Iloperidone
A summary of results from four short-term, multi-site, rand-
omized, controlled efcacy studies of iloperidone in adults (aged
1865 years) with acute schizophrenia is presented in TABLE 3. The
rst study by Cutler et al. was a 4-week, Phase III study of 606
patients randomized to xed doses of iloperidone (12 mg b.i.d.),
ziprasidone (160 mg daily) or placebo [35]. Eligible patients had
Clinical Global Impression-Severity (CGI-S) [36] scores >4 (indi-
cating at least moderate illness severity) at baseline, a Positive and
Negative Syndrome Scale (PANSS) [37] total score of >70, and
ratings of >4 on at least two PANSS positive symptom items (hal-
lucinations, delusions, suspiciousness/persecution and conceptual
disorganization) at screening and at baseline. Study drugs were
titrated to their target doses over 7 days. Iloperidone and ziprasi-
done resulted in signicantly greater improvement in PANSS-total
scores, the primary efcacy end point, compared with placebo
(TABLE 3). Similar results were observed for PANSS-positive and
-negative subscale, and CGI-S scores. A signicantly higher pro-
portion of iloperidone-treated patients were classied as positive
treatment responders (TABLE 3), dened as those who achieved a
>20% reduction in PANSS-positive symptom subscale scores from
baseline. Neither iloperidone nor ziprasidone treatment resulted in
signicantly greater improvement in Calgary Depression Scale for
Schizophrenia (CDSS) [38] scores compared with placebo.
Another report by Potkin et al. summarized results of three
6-week, Phase III, randomized, double-blind, placebo- and
active comparator-controlled trials of identical design (Studies 1,
2 and 3) [39]. Results were presented for each study separately
(TABLE 3), and in a pooled data analysis. In all studies, eligible sub-
jects had a diagnosis of schizophrenia and a PANSS total score
of >60 at screening and baseline. Randomization occurred fol-
lowing a 3-day placebo run-in period. Study drugs were titrated
to target doses over the rst 7 days of follow-up. In Study 1,
621 patients were randomly assigned to receive one of three xed
doses of iloperidone (2, 4 or 6 mg b.i.d.), haloperidol (15 mg daily)
or placebo [39]. Compared with placebo, there was signicantly
greater improvement in PANSS total scores with iloperidone 6 mg
b.i.d. and with haloperidol (TABLE 3). Improvements in PANSS total
scores with 4 or 8 mg of iloperidone were not signicantly greater
than with placebo. Iloperidone 6 mg b.i.d. and haloperidol (but
not the lower iloperidone doses) were also associated with greater
improvement in Brief Psychiatric Rating Scale (BPRS) [40] scores
than placebo (TABLE 3). There was signicantly greater improve-
ment in PANSS-positive subscale scores in the haloperidol-treated
group (TABLE 3) and a strong statistical trend-level advantage for
iloperidone (p = 0.06) compared with placebo. None of the ilo-
peridone groups resulted in signicant separation from placebo
on PANSS-negative subscale scores.
In Study 2 [39], 616 subjects were randomized to one of two
iloperidone-treated groups (48 or 1016 mg/day), risperidone
(48 mg/day) or placebo. Signicantly greater improvement in
BPRS scores was observed with both iloperidone groups and with
risperidone compared with placebo (TABLE 3). Similar results were
Review
Table 3. Summary of study design and main efcacy results of short-term randomized, controlled trials of
iloperidone in adults with acute schizophrenia.
Study (year) Design Exposure groups Main results Ref.
Cutler et al.
(2008)
Four-week, randomized,
double-blind,
placebo-controlled trial
Iloperidone 12 mg b.i.d.,
n = 295
Ziprasidone 80 mg b.i.d.,
n = 149
Placebo, n = 149
Signicantly greater reduction from baseline in
PANSS total scores for iloperidone (-12.0) and
ziprasidone (-12.3) than placebo (-7.1) (p < 0.05 for
all comparisons)
Similar results reported for change in PANSS-
positive, PANSS-negative and Clinical Global
ImpressionSeverity scale scores
Signicantly greater rates of positive treatment
response
observed with iloperidone (72%) than

placebo (52%; p = 0.005); comparison of positive
response rates for ziprasidone vs placebo were not
reported
No signicant differences (vs placebo) in mean
baseline-to-end point change in Calgary
Depression Scale for Schizophrenia scores were
observed with either iloperidone or ziprasidone
(mean changes were not reported)
[35]
Potkin et al.
(2008)
Study 1: 6-week,
randomized, double-blind,
n = 121
n = 125
n = 124
Haloperidol 7.5 mg b.i.d.,
n = 124
Placebo, n = 127
PANSS total scores for iloperidone 6 mg b.i.d.
(-9.9) and haloperidol (-13.9) than placebo (-4.6;
p < 0.05 for all comparisons). No signicantly
greater reduction in PANSS total scores observed
in other iloperidone-dose groups
PANSS-positive subscale scores with haloperidol
than placebo (-4.8 vs -1.9; p < 0.001), but not
with iloperidone 6 mg b.i.d. (-3.5, p = NS) or any
other iloperidone-dose group
PANSS-negative subscale scores with haloperidol
than placebo (-2.5 vs -0.9; p = 0.02), but not with
iloperidone 6 mg b.i.d. (-1.8, p = NS) or any other
iloperidone-dose group
BPRS scores for iloperidone 6 mg b.i.d. (-6.8) and
haloperidol (-9.0) than placebo (-3.6); (p < 0.04
for all comparisons). No signicantly greater
reduction in BPRS scores observed in other
iloperidone-dose groups
[39]
In the study by Cutler et al. [35], 913 patients were screened and 593 were randomized to study drug. Patients assigned to iloperidone or ziprasidone were titrated to
their target drug doses over 7 days.
Positive response was dened as >20% reduction from baseline in PANSS-positive symptom subscale scores.
The paper by Potkin et al. [39] reported the results of three similarly designed 6-week randomized, controlled trials (n = 1943 randomized subjects). In each study,
patients were titrated to target doses of study drug over 7 days following a 3-day placebo run-in period. Study 1 compared the efcacy of three xed doses of
iloperidone, haloperidol xed at 15 mg daily, and placebo. Study 2 consisted of two iloperidone arms (48 and 1016 mg/day, with total dose divided b.i.d.), one
risperidone arm and a placebo arm. Study 3 also consisted of two iloperidone arms (1216 and 2024 mg/day, with total dose divided b.i.d.), one risperidone arm
and a placebo arm.
b.i.d.: Twice a day; BPRS: Brief Psychiatric Rating Scale; NS: Not signicant; PANSS: Positive and Negative Syndrome Scale.
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67
Review
observed for most secondary efcacy measures, including PANSS-
total and -positive subscale scores, and CGI-S scores (TABLE 3). Only
the iloperidone 1016-mg and risperidone groups were associ-
ated with signicantly greater improvement in PANSS-negative
subscale scores than placebo (TABLE 3).
In Study 3 [39], 706 patients were randomized to receive ilop-
eridone (1216 or 2024 mg/day), risperidone (68 mg/day) or
placebo. Both iloperidone 2024 mg and risperidone demon-
strated signicantly greater improvement in BPRS scores than
placebo (TABLE 3), while a trend-level difference was noted with
iloperidone 1216 mg (p = 0.09 vs placebo). Signicantly greater
improvement in CGI-S scores was observed in both iloperidone
dose groups and the risperidone group, compared with placebo
(TABLE 3). However, only the iloperidone 2024 mg and risperidone
iloperidone in adults with acute schizophrenia (cont.).
Potkin et al.
(2008)
Study 2: 6-week,
Iloperidone 48 mg/day,
n = 153
n = 154
Risperidone 48 mg/day,
n=153
Placebo, n = 156
BPRS scores with iloperidone 48 mg/day (-6.2),
iloperidone 1016 mg/day (-7.2) and risperidone
(-10.3) than placebo (-2.5; p < 0.01 for all
comparisons)
Similar results were reported for mean change in
PANSS total and Clinical Global Impression
Severity scale scores from baseline
PANSS-positive subscale scores with iloperidone
48 mg/day (-3.5), iloperidone 1016 mg/day
(-4.1) and risperidone (-6.0) than placebo (-3.5;
p < 0.02 for all comparisons)
PANSS-negative subscale scores with iloperidone
1016 mg/day (-2.4), and risperidone (-3.0) than
placebo (-1.0; p < 0.02 for all comparisons). No
signicantly greater reduction in PANSS-negative
subscale scores observed with iloperidone
48 mg/day (-1.9), compared with placebo
[39]
Potkin et al.
(2008)
Study 3: 6-week,
n = 244
n = 145
Risperidone 68 mg/day,
n = 157
Placebo, n = 160
BPRS scores with iloperidone 2024 mg/day (-8.6)
and risperidone (-11.5) than placebo (-5.0),
(p < 0.01 for all comparisons). Trend-level
difference (vs placebo) was observed with
iloperidone 1216 mg/day (-7.1; p = 0.09)
Similar results were reported for mean change
from baseline in PANSS total scores
PANSS-positive subscale scores with iloperidone
2024 mg/day (-5.1) and risperidone (-7.2) than
placebo (-3.1; p < 0.01 for all comparisons).
Change in PANSS-positive subscale score was not
signicantly greater with iloperidone
1216 mg/day (-4.2) than placebo
PANSS-negative subscale scores with iloperidone
2024 mg/day (-2.8) and risperidone (-3.4) than
placebo (-1.5; p < 0.02 for all comparisons);
Change in PANSS-negative subscale score was
not signicantly greater with iloperidone
1216 mg/day (-2.2) than placebo
[39]
In the study by Cutler et al. [35], 913 patients were screened and 593 were randomized to study drug. Patients assigned to iloperidone or ziprasidone were titrated to
their target drug doses over 7 days.
Positive response was dened as >20% reduction from baseline in PANSS-positive symptom subscale scores.
The paper by Potkin et al. [39] reported the results of three similarly designed 6-week randomized, controlled trials (n = 1943 randomized subjects). In each study,
patients were titrated to target doses of study drug over 7 days following a 3-day placebo run-in period. Study 1 compared the efcacy of three xed doses of
iloperidone, haloperidol xed at 15 mg daily, and placebo. Study 2 consisted of two iloperidone arms (48 and 1016 mg/day, with total dose divided b.i.d.), one
risperidone arm and a placebo arm. Study 3 also consisted of two iloperidone arms (1216 and 2024 mg/day, with total dose divided b.i.d.), one risperidone arm
and a placebo arm.
b.i.d.: Twice a day; BPRS: Brief Psychiatric Rating Scale; NS: Not signicant; PANSS: Positive and Negative Syndrome Scale.
Review
groups were associated with signicantly greater improvement in
PANSS total and subscale scores (TABLE 3).
A pooled analysis of Studies 13 [39] examined the com-
bined effects of each iloperidone dose group (48, 1016 or
2014 mg/day), haloperidol, risperidone, or placebo on baseline-
to-end point change in BPRS scores. The pooled data set consisted
of 1,553 patients who had at least 2 weeks of post-randomization
follow-up. All active treatment groups, including all three ilop-
eridone dose ranges, were associated with signicantly greater
improvement in BPRS scores, relative to placebo. In another
pooled analysis that included data from all four prospective,
randomized, double-blind, placebo- and active-controlled trials
of patients with schizophrenia and schizoaffective disorder, sig-
nicantly greater improvement in PANSS total, PANSS-positive
and -negative subscale, and BPRS scores was also reported with
iloperidone (1016 and 2024 mg/day) compared with placebo
[41]. Similar results were obtained when the data from patients
with schizoaffective disorder were excluded.
Asenapine
The efcacy of asenapine for acute-phase treatment of schizo-
phrenia has been demonstrated in two randomized, Phase III,
multi-site, double-blind, placebo- and active comparator-con-
trolled trials (TABLE 4). Potkin et al. conducted a 6-week rand-
omized, xed-dose study of asenapine 10 mg/day (5 mg b.i.d.),
risperidone 6 mg (3 mg b.i.d.) or placebo [42]. Eligible patients
were adults (>18 years of age) with acutely exacerbated schizo-
phrenia (n = 182 randomized subjects), dened by baseline CGI-S
scores of >4, PANSS total score of >60, and a score >4 on at least
two PANSS-positive subscale items (hallucinations, delusions,
suspiciousness/persecution, grandiosity or conceptual disorgani-
zation). Eligible subjects also had to have had a prior history of
positive anti psychotic drug treatment response. Study drugs were
titrated to target dose over 35 days. All asenapine-treated sub-
jects also received two solid oral placebo tablets, while risperidone-
treated subjects also received sublingual placebo. Patients in the
placebo group received both solid oral and sublingual placebo
b.i.d. formulations. Baseline-to-end point improvement in PANSS
total scores, the primary study end point, was signicantly greater
with asenapine than placebo but not with risperidone (TABLE 4).
Signicantly greater decreases in PANSS total scores in the
asenapine group (vs placebo) were observed beginning at week 2
and continued through the end of the study period. As com-
pared with placebo, both asenapine and risperidone resulted in
signicantly greater improvement in PANSS-positive subscale and
CGI-S scores (TABLE 4) [42]. However, only asenapine resulted in sig-
nicantly greater improvement in PANSS-negative and -general
psychopathology subscale scores, compared with placebo (TABLE 4).
In a second 6-week study by Kane et al., 458 patients (aged
18 years or older) with acutely exacerbated schizophrenia were
randomized to receive one of two xed doses of asenapine (5 or
10 mg b.i.d.), haloperidol (4 mg b.i.d.) or placebo [43]. Eligible
subjects had a PANSS total score of >60, a score of >4 on at
least two PANSS-positive subscale items (delusions, hallucina-
tions, suspiciousness/persecution, grandiosity, or conceptual
disorganization) and CGI-S score of >4 at baseline. In the primary
last-observation-carried-forward analysis, asenapine 5 mg b.i.d.
and haloperidol, but not asenapine 10 mg b.i.d., resulted in signi-
cantly greater baseline-to-end point improvement in PANSS total
scores (the primary efcacy end point) and PANSS-positive sub-
scale scores (TABLE 4) [43]. Advantages of asenapine 5 mg b.i.d. and
haloperidol over placebo on PANSS-total and -positive subscale
scores were apparent beginning at week 3, and continued through-
out the remainder of the study period. All active treatments were
superior to placebo on change in PANSS Marder positive factor
scores (TABLE 4) [44]. Only asenapine (5 mg b.i.d.) resulted in sig-
nicantly greater improvement in PANSS-negative and -general
psychopathology subscale scores, while no active treatment was
superior to placebo for change in PANSS Marder negative factor
scores (TABLE 4). Only haloperidol was associated with signicantly
greater improvement in PANSS Marder hostility/excitement fac-
tor scores than placebo, and only asenapine 5 mg b.i.d. was associ-
ated with greater improvement in PANSS Marder disorganized
thought processes factor (TABLE 4). Both asenapine dose groups,
but not the haloperidol group, were associated with a signi-
cantly higher proportion of positive treatment response, dened
a priori as a >30% decrease from baseline in PANSS total scores
(TABLE 4). A signicantly higher proportion of subjects achieving a
CGI-Improvement score of 1 (very much improved) or 2 (much
improved) was observed in the asenapine 5 mg b.i.d. group, but
not the asenapine 10 mg b.i.d. or haloperidol groups, relative to
placebo (TABLE 4).
It is worth noting that the acute-phase efcacy of asenapine in
adults with schizophrenia has been evaluated in two additional
6-week placebo-controlled trials that also included olanzapine as
an active control group [45]. The rst study compared the efcacy
of two xed doses of asenapine with olanzapine or placebo. Only
olanzapine (15 mg daily) resulted in signicant baseline-to-end
point decreases in PANSS total score, compared with placebo. As
such, this was considered a negative trial for asenapine. The sec-
ond study compared the clinical effects of exibly dosed asenapine
(510 mg b.i.d.), olanzapine (1020 mg b.i.d.) and placebo. In
this study, neither active treatment group showed signicantly
greater improvement in PANSS total scores, the primary efcacy
variable, than placebo. As such, this was considered a failed trial.
Lurasidone
The short-term, acute-phase efcacy of lurasidone for the treat-
ment of schizophrenia in adults has been evaluated in several
6-week double-blind, placebo-controlled trials (of which three
were Phase II studies) [33,46]. One Phase II [47] and one Phase III [48]
study have been published (TABLE 5). One 6-week, Phase II,
placebo-controlled study (with an additional haloperidol- treated
arm for assay s ensitivity) was considered a failed trial [46].
In the rst Phase II study conducted in the USA, 149 patients
with acute schizophrenia were randomized to one of two xed
doses of lurasidone (40 or 120 mg/day) or placebo [46]. No active
control group was included in this study. Signicantly greater
mean improvement in BPRS scores (lurasidone 40 mg [-9.4 1.6]
vs placebo [-3.8 1.6], p = 0.02; lurasidone 120 mg [-11.0 1.6],
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69
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asenapine in adults with acute schizophrenia
.
Potkin et al.
(2007)
6-week,
randomized,
double-blind,
placebo-controlled
trial
Asenapine 5 mg
b.i.d., n = 60
Risperidone 3 mg
b.i.d., n = 62
Placebo, n = 60
Signicantly greater reduction from baseline in PANSS total
scores for asenapine (-12.0) than placebo (-7.1; p < 0.005), but
not risperidone (-10.0; p = NS vs placebo)
[42]
Signicantly greater reduction from baseline in PANSS-positive
subscale scores with asenapine (-5.5) and risperidone (-5.1)
than placebo (-2.5; p < 0.05 for all comparisons)
Signicantly greater reduction from baseline in PANSS-
negative subscale scores with asenapine (-3.2) than placebo
(-0.6; p = 0.01), but not risperidone (-1.1; p = NS vs placebo)
Signicantly greater reduction from baseline in CGI-S subscale
scores with asenapine (-0.7) and risperidone (-0.8) than
placebo (-0.3; p < 0.01 for all comparisons)
Kane et al.
(2010)
6-week,
randomized,
double-blind,
placebo-controlled
trial
Asenapine 5 mg
b.i.d., n = 114
Asenapine 10 mg
b.i.d., n = 106
Haloperidol 4 mg
b.i.d., n = 115
Placebo, n = 123
scores for asenapine 5 mg b.i.d. and haloperidol than placebo
(p < 0.05 from week 3 until the end of the study, LOCF and
MMRM analyses, mean scores not reported). Reduction in
PANSS total scores were not statistically signicantly greater
than placebo for asenapine 10 mg b.i.d. at any time point in
the LOCF analysis, but was signicantly greater at week 6
using MMRM analysis (p < 0.05, mean scores not reported)
[43]
Signicantly greater reduction from baseline in PANSS-positive
subscale scores for asenapine 5 mg b.i.d. and haloperidol than
placebo (p < 0.05 from week 3 until the end of the study,
LOCF and MMRM analyses, mean scores not reported).
Reduction in PANSS-positive subscale scores were signicantly
greater than placebo for asenapine at week 6 (p < 0.05, LOCF
and MMRM analyses, mean scores not reported)
negative subscale scores for asenapine 5 mg b.i.d. than
placebo at weeks 5 and 6 (p < 0.05, MMRM analysis only,
mean scores not reported). Reductions in PANSS-negative
subscale scores were not signicantly greater than placebo in
the asenapine 10 mg b.i.d. or haloperidol groups in either the
LOCF or MMRM analyses
Signicantly greater reduction in PANSS-derived Marder factor
positive-symptom score [44] for asenapine 5 mg b.i.d. (-7.7),
asenapine 10 mg b.i.d. (-7.3), and haloperidol (-7.3) than
disorganized thought score [44] for asenapine 5 mg b.i.d. (-4.7)
than placebo (-3.2; p < 0.05). Reductions in disorganized-
thought scores were not signicantly greater than placebo in
the asenapine 10 mg b.i.d. (-4.2) or haloperidol (-4.2) groups
This table does not present the study design features or results of one negative or one failed trial for asenapine [45].
A total of 182 patients were randomized to study drug. Patients assigned to asenapine were titrated to their target drug doses over 5 days, while patients
randomized to risperidone were titrated to their target drug doses over 3 days. Asenapine was administered in sublingual form. To preserve the blind, a double-
dummy design was employed in which all asenapine-treated subjects also received two solid oral placebo tablets, risperidone-treated subjects also received
sublingual placebo, and patients assigned to the placebo group received both solid oral and sublingual placebo formulations.
A total of 513 patients were screened and 458 randomized to the study drug. Post hoc analysis showed no signicant differences in efcacy between asenapine and
haloperidol except for signicantly higher positive response rate with asenapine 5 mg b.i.d. than haloperidol.
Dened a priori as a >30% decrease in PANSS total score from baseline.

#
Dened a priori as a Clinical Global Impression-Improvement scale score of 1 (very much improved) or 2 (much improved).
b.i.d.: Twice a day; CGI-S: Clinical Global Impression-Severity scale; LOCF: Last observation carried forward; MMRM: Mixed model repeated measures analysis;
NNT: Number needed to treat; NS: Not signicant; PANSS: Positive and Negative Syndrome Scale.
Review
p = 0.004 vs placebo), the primary study end point, as well as
CGI-S and Clinical Global Impression-Improvement scores,
were observed with both lurasidone doses than with placebo.
The lurasidone 120-mg dose group experienced signicantly
greater improvement in PANSS total scores. Both lurasidone
groups had higher rates of positive treatment response (dened
as >20% improvement from baseline in PANSS total scores),
compared with the placebo group (lurasidone 40 mg [55.3%,
number needed to treat (NNT) 3, 95% CI: 27]; lurasidone
120 mg [50.0%, NNT 4, 95% CI: 311]).
In a second USA Phase II study published by Nakamura et al.,
180 patients (aged 18 to 65 years) with an acute exacerbation of
schizophrenia were randomized to receive lurasidone at a xed
dose of 80 mg/day or placebo [47]. Eligible subjects had a BPRS
score of >42, a CGI-S score of >4 (moderately ill), and mini-
mal EPS (Simpson-Angus Scale [SAS] [49] score of <2 and an
Abnormal Involuntary Movement Scale [AIMS] [50] score of <3)
at baseline. Signicantly greater baseline-to-end point improve-
ment in BPRS scores was observed with lurasidone than placebo
(TABLE 5). Statistical advantages of lurasidone over placebo were
observed as early as day 3, and continued throughout the remain-
der of the study. Lurasidone treatment also resulted in signi-
cantly greater baseline-to-end point improvement in all secondary
effect measures, including PANSS total and subscale scores, as
well as the CGI-S and MontgomeryAsberg Depression Rating
Scale (MADRS) (TABLE 5). A signicantly higher proportion of
lurasidone-treated patients achieved a positive treatment response
(TABLE 5), dened a priori as a >20% reduction in PANSS total
score from baseline.
Three Phase III studies have been conducted [46,51]; however,
only one study (PEARL 2) has been published [48]. The rst study
(PEARL 1) compared the efcacy of lurasidone at one of three
xed doses (40, 80, or 120 mg/day) with placebo in a 6-week,
multination (51 sites worldwide), randomized study of 500
patients with acute schizophrenia [46]. The primary efcacy end
point was baseline-to-end point change in PANSS total scores;
change in CGI-S score was a secondary measure. Lurasidone
80 mg/day, but not 40 or 120 mg/day, resulted in signicantly
greater improvement in PANSS total and CGI-S scores, as com-
pared with placebo. Signicantly greater improvement in PANSS-
positive subscale scores and a signicantly higher proportion of
positive treatment responders (e.g., persons who achieved a >30%
decrease in PANSS total scores from baseline) were observed for
both the 80-and 120-mg/day lurasidone dose groups, compared
with placebo.
Meltzer et al. published results of the second Phase III
study (PEARL 2), in which 478 patients were randomized
to one of four xed-dose treatment groups: lurasidone (40 or
120 mg/day), olanzapine (15 mg/day) or placebo [48]. Eligible
subjects had a Mini-International Neuropsychiatric Interview-
conrmed diagnosis of schizophrenia, and a CGI-S score >4,
PANSS total score >80, and a score of >4 on at least two
Table 4. Summary of study design and main efcacy results of short-term randomized, controlled
trials of asenapine in adults with acute schizophrenia (cont.).

Kane et al.
(2010) (cont.)

hostility/excitement score [44] for haloperidol (-2.4) than
placebo (-1.3; p < 0.05). Reductions in hostility/excitement
scores were not signicantly greater than placebo in the
asenapine 5 mg b.i.d. (-1.8) or 10 mg b.i.d. (-1.8) groups
[43]
No signicant difference from baseline in PANSS-derived
Marder factor negative-symptom or anxiety/depression scores
[44] between any active treatment group and placebo
Signicantly higher rates of positive treatment response
with
asenapine 5 mg b.i.d. (55%) and asenapine 10 mg b.i.d. (49%)
than placebo (33%; p < 0.05, NNT 57 for all comparisons).
Comparison of response rate between haloperidol (43%) and
placebo was not statistically signicant
Comparison of response rates using alternative CGI-based
denition
#
vs placebo was signicantly higher for asenapine
5 mg b.i.d. (48 vs 34%; p < 0.05, NNT 8), but not asenapine
10 mg b.i.d. or haloperidol
This table does not present the study design features or results of one negative or one failed trial for asenapine [45].
A total of 182 patients were randomized to study drug. Patients assigned to asenapine were titrated to their target drug doses over 5 days, while patients
randomized to risperidone were titrated to their target drug doses over 3 days. Asenapine was administered in sublingual form. To preserve the blind, a double-
dummy design was employed in which all asenapine-treated subjects also received two solid oral placebo tablets, risperidone-treated subjects also received
sublingual placebo, and patients assigned to the placebo group received both solid oral and sublingual placebo formulations.
A total of 513 patients were screened and 458 randomized to the study drug. Post-hoc analysis showed no signicant differences in efcacy between asenapine and
haloperidol except for signicantly higher positive response rate with asenapine 5 mg b.i.d. than haloperidol.

#
Dened a priori as a Clinical Global Impression-Improvement scale score of 1 (very much improved) or 2 (much improved).
b.i.d.: Twice a day; CGI-S: Clinical Global Impression-Severity scale; LOCF: Last observation carried forward; MMRM: Mixed model repeated measures analysis;
NNT: Number needed to treat; NS: Not signicant; PANSS: Positive and Negative Syndrome Scale.
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PANSS-positive subscale items (delusions, hallucinations, suspi-
ciousness/persecution, unusual thought content, or conceptual
disorganization), at baseline [52]. Baseline-to-end point improve-
ment in PANSS total scores, the primary efcacy end point,
was signicantly greater for all of the active treatment groups,
compared with the placebo group (TABLE 5). Superiority of lurasi-
done 40 mg and olanzapine over placebo on PANSS total score
reduction was observed from week 1 onward, while signicantly
greater improvement in this effect measure for lurasidone 120 mg
was observed from week 3 onward. Similar results for all active
treatment groups were observed on secondary efcacy measures,
including baseline to end point change in PANSS-positive, -nega-
tive, -general psychopathology and CGI-S scores (TABLE 5). Only
the olanzapine group experienced signicantly greater baseline-
to-end point improvement in MADRS scores than the placebo
group (TABLE 5). A signicantly higher proportion of olanzapine but
not lurasidone treated patients were considered positive treatment
responders (TABLE 5).
The nal Phase III trial (PEARL 3) compared the effects of
two lurasidone xed doses (80 and 160 mg/day) with placebo
and quetiapine XR (600 mg/day) in adults with acute schizophre-
nia over 6 weeks [46,51,53]. All active treatments were associated
with signicant improvement from baseline to study end point
in PANSS total scores, the primary efcacy end point, as well
was CGI-S scores, compared with placebo. Signicant improve-
ment in PANSS total scores for both lurasidone dose groups was
observed at day 4 and persisted throughout the remainder of the
study period. Improvements in mean PANSS total scores from
baseline were signicantly greater with lurasidone 80-mg (-22.2),
lurasidone 160-mg (-26.5) group, and quetiapine XR (-27.8),
compared with placebo (-10.3, p < 0.001 for all comparisons)
[53]. All active treatments resulted in signicantly greater improve-
ment than placebo in depressive symptoms, as assessed by the
Montgomery Asberg Depression Rating Scale [54] (p < 0.001 for
all comparisons).
Longer-term studies
Iloperidone
The long-term safety and efcacy of iloperidone was evaluated
in three 52-week, randomized, double-blind, multicenter trials.
Pooled data from these studies have been published [55]. Each of
the studies were identical in design and compared the clinical
effects of exibly dosed iloperidone (416 mg/day) and halop-
eridol (520 mg/day) in patients with schizophrenia or schizo-
affective disorder. A total of 1,239 patients were randomized to
iloperidone and 405 to haloperidol during an initial 6-week,
double-blind treatment phase. Those who completed the initial
treatment phase and achieved a positive treatment response (ilo-
peridone: n = 371; haloperidol: n = 118) were eligible for the
46-week double-blind maintenance phase.
Relapse was dened on the basis of worsening symptoms
(increase in PANSS total scores of >25% or >10 points com-
pared with PANSS total scores taken at the end of the initial
6-week phase), global clinical state (increase in Clinical Global
Impression of Change scores by >2 points), hospitalization
because of psychotic symptom exacerbation or discontinuation
of study medication owing to lack of efcacy [55]. Maintenance
phase relapse rates were very similar between the iloperidone and
haloperidol treatment groups (43.5 vs 41.2%; TABLE 6). Mean time
to relapse was slightly longer with haloperidol (101.8 days) than
iloperidone (89.8 days); however, this difference was not statisti-
cally signicant. Assuming a relapse rate of 30% with haloperidol,
the statistical threshold for equivalence between iloperidone and
haloperidol (hazard ratio < 1.676 at [one-sided] = 0.025) was
achieved in the pooled data set. Baseline-to-end point improve-
ment PANSS-positive subscale scores were greater with haloperi-
dol (TABLE 6); however, there were no signicant between-group
differences in other secondary end points, including PANSS total
and other subscale scores, BPRS scores, rate of discontinuation
for unsatisfactory therapeutic effect, or rates of positive treatment
response.
Asenapine
Two published randomized studies focused on the long-term ef-
cacy and safety of asenapine in adults with schizophrenia [56,57],
including one relapse prevention study [56]. Two additional reports
summarized the extension-phase results of trials comparing the
effectiveness of asenapine and olanzapine [58,59], one of which
focused on primary negative symptoms [59]. In the relapse preven-
tion study [56], 700 patients were treated with open-label sublin-
gual asenapine (10 mg b.i.d.) for up to 26 weeks. Patients who
were clinically stable at the end of the open-label phase were ran-
domized to double-blind continuation treatment with sub lingual
asenapine or placebo for an additional 26 weeks. Relapse was the
primary end point and was broadly dened (TABLE 6, footnote)
on the basis of symptom worsening, worsening global clinical
state, or the emergence of violent or suicidal behaviors. During
double-blind treatment, 12.1% of asenapine-treated patients and
47.4% of placebo-treated patients in the intent-to-treat population
experienced a relapse event (p < 0.0001). Mean time to relapse
(p < 0.0001) and rst quartile of the time to relapse (asenapine,
156 days vs placebo, 41 days) was signicantly longer with asenap-
ine than with placebo. Rates of all-cause discontinuation were
also higher with placebo (62.5%) than with asenapine (30.4%).
Changes from baseline in favor of asenapine were observed for
all secondary measures, including PANSS total, PANSS Marder
factor [44], CGI-S and CDSS scores (TABLE 6).
A second randomized, double-blind, multisite study evaluated
the long-term (52 week) tolerability of asenapine (510 mg b.i.d.,
n = 913) or olanzapine (1020 mg daily, n = 312) in adults with
schizophrenia or schizoaffective disorder, and a baseline PANSS
total score of >60 (including scores of >4 on two or more PANSS-
positive subscale items) [57]. Patients who completed the 52-week
core study were given the option of continuing treatment until the
study blind was broken (extension study). Clinical symptoms (as
measured by the PANSS total and Marder factors), global clinical
state (CGI-S) and other effectiveness measures (Subjective Well-
Being Under Neuroleptic Treatment [60] and Medical Outcomes
Study 12-Item Short Form [61]) were examined as secondary end
points. Improvements in PANSS total scores were similar between
Review
treatment groups at week 6 (asenapine [-17.9] vs olanzapine
[-19.0], p = not signicant [NS]), but were signicantly greater
for the olanzapine group at study end point in the 52-week core
study (TABLE 6). In the core study, no signicant differences were
observed between groups in a secondary observed-case analysis.
Similar results were observed for baseline-to-end point change in
PANSS Marder factor and CGI-S scores (TABLE 6). There were no
signicant between-group differences in SWN or SF-12 scores at
any time during the study.
Results of the extension phase of this study were reported sep-
arately [58]. Patients who continued asenapine (n = 290, mean
daily dosage 13.4 4.6 mg) were followed for an additional
311.0 146.1 days (range: 10653 days), while those who con-
tinued olanzapine (n = 150, mean daily dosage 13.4 4.1 mg) were
lurasidone in adults with acute schizophrenia.
Reference Design Exposure groups Main results Ref.

Nakamura et al.
(2009)
6-week, randomized,
double-blind,
Lurasidone
80 mg/day,
n = 90
Placebo,
n = 90
Signicantly greater reduction from baseline in BPRS scores
for lurasidone (-8.9) than placebo (-4.2, p = 0.01). Similar
results were observed for baseline-to-end point change in
PANSS total scores (-14.1 vs -5.5; p = 0.004)
Signicantly greater reduction from baseline with lurasidone
(vs placebo) on PANSS-positive subscale scores (-4.3 vs -1.7;
p = 0.006), PANSS-negative subscale scores (-2.9 vs -1.3,
p = 0.03), and CGI-S subscale scores (-0.6 vs -0.2; p = 0.007)
Signicantly greater reduction from baseline in MADRS
scores for lurasidone (-2.9) than placebo (-0.1; p = 0.02)
Signicantly higher rate of positive treatment response
with
lurasidone (44.4%) than placebo (26.7%; p = 0.007, NNT: 6)
[47]
Meltzer et al.
(2011)
6-week, randomized,
double-blind,
Lurasidone
40 mg/day,
n = 120
Lurasidone
120 mg/day,
n = 119
Olanzapine
15 mg/day,
n = 123
Placebo,
n = 116
scores for lurasidone 40 mg/day (-25.7), lurasidone
120 mg/day (-23.6) and olanzapine (-28.7) than placebo
(-16.0; p < 0.002 for all comparisons)
positive subscale scores for lurasidone 40 mg/day (-7.7),
lurasidone 120 mg/day (-7.5) and olanzapine (-9.3) than
negative subscale scores for lurasidone 40 mg/day (-6.0),
lurasidone 120 mg/day (-5.2), and olanzapine (-6.2) than
placebo (-3.6) (p < 0.05 for all comparisons)
Signicantly greater reduction in CGI-S subscale scores for
lurasidone 40 mg/day (-1.5), lurasidone 120 mg/day (-1.4),
and olanzapine (-1.5) placebo (-1.1; p < 0.05 for all
comparisons)
Signicantly greater reduction in MD Scale MADRS scores
with olanzapine (-5.0) than placebo (-2.8; p = 0.003).
Reductions in MADRS scores were not signicantly greater
than placebo in the lurasidone 40 mg/day (-3.5) or
120 mg/day (-3.2) groups
Signicantly higher rates of positive treatment response

with olanzapine (74%) than placebo (49%; p < 0.001,
OR: 2.9). Response rates between neither lurasidone
40 mg/day not 120 mg/day were signicantly greater than
that observed with placebo (response rates not reported for
lurasidone groups)
[48]
This table does not present the design features or results of two unpublished positive 6-week, Phase III randomized, double-blind, placebo-controlled acute-phase
studies [46,51,53]. In the rst study, lurasidone 80 mg/day, but not lurasidone at 40 or 120 mg/day, resulted in signicantly greater improvement in PANSS total and
CGI-S scores, as compared with placebo. In a second placebo- and quetiapine-controlled trial, signicantly greater improvement in PANSS total and CGI-S scores were
observed with lurasidone at xed doses of 80 and 160 mg/day and quetiapine XR (600 mg/day) than with placebo [46,51]. This table also does not present design
features or results of one failed trial [46].
The study by Nakamura et al. [47] is the second of three US Phase II studies. A total of 180 patients were randomized to study drug. All study medications were taken
with (or immediately following) breakfast. Study subjects were hospitalized during a 37 days placebo washout period, and for the rst 28 days of follow-up.
The study by Meltzer et al. (PEARL 2) [48] is the second of three US Phase III studies. A total of 478 patients were randomized to study drugs. All doses were
administered in the morning at (or within 30 min following) breakfast. Patients assigned to the lurasidone groups started treatment at their assigned target doses.
BPRS: Brief Psychiatric Rating Scale; CGI-S: Clinical Global Impression-Severity scale; MADRS: MontgomeryAsberg Depression Rating Scale; NNT: Number needed to
treat; OR: Odds ratio; PANSS: Positive and Negative Syndrome Scale.
Bobo
73
Review
followed for an additional 327 139.6 days (range: 15631 days).
During the extension phase, only minor additional changes in
mean PANSS total scores were observed in both groups (asenap-
ine [+1.6], olanzapine [0.8]). No signicant further change in
PANSS subscales, PANSS Marder factors, and CGI or CDSS
scores were observed in either treatment group.
One additional report by Buchanan et al. presented the com-
bined results of two identically-designed 26-week extension
studies that evaluated the long-term efcacy of asenapine and
olanzapine on persisting primary negative symptoms [59]. Eligible
participants had a diagnosis of schizophrenia, baseline PANSS-
negative subscale score of >20 and a score of >4 on at least three of
seven PANSS negative symptom factor items (affective blunting,
emotional withdrawal, passive social withdrawal, active social
avoidance, poor rapport, motor retardation, or lack of spontane-
ity). Each study was conducted in two phases (a 26-week, double-
blind core phase, followed by a 26-week double-blind extension
phase). In the extension phase, patients were continued on their
core study regimens. There were no signicant between-group
differences in negative symptom change, as measured by 16-item
Negative Symptom Assessment Scale (NSA-16) [62], PANSS-
negative symptom subscale, or PANSS Marder negative factor
items [44] at 26 weeks (core studies). Improvement in PANSS
-positive subscale and PANSS positive symptom factor scores was
noted in both groups, with greater improvement occurring in the
olanzapine group. In one of the two extension studies, baseline-
to-end point change in NSA-16 scores (-15.8 vs -11.0; p = 0.03)
and PANSS Marder negative factor scores (-9.2 vs -7.4; p < 0.05)
were signicantly greater with asenapine than olanzapine, while
improvement in PANSS-positive subscale scores was greater with
olanzapine than asenapine (-0.4 vs -1.5; p = 0.04). There were
no signicant between-group differences on the PANSS-negative
subscale scores in either extension study.
Lurasidone
The long-term effectiveness and safety of lurasidone in adults with
schizophrenia has been evaluated in one unpublished 6-month,
open-label extension study [32] and one published 52-week
randomized, double-blind study [63]. In the 52-week study by
Citrome et al., 639 patients with stable schizophrenia or schiz-
oaffective disorder were randomized to exibly dosed lurasidone
(40120 mg daily, mean 84.7 mg daily) or risperidone (26 mg
daily; mean: 4.3 mg daily) [63]. The primary objective was to eval-
uate the long-term safety and tolerability of lurasidone; however,
clinical efcacy was also assessed. All-cause discontinuation rates
were higher for lurasidone-treated patients (269/419 [64%]) than
those who received risperidone (105/202 [52%], NNT 9 [95%
CI: 526]). Median survival time to all-cause study medication
discontinuation was longer for the risperidone group (293 days)
than the lurasidone group (181 days), and the probability of all-
cause discontinuation at 12 months was 0.52 for risperidone-
and 0.64 for lurasidone-treated subjects (log-rank p = 0.018).
There were no signicant between-group differences in the
occurrence of relapse (lurasidone [20%] vs risperidone [16%],
HR 1.31 [95% CI: 0.871.97]), dened a priori as an increase
from baseline in PANSS total score by >30% (with CGI-S >3),
rehospitalization for management of exacerbated psychotic symp-
toms, occurrence of suicidal (or homicidal) thinking, or increased
risk of harm to self or others as judged by the study clinician.
A preplanned test of noninferiority between treatment groups
could not be conducted owing to the small number of relapses.
PANSS total scores improved between baseline and 12 months in
both treatment groups (lurasidone -4.7 [95% CI -6.4 to -3.0] vs
risperidone -6.5 [95% CI: -8.8 to -4.3]), with no signicant dif-
ferences observed. There were no signicant differences between
treatment groups in PANSS subscale, CGI-S or MADRS scores
at study end point or during follow-up, with the exception of
greater improvement in MADRS scores with lurasidone at month
12 (difference = 1.6, p = 0.007).
Safety & tolerability
Short-term safety & tolerability
Iloperidone
The short-term safety prole of iloperidone was systematically
evaluated in a pooled analysis of three 6-week, randomized studies
in patients with schizophrenia [64]. Included in the safety analysis
were patients who received at least one dose of study medica-
tion (n = 1912 total). The most common treatment-emergent
adverse effects for all iloperidone dosage groups (48, 1016
and 2024 mg/day) were dizziness (1023%), dry mouth
(510%), somnolence (58%) and dyspepsia (58%). The occur-
rence of dizziness, somnolence and dry mouth was higher for
the 2024 mg dose group than the lower dose groups [64,202].
Iloperidone was not shown to increase the risk of EPS in any
of the three dosage groups or to increase prolactin levels in the
48-mg and 1016-mg dosage groups (prolactin levels were not
measured in the study that included a 2024-mg iloperidone
dose group) (TABLE 7) [64]. Worsening of akathisia occurred less
frequently in the iloperidone groups than with risperidone and
was similar to that observed in the placebo group. For prolactin
elevation, the pooled results contrast with those of the 4-week
pivotal study by Cutler et al, in which elevated prolactin levels
were observed in 26% of iloperidone-treated and 12% of placebo-
treated patients [35]. Iloperidone was associated with moderate
increases in body weight (1.72.1 kg) over 6 weeks, similar to that
observed with risperidone (1.7 kg). Clinically signicant weight
gain, dened as an increase in body weight of >7% from base-
line, was observed in 12.3% of iloperidone-treated subjects dur-
ing this time period (TABLE 7) [64]. Mild changes in blood glucose,
and only minimal changes in total cholesterol and triglyceride
values, were observed in all treatment groups (TABLE 7); however,
increases in glucose values were statistically signicant in all three
iloperidone dose groups and in the haloperidol group (TABLE 7).
Rates of orthostatic hypotension were 19.5, 15.3 and 12%,
respectively, with iloperidone (all dosage groups combined),
haloperidol and risperidone [64]. In most cases, orthostatic
hypo tension with iloperidone occurred within the rst 7 days
of treatment and generally did not persist. There were statisti-
cally signicant increases in the corrected QT (QTc) interval
from baseline were signicant with all three iloperidone dosage
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.
Review
groups and in the haloperidol group (TABLE 7) [64]. No deaths due
to fatal arrhythmias occurred in any of the short-term clinical
trials [202].
Asenapine
Pooled safety data from three 6-week, xed-dose trials and one
6-week exible-dose trial of sublingual asenapine (510 mg b.i.d.)
for the treatment of adults with schizophrenia (asenapine, n = 572;
placebo, n = 378) indicated that the most common adverse effects
were insomnia (asenapine [15%]; placebo [13%]), somnolence
(asenapine [13%]; placebo [7%]), EPS other than akathisia
(asenapine [10%], placebo [7%]) and akathisia (asenapine [6%];
placebo [3%]) [203]. Transient oral hypoesthesias that typically
resolved within 1 h of study drug administration were reported in
5% of asenapine-treated subjects and 1% of subjects who received
placebo [203]. Increases in body weight occurred in 5% of patients
randomized to asenapine, and <1% of individuals who received
placebo [203]. Of all these effects, only the occurrence of akathisia
showed an apparent dose-related increase (asenapine 5 mg b.i.d.
[4%] vs asenapine 10 mg b.i.d. [11%]). Minimal change in fast-
ing glucose (asenapine [+3.2 mg/dL]; placebo [1.6 mg/dL]),
total cholesterol (asenapine [+0.4 mg/dL]; placebo [3.6 mg/dL]),
triglyceride (asenapine [+3.8 mg/dL]; placebo [13.5 mg/dL])
and prolactin (asenapine [6.5 ng/mL]; placebo [10.7 ng/mL])
values were observed [203]. Only minimal increases in QTc interval
(25 ms) occurred with asenapine at doses of 520 mg b.i.d., and
there were no signicant differences in post-baseline QT increases
between asenapine (510 mg b.i.d.) and placebo [203].
Lurasidone
On the basis of pooled safety data from short-term, placebo-
controlled studies of lurasidone (20160 mg) for treating adults
with schizophrenia (lurasidone, n = 1,508; placebo, n = 709), the
most common adverse effects were somnolence (lurasidone [17%];
placebo [7%]), akathisia (lurasidone [13%]; placebo [3%]), nau-
sea (lurasidone [10%]; placebo [5%]) and parkinsonism (lur-
asidone [10%]; placebo [5%]) [204]. Minimal changes in body
weight were observed among lurasidone-treated subjects (-0.15 to
+0.68 kg) and those who received placebo (-0.02 kg). Signicant
weight gain, dened as a >7% increase in body weight from base-
line, was observed in 4.8% of lurasidone-treated and 3.3% of
placebo-treated patients. The incidence of adverse events related
to EPS (not including akathisia) was 13.5 and 5.8%, respectively,
among lurasidone- and placebo-treated patients, while the overall
incidence of akathisia with lurasidone and placebo was 12.9 and
3.0%, respectively. The occurrence of akathisia increased with
lurasidone in a dose-dependent manner up to 120 mg/day (5.6%
at 20 mg; 10.7% at 40 mg; 12.3% at 80 mg; 22.0% at 120 mg).
The incidence of akathisia in the 160-mg group was 7.4%.
A recently published systematic review and meta-analysis by
De Hert et al. compared the anthropometric and metabolic
effects of iloperidone, asenapine, lurasidone and paliperidone in
short-term, randomized, placebo-controlled or head-to-head tri-
als of patients with acute schizophrenia or bipolar disorder [65].
Analyzable data from longer-term studies were available only
for asenapine and paliperidone. In the short-term studies, the
risk of clinically signicant weight gain (dened as an increase
in body weight of > 7% from baseline) relative to placebo was
highest with asenapine (n = 5 trials [1360 randomized sub-
jects]; pooled RR: 4.09 [95% CI: 2.257.43]; number needed
to harm [NNH]: 17), followed by iloperidone (n = 4 trials [1931
randomized subjects]; pooled RRs 3.13 [95% CI: 2.084.70];
NNH: 11) and paliperidone (n = 12 trials [4087 randomized
subjects]; pooled RR: 2.17 [95% CI: 1.642.86]; NNH: 20).
Lurasidone was not associated with a statistically signicant
change in body weight (n = 6 trials [1793 randomized subjects];
pooled RR: 1.42 [95% CI: 0.872.29]). Iloperidone was associ-
ated with a statistically signicant increase in total-cholesterol
(n = 1 trial [300 randomized subjects]; +11.6 mg/dL [95%
CI: 5.018.2]), HDL-cholesterol (n = 1 trial [300 randomized
subjects]; +3.6 mg/dL [95% CI: 1.65.6]), and LDL-cholesterol
(n = 1 trial [300 randomized subjects]; +10.3 mg/dL [95%
CI: 4.915.7]), while lurasidone was associated with a statistically
signicant increase in HDL-cholesterol (n = 5 trials [1004 rand-
omized subjects]; +1.5 mg/dL [95% CI: 0.62.4]). As reported
by the authors, no other clinically signicant short-term changes
in glycemic or lipid indices were observed.
Longer-term safety & tolerability
Iloperidone
Safety data were also included in the previously reviewed pooled
analysis of long-term randomized, double-blind iloperidone trials
[55]. The safety data set consisted of subjects who achieved a posi-
tive treatment response during an initial 6-week phase, received
at least one dose of double-blind study medication, and had at
least one safety evaluation during the long-term phase (n = 489).
Insomnia (18.1%), anxiety (10.8%) and aggravation of schizo-
phrenia symptoms (8.9%) were the most commonly observed
adverse effects associated with iloperidone, and occurred at rates
similar to those observed with haloperidol. Rates of study drug
discontinuation owing to intolerable adverse effects were 4.3 and
8.5%, for iloperidone and haloperidol, respectively.
At the end of the 6-week phase, mean Extrapyramidal
Symptoms Rating Scale (ESRS) [66] scores decreased in the ilop-
eridone group (-1.5) and increased in the haloperidol group (+0.3,
p < 0.0001). At the end of the long-term treatment phase, 48.2%
of patients who received iloperidone and 34.7% of those who
received halperidol indicated improvement in overall EPS rat-
ings. A signicantly lower proportion of patients who received
iloperidone reported worsening of EPS compared with those who
receive haloperidol (13.5 vs 36.4%; p < 0.001). Worsening of
Barnes Akathisia Scale [67] scores occurred in 9.2% of iloperidone-
and 23.7% of haloperidol-treated subjects during the long-term
treatment phase (p < 0.001).
Mean baseline to last observation change in body weight and
metabolic indices were also assessed [55]. Modest changes in body
weight (iloperidone [+ 3.8 kg] vs haloperidol [+2.3 kg]; p = NS),
total cholesterol (iloperidone [+ 0.9 kg] vs haloperidol [+7.0 kg];
p = NS), triglycerides (iloperidone [+6.8 kg] vs haloperidol
[+12.1 kg]; p = NS) and glucose values (iloperidone [+5.8 kg]
Bobo
77
Review
vs haloperidol [-0.5 kg]; p = NS) were observed in both treat-
ment groups. Mean weight gain for subjects who completed all
52 weeks of follow up was 4.8 kg in the iloperidone group and
3.0 kg in the haloperidol group.
Both iloperidone and haloperidol were associated with minor
changes in the QTcF interval at week 6 (iloperidone [+3.2 ms]
vs haloperidol [+4.0 msec]) and at study end point (iloperidone
[+10.3 ms] vs haloperidol [+9.4 msec]) [55].
Asenapine
In the long-term relapse-prevention study by Kane et al., anxi-
ety (8.2%), weight gain (6.7%) and insomnia (6.2%) were the
most frequently reported adverse effects observed in the asenapine
group [56]. The incidence of EPS-related adverse events (3.1% vs
4.7%; p = NS) and mean changes in BARS, SIMS and SAS scores
were similar in the asenapine and placebo groups. Mean changes
in weight during the 26-week double-blind treatment phase was
0.0 3.4 kg with asenapine and 1.2 4.0 kg with p lacebo, while
the proportion of patients who experienced weight increases of
>7% from baseline was 3.7% with asenapine and 3.2% with pla-
cebo (p = NS). Minimal changes from

baseline in f asting glucose
(asenapine [+2.09 mg/dL] vs placebo [+ 0.02 mg/dL]), glyco-
sylated hemoglobin (asenapine [+0.05%] vs placebo [0.06%]),
total cholesterol (asenapine [+0.9 mg/dL] vs placebo [5.6 mg/
dL]) and triglyceride values (asenapine [+0.9 mg/dL] vs placebo
[11.2 mg/dL]) were observed during the double-blind phase.
In the 52-week, double-blind comparison of asenapine and olan-
zapine by Schoemaker et al., the most commonly reported adverse
events were weight gain (asenapine [12%] vs olanzapine [29%]),
sedation (asenapine [8%] vs olanzapine [10%]), somnolence
(asenapine [9%] vs olanzapine [10%]) and gastro intestinal symp-
toms (asenapine [9%] vs olanzapine [7%]) [57]. Mean increases in
body weight were greater in the olanzapine group than the asenap-
ine group (+0.9 4.8 kg vs +4.2 7.6 kg) in the last observation
carried forward analysis, and in a secondary completer analysis. A
signicant treatment time interaction effect favoring asenapine
was observed for body weight beginning at week 1 and persisted
throughout the remainder of the study (p < 0.0001). The incidence
of weight gain >7% above baseline values was higher with olanzap-
ine (57.1%) than with asenapine (22.0%). There were no signi-
cant changes from baseline, or between group differences, in total
cholesterol or glucose values. However, fasting triglyceride values
increased from baseline in the olanzapine group (+30.4 202.6 mg/
dL) and decreased in the asenapine group (9.8 92.2 mg/dL).
Predominantly mild EPS-related symptoms were reported among
18% (14% akathisia) of asenapine- and 8% (4% akathisia) of
olanzapine-treated patients. Only minimal changes in Abnormal
Involuntary Movement Scale, BARS or SAS scores were observed
during follow-up in both treatment groups. Prolactin levels
decreased from baseline in both groups within the rst two weeks
of follow-up and remained relatively stable during the remainder of
the study. Electrocardiographic abnormalities (asenapine [2.4%],
olanzapine [1.3%]) were generally related to QTc prolongation;
however, no incident cases of QTc prolongation >500 ms were
observed. During the extension phase [58], there were only minor
further changes in body weight, cholesterol or prolactin levels, and
incident EPS-related adverse events in both groups.
The previously reviewed meta-analysis by De Hert et al.
summarized anthropometric and metabolic safety data from
longer-term studies (13 weeks in duration) of asenapine and pali-
peridone [65]. Compared with placebo, asenapine was associated
with a signicantly greater increase in body weight (n = 3 trials
[568 randomized subjects]; weighted mean difference +1.3 kg
[95% CI: 0.62.0]) and a higher rate of clinically signicant
weight gain (n = 3 trials [568 randomized subjects]; pooled RR:
2.05 [95% CI: 1.213.46]; NNH: 9). Paliperidone was also asso-
ciated with signicantly greater increases in body weight (n = 6
trials [1174 randomized subjects]; weighted mean difference
+0.5 kg [95% CI: 0.20.8]) and a higher rate of clinically sig-
nicant weight gain than placebo (n = 6 trials [1174 randomized
subjects]; pooled RR: 1.76 [95% CI: 1.062.90]; NNH: 29).
Lurasidone
Longer-term safety and tolerability were assessed in the 52-week
study by Citrome et al. that compared the clinical effects of
l urasidone with risperidone [63]. The most commonly reported
adverse effects in both treatment groups were nausea (lurasi-
done [16.7%] vs risperidone [10.9%]; p < 0.05; NNH: 18; 95%
CI: 9438), insomnia (lurasidone [15.8%] vs risperidone [13.4%];
p = NS), sedation (lurasidone [14.6%] vs risperidone [13.9%];
p = NS), akathisia (lurasidone [14.3%] vs risperidone [7.9%];
p < 0.05; NNH: 16; 95% CI: 973), somnolence (lurasidone
[13.6%] vs risperidone [17.8%]; p = NS), headache (lurasidone
[10.0%] vs risperidone [14.9%]; p = NS) and vomiting (lurasi-
done [10.0%] vs risperidone [3.5%], p < 0.05; NNH: 16; 95%
CI: 1037). A signicantly lower proportion of lurasidone-treated
subjects reported treamtent-emergent weight gain (lurasidone
[9.3%] vs risperidone [19.8%]; p < 0.05; NNH: 10; 95% CI: -6
to -24). There were statistically signicant between-group differ-
ences in body weight and BMI (p < 0.001 for each comparison);
however, changes from baseline in least-square-mean (standard
error) body weight (lurasidone [-0.97 5.06 kg] vs risperidone
[+1.47 5.03 kg] and BMI (lurasidone [-0.33 1.71 kg/m
2
] vs ris-
peridone [+0.53 1.76 kg/m
2
]) for each respective treatment group
were nonsignicant. A higher proportion of patients experienced
a >7% increase in body weight from baseline in the risperidone
group (14%) than the lurasidone group (7%; NNH: -16; 95% CI:
-9 to -104). Baseline to end point changes in total cholesterol (lur-
asidone [-3.7 29.5 mg/dL] vs risperidone [-4.3 34.0 mg/dL]),
triglycerides (lurasidone [-8.4 89.7 mg/dL] vs risperidone
[+8.5 97.9 mg/dL]), glucose (lurasidone [+2.4 26.1 mg/dL]
vs risperidone [+4.8 20.4 mg/dL], p = 0.005), and glyco-
sylated hemoglobin (lurasidone [+0.04 0.34 %] vs risperidone
[+0.07 0.32%]) were minimal or mild in each treatment group.
Greater increases in prolactin concentration were observed among
risperidone-treated women (lurasidone [+5.16 34.89 ng/mL] vs
risperidone [+33.90 53.31 ng/mL], p < 0.001) and men (lurasi-
done [+2.51 13.46 ng/mL] vs risperidone [+9.45 14.13 ng/mL],
p < 0.001). No clinically signicant electrocardiographic changes
were observed in either treatment group.
Review
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Bobo
79
Review
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Bobo
81
Review
Expert commentary
Schizophrenia is a severe, chronic, impairing and costly mental
disorder. In spite of remarkable advances in terms of pharmaco-
therapeutic options for treating the disorder, many unmet
therapeutic needs remain. Positive signs and symptoms such as
hallucinations, delusions, and disorganized thinking and behav-
ior, long considered the dening psychopathological features of
schizophrenia, have continued to be the symptom domain most
responsive to antipsychotic drug treatment. However, the clinical
signicance of other psychopathological domains, such as nega-
tive (or decit) signs and symptoms, depression and cognitive
impairment are now widely recognized. In particular, negative
signs and symptoms, and cognitive dysfunction may be more
directly related to the profound levels of functional incapacity
observed in many patients with schizophrenia than positive signs
and symptoms. Thus far, available antipsychotic drugs, appear
to be far less effective for reducing primary negative signs and
symptoms and improving cognitive performance than they are
for treating positive signs and symptoms [6870]. Improvement in
cognition with atypical antipsychotic drugs is typically modest
in comparison with the total degree of impairment wrought by
the underlying disorder [71].
Many patients with schizophrenia and related psychotic dis-
orders, such as schizoaffective disorder, still respond poorly to a
given antipsychotic agent in spite of adequate treatment adher-
ence. For patients that do have a positive antipsychotic response,
many continue to experience residual, persisting symptoms that
are associated with poor clinical outcomes and low function-
ing. With the exception of clozapine for treatment-resistant
schizophrenia [14,15,72], recent evidence suggests that, on the one
hand, there is considerable overlap in the effectiveness of most
anti psychotics [73,74]. On the other hand, the interindividual
variability in therapeutic response to antipsychotic treatment
is considerable. To optimize pharmacotherapeutic benet for
patients with schizophrenia, the wide array of anti psychotic
drugs available to practitioners may be considered benecial.
At the same time, this presents a formidable challenge each
drug must be evaluated by clinicians, patients and caregivers on
their individual merits and limitations within, ideally, a shared
decision making framework [75].
Iloperidone, asenapine and lurasidone are the newest agents
from a very large therapeutic class of atypical antipsychotic
drugs. In broad terms, they appear to share a lot in common.
First, like most other atypical antipsychotic drugs, iloperidone
and asenapine display more potent antagonist activity at 5-HT
2A

receptors than D
2
receptors, while lurasidone displays relatively
equivalent binding at both sites. Second, all three are approved
for the treatment of acute schizophrenia in adults, while asenap-
ine is additionally approved for maintenance treatment of schizo-
phrenia, and manic or mixed episodes in adults with bipolar I
disorder (with or without psychotic features, as a single agent or
as a pharmacological adjunct or lithium or valproic acid). There
is currently no evidence of differential efcacy in acute- or main-
tenance-phase treatment of schizophrenia in adults for any of
these agents. Finally, prior to the release of these medications and
paliperidone, another relatively new atypical antipsychotic, there
were only two antipsychotic drugs (ziprasidone and aripiprazole)
that were classied widely as having low risk of clinically signicant
treatment-emergent weight gain, glycemic dysregulation, hyper-
glycemia and atherogenic dyslipidemia. Thus far, iloperidone,
asenapine, and lurasidone have been associated with only limited
changes in body weight, and nonclinically signicant changes in
glycemic and lipid indices. Available evidence therefore suggests
that these agents may eventually be classied as also having low
metabolic risk as additional data accumulates, and will be reason-
able therapeutic options in patients for whom metabolic concerns
are treatment-limiting.
While iloperidone, asenapine and lurasidone are similar in many
ways, there are some practical and theoretical differences between
these drugs based on their individual pharmacological properties
[76], which may translate clinically to particular advantages and
disadvantages. These are summarized in TABLE 8 and discussed in
greater detail below.
For example, iloperidone has been associated with strikingly low
rates of treatment-emergent akathisia in short-term trials [202] and
has the lowest rates of treatment-emergent akathisia of the three
newest antipsychotics, and lower rates of incident akathisia than
two other atypical antipsychotics, ziprasidone and risperidone,
in short-term trials [64]. Even within the atypical class, the risk
of EPS is not absent [77]. Thus, limiting EPS liability remains an
important therapeutic objective. This is especially true for patients
who are highly EPS-sensitive (e.g., patients with rst-episode psy-
chosis, clinically signicant parkinsonism, history of neuroleptic
malignant syndrome or a history of severe or difcult-to-control
akathisia or parkinsonism) or EPS-intolerant (i.e., patients with
histories of poor adherence because of EPS, regardless of severity).
Clozapine and quetiapine have long been considered to have the
lowest EPS risk among the available antipsychotics [78]; however,
wider use of both agents may be limited by adverse metabolic risk
and potentially severe (even life-threatening) side-effects in the
case of clozapine. Based on this, iloperidone may be preferred for
treating patients with who are highly EPS-sensitive or -intoler-
ant. These advantages may be offset, however, by a number of
factors, the rst one being risk of orthostatic hypotension and
dizziness. Although slow titration can reliably limit the incidence
of orthostatic hypotension, it can also limit the clinical utility of
iloperidone in acute settings, where limited lengths of stay often
make even brief delays in achieving therapeutic doses and adequate
symptom control unacceptable. Given the need for titration to
limit side effects, it is not likely that oral iloperidone will be useful
for spot-management of agitation. An even slower titration may be
required for individuals who are particularly sensitive to dizziness
or orthostasis, including elderly patients, patients with heart dis-
ease, and persons taking antihypertensive drugs and other medica-
tions associated with orthostatic blood pressure changes. Second,
although no cases of iloperidone-associated torsades de pointes or
sudden death due to ventricular arrhythmias have been reported,
prolongation of the QTc interval has been observed across all
iloperidone doses. Avoidance of iloperidone may be prudent for
patients who are medically susceptible to ventricular arrythmias
Review
because of underlying heart disease, or for patients taking medi-
cally necessary concomitant medications that lengthen the QT
interval (e.g., anti-arrhythmics, or certain antibiotics, antihis-
tamines, antidepressants, and so on), or who have other known
risk factors for ventricular arrhythmias [79]. These precautions
are similar to those for ziprasidone. When the balance between
clinical benet and cardiac safety is uncertain, consultation with
a cardiologist may be warranted. Fourth, monitoring for emer-
gence of orthostatic blood pressure changes and QTc interval
prolongation may be especially important during a switch from
another antipsychotic to iloperidone and vice-versa, since some
other antipsychotics also carry signicant risk of orthostasis and
QTc lengthening. This clearly applies when cross-tapering from
one drug to another (resulting in a short period of time when both
drugs are ingested), a reasonable switch method in ambulatory
settings given the slow titration required to achieve therapeutic
doses of iloperidone. However, due caution would also apply when
abrupt switching is performed, since several days may be required
to clear most preswitch antipsychotics. Finally, concomitant med-
ications must be closely monitored the dose of iloperidone needs
to be reduced in the presence of concomitant drugs that are strong
CYP450 2D6 and 3A4 inhibitors, and increased if these agents
are discontinued.
Asenapine is the only antipsychotic drug available exclusively
in a rapidly dissolvable sublingual form, with reliable buccal
absorption. This can have a number of advantages rst, rap-
idly dissolvable formulations may be preferred by some patients
to swallowing solid oral tablets, including those with impaired
swallowing mechanisms or gastrointestinal malabsorption
problems. Second, rapidly dissolving asenapine is more dif-
cult to cheek than solid oral tablets, making adherence easier
to monitor, especially in inpatient or other controlled settings.
Third, because it is rapidly absorbed and associated with mild
to moderate somnolence, oral asenapine may be appropriate for
spot-management of acute agitation and is being clinically inves-
tigated for this purpose (NCT 01400113). Of the three newest
antipsychotics, asenapine appears to have the lowest propensity
for elevating prolactin levels, although increases in prolactin
concentrations were modest with iloperidone and lurasidone, and
clinically signicant prolactin-related adverse effects occurred
only rarely. Still, for patients in whom these effects could be
especially bothersome (including young people) or patients with
a history of treatment-emergent galactorrhea, menstrual changes,
gynecomastia or sexual dysfunction clearly correlated with eleva-
tions in prolactin concentration, asenapine may be an especially
attractive option. Asenapines approval for treating acute mixed
or manic episodes in patients with bipolar I disorder may also
be considered an advantage, at least, for the time being, as most
other atypical antipsychotics were rst approved for treating
acute schizo phrenia, with subsequent approval for the treat-
ment of acute bipolar manic or mixed episodes. Finally, because
asenapine undergoes direct glucuronidation and is dependent
on the CYP450 system to a relatively limited degree, there may
also be low potential for clinically signicant drugdrug inter-
actions. For example, lack of CYP3A4 metabolism may make
asenapine the best choice of the three newest agents to combine
Table 8. Potential relative advantages or disadvantages of iloperidone, asenapine and lurasidone.
Advantages Disadvantages
Iloperidone Very low EPS liability
No dose adjustment required on basis of renal
functioning
Administered b.i.d.
Risk of orthostatic hypotension requires slow titration to
therapeutic doses, which may delay onset of therapeutic effect
May need to be avoided in some patients who are at high risk of
orthostasis or hypotension
May need to be avoided in some patients who are at risk for
clinically signicant QTc prolongation
Potentially signicant interactions with CYP2D6 and CYP3A4
inhibitors or inducers
Asenapine Regulatory approval for maintenance treatment
in patients with schizophrenia and manic/mixed
episodes in adults with bipolar I disorder
Some patients may prefer rapidly dissolvable tablets
Easier to monitor adherence in controlled
settings (difcult to cheek)
Minimal effects on prolactin concentration
Few clinically signicant drugdrug
interactions anticipated
Administered b.i.d.
Requires proper handling and cannot be crushed, chewed or
swallowed (may be difcult for some patients)
Dose-related somnolence and akathisia may be limiting for some
patients
Dysgeusia or oral hypoesthesia, though not severe, may
occasionally threaten adherence
Lurasidone Once-daily administration
No titration required to reach initial
therapeutic dose
Lowest propensity for clinically signicant
weight gain or adverse changes in metabolic
indices of the three newest antipsychotics
Must be taken with food (may be impractical or impossible for
some patients)
Dose-related somnolence and akathisia may be limiting for some
patients
b.i.d.: Twice a day; EPS: Extrapyramidal side effects.
Bobo
83
Review
with carbamazepine, where clinically indicated. There are some
potential disadvantages with asenapine. First, patients and car-
egivers must be carefully educated regarding the proper han-
dling (with dry hands) and administration of asenapine. Critical
details must include avoidance of swallowing the medication;
most patients with extensive prior treatment histories will be used
to swallowing their medication. Allowing a tablet to dissolve
orally and avoiding food or drink to allow full absorption may
represent a considerable break from routine that can be surpris-
ingly hard to accomplish for many patients. Patients may also be
tempted to chew the tablets, which must also be avoided. Second,
because of its negligible bioavailability if ingested, swallowing
asenapine can lead to covert or unintended problems with adher-
ence, thus threatening clinical stability outside of supervised
settings. Finally, some patients will experience dysgeusia or oral
hypoesthesia, which can occasionally prove bothersome enough
to threaten adherence. Switching to the black cherry-avored
formulation may be helpful in such cases. Use of gum, candy,
breath mints, or related measures to overcome these effects must
be strictly avoided; at least, in the 10 min following asenapine
administration.
Lurasidone has the lowest short-term risk of clinically signi-
cant weight increases and the most favorable glycemic and lipid
prole among the newest atypical antipsychotic drugs based on
indirect comparisons. That said, the overall metabolic proles of
each of these new agents appears favorable in comparison with
several older atypical antipsychotics (excluding aripiprazole and
ziprasidone) and low-potency typical neuroleptics, and the meta-
bolic proles of each have not been directly compared. Still, the
available data indicate that lurasidone will be considered a low-
risk agent in terms of metabolic adverse effect burden alongside
ziprasidone and aripiprazole. This would be advantageous for
any patient with schizophrenia, given the high long-term cardio-
vascular morbidity and early mortality associated with the dis-
order [6,80]. This may be especially true for patient subgroups
who are particularly vulnerable to the dysmetabolic effects of
antipsychotic drugs (i.e., young people, rst-episode patients and
patients who have already begun to show substantial weight gain
or adverse changes in glycemic or lipid indices) [8184]. For these
individuals, even small differences between agents in terms of
weight gain or metabolic prole can be clinically meaningful
and drive patient or caregiver preferences. Pragmatic advantages
of lurasidone include once-daily dosing, which may improve
adherence, and the ability to initiate treatment at a clinically
effective dose, which may result in more rapid symptom control
during acute-phase treatment. On the other hand, there are some
potential disadvantages. First, lurasidone may be associated with
higher rates of akathisia than iloperidone or asenapine, although
direct comparisons are needed to conrm this observation. Should
treatment-emergent akathisia become problematic, administering
lurasidone at bedtime may be helpful and even preferable, at least
initially, to dose reduction (which risks symptomatic worsening)
or pharmacological augmentation (which may increase overall
adverse effect burden). Night time administration of lurasidone
to reduce daytime somnolence is practicable if evening meals can
be timed accordingly and onset of akathisia does not adversely
impact sleep. Second, lurasidone, like ziprasidone, must be taken
with food (at least 350 kilocalories). Otherwise, drug absorption
will likely be substantially reduced. While this will not present
a pragmatic challenge for most patients, the requirement that
lurasidone be taken in a fed state may be a limitation for low-func-
tioning or very resource-poor patients with inconsistent access to
regular meals, hypocaloric diets or highly irregular mealtimes.
Finally, of the three newest antipsychotics, lurasidone appears to
be associated with the highest rate of treatment-emergent som-
nolence, an often under-appreciated adverse effect that can pro-
foundly impact daytime functioning and prove inconvenient or
embarrassing for patients. To reduce daytime somnolence, dosing
lurasidone at night may be helpful, provided that the medica-
tion can still be taken with (or in close proximity to) evening
meals and that akathisia, if present, does not interfere with sleep
initiation.
Five-year view
Iloperidone, asenapine and lurasidone are the latest agents to
enter the very competitive atypical antipsychotic market. Over
50 antipsychotic drugs are available worldwide, including
14 atypical agents, of which ten are now available in the USA.
The broad availability of such a large number of anti psychotics
raises the question of what additional benet these three new
antipsychotics may bring. On the one hand, the availability
of three new atypical anti psychotics with low impact on body
weight and metabolic indices is highly desirable. Indeed, most
recent antipsychotic drug development efforts have focused on
improving metabolic safety and overall tolerability, an impor-
tant consideration given the high prevalence of cardiovascular
risk factors and premature mortality from cardiovascular causes
among persons with chronic and severe mental disorders who are
most likely to require long-term antipsychotic treatment [6,85],
and notoriously high rates of treatment nonadherence to which
poor anti psychotic tolerability is a known contributor [86,87].
Concerns about long-term metabolic safety with some atypical
antipsychotics have already begun to inuence recommenda-
tions in published clinical practice guidelines. Owing to meta-
bolic safety concerns, olanzapine is no longer recommended as a
rst-line treatment for patients with rst-episode schizophrenia
in the 2009 Schizophrenia Patient Outcomes Research Team
(PORT) treatment recommendations [88], or patients with bipo-
lar disorder in the 2005 update of Texas Medication Algorithm
Project (TMAP) guideline [89]. Based in part on their advanta-
geous metabolic proles, iloperidone, asenapine and lurasidone
will likely be considered rst-line therapeutic options in future
practice guidelines for treating schizophrenia, particularly for
patients with rst-episode psychosis.
On the other hand, clinicians, patients and caregivers will be
looking for specic advantages for each of these compounds in
addition to their favorable metabolic proles and the bar will be
set very high in terms of distinguishing themselves among the
other atypical antipsychotic drugs. Nearly all of the older atypi-
cal antipsychotics (with the exception of paliperidone) have been
Review
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Review
around for more than 10 years; thus, each has an established place
within the therapeutic armamentarium based on years of clinical
experience and research efforts. Although iloperidone, asenapine,
and lurasidone are not new, they have been available to clinicians
for only a brief period of time. Because practice experience is
so limited with these agents, direct head-to-head comparative
effectiveness studies are needed. Currently, there is no evidence of
clinical superiority for iloperidone, asenapine, or lurasidone over
other antipsychotics, and any potential tolerability advantages
discussed in this review would also need to be conrmed by direct
comparison trials.
Although many acute-phase, placebo-controlled studies
reviewed herein also included an active control group consisting
of treatment with older and more established antipsychotics, they
were not sufciently powered to provide valid comparisons, other
than with placebo. Even if they were adequately powered, results
of short-term, registration-type clinical trials would generalize
poorly to real-world care [90]. Long-term efcacy and safety data
are also limited, and consist chiey of extension or responder-
enriched studies. Until data from real-world comparative effect-
iveness studies of iloperidone, asenapine and lurasidone become
available, clinical impressions will be based solely on indirect
comparisons with other antipsychotics.
Of course, for such studies to be conducted with sufcient
validity to guide clinical practice, very large sample sizes and
long-term follow-up will be required. The expense and logistical
challenges involved make it unlikely that such data will be avail-
able any time soon. Future research endeavors involving iloperi-
done, asenapine and lurasidone will instead focus on broadening
the therapeutic range of these compounds. Indeed, the number
of approved indications for several atypical antipsychotics has
expanded well beyond schizophrenia and acute manic/mixed
bipolar mood episodes to now include acute bipolar depression
(olanzapine combined with uoxetine, and quetiapine) and
treatment- resistant major depression (aripiprazole, olanzapine,
and quetiapine as adjuncts to antidepressants) [9195]. Several
large-scale research efforts in this regard are underway or have
been recently completed for asenapine, iloperidone, and lurasi-
done (TABLE 9), particularly for treating mood disorders. Asenapine
is already approved for treating manic or mixed bipolar mood
episodes; however, the efcacy of all reviewed agents for the treat-
ment of major depression or the depressive phase of bipolar I dis-
order is being actively investigated. Signicantly greater reduction
in depressive symptoms with lurasidone, as both a monotherapy
and an adjunct with lithium or divalproex, has been recently
demonstrated in two randomized, placebo-controlled, Phase III
studies, resulting in submission of two supplemental New Drug
Applications to the US FDA [96,97]. Given the limited number
of well-established options for managing the depressed phase of
bipolar disorder [98], considerable therapeutic potential exists for
lurasidone to address a critical unmet need in managing patients
with bipolar disorder.
The clinical effects of iloperidone, asenapine and lurasidone
are also being investigated in clinically important patient sub-
groups, including treatment-resistant patients, elderly patients
and youth (TABLE 9). The need is especially great for persons
with treatment-resistant schizophrenia. Up to 30% of patients
with schizophrenia are considered treatment resistant [99101].
Clozapine continues to be the sole evidence-based pharmaco-
therapy for treatment-resistant illness [102]; thus, no credible
evidence-supported alternatives to clozapine exist. Broader
use of clozapine is limited, even for patients who require such
treatment, by well-characterized but severe adverse effects,
including dose-dependent seizure risk, idio syncratic risk of
bone marrow suppression and agranulocytosis, cardiac effects
(cardio myopathy, myocarditis), clinically signicant weight gain,
hyperglycemia and new-onset Type 2 diabetes, and atherogenic
hyperlipidoses [103]. The efcacy of lurasidone (at higher than
usual doses up to 240 mg/day) for treatment-resistant schizo-
phrenia or schizoaffective disorder is being investigated (TABLE 9)
and similar research efforts may be pursued in the future for
iloperidone and asenapine.
The development of reliable biological predictors of clinical
benet and adverse effects under antipsychotic treatment will be
an additional research focus. Currently, no genetic or biological
response predictors are yet sufciently valid for routine clinical
use. Whole-genome association studies have been conducted
using data from the randomized, double-blind, placebo- and
ziprasidone-controlled Phase III study by Cutler et al. to identify
genetic predictors of efcacy response and risk markers for QT
interval prolongation [35,104,105]. These analyses uncovered several
DNA polymorphisms that were signicantly associated with clini-
cal response and QT prolongation in iloperidone-treated patients
[104106]. While these results are promising, further study is needed
and routine genetic testing of patients who require antipsychotic
treatment is not likely to become adopted outside of the clinical
research setting in the immediate future.
Finally, development of new formulations for expanded
clinical use will be also be given high priority. An injectable
depot formulation of iloperidone has already been developed
and is in Phase II testing (NCT 1348100). If further devel-
oped, depot iloperidone would be only the second long-acting
injectable atypical antipsychotic (other than paliperidone pal-
mitate) formulated for administration every 4 weeks. However,
a long-acting injectable form of aripiprazole, also formulated for
administration once monthly, is nearing the end of Phase III
testing (NCT 00705783, 01432444) and may be available for
clinical use relatively soon.
In conclusion, iloperidone, asenapine and lurasidone are the
newest agents from a long line of atypical antipsychotic drugs.
While none of these agents appear to be more clinically effective
than other antipsychotics for treating adults with schizophrenia,
they may have advantages over some available antipsychotics in
terms of metabolic safety. Comparative effectiveness studies with
older and more established antipsychotics are lacking, and long-
term pragmatic trials are needed in order to assess the effectiveness
of the newer agents in patients under usual-care conditions. Until
such data are available, the exact place of iloperidone, asenapine
or lurasidone within a broader clinical context will be based on
indirect comparisons of available outcome data, and consideration
Bobo
87
Review
of pharmacological differences between agents that may confer
putative advantages and disadvantages for each drug. Wider test-
ing of these newer agents will be needed to determine the extent to
which these differences are clinically meaningful, and to explore
the therapeutic potential of each for indications outside of schizo-
phrenia (and acute manic or mixed bipolar mood episodes in the
case of asenapine) and in clinically important patient populations
that were not included in Phase III testing. Ultimately, newer
agents with novel mechanisms are likely to be required [107].
Financial & competing interests disclosure
WV Bobo has received grant/research support from Cephalon, Inc. and
previously served on speaker bureaus for Janssen Pharmaceutica and Pzer,
Inc. This work was supported, in part, by NIMH grant MH087747. The
author has no other relevant afliations or nancial involvement with any
organization or entity with a nancial interest in or nancial conict with
the subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Iloperidone, asenapine and lurasidone are the newest agents from a very large therapeutic class of atypical antipsychotic drugs. Like
most other atypical antipsychotic drugs, each binds with high potency to 5-HT
2A
and D
2
receptors; however, they display variable
afnity for other neuroreceptors.
Regulatory approval for the acute-phase treatment of adults with schizophrenia has been established for each agent on the basis
of multiple short-term, placebo-controlled, registration-type studies. Data from longer-term studies are more limited. Thus far, only
asenapine has regulatory approval in the USA for maintenance treatment of schizophrenia and acute treatment of manic/mixed
episodes in adults with bipolar I disorder.
To date, all agents appear to be well tolerated and there is no evidence of superior clinical effectiveness for one agent over other
available antipsychotic drugs, although adverse effect proles vary. On the basis of available data, iloperidone appears to have
the lowest extrapyramidal symptoms liability, although relatively higher risk of orthostasis and dizziness require slow titration to
therapeutic doses, and monitoring of QT intervals may be required for some patients. Asenapine has only a minimal effect on prolactin
concentration, while lurasidone appears to have the lowest impact on body weight and metabolic indices; however, dose-related
extrapyramidal symptoms and somnolence with both may be limiting for some patients.
Comparative effectiveness studies conducted over the long term and in broader, representative patient samples are needed to guide
clinicians when choosing among the available antipsychotic agents. Until then, individual medications must be evaluated on the basis
of their individual merits and liabilities, including adverse effect and safety prole, ease of use, patient acceptability and potential for
drugdrug interactions.
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Critical Apprasal of Newly Approved Drugs Used To Treat Schizophrenia

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Critical Apprasal of Newly Approved Drugs Used To Treat Schizophrenia

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10.1586/ECP.12.70 61 ISSN 1751-2433 2013 Expert Reviews Ltd www.expert-reviews.

All values are K

Iloperidone Asenapine Lurasidone

Approved adult indications (USA) Schizophrenia Schizophrenia Schizophrenia

observed with iloperidone (72%) than

Dened a priori as a >30% decrease in PANSS total score from baseline.

Study (year) Design Exposure groups Main results Ref.

Signicantly greater reduction in PANSS-derived Marder factor

Dened a priori as a >30% decrease in PANSS total score from baseline.

Reference Design Exposure groups Main results Ref.

Dened a priori as a >20% decrease in PANSS total score from baseline.

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