Critical Apprasal of Newly Approved Drugs Used to Treat Schizophrenia

10.1586/ECP.12.70 61ISSN 1751-2433© 2013 Expert Reviews Ltdwww.expert-reviews.com

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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 [2–4], and increased risk of early mortality owing to poor physical health and sui-cide [5–7]. 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

‘deficit’ 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 classified 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 efficacy 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 BoboDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USATel.: +1 615 327 7049 Fax: +1 615 322 1578 [email protected]

This article reviews the pharmacological profile and published efficacy 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 efficacy and low propensity for clinically significant weight gain or adverse changes in glycemic or lipid profile. However, these agents differ from one another in terms of formulations, pharmacokinetics, and dosing and nonmetabolic adverse effect profile. 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 difficult 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 adultsExpert Rev. Clin. Pharmacol. 6(1), 61–91 (2013)

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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 (FanaptTM, Vanda Pharmaceuticals, MD, USA; approved in May 2009), asenapine (SaphrisTM, Schering-Plough, Kenilworth, NJ, USA; approved in August 2009) and lurasidone (LatudaTM, 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 profilePharmacodynamicsIloperidone exhibits high affinity for dopamine D

2 and D

3, and

serotonin 5-HT2A

receptors, where they act as antagonists (Table 1) [17–19], a pattern consistent with its atypical antipsychotic profile; however, the functional significance of iloperidone’s antagonist activity at dopamine D

3 receptors is unknown. Iloperidone binds

with moderate affinity to dopamine D4, serotonin 5-HT

6 and

5-HT7, and noradrenergic α

1 receptors; and with low affinity

to dopamine D1, serotonin 5-HT

1A and histamine H

1 receptors

[17,18]. Iloperidone has no significant binding activity at muscarinic cholinergic M

1 receptors [18]. Iloperidone functions as an anta-

gonist at noradrenergic α1 receptors, which predicts its orthostatic

hypotensive effects [17,18].Asenapine, like most other atypical antipsychotics, is also a

potent antagonist at dopamine D2 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

α1 receptors, but has negligible affinity for muscarinic M

1 recep-

tors [17,20,201]. With the exception of muscarinic M1 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

profile (reviewed below) [23,24]. In addition, clinical studies of asenapine document a low incidence of orthostatic hypotension

and dizziness despite asenapine’s potent antagonist effects at noradrenergic α

1 receptors [25].

Lurasidone also binds with high affinity to dopamine D2 and

serotonin 5-HT2A

receptors, and to 5-HT7 receptors (Table 1) [26].

As shown in Table 1, lurasidone binds with marginally higher affinity to D

2 than 5-HT

2A receptors. Lurasidone has moderate

binding affinity for serotonin 5-HT1A

receptors; weak affinity for noradrenergic α

1 and α

2c, and serotonin 5-HT

2C receptors; and

no significant binding activity at histamine H1 or muscarinic M

1

receptors [26]. Lurasidone acts as an antagonist at D2 and serotonin

5-HT2A

and 5-HT7 receptors, and a partial agonist at serotonin

5-HT1A

receptors [26].

Pharmacokinetics & metabolismIloperidone 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 2–4 hours [202]. Administration with food has no significant effect on the area under the curve, t

max

or Cmax

[27]. Steady-state concentration is reached within 3–4 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 iloperidone’s two primary metabolites (P88-8991) has a receptor binding profile similar to that of the parent compound, while the other (P95-12113) does not appear to cross the blood–brain barrier to a significant 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 0.5–1.5 hours [203]. However, drinking liquids within 10 minutes of sublingual administra-tion of asenapine can significantly 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 significantly to its overall pharma cological profile. The mean elimination half-life of asenapine is 13–39 hours. Severe hepatic impairment (Child–Pugh class C), but not mild to moderate impairment (Child–Pugh 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 1–3 hours

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[204]. The absorption of lurasidone is significantly 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 profile 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 & dosingThe recommended starting doses, dose titration schedules and usual clinical dose ranges are presented in Table 2.

IloperidoneEven though the clinically effective dose range of iloperidone for treating adults with schizophrenia is 6–12 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 specified 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 Ki (nM)†,‡

Iloperidone Ref. Asenapine Ref. Lurasidone Ref.

Dopamine receptors

D1 216.0 [19] 2.9 [201] – –

D2 3.3 [17] 2.0 [17] 1.7 [26]

D3 7.1 [19] 46.2 [201] – –

D4 25.0 [19] 1.8 [201] 0.3 [24]

D5 319.0 [19] 22.7 [201] – –

Serotonin receptors

5-HT1A 33.0 [17] 15.0 [17] 6.8 [26]

5-HT2A 0.2 [17] 0.8 [17] 2.0 [26]

5-HT2C 14.0 [17] 0.3 [17] – –

5-HT6 63.1 [18] 1.4 [201] – –

5-HT7 112.0 [18] 0.9 [201] 0.5 [26]

Norepinephrine receptors

α1 0.3 [17] 1.1 [17] 47.9 [26]

α2 3.0 [17] 16.1 [17] 40.7§ [26]

Histamine receptors

H1 12.3 [17] 9.3 [17] >1000 [26]

Muscarinic (cholinergic) receptors

M1 >1000 [18] 24.3 [201] >1000# [26]

M2 >1000 [18] 79.1 [201] – –

M3 >1000 [18] 38.7 [201] – –

M4 >1000 [18] >1000 [201] – –

M5 >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 Ki (nM) based on Psychoactive Drug Screening Program certified data using human cloned receptors [201], human brain receptors [17] or other human cloned receptor data [18,19,26], unless otherwise specified. Lower numbers indicate higher binding affinity.‡Receptor binding profile data and references were accessed using the Psychoactive Drug Screening Program Ki Database [201]. Data for asenapine and lurasidone were identified using the designations ‘ORG-5222’ and ‘SM 13496’, respectively.§Ki values for lurasidone binding at α-2a and -2c adrenergic receptors as reported by Ishibashi et al. [26] were 40.7 and 10.8 nM, respectively.#Binding affinity for muscarinic cholinergic receptors, but not muscarinic receptor subtypes, was reported by Ishibashi et al. [26].

Recently approved antipsychotic drugs for schizophrenia


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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

flavored 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 6–12 mg b.i.d. 5–10 mg b.i.d.‡ 40–160 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: CYP3A4Metabolized (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 α

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)†Reflects information provided in the latest manufacturer label for each product, unless otherwise specified.‡Information in the table reflects 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, fluoxetine, paroxetine, quinidine [205].‡‡Strong inhibitors of CYP3A4 include indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir and telithromycin [205].§§Inducers of CYP3A4, 5 and 7 include efavirenz, nevirapine, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John’s 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 drug–drug interaction; PK: Pharmacokinetic drug–drug interaction.

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clinically effective doses [204]. Strong inhibitors of CYP2D6 (i.e., fluoxetine, paroxetine, and so on) or CYP3A4 (i.e., keto-conazole, clarithromycin, and so on) can significantly 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 significantly alter drug levels in absence of other pharmacokinetic factors [28,202], dosage adjustment is not likely to be required.

AsenapineThe recommended starting dose for asenapine is 5 mg b.i.d., with an effective dose range of 5–10 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 significant drug–drug interactions involving asenapine has not been extensively evaluated. Caution is advised when admin-istering asenapine with CYP1A2 inhibitors (i.e., fluvoxamine, and so on), which may significantly 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 α

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 (Child–Pugh class C), while dosage adjustment is not required based solely on level of renal impairment [31]. Smoking has not been shown to si gnificantly alter asenapine exposure [34].

LurasidoneThe recommended starting dose of lurasidone is 40 mg daily, and recent changes to product labeling reflect an expanded effec-tive dose range of 40–160 mg daily [204]. All lurasidone doses should be taken with food (>350 calories), as also reflected 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 significantly 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 efficacyAcute-phase treatmentIloperidoneA summary of results from four short-term, multi-site, rand-omized, controlled efficacy studies of iloperidone in adults (aged 18–65 years) with acute schizophrenia is presented in Table 3. The first study by Cutler et al. was a 4-week, Phase III study of 606 patients randomized to fixed 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 significantly greater improvement in PANSS-total scores, the primary efficacy end point, compared with placebo (Table 3). Similar results were observed for PANSS-positive and -negative subscale, and CGI-S scores. A significantly higher pro-portion of iloperidone-treated patients were classified as positive treatment responders (Table 3), defined as those who achieved a >20% reduction in PANSS-positive symptom subscale scores from baseline. Neither iloperidone nor ziprasidone treatment resulted in significantly 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 first 7 days of follow-up. In Study 1, 621 patients were randomly assigned to receive one of three fixed doses of iloperidone (2, 4 or 6 mg b.i.d.), haloperidol (15 mg daily) or placebo [39]. Compared with placebo, there was significantly 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 significantly 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 significantly 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 significant separation from placebo on PANSS-negative subscale scores.

In Study 2 [39], 616 subjects were randomized to one of two iloperidone-treated groups (4–8 or 10–16 mg/day), risperidone (4–8 mg/day) or placebo. Significantly greater improvement in BPRS scores was observed with both iloperidone groups and with risperidone compared with placebo (Table 3). Similar results were



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Table 3. Summary of study design and main efficacy 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 = 295Ziprasidone 80 mg b.i.d., n = 149Placebo, n = 149

Significantly 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 Impression–Severity scale scoresSignificantly 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 reportedNo significant 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, placebo-controlled trial

Iloperidone 2 mg b.i.d., n = 121Iloperidone 4 mg b.i.d., n = 125Iloperidone 6 mg b.i.d., n = 124Haloperidol 7.5 mg b.i.d., n = 124Placebo, n = 127

Significantly greater reduction from baseline in 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 significantly greater reduction in PANSS total scores observed in other iloperidone-dose groupsSignificantly greater reduction from baseline in 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 groupSignificantly greater reduction from baseline in 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 groupSignificantly greater reduction from baseline in 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 significantly 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 defined 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 efficacy of three fixed doses of iloperidone, haloperidol fixed at 15 mg daily, and placebo. Study 2 consisted of two iloperidone arms (4–8 and 10–16 mg/day, with total dose divided b.i.d.), one risperidone arm and a placebo arm. Study 3 also consisted of two iloperidone arms (12–16 and 20–24 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 significant; PANSS: Positive and Negative Syndrome Scale.

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observed for most secondary efficacy measures, including PANSS-total and -positive subscale scores, and CGI-S scores (Table 3). Only the iloperidone 10–16-mg and risperidone groups were associ-ated with significantly greater improvement in PANSS-negative subscale scores than placebo (Table 3).

In Study 3 [39], 706 patients were randomized to receive ilop-eridone (12–16 or 20–24 mg/day), risperidone (6–8 mg/day) or

placebo. Both iloperidone 20–24 mg and risperidone demon-strated significantly greater improvement in BPRS scores than placebo (Table 3), while a trend-level difference was noted with iloperidone 12–16 mg (p = 0.09 vs placebo). Significantly 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 20–24 mg and risperidone

Table 3. Summary of study design and main efficacy results of short-term randomized, controlled trials of iloperidone in adults with acute schizophrenia (cont.).




Iloperidone 4–8 mg/day, n = 153Iloperidone 10–16 mg/day, n = 154Risperidone 4–8 mg/day, n=153Placebo, n = 156

Significantly greater reduction from baseline in BPRS scores with iloperidone 4–8 mg/day (-6.2), iloperidone 10–16 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 baselineSignificantly greater reduction from baseline in PANSS-positive subscale scores with iloperidone 4–8 mg/day (-3.5), iloperidone 10–16 mg/day (-4.1) and risperidone (-6.0) than placebo (-3.5; p < 0.02 for all comparisons)Significantly greater reduction from baseline in PANSS-negative subscale scores with iloperidone 10–16 mg/day (-2.4), and risperidone (-3.0) than placebo (-1.0; p < 0.02 for all comparisons). No significantly greater reduction in PANSS-negative subscale scores observed with iloperidone 4–8 mg/day (-1.9), compared with placebo

[39]



Iloperidone 12–16 mg/day, n = 244Iloperidone 20–24 mg/day, n = 145Risperidone 6–8 mg/day, n = 157Placebo, n = 160

Significantly greater reduction from baseline in BPRS scores with iloperidone 20–24 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 12–16 mg/day (-7.1; p = 0.09)Similar results were reported for mean change from baseline in PANSS total scoresSignificantly greater reduction from baseline in PANSS-positive subscale scores with iloperidone 20–24 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 significantly greater with iloperidone 12–16 mg/day (-4.2) than placeboSignificantly greater reduction from baseline in PANSS-negative subscale scores with iloperidone 20–24 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 significantly greater with iloperidone 12–16 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 defined 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 efficacy of three fixed doses of iloperidone, haloperidol fixed at 15 mg daily, and placebo. Study 2 consisted of two iloperidone arms (4–8 and 10–16 mg/day, with total dose divided b.i.d.), one risperidone arm and a placebo arm. Study 3 also consisted of two iloperidone arms (12–16 and 20–24 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 significant; PANSS: Positive and Negative Syndrome Scale.



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groups were associated with significantly greater improvement in PANSS total and subscale scores (Table 3).

A pooled analysis of Studies 1–3 [39] examined the com-bined effects of each iloperidone dose group (4–8, 10–16 or 20–14 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 significantly 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-nificantly greater improvement in PANSS total, PANSS-positive and -negative subscale, and BPRS scores was also reported with iloperidone (10–16 and 20–24 mg/day) compared with placebo [41]. Similar results were obtained when the data from patients with schizoaffective disorder were excluded.

AsenapineThe efficacy 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, fixed-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), defined 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 3–5 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 significantly greater with asenapine than placebo but not with risperidone (Table 4). Significantly 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 significantly greater improvement in PANSS-positive subscale and CGI-S scores (Table 4) [42]. However, only asenapine resulted in sig-nificantly 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 fixed 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 signifi-cantly greater baseline-to-end point improvement in PANSS total scores (the primary efficacy 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-nificantly 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 significantly 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 signifi-cantly higher proportion of positive treatment response, defined a priori as a >30% decrease from baseline in PANSS total scores (Table 4). A significantly 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 efficacy 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 first study compared the efficacy of two fixed doses of asenapine with olanzapine or placebo. Only olanzapine (15 mg daily) resulted in significant 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 flexibly dosed asenapine (5–10 mg b.i.d.), olanzapine (10–20 mg b.i.d.) and placebo. In this study, neither active treatment group showed significantly greater improvement in PANSS total scores, the primary efficacy variable, than placebo. As such, this was considered a failed trial.

LurasidoneThe short-term, acute-phase efficacy 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 first Phase II study conducted in the USA, 149 patients with acute schizophrenia were randomized to one of two fixed doses of lurasidone (40 or 120 mg/day) or placebo [46]. No active control group was included in this study. Significantly 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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Table 4. Summary of study design and main efficacy results of short-term randomized, controlled trials of 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

Significantly 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]

Significantly 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)

Significantly 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)

Significantly 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)§




Haloperidol 4 mg b.i.d., n = 115

Placebo, n = 123

Significantly greater reduction from baseline in PANSS total 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 significantly greater than placebo for asenapine 10 mg b.i.d. at any time point in the LOCF analysis, but was significantly greater at week 6 using MMRM analysis (p < 0.05, mean scores not reported)

[43]

Significantly 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 significantly greater than placebo for asenapine at week 6 (p < 0.05, LOCF and MMRM analyses, mean scores not reported)

Significantly greater reduction from baseline in PANSS-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 significantly greater than placebo in the asenapine 10 mg b.i.d. or haloperidol groups in either the LOCF or MMRM analyses

Significantly 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 placebo (-5.1; p < 0.05 for all comparisons)

Significantly greater reduction in PANSS-derived Marder factor 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 significantly 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 significant differences in efficacy between asenapine and haloperidol except for significantly higher positive response rate with asenapine 5 mg b.i.d. than haloperidol.¶Defined a priori as a >30% decrease in PANSS total score from baseline.#Defined 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 significant; PANSS: Positive and Negative Syndrome Scale.



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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 significantly greater improvement in PANSS total scores. Both lurasidone groups had higher rates of positive treatment response (defined 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: 2–7]; lurasidone 120 mg [50.0%, NNT 4, 95% CI: 3–11]).

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 fixed 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. Significantly 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 signifi-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 Montgomery–Asberg Depression Rating Scale (MADRS) (Table 5). A significantly higher proportion of

lurasidone-treated patients achieved a positive treatment response (Table 5), defined 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 first study (PEARL 1) compared the efficacy of lurasidone at one of three fixed 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 efficacy 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 significantly greater improvement in PANSS total and CGI-S scores, as com-pared with placebo. Significantly greater improvement in PANSS-positive subscale scores and a significantly 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 fixed-dose treatment groups: lurasidone (40 or 120 mg/day), olanzapine (15 mg/day) or placebo [48]. Eligible subjects had a Mini-International Neuropsychiatric Interview-confirmed 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 efficacy results of short-term randomized, controlled trials of asenapine in adults with acute schizophrenia (cont.).†


Kane et al. (2010) (cont.)§

Significantly greater reduction in PANSS-derived Marder factor hostility/excitement score [44] for haloperidol (-2.4) than placebo (-1.3; p < 0.05). Reductions in hostility/excitement scores were not significantly greater than placebo in the asenapine 5 mg b.i.d. (-1.8) or 10 mg b.i.d. (-1.8) groups

[43]

No significant difference from baseline in PANSS-derived Marder factor negative-symptom or anxiety/depression scores [44] between any active treatment group and placebo

Significantly 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 5–7 for all comparisons). Comparison of response rate between haloperidol (43%) and placebo was not statistically significant

Comparison of response rates using alternative CGI-based definition# vs placebo was significantly 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 significant differences in efficacy between asenapine and haloperidol except for significantly higher positive response rate with asenapine 5 mg b.i.d. than haloperidol.¶Defined a priori as a >30% decrease in PANSS total score from baseline.#Defined 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 significant; 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 efficacy end point, was significantly 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 significantly 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 efficacy 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 significantly greater baseline-to-end point improvement in MADRS scores than the placebo group (Table 5). A significantly higher proportion of olanzapine but not lurasidone treated patients were considered positive treatment responders (Table 5).

The final Phase III trial (PEARL 3) compared the effects of two lurasidone fixed 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 significant improvement from baseline to study end point in PANSS total scores, the primary efficacy end point, as well was CGI-S scores, compared with placebo. Significant 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 significantly 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 significantly 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 studiesIloperidoneThe long-term safety and efficacy 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 flexibly dosed iloperidone (4–16 mg/day) and halop-eridol (5–20 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 defined 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 efficacy [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 significant. Assuming a relapse rate of 30% with haloperidol, the statistical threshold for equivalence between iloperidone and haloperidol (hazard ratio < 1.676 at α [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 significant 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.

AsenapineTwo published randomized studies focused on the long-term effi-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 defined (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 first quartile of the time to relapse (asenapine, 156 days vs placebo, 41 days) was significantly 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 (5–10 mg b.i.d., n = 913) or olanzapine (10–20 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



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treatment groups at week 6 (asenapine [-17.9] vs olanzapine [-19.0], p = not significant [NS]), but were significantly greater for the olanzapine group at study end point in the 52-week core study (Table 6). In the core study, no significant 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

significant 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: 10–653 days), while those who con-tinued olanzapine (n = 150, mean daily dosage 13.4 ± 4.1 mg) were

Table 5. Summary of study design and main efficacy results of short-term randomized, controlled trials of lurasidone in adults with acute schizophrenia.†

Reference Design Exposure groups Main results Ref.

Nakamura et al. (2009)†


Lurasidone 80 mg/day, n = 90Placebo, n = 90

Significantly 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)Significantly 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)Significantly greater reduction from baseline in MADRS scores for lurasidone (-2.9) than placebo (-0.1; p = 0.02)Significantly higher rate of positive treatment response‡ with lurasidone (44.4%) than placebo (26.7%; p = 0.007, NNT: 6)

[47]

Meltzer et al. (2011)§


Lurasidone 40 mg/day, n = 120Lurasidone 120 mg/day, n = 119Olanzapine 15 mg/day, n = 123Placebo, n = 116

Significantly greater reduction from baseline in PANSS total 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)Significantly greater reduction from baseline in PANSS-positive subscale scores for lurasidone 40 mg/day (-7.7), lurasidone 120 mg/day (-7.5) and olanzapine (-9.3) than placebo (-5.4; p < 0.05 for all comparisons)Significantly greater reduction from baseline in PANSS-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)Significantly 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)Significantly greater reduction in M–D Scale MADRS scores with olanzapine (-5.0) than placebo (-2.8; p = 0.003). Reductions in MADRS scores were not significantly greater than placebo in the lurasidone 40 mg/day (-3.5) or 120 mg/day (-3.2) groupsSignificantly 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 significantly 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 first study, lurasidone 80 mg/day, but not lurasidone at 40 or 120 mg/day, resulted in significantly greater improvement in PANSS total and CGI-S scores, as compared with placebo. In a second placebo- and quetiapine-controlled trial, significantly greater improvement in PANSS total and CGI-S scores were observed with lurasidone at fixed 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 3–7 days placebo washout period, and for the first 28 days of follow-up.‡Defined a priori as a >20% decrease in PANSS total score from baseline.¶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: Montgomery–Asberg Depression Rating Scale; NNT: Number needed to treat; OR: Odds ratio; PANSS: Positive and Negative Syndrome Scale.

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Review

followed for an additional 327 ± 139.6 days (range: 15–631 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 significant 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 efficacy 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 significant 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 significantly 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 significant between-group differences on the PANSS-negative subscale scores in either extension study.

LurasidoneThe 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 flexibly dosed lurasidone (40–120 mg daily, mean 84.7 mg daily) or risperidone (2–6 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 efficacy 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: 5–26]). 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 significant between-group differences in the occurrence of relapse (lurasidone [20%] vs risperidone [16%], HR 1.31 [95% CI: 0.87–1.97]), defined 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 significant dif-ferences observed. There were no significant 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 & tolerabilityShort-term safety & tolerabilityIloperidoneThe short-term safety profile 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 (4–8, 10–16 and 20–24 mg/day) were dizziness (10–23%), dry mouth (5–10%), somnolence (5–8%) and dyspepsia (5–8%). The occur-rence of dizziness, somnolence and dry mouth was higher for the 20–24 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 4–8-mg and 10–16-mg dosage groups (prolactin levels were not measured in the study that included a 20–24-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 (1.7–2.1 kg) over 6 weeks, similar to that observed with risperidone (1.7 kg). Clinically significant weight gain, defined 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 significant 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 first 7 days of treatment and generally did not persist. There were statisti-cally significant increases in the corrected QT (QTc) interval from baseline were significant with all three iloperidone dosage



ReviewTa

ble

6. S

um

mar

y o

f st

ud

y d

esig

n a

nd

mai

n e

ffica

cy r

esu

lts

of

pu

blis

hed

lon

ger

-ter

m r

and

om

ized

, co

ntr

olle

d t

rial

s o

f ilo

per

ido

ne,

as

enap

ine,

or

lura

dis

on

e in

ad

ult

s w

ith

acu

te s

chiz

op

hre

nia

.†

Stu

dy

(yea

r)D

ura

tio

nTr

eatm

ent

gro

up

sPa

tien

ts (

n,

ran

do

miz

ed)

Do

seEn

d p

oin

tsM

ain

effi

cacy

res

ult

s vs

PLC

Ref

.

Ilop

erid

on

e

Kan

e et

al.

(2

00

8)§

52 w

eeks

(ILO

)(H

AL)

1239

405

Mea

n, 1

2.5

mg

/day

Mea

n, 1

2.5

mg

/day

Rela

pse¶

:Ti

me

to r

elap

se:

Δ PA

NSS

tot

al:

Δ PA

NSS

-pos

itive

:Δ

PAN

SS-n

eg/-

gp:

CG

I-C

:

ILO

(43.

5%) v

s H

AL

(41.

2%),

H

R 1.

03, 9

5% C

I: 0.

74 –

1.4

3IL

O (

89.8

day

s) v

s H

AL

(101

.8 d

ays)

, p =

NS

(p

rimar

y en

d po

int)

No

sign

ifica

nt b

etw

een

grou

p di

ffer

ence

sIL

O (

-4.2

) vs

HA

L (-

5.3

), p

= 0

.00

6N

o si

gnifi

cant

bet

wee

n-gr

oup

diff

eren

ces

No

sign

ifica

nt b

etw

een-

grou

p di

ffer

ence

s

[55]

Ase

nap

ine

Kan

e et

al.

(2

011)

#

52 w

eeks

(ASP

)(P

LC)

194

192

Mea

n, 1

7.6

mg

/day

Rela

pse††

:Ti

me

to r

elap

se:

Δ PA

NSS

-T:

Δ PA

NSS

Mar

der

Posi

tive

sy

mpt

oms:

Neg

ativ

e sy

mpt

oms:

Hos

tilit

y/ex

cite

men

t:A

nxie

ty/

depr

essi

on:

Dis

orga

nise

d th

ough

t:Δ

CG

I-S:

Δ C

DSS

:

ASP

(12.

1%) v

s PL

C (4

7.4%

); p

< 0

.00

01Si

gnifi

cant

ly lo

nger

with

ASP

(lo

g-ra

nk t

est;

p <

0.0

001

)A

SP (+

1.3

) vs

PLC

(+12

.1);

p <

0.0

001

(p

ositi

ve v

alue

s in

dica

te w

orse

ning

)(p

ositi

ve v

alue

s in

dica

te w

orse

ning

)A

SP (+

0.5)

vs

PLC

(+3.

9);

p <

0.0

001

ASP

(+0.

0) v

s PL

C (+

1.7)

; p <

0.0

001

ASP

(+0.

4) v

s PL

C (+

2.4

); p

< 0

.00

01A

SP (+

0.4

) vs

PLC

(+1.

8);

p <

0.0

001

ASP

(+0.

0) v

s PL

C (+

2.4

); p

< 0

.00

01A

SP (+

0.2)

vs

PLC

(+0.

8);

p <

0.0

001

ASP

(+0.

4) v

s PL

C (+

1.1)

; p =

0.0

27

[56]

This

tab

le d

oes

not

pres

ent

the

desi

gn f

eatu

res

or r

esul

ts o

f un

publ

ishe

d st

udie

s.§ T

he p

aper

by

Kan

e et

al.

[55]

pre

sent

s po

oled

res

ults

fro

m t

hree

ran

dom

ized

, mul

ti-c

ente

r, pr

ospe

ctiv

e, fl

exib

le-d

ose,

par

alle

l-gr

oup

stud

ies

of id

entic

al d

esig

n. E

ach

stud

y co

mpa

red

the

clin

ical

eff

ects

of

flexi

bly

dose

d IL

O (

n =

123

9 ra

ndom

ized

sub

ject

s, 4

–16

mg

/day

) and

HA

L (n

= 4

05 r

ando

miz

ed s

ubje

cts,

5–2

0 m

g/d

ay) i

n pa

tien

ts w

ith s

chiz

ophr

enia

or

schi

zoaf

fect

ive

diso

rder

. A t

otal

of

1239

pat

ient

s w

ere

rand

omiz

ed

to IL

O a

nd 4

05 t

o ha

lope

ridol

dur

ing

an in

itial

6-w

eek,

dou

ble-

blin

d tr

eatm

ent

phas

e. T

hose

who

com

plet

ed a

n in

itial

6-w

eek

doub

le-b

lind

trea

tmen

t ph

ase

and

achi

eved

a p

ositi

ve t

reat

men

t re

spon

se (

ILO

, n

= 3

71 [3

6.6%

]; H

AL,

n =

118

[37.

8%])

wer

e in

clud

ed in

a 4

6-w

eek

doub

le-b

lind

mai

nten

ance

tre

atm

ent

phas

e.¶Re

laps

e w

as d

efine

d a

prio

ri as

an

incr

ease

in P

AN

SS t

otal

sco

res

of >

25%

or

>10

poin

ts (

com

pare

d w

ith P

AN

SS t

otal

sco

res

take

n at

the

end

of

the

initi

al 6

-wee

k ph

ase)

; or

an in

crea

se in

CG

I-C

sco

res

by >

2 po

ints

, hos

pita

lizat

ion

beca

use

of p

sych

otic

sym

ptom

exa

cerb

atio

n, o

r di

scon

tinua

tion

of

stud

y m

edic

atio

n du

e to

lack

of

effic

acy

at a

ny t

ime

afte

r 6

wee

ks.

#Th

e re

laps

e pr

even

tion

stu

dy b

y K

ane

et a

l. in

clud

ed 7

00

pati

ents

with

clin

ical

ly s

tabl

e sc

hizo

phre

nia

who

wer

e in

itial

ly t

reat

ed w

ith o

pen

-lab

el s

ublin

gual

ASP

for

up

to 2

6 w

eeks

. Pat

ient

s w

ho w

ere

clin

ical

ly s

tabl

e at

the

end

of

the

open

-lab

el p

hase

wer

e ra

ndom

ized

to

doub

le-b

lind

cont

inua

tion

tre

atm

ent

with

sub

lingu

al A

SP (

n =

19

4) o

r pl

aceb

o (n

= 1

92) f

or 2

6 w

eeks

.††

Rela

pse/

impe

ndin

g re

laps

e w

as d

efine

d a

prio

ri as

occ

urre

nce

of C

GI-

S sc

ore

>4

on a

t le

ast

two

days

with

in a

sin

gle

wee

k of

fol

low

-up,

acc

ompa

nied

by

any

of t

he f

ollo

win

g: i

ncre

ase

in P

AN

SS t

otal

sco

re

by >

20%

as

com

pare

d w

ith d

oubl

e-bl

ind

base

line

scor

e (t

aken

at

wee

k 26

); in

crea

se in

PA

NSS

tot

al s

core

by

>10

poin

ts if

the

dou

ble-

blin

d ba

selin

e sc

ore

(at

wee

k 26

) was

<50

; a s

core

>5

on P

AN

SS ‘h

ostil

ity’

or

‘unc

oope

rati

vene

ss’ i

tem

s; a

sco

re >

5 on

any

PA

NSS

-pos

itive

sym

ptom

item

(ha

lluci

nati

ons,

unu

sual

tho

ught

con

tent

, or

conc

eptu

al d

isor

gani

zati

on);

or

sym

ptom

s w

orse

ned

in t

he o

pini

on o

f th

e st

udy

clin

icia

n to

th

e po

int

that

con

com

itan

t re

scue

med

icat

ions

, add

ition

or

dosa

ge in

crea

se o

f co

ncom

itan

t m

edic

atio

ns, o

r a

leve

l of

care

hig

her

than

out

pati

ent

was

nec

essa

ry.

‡‡Th

e st

udy

by S

choe

mak

er e

t al

. [57

] was

a 5

2-w

eek,

ran

dom

ized

, mul

ti-c

ente

r, do

uble

-blin

d, fl

exib

le-d

ose

com

paris

on o

f A

SP a

nd O

LZ in

121

9 ad

ults

(in

pati

ent

or o

utpa

tien

t) w

ith s

chiz

ophr

enia

or

schi

zoaf

fect

ive

diso

rder

who

had

his

tory

of

posi

tive

res

pons

e to

tre

atm

ent

with

a n

oncl

ozap

ine

antip

sych

otic

dru

g. A

dou

ble-

dum

my

desi

gn w

as u

sed

to p

rese

rve

the

blin

d.§§

The

stud

y by

Citr

ome

et a

l. [6

3] w

as a

52-

wee

k, r

ando

miz

ed, m

ultic

ente

r, do

uble

-blin

d, fl

exib

le-d

ose

com

paris

on o

f LU

R an

d RI

S in

629

adu

lts

with

clin

ical

ly s

tabl

e sc

hizo

phre

nia

or s

chiz

oaff

ecti

ve d

isor

der.

The

prim

ary

obje

ctiv

e of

thi

s st

udy

was

to

com

pare

the

long

-ter

m t

oler

abili

ty a

nd s

afet

y of

stu

dy d

rugs

. Effi

cacy

var

iabl

es w

ere

asse

ssed

sec

onda

rily.

¶¶Re

laps

e w

as d

efine

d a

prio

ri as

sym

ptom

wor

seni

ng (

incr

ease

of

>30

% in

PA

NSS

tot

al s

core

fro

m b

asel

ine

and

CG

I-S

>3

), h

ospi

taliz

atio

n to

man

age

psyc

hotic

sym

ptom

exa

cerb

atio

n, o

r em

erge

nce

of s

uici

dal o

r ho

mic

idal

idea

tion

or

beha

vior

dur

ing

follo

w-u

p.

Δ: C

hang

e in

a s

peci

fied

effe

ct m

easu

re; A

SP: A

sena

pine

; CD

SS: C

alga

ry D

epre

ssio

n Sc

ale

for

Schi

zoph

reni

a; C

GI-

C: C

linic

al G

loba

l Im

pres

sion

of

Cha

nge

scal

e; C

GI-

S: C

linic

al G

loba

l Im

pres

sion

–Sev

erit

y sc

ale;

H

AL:

Hal

oper

idol

; ILO

: Ilo

perid

one;

LU

R: L

uras

idon

e; M

AD

RS:

Mon

tgom

ery–

Asb

erg

Dep

ress

ion

Ratin

g Sc

ale;

OLZ

: Ola

nzap

ine;

PA

NSS

: Pos

itive

and

Neg

ativ

e Sy

ndro

me

Scal

e -p

ositi

ve (

pos)

and

-ne

gati

ve (

neg

) sy

mpt

om s

ubsc

ales

, and

gen

eral

psy

chop

atho

logy

(gp

) sub

scal

e; P

AN

SS M

arde

r: P

AN

SS-d

eriv

ed M

arde

r Fa

ctor

Sco

res;

PA

NSS

-T: P

ositi

ve a

nd N

egat

ive

Synd

rom

e Sc

ale

Tota

l sco

re; P

LC: P

lace

bo; R

IS: R

ispe

ridon

e;

SF-1

2: M

edic

al O

utco

mes

Stu

dy 1

2-ite

m S

hort

For

m (

men

tal a

nd p

hysi

cal c

ompo

nent

sca

les)

; SW

N: S

ubje

ctiv

e W

ell-

Bein

g on

Neu

role

ptic

sca

le.

Bobo


ReviewTa

ble

6. S

um

mar

y o

f st

ud

y d

esig

n a

nd

mai

n e

ffica

cy r

esu

lts

of

pu

blis

hed

lon

ger

-ter

m r

and

om

ized

, co

ntr

olle

d t

rial

s o

f ilo

per

ido

ne,

as

enap

ine,

or

lura

dis

on

e in

ad

ult

s w

ith

acu

te s

chiz

op

hre

nia

(co

nt.

).†

Stu

dy

(yea

r)D

ura

tio

nTr

eatm

ent

gro

up

sPa

tien

ts (

n,

ran

do

miz

ed)

Do

seEn

d p

oin

ts‡

Mai

n e

ffica

cy r

esu

lts

vs P

LCR

ef.

Ase

nap

ine

(co

nt.

)

Scho

emak

er

et a

l. (2

010

)‡‡

52 w

eeks

(ASP

)

(OLZ

)

90

8

311

Mea

n, 1

3.5

mg

/day

Mea

n, 1

3.6

mg

/day

Δ PA

NSS

tot

al:

Δ PA

NSS

Mar

der

Posi

tive

sym

ptom

s:N

egat

ive

sym

ptom

s:H

ostil

ity/

exci

tem

ent:

Anx

iety

/dep

ress

ion:

Dis

orga

nise

d th

ough

t:Δ

CG

I-S:

SWN

:SF

-12:

ASP

(-2

1.0

) vs

OLZ

(-2

7.5)

; p <

0.0

001

ASP

(-7

.9) v

s PL

C (

-10.

0);

p <

0.0

01A

SP (

-4.6

) vs

PLC

(-6

.0);

p <

0.0

01A

SP (

-1.5

) vs

PLC

(-2

.4),

p <

0.0

01A

SP (

-2.7

) vs

PLC

(-3

.3),

p <

0.0

01A

SP (

-4.4

) vs

PLC

(-5

.9),

p <

0.0

01A

SP (

-1.2

) vs

OLZ

(-1

.6),

p <

0.0

01N

o si

gnifi

cant

bet

wee

n gr

oup

diff

eren

ces

No

sign

ifica

nt b

etw

een

grou

p di

ffer

ence

s

[57]

Lura

sid

on

e

Citr

ome

et a

l. (2

012)

§§

52 w

eeks

(LU

R)

(RIS

)42

720

2M

ean,

84.

7 m

g/d

ayM

ean,

4.3

mg

/day

Rela

pse¶

¶:

Δ PA

NSS

-T:

PAN

SS-p

os:

PAN

SS-n

eg:

PAN

SS-g

p:C

GI-S

:M

AD

RS:

LUR

(20%

) vs

RIS

(16%

); H

R: 1

.31

(95%

C

I: 0.

9–2

.0);

p =

NS

LUR

(-4.

7) v

s RI

S (-

6.5)

; p =

NS

No

sign

ifica

nt b

etw

een

grou

p di

ffer

ence

sN

o si

gnifi

cant

bet

wee

n gr

oup

diff

eren

ces

No

sign

ifica

nt b

etw

een

grou

p di

ffer

ence

sLU

R (-

0.4

) vs

RIS

(-0.

4);

p =

NS

LUR

(-0.

8) v

s RI

S (-

2.4

); p

= 0

.007

[63]

This

tab

le d

oes

not

pres

ent

the

desi

gn f

eatu

res

or r

esul

ts o

f un

publ

ishe

d st

udie

s.§ T

he p

aper

by

Kan

e et

al.

[55]

pre

sent

s po

oled

res

ults

fro

m t

hree

ran

dom

ized

, mul

ti-c

ente

r, pr

ospe

ctiv

e, fl

exib

le-d

ose,

par

alle

l-gr

oup

stud

ies

of id

entic

al d

esig

n. E

ach

stud

y co

mpa

red

the

clin

ical

eff

ects

of

flexi

bly

dose

d IL

O (

n =

123

9 ra

ndom

ized

sub

ject

s, 4

–16

mg

/day

) and

HA

L (n

= 4

05 r

ando

miz

ed s

ubje

cts,

5–2

0 m

g/d

ay) i

n pa

tien

ts w

ith s

chiz

ophr

enia

or

schi

zoaf

fect

ive

diso

rder

. A t

otal

of

1239

pat

ient

s w

ere

rand

omiz

ed

to IL

O a

nd 4

05 t

o ha

lope

ridol

dur

ing

an in

itial

6-w

eek,

dou

ble-

blin

d tr

eatm

ent

phas

e. T

hose

who

com

plet

ed a

n in

itial

6-w

eek

doub

le-b

lind

trea

tmen

t ph

ase

and

achi

eved

a p

ositi

ve t

reat

men

t re

spon

se (

ILO

, n

= 3

71 [3

6.6%

]; H

AL,

n =

118

[37.

8%])

wer

e in

clud

ed in

a 4

6-w

eek

doub

le-b

lind

mai

nten

ance

tre

atm

ent

phas

e.¶Re

laps

e w

as d

efine

d a

prio

ri as

an

incr

ease

in P

AN

SS t

otal

sco

res

of >

25%

or

>10

poin

ts (

com

pare

d w

ith P

AN

SS t

otal

sco

res

take

n at

the

end

of

the

initi

al 6

-wee

k ph

ase)

; or

an in

crea

se in

CG

I-C

sco

res

by >

2 po

ints

, hos

pita

lizat

ion

beca

use

of p

sych

otic

sym

ptom

exa

cerb

atio

n, o

r di

scon

tinua

tion

of

stud

y m

edic

atio

n du

e to

lack

of

effic

acy

at a

ny t

ime

afte

r 6

wee

ks.

#Th

e re

laps

e pr

even

tion

stu

dy b

y K

ane

et a

l. in

clud

ed 7

00

pati

ents

with

clin

ical

ly s

tabl

e sc

hizo

phre

nia

who

wer

e in

itial

ly t

reat

ed w

ith o

pen

-lab

el s

ublin

gual

ASP

for

up

to 2

6 w

eeks

. Pat

ient

s w

ho w

ere

clin

ical

ly s

tabl

e at

the

end

of

the

open

-lab

el p

hase

wer

e ra

ndom

ized

to

doub

le-b

lind

cont

inua

tion

tre

atm

ent

with

sub

lingu

al A

SP (

n =

19

4) o

r pl

aceb

o (n

= 1

92) f

or 2

6 w

eeks

.††

Rela

pse/

impe

ndin

g re

laps

e w

as d

efine

d a

prio

ri as

occ

urre

nce

of C

GI-

S sc

ore

>4

on a

t le

ast

two

days

with

in a

sin

gle

wee

k of

fol

low

-up,

acc

ompa

nied

by

any

of t

he f

ollo

win

g: i

ncre

ase

in P

AN

SS t

otal

sco

re

by >

20%

as

com

pare

d w

ith d

oubl

e-bl

ind

base

line

scor

e (t

aken

at

wee

k 26

); in

crea

se in

PA

NSS

tot

al s

core

by

>10

poin

ts if

the

dou

ble-

blin

d ba

selin

e sc

ore

(at

wee

k 26

) was

<50

; a s

core

>5

on P

AN

SS ‘h

ostil

ity’

or

‘unc

oope

rati

vene

ss’ i

tem

s; a

sco

re >

5 on

any

PA

NSS

-pos

itive

sym

ptom

item

(ha

lluci

nati

ons,

unu

sual

tho

ught

con

tent

, or

conc

eptu

al d

isor

gani

zati

on);

or

sym

ptom

s w

orse

ned

in t

he o

pini

on o

f th

e st

udy

clin

icia

n to

th

e po

int

that

con

com

itan

t re

scue

med

icat

ions

, add

ition

or

dosa

ge in

crea

se o

f co

ncom

itan

t m

edic

atio

ns, o

r a

leve

l of

care

hig

her

than

out

pati

ent

was

nec

essa

ry.

‡‡Th

e st

udy

by S

choe

mak

er e

t al

. [57

] was

a 5

2-w

eek,

ran

dom

ized

, mul

ti-c

ente

r, do

uble

-blin

d, fl

exib

le-d

ose

com

paris

on o

f A

SP a

nd O

LZ in

121

9 ad

ults

(in

pati

ent

or o

utpa

tien

t) w

ith s

chiz

ophr

enia

or

schi

zoaf

fect

ive

diso

rder

who

had

his

tory

of

posi

tive

res

pons

e to

tre

atm

ent

with

a n

oncl

ozap

ine

antip

sych

otic

dru

g. A

dou

ble-

dum

my

desi

gn w

as u

sed

to p

rese

rve

the

blin

d.§§

The

stud

y by

Citr

ome

et a

l. [6

3] w

as a

52-

wee

k, r

ando

miz

ed, m

ultic

ente

r, do

uble

-blin

d, fl

exib

le-d

ose

com

paris

on o

f LU

R an

d RI

S in

629

adu

lts

with

clin

ical

ly s

tabl

e sc

hizo

phre

nia

or s

chiz

oaff

ecti

ve d

isor

der.

The

prim

ary

obje

ctiv

e of

thi

s st

udy

was

to

com

pare

the

long

-ter

m t

oler

abili

ty a

nd s

afet

y of

stu

dy d

rugs

. Effi

cacy

var

iabl

es w

ere

asse

ssed

sec

onda

rily.

¶¶Re

laps

e w

as d

efine

d a

prio

ri as

sym

ptom

wor

seni

ng (

incr

ease

of

>30

% in

PA

NSS

tot

al s

core

fro

m b

asel

ine

and

CG

I-S

>3

), h

ospi

taliz

atio

n to

man

age

psyc

hotic

sym

ptom

exa

cerb

atio

n, o

r em

erge

nce

of s

uici

dal o

r ho

mic

idal

idea

tion

or

beha

vior

dur

ing

follo

w-u

p.

Δ: C

hang

e in

a s

peci

fied

effe

ct m

easu

re; A

SP: A

sena

pine

; CD

SS: C

alga

ry D

epre

ssio

n Sc

ale

for

Schi

zoph

reni

a; C

GI-

C: C

linic

al G

loba

l Im

pres

sion

of

Cha

nge

scal

e; C

GI-

S: C

linic

al G

loba

l Im

pres

sion

–Sev

erit

y sc

ale;

H

AL:

Hal

oper

idol

; ILO

: Ilo

perid

one;

LU

R: L

uras

idon

e; M

AD

RS:

Mon

tgom

ery–

Asb

erg

Dep

ress

ion

Ratin

g Sc

ale;

OLZ

: Ola

nzap

ine;

PA

NSS

: Pos

itive

and

Neg

ativ

e Sy

ndro

me

Scal

e -p

ositi

ve (

pos)

and

-ne

gati

ve (

neg

) sy

mpt

om s

ubsc

ales

, and

gen

eral

psy

chop

atho

logy

(gp

) sub

scal

e; P

AN

SS M

arde

r: P

AN

SS-d

eriv

ed M

arde

r Fa

ctor

Sco

res;

PA

NSS

-T: P

ositi

ve a

nd N

egat

ive

Synd

rom

e Sc

ale

Tota

l sco

re; P

LC: P

lace

bo; R

IS: R

ispe

ridon

e;

SF-1

2: M

edic

al O

utco

mes

Stu

dy 1

2-ite

m S

hort

For

m (

men

tal a

nd p

hysi

cal c

ompo

nent

sca

les)

; SW

N: S

ubje

ctiv

e W

ell-

Bein

g on

Neu

role

ptic

sca

le.



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].

AsenapinePooled safety data from three 6-week, fixed-dose trials and one 6-week flexible-dose trial of sublingual asenapine (5–10 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 (2–5 ms) occurred with asenapine at doses of 5–20 mg b.i.d., and there were no significant differences in post-baseline QT increases between asenapine (5–10 mg b.i.d.) and placebo [203].

LurasidoneOn the basis of pooled safety data from short-term, placebocontrolled studies of lurasidone (20–160 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). Significant weight gain, defined 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 significant weight gain (defined 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: 2.25–7.43]; number needed to harm [NNH]: 17), followed by iloperidone (n = 4 trials [1931 randomized subjects]; pooled RRs 3.13 [95% CI: 2.08–4.70]; NNH: 11) and paliperidone (n = 12 trials [4087 randomized subjects]; pooled RR: 2.17 [95% CI: 1.64–2.86]; NNH: 20). Lurasidone was not associated with a statistically significant change in body weight (n = 6 trials [1793 randomized subjects]; pooled RR: 1.42 [95% CI: 0.87–2.29]). Iloperidone was associ-ated with a statistically significant increase in total-cholesterol (n = 1 trial [300 randomized subjects]; +11.6 mg/dL [95% CI: 5.0–18.2]), HDL-cholesterol (n = 1 trial [300 randomized subjects]; +3.6 mg/dL [95% CI: 1.6–5.6]), and LDL-cholesterol (n = 1 trial [300 randomized subjects]; +10.3 mg/dL [95% CI: 4.9–15.7]), while lurasidone was associated with a statistically significant increase in HDL-cholesterol (n = 5 trials [1004 rand-omized subjects]; +1.5 mg/dL [95% CI: 0.6–2.4]). As reported by the authors, no other clinically significant short-term changes in glycemic or lipid indices were observed.

Longer-term safety & tolerabilityIloperidoneSafety 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 significantly 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


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].

AsenapineIn 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 significant 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 signifi-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 first 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 significantly greater increase in body weight (n = 3 trials [568 randomized subjects]; weighted mean difference +1.3 kg [95% CI: 0.6–2.0]) and a higher rate of clinically significant weight gain (n = 3 trials [568 randomized subjects]; pooled RR: 2.05 [95% CI: 1.21–3.46]; NNH: 9). Paliperidone was also asso-ciated with significantly greater increases in body weight (n = 6 trials [1174 randomized subjects]; weighted mean difference +0.5 kg [95% CI: 0.2–0.8]) and a higher rate of clinically sig-nificant weight gain than placebo (n = 6 trials [1174 randomized subjects]; pooled RR: 1.76 [95% CI: 1.06–2.90]; NNH: 29).

LurasidoneLonger-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: 9–438), 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: 9–73), 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: 10–37). A significantly 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 significant 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/m2] vs ris-peridone [+0.53 ± 1.76 kg/m2]) for each respective treatment group were nonsignificant. 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 significant electrocardiographic changes were observed in either treatment group.



ReviewTa

ble

7. P

oo

led

saf

ety

dat

a fr

om

sh

ort

-ter

m s

tud

ies

of

ilop

erid

on

e, a

sen

apin

e an

d lu

rasi

do

ne

in a

du

lts

wit

h s

chiz

op

hre

nia

.†

Para

met

erIlo

per

ido

ne

[64]

†A

sen

apin

e [2

03]‡

Lura

sid

on

e [2

04]§

Allo

cati

on

g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

lt

Dis

con

tin

uat

ion

, TEA

Es (

%)

Prop

ortio

n (%

)IL

O 4

–8 m

g/d

ay5.

4%A

SP (o

vera

ll)9.

0%LU

R (o

vera

ll)9.

5%

ILO

1–1

6 m

g/d

ay3.

9%PL

C10

.0%

PLC

9.3%

ILO

20

–24

mg

/day

5.6%

HA

L 15

mg

/day

7.6%

RIS

4–8

mg

/day

6.2%

PLC

4.8%

Ant

hrop

omet

ric

chan

ge in

wei

ght

(kg

)

ILO

4–8

mg

/day

+1.5

kg*

ASP

(ove

rall)

+1.1

kg

LUR

20 m

g/d

ay-0

.2 k

g

ILO

1–1

6 m

g/d

ay+

2.1

kg*

PLC

+0.

1 kg

LUR

40

mg

/day

+0.

2 kg

ILO

20

–24

mg

/day

+1.7

kg*

LUR

80

mg

/day

+0.

5 kg

HA

L 15

mg

/day

-0.1

kg

LUR

120

mg

/day

+0.

7 kg

RIS

4–8

mg

/day

+1.5

kg*

LUR

160

mg

/day

+0.

6 kg

PLC

-0.3

kg

PLC

-0.0

2 kg

Sign

ifica

nt w

eigh

t ga

in (%

)¶

ILO

4–8

mg

/day

10.9

%A

SP (o

vera

ll)4.

9%LU

R (o

vera

ll)4.

8%

ILO

1–1

6 m

g/d

ay12

.8%

PLC

2.0%

PLC

3.3%

ILO

20

–24

mg

/day

15.2

%

HA

L 15

mg

/day

5.1%

RIS

4–8

mg

/day

11.9

%

PLC

5.1%

All

valu

es a

re m

ean

chan

ges

from

bas

elin

e or

pro

port

ions

of

indi

vidu

als

per

allo

cati

on g

roup

, unl

ess

othe

rwis

e sp

ecifi

ed.

† The

poo

led

safe

ty d

ata

set

cons

iste

d of

per

sons

enr

olle

d in

eac

h st

udy

who

rec

eive

d at

leas

t on

e do

se o

f do

uble

-blin

d st

udy

med

icat

ion.

Exp

osur

e gr

oups

wer

e as

fol

low

s: IL

O 4

–8 m

g/d

ay (

n =

463

); IL

O 1

0–1

6 m

g/

day

(n =

456

); IL

O 2

0–2

4 m

g/d

ay (

n =

125

); H

AL

15 m

g/d

ay (

n =

118

); R

IS 4

–8 m

g/d

ay (

n =

30

6);

and

pla

cebo

(n

= 4

40

).‡ T

he p

oole

d sa

fety

dat

a an

alys

is a

s re

port

ed in

the

ase

napi

ne p

rodu

ct la

bel [

208]

and

pre

sent

ed in

thi

s ta

ble

wer

e de

rive

d fr

om a

poo

l of

thre

e sh

ort-

term

(6

wee

k), p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s th

at

incl

uded

950

pat

ient

s w

ith s

chiz

ophr

enia

who

wer

e ra

ndom

ized

to

asen

apin

e (5

mg

[n =

274

], 1

0 m

g [n

= 2

08

]) o

r pl

aceb

o (n

= 3

78).

§ The

poo

led

safe

ty d

ata

anal

ysis

as

repo

rted

in t

he L

UR

prod

uct

labe

l [20

9] c

onsi

sted

of

a co

mbi

ned

2905

pat

ient

with

sch

izop

hren

ia w

ho r

ecei

ved

at le

ast

one

dose

of

stud

y dr

ug. P

oole

d sa

fety

dat

a fr

om

shor

t-te

rm, p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s ar

e pr

esen

ted

in t

his

tabl

e, a

nd in

clud

ed 2

217

pati

ents

with

sch

izop

hren

ia w

ho w

ere

rand

omiz

ed t

o LU

R (2

0 m

g [n

= 7

1], 4

0 m

g [n

= 4

87],

80

mg

[n =

538

],

120

mg

[n =

291

] or

160

mg

[n =

121

]) o

r pl

aceb

o (n

= 7

09).

¶Su

bsta

ntia

l wei

ght

gain

was

defi

ned

as a

n in

crea

se in

bod

y w

eigh

t of

>7%

fro

m b

asel

ine

valu

e.*p

< 0

.05

vs p

lace

bo.

**p

< 0

.05

vs b

asel

ine

valu

es.

AIM

S: A

bnor

mal

Invo

lunt

ary

Mov

emen

t Sc

ale;

ASP

: Ase

napi

ne; B

AR

S: B

arne

s A

kath

isia

Sca

le; H

AL:

Hal

oper

idol

; ILO

: Ilo

perid

one;

LU

R: L

uras

idon

e; P

LC: P

lace

bo; R

IS: R

ispe

ridon

e; S

AS:

Sim

pson

–Ang

us

Extr

apyr

amid

al S

ide-

Effe

cts

Scal

e; T

EAEs

: Tre

atm

ent-

emer

gent

adv

erse

eff

ects

.

Bobo


ReviewTa

ble

7. P

oo

led

saf

ety

dat

a fr

om

sh

ort

-ter

m s

tud

ies

of

ilop

erid

on

e, a

sen

apin

e an

d lu

rasi

do

ne

in a

du

lts

wit

h s

chiz

op

hre

nia

(co

nt.

).†

Para

met

erIlo

per

ido

ne

[64]

†A

sen

apin

e [2

03]‡

Lura

sid

on

e [2

04]§

Allo

cati

on

g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

lt

Dis

con

tin

uat

ion

, TEA

Es (

%)

(co

nt.

)

Glu

cose

, cha

nge

(mg

/dL)

ILO

4–8

mg

/day

+7.2

mg

/dL

(1.8

, 12.

6)*

ASP

(ove

rall)

+2.

3 m

g/d

LLU

R 20

mg

/day

-0.6

mg

/dL

ILO

1–1

6 m

g/d

ay+

9.0

mg

/dL

(3.6

, 14.

4)*

PLC

-1.6

mg

/dL

LUR

40

mg

/day

+2.

6 m

g/d

L

ILO

20

–24

mg

/day

+16.

2 m

g/d

L (3

.6, 2

7.0

)*LU

R 8

0 m

g/d

ay-0

.4 m

g/d

L

HA

L 15

mg

/day

+10.

8 m

g/d

L (0

.0, 2

1.6

)*LU

R 12

0 m

g/d

ay+

2.5

mg

/dL

RIS

4–8

mg

/day

+3.

6 m

g/d

L (-

3.6,

9.0

)LU

R 16

0 m

g/d

ay+

2.5

mg

/dL

PLC

-3.6

mg

/dL

(-9.

0, 1

.8)

PLC

-0.0

mg

/dL

Tota

l cho

lest

erol

, ch

ange

(mg

/dL)

ILO

4–8

mg

/day

0.0

mg

/dL

(-3.

9, 3

.9)*

ASP

(ove

rall)

+0.

4 m

g/d

LLU

R 20

mg

/day

-12.

3 m

g/d

L

ILO

1–1

6 m

g/d

ay0.

0 m

g/d

L (-

7.7,

3.9

)PL

C-3

.6 m

g/d

LLU

R 4

0 m

g/d

ay-5

.7 m

g/d

L

ILO

20

–24

mg

/day

0.0

mg

/dL

(-11

.6, 7

.7)

LUR

80

mg

/day

-6.2

mg

/dL

HA

L 15

mg

/day

0.0

mg

/dL

(-7.

7, 1

1.6

)LU

R 12

0 m

g/d

ay-3

.8 m

g/d

L

RIS

4–8

mg

/day

-3.9

mg

/dL

(-7.

7, 3

.9)

LUR

160

mg

/day

-6.9

mg

/dL

PLC

-7.7

mg

/dL

(-11

.6, -

3.9

)PL

C-5

.8 m

g/d

L

Trig

lyce

rides

, ch

ange

(mg

/dL)

ILO

4–8

mg

/day

-26.

5 m

g/d

L (-

35.4

, -17

.7)*

ASP

(ove

rall)

+3.

8 m

g/d

LLU

R 20

mg

/day

-29.

1 m

g/d

L

ILO

1–1

6 m

g/d

ay-2

6.5

mg

/dL

(-35

.4, -

17.7

)PL

C-1

3.5

mg

/dL

LUR

40

mg

/day

-5.1

mg

/dL

ILO

20

–24

mg

/day

-26.

5 m

g/d

L (-

44.

4, -

8.8

)LU

R 8

0 m

g/d

ay-1

3.0

mg

/dL

HA

L 15

mg

/day

0.0

mg

/dL

(-17

.7, 1

7.7)

*LU

R 12

0 m

g/d

ay-3

.1 m

g/d

L

RIS

4–8

mg

/day

-26.

5 m

g/d

L (-

35.4

, -17

.7)

LUR

160

mg

/day

-10.

6 m

g/d

L

PLC

-35.

4 m

g/d

L (-

44.

4, -

26.5

)PL

C-1

3.4

mg

/dL

All

valu

es a

re m

ean

chan

ges

from

bas

elin

e or

pro

port

ions

of

indi

vidu

als

per

allo

cati

on g

roup

, unl

ess

othe

rwis

e sp

ecifi

ed.

† The

poo

led

safe

ty d

ata

set

cons

iste

d of

per

sons

enr

olle

d in

eac

h st

udy

who

rec

eive

d at

leas

t on

e do

se o

f do

uble

-blin

d st

udy

med

icat

ion.

Exp

osur

e gr

oups

wer

e as

fol

low

s: IL

O 4

–8 m

g/d

ay (

n =

463

); IL

O 1

0–1

6 m

g/

day

(n =

456

); IL

O 2

0–2

4 m

g/d

ay (

n =

125

); H

AL

15 m

g/d

ay (

n =

118

); R

IS 4

–8 m

g/d

ay (

n =

30

6);

and

pla

cebo

(n

= 4

40

).‡ T

he p

oole

d sa

fety

dat

a an

alys

is a

s re

port

ed in

the

ase

napi

ne p

rodu

ct la

bel [

208]

and

pre

sent

ed in

thi

s ta

ble

wer

e de

rive

d fr

om a

poo

l of

thre

e sh

ort-

term

(6

wee

k), p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s th

at

incl

uded

950

pat

ient

s w

ith s

chiz

ophr

enia

who

wer

e ra

ndom

ized

to

asen

apin

e (5

mg

[n =

274

], 1

0 m

g [n

= 2

08

]) o

r pl

aceb

o (n

= 3

78).

§ The

poo

led

safe

ty d

ata

anal

ysis

as

repo

rted

in t

he L

UR

prod

uct

labe

l [20

9] c

onsi

sted

of

a co

mbi

ned

2905

pat

ient

with

sch

izop

hren

ia w

ho r

ecei

ved

at le

ast

one

dose

of

stud

y dr

ug. P

oole

d sa

fety

dat

a fr

om

shor

t-te

rm, p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s ar

e pr

esen

ted

in t

his

tabl

e, a

nd in

clud

ed 2

217

pati

ents

with

sch

izop

hren

ia w

ho w

ere

rand

omiz

ed t

o LU

R (2

0 m

g [n

= 7

1], 4

0 m

g [n

= 4

87],

80

mg

[n =

538

],

120

mg

[n =

291

] or

160

mg

[n =

121

]) o

r pl

aceb

o (n

= 7

09).

¶Su

bsta

ntia

l wei

ght

gain

was

defi

ned

as a

n in

crea

se in

bod

y w

eigh

t of

>7%

fro

m b

asel

ine

valu

e.*p

< 0

.05

vs p

lace

bo.

**p

< 0

.05

vs b

asel

ine

valu

es.

AIM

S: A

bnor

mal

Invo

lunt

ary

Mov

emen

t Sc

ale;

ASP

: Ase

napi

ne; B

AR

S: B

arne

s A

kath

isia

Sca

le; H

AL:

Hal

oper

idol

; ILO

: Ilo

perid

one;

LU

R: L

uras

idon

e; P

LC: P

lace

bo; R

IS: R

ispe

ridon

e; S

AS:

Sim

pson

–Ang

us

Extr

apyr

amid

al S

ide-

Effe

cts

Scal

e; T

EAEs

: Tre

atm

ent-

emer

gent

adv

erse

eff

ects

.



ReviewTa

ble

7. P

oo

led

saf

ety

dat

a fr

om

sh

ort

-ter

m s

tud

ies

of

ilop

erid

on

e, a

sen

apin

e an

d lu

rasi

do

ne

in a

du

lts

wit

h s

chiz

op

hre

nia

(co

nt.

).†

Para

met

erIlo

per

ido

ne

[64]

†A

sen

apin

e [2

03]‡

Lura

sid

on

e [2

04]§

Allo

cati

on

g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

ltA

lloca

tio

n g

rou

pR

esu

lt

Dis

con

tin

uat

ion

, TEA

Es (

%)

(co

nt.

)

Prol

actin

, cha

nge

(µg

/L)

ILO

4–8

mg

/day

-38.

0 µg

/L (

-65.

9, 1

0.1)

ASP

(ove

rall)

+6.

5 µg

/LLU

R 20

mg

/day

-1.1

µg

/L

ILO

1–1

6 m

g/d

ay-2

3.1

µg/L

(-5

7.6,

11.

4)

PLC

+10.

7 µg

/LLU

R 4

0 m

g/d

ay-1

.4 µ

g/L

ILO

20

–24

mg

/day

Dat

a no

t av

aila

ble

LUR

80

mg

/day

-0.2

µg

/L

HA

L 15

mg

/day

115.

8 µg

/L (

66.8

, 16

4.8

)*LU

R 12

0 m

g/d

ay+

3.3

µg/L

RIS

4–8

mg

/day

214.

5 µg

/L (1

65.2

, 263

.8)*

LUR

160

mg

/day

+3.

3 µg

/L

PLC

-57.

4 µg

/L (

-90.

5, -

24.4

)PL

C-1

.9 µ

g/L

Neu

rom

usc

ula

r ef

fect

s

ESRS

, cha

nge

ILO

4–8

mg

/day

-0.3

**C

ompa

rabl

e ch

ange

s fr

om

base

line

in A

IMS,

BA

RS, a

nd S

AS

scal

es in

ase

napi

ne 5

mg,

as

enap

ine

10 m

g, a

nd p

lace

bo

grou

ps w

ere

repo

rted

. Mea

n ch

ange

s fo

r th

ese

mea

sure

s w

ere

not

repo

rted

Com

para

ble

chan

ges

from

bas

elin

e in

AIM

S, B

ARS

, an

d SA

S in

lura

sido

ne-

and

plac

ebo

-tre

ated

pat

ient

s w

ere

repo

rted

; a h

ighe

r pr

opor

tion

of lu

rasi

done

-tr

eate

d pa

tient

s sh

ifte

d fr

om n

orm

al t

o ab

norm

al

BARS

(14.

4 vs

7.1

%) a

nd S

AS

scor

es (

5.0

vs. 2

.3%

)

ILO

1–1

6 m

g/d

ay-0

.4**

ILO

20

–24

mg

/day

-0.6

**

HA

L 15

mg

/day

+1.7

**

RIS

4–8

mg

/day

-0.2

PLC

-0.3

*

Car

dio

vasc

ula

r ef

fect

s

QTc

inte

rval

, ch

ange

(ms)

ILO

4–8

mg

/day

+2.

9* m

sFo

r as

enap

ine,

incr

ease

s in

Q

Tc-in

terv

al r

ange

d fr

om 2

–5

mse

c, a

s co

mpa

red

with

pla

cebo

. Ra

tes

of p

ostb

asel

ine

incr

ease

s in

Q

Tc >

500

ms

wer

e re

port

ed a

s co

mpa

rabl

e be

twee

n A

SP a

nd

plac

ebo

(rat

es n

ot r

epor

ted

)

No

post

base

line

incr

ease

s in

QTc

>50

0 m

s w

ere

obse

rved

ILO

1–1

6 m

g/d

ay+

3.9*

ms

ILO

20

–24

mg

/day

+9.

1* m

s

HA

L 15

mg

/day

+5.

0* m

s

RIS

4–8

mg

/day

+0.

6 m

s

PLC

0.0

ms

All

valu

es a

re m

ean

chan

ges

from

bas

elin

e or

pro

port

ions

of

indi

vidu

als

per

allo

cati

on g

roup

, unl

ess

othe

rwis

e sp

ecifi

ed.

† The

poo

led

safe

ty d

ata

set

cons

iste

d of

per

sons

enr

olle

d in

eac

h st

udy

who

rec

eive

d at

leas

t on

e do

se o

f do

uble

-blin

d st

udy

med

icat

ion.

Exp

osur

e gr

oups

wer

e as

fol

low

s: IL

O 4

–8 m

g/d

ay (

n =

463

); IL

O 1

0–1

6 m

g/

day

(n =

456

); IL

O 2

0–2

4 m

g/d

ay (

n =

125

); H

AL

15 m

g/d

ay (

n =

118

); R

IS 4

–8 m

g/d

ay (

n =

30

6);

and

pla

cebo

(n

= 4

40

).‡ T

he p

oole

d sa

fety

dat

a an

alys

is a

s re

port

ed in

the

ase

napi

ne p

rodu

ct la

bel [

208]

and

pre

sent

ed in

thi

s ta

ble

wer

e de

rive

d fr

om a

poo

l of

thre

e sh

ort-

term

(6

wee

k), p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s th

at

incl

uded

950

pat

ient

s w

ith s

chiz

ophr

enia

who

wer

e ra

ndom

ized

to

asen

apin

e (5

mg

[n =

274

], 1

0 m

g [n

= 2

08

]) o

r pl

aceb

o (n

= 3

78).

§ The

poo

led

safe

ty d

ata

anal

ysis

as

repo

rted

in t

he lu

rasi

done

pro

duct

labe

l [20

9] c

onsi

sted

of

a co

mbi

ned

2905

pat

ient

with

sch

izop

hren

ia w

ho r

ecei

ved

at le

ast

one

dose

of

stud

y dr

ug. P

oole

d sa

fety

dat

a fr

om

shor

t-te

rm, p

lace

bo-c

ontr

olle

d, fi

xed

-dos

e st

udie

s ar

e pr

esen

ted

in t

his

tabl

e, a

nd in

clud

ed 2

217

pati

ents

with

sch

izop

hren

ia w

ho w

ere

rand

omiz

ed t

o LU

R (2

0 m

g [n

= 7

1], 4

0 m

g [n

= 4

87],

80

mg

[n =

538

],

120

mg

[n =

291

] or

160

mg

[n =

121

]) o

r pl

aceb

o (n

= 7

09).

¶Su

bsta

ntia

l wei

ght

gain

was

defi

ned

as a

n in

crea

se in

bod

y w

eigh

t of

>7%

fro

m b

asel

ine

valu

e.*p

< 0

.05

vs p

lace

bo.

**p

< 0

.05

vs b

asel

ine

valu

es.

AIM

S: A

bnor

mal

Invo

lunt

ary

Mov

emen

t Sc

ale;

ASP

: Ase

napi

ne; B

AR

S: B

arne

s A

kath

isia

Sca

le; H

AL:

Hal

oper

idol

; ILO

: Ilo

perid

one;

LU

R: L

uras

idon

e; P

LC: P

lace

bo; R

IS: R

ispe

ridon

e; S

AS:

Sim

pson

–Ang

us

Extr

apyr

amid

al S

ide-

Effe

cts

Scal

e; T

EAEs

: Tre

atm

ent-

emer

gent

adv

erse

eff

ects

.

Bobo


Review

Expert commentarySchizophrenia 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 defining psychopathological features of schizophrenia, have continued to be the symptom domain most responsive to antipsychotic drug treatment. However, the clinical significance of other psychopathological domains, such as nega-tive (or deficit) 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 [68–70]. 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 benefit for patients with schizophrenia, the wide array of anti psychotic drugs available to practitioners may be considered beneficial. 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 D2 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 efficacy 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 classified widely as having low risk of clinically significant 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 significant changes in glycemic and lipid indices. Available evidence therefore suggests that these agents may eventually be classified 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 first-episode psy-chosis, clinically significant parkinsonism, history of neuroleptic malignant syndrome or a history of severe or difficult-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 first 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 benefit 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 significant 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 – first, 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 diffi-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 significant 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. Asenapine’s 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 first 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 significant drug–drug 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 liabilityNo 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 effectMay need to be avoided in some patients who are at high risk of orthostasis or hypotensionMay need to be avoided in some patients who are at risk for clinically significant QTc prolongationPotentially significant 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 disorderSome patients may prefer rapidly dissolvable tabletsEasier to monitor adherence in controlled settings (difficult to ‘cheek’)Minimal effects on prolactin concentrationFew clinically significant drug–drug interactions anticipated

Administered b.i.d.Requires proper handling and cannot be crushed, chewed or swallowed (may be difficult for some patients)Dose-related somnolence and akathisia may be limiting for some patientsDysgeusia or oral hypoesthesia, though not severe, may occasionally threaten adherence

Lurasidone Once-daily administrationNo titration required to reach initial therapeutic doseLowest propensity for clinically significant 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


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-flavored 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 signifi-cant weight increases and the most favorable glycemic and lipid profile among the newest atypical antipsychotic drugs based on indirect comparisons. That said, the overall metabolic profiles 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 profiles 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, first-episode patients and patients who have already begun to show substantial weight gain or adverse changes in glycemic or lipid indices) [81–84]. For these individuals, even small differences between agents in terms of weight gain or metabolic profile 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 confirm 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 viewIloperidone, 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 benefit 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 influence recommenda-tions in published clinical practice guidelines. Owing to meta-bolic safety concerns, olanzapine is no longer recommended as a first-line treatment for patients with first-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 profiles, iloperidone, asenapine and lurasidone will likely be considered first-line therapeutic options in future practice guidelines for treating schizophrenia, particularly for patients with first-episode psychosis.

On the other hand, clinicians, patients and caregivers will be looking for specific advantages for each of these compounds in addition to their favorable metabolic profiles 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



ReviewTa

ble

9. S

elec

ted

reg

iste

red

clin

ical

tri

als

of

ilop

erid

on

e, a

sen

apin

e an

d lu

rasi

do

ne.

†

Dru

g n

ame

Clin

ical

Tria

ls.g

ov

iden

tifi

erIn

dic

atio

n/

pat

ien

t su

bg

rou

pPh

ase

of

dev

elo

pm

ent

Trea

tmen

t ar

ms

Key

en

d p

oin

t(s)

Des

ign

Ilope

ridon

eN

CT

0149

5169

Ado

lesc

ent

patie

nts

(a

ge 1

2–17

yea

rs)

Phas

e I

Ilope

ridon

e

(6–2

4 m

g/d

ay)

Phar

mac

okin

etic

s,

tole

rabi

lity

Ope

n-la

bel,

14-d

ay d

ose-

esca

latio

n st

udy

(12–

24 m

g/d

ay),

fol

low

ed b

y 26

-wee

k fle

xibl

e do

sing

(6

–24

mg

/day

)

NC

T 01

2915

11Sc

hizo

phre

nia,

adu

lts

Phas

e III

Ilope

ridon

e

(8–2

4 m

g/d

ay)

or p

lace

bo

Rela

pse

prev

entio

n,

long

-ter

m s

afet

y an

d to

lera

bilit

y

25-w

eek,

ran

dom

ized

, dou

ble-

blin

d, p

lace

bo-c

ontr

olle

d st

udy

(fol

low

ed b

y 52

-wee

k op

en-la

bel

exte

nsio

n ph

ase)

NC

T 01

4642

29M

ajor

dep

ress

ive

di

sord

er w

ith r

esid

ual

ange

r/irr

itabi

lity,

adu

lts

Phas

e IV

Ilope

ridon

e (1

–8 m

g/d

ay)

or p

lace

bo, a

s ad

junc

ts t

o SS

RI

Psyc

hom

etric

mea

sure

s

of a

nger

/hos

tilit

y,

tole

rabi

lity

12-w

eek,

pla

cebo

-con

trol

led

cros

sove

r st

udy

Ase

napi

neN

CT

0139

6291

Bipo

lar

I Dis

orde

r,

adul

tsPh

ase

IIIA

sena

pine

(5

–10

mg

b.i.d

.)

or p

lace

bo

Tim

e to

rec

urre

nce

(a

ny m

ood

even

t)26

-wee

k, r

ando

miz

ed, d

oubl

e-bl

ind,

pla

cebo

-con

trol

led,

re

curr

ence

pre

vent

ion

stud

y (f

ollo

win

g 12

–16

wee

k op

en-la

bel,

lead

-in a

sena

pine

tre

atm

ent

phas

e)

NC

T 0

0281

320‡

Psyc

hosi

s, e

lder

ly

(age

: 65

year

s an

d ov

er)

Phas

e III

Ase

napi

ne

(2–1

0 m

g b.

i.d.)

Phar

mac

okin

etic

mea

sure

s,

tole

rabi

lity,

saf

ety

6-w

eek,

ran

dom

ized

, pa

ralle

l-gr

oup,

mul

tiple

-dos

e st

udy

NC

T 01

1902

54Sc

hizo

phre

nia,

ad

oles

cent

s

(age

12–

17 y

ears

)

Phas

e III

Ase

napi

ne 2

.5 m

g

b.i.d

., as

enap

ine

5

mg

b.i.d

. or

plac

ebo

Effic

acy

(cha

nge

in P

AN

SS

tota

l and

sub

scal

e sc

ores

),

glob

al c

linic

al s

tate

(c

hang

e in

CG

I-S s

core

s)

8-w

eek,

ran

dom

ized

, dou

ble-

blin

d,

plac

ebo

-con

trol

led,

fixe

d-do

se

stud

y (f

ollo

wed

by

open

-labe

l ex

tens

ion

phas

e)

NC

T 01

244

815

Bipo

lar

I dis

orde

r,

man

ic o

r m

ixed

epi

sode

, ch

ildre

n an

d ad

oles

cent

s (a

ge 1

0–1

7 ye

ars)

Phas

e III

Ase

napi

ne 2

.5 m

g b.

i.d.,

asen

apin

e 5

mg

b.i.d

., as

enap

ine

10 m

g b.

i.d.,

or

plac

ebo

Effic

acy

(cha

nge

in Y

MRS

to

tal s

core

), g

loba

l clin

ical

st

ate

(CG

I-BP

and

CG

AS

scor

es),

qua

lity

of li

fe

(PQ

-LES

-Q s

core

s)

3-w

eek,

ran

dom

ized

, dou

ble-

blin

d,

plac

ebo

-con

trol

led,

fixe

d-do

se

stud

y

NC

T 01

4602

90

Bipo

lar

I dis

orde

r,

olde

r ad

ults

(a

ge 6

0 ye

ars

or o

ver)

Phas

e IV

Ase

napi

ne 5

–10

mg

b.

i.d.

Effic

acy

(cha

nge

in H

AM

-D

and

YM

RS s

core

s)12

-wee

k, o

pen-

labe

l, si

ngle

-arm

st

udy

NC

T 01

670

019

Maj

or d

epre

ssiv

e di

sord

er, a

dult

sPh

ase

IVA

sena

pine

(5

–20

mg

/day

),

or p

lace

bo,

as a

djun

ct t

o

antid

epre

ssan

t

trea

tmen

t

Effic

acy

(cha

nge

in

MA

DRS

tot

al s

core

)6

-wee

k, r

ando

miz

ed, d

oubl

e-bl

ind,

pl

aceb

o-c

ontr

olle

d st

udy

† Thi

s ta

ble

incl

udes

sel

ecte

d st

udie

s of

ilop

erid

one,

ase

napi

ne a

nd lu

rasi

done

reg

iste

red

onlin

e [2

10].

‡ The

stu

dy h

as b

een

com

plet

ed, a

nd p

relim

inar

y re

sult

s ar

e av

aila

ble

onlin

e [2

10].

§ The

stu

dy h

as b

een

com

plet

ed, b

ut p

relim

inar

y re

sult

s ar

e no

t ye

t av

aila

ble

onlin

e [2

10].

b.i.d

: Tw

ice

daily

; CA

PS: C

linic

ian

Adm

inis

tere

d Po

sttr

aum

atic

Str

ess

Dis

orde

r Sc

ale;

CG

AS:

Chi

ldre

n’s

Glo

bal A

sses

smen

t Sc

ale;

CG

I-BP

: Clin

ical

Glo

bal I

mpr

essi

on S

cale

for

use

in B

ipol

ar D

isor

der;

CG

I-S:

Clin

ical

G

loba

l Im

pres

sion

-Sev

erit

y su

bsca

le; H

AM

-D: H

amilt

on D

epre

ssio

n Ra

ting

Scal

e; M

AD

RS:

Mon

tgom

ery–

Asb

erg

Dep

ress

ion

Ratin

g Sc

ale;

PA

NSS

: Pos

itive

and

Neg

ativ

e Sy

ndro

me

Scal

e; P

Q-L

ES-Q

: Ped

iatr

ic Q

ualit

y of

Life

Enj

oym

ent

and

Satis

fact

ion

Que

stio

nnai

re; S

SRI:

Sele

ctiv

e-se

roto

nin

rece

ptor

inhi

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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 confirmed 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 sufficiently 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 efficacy and safety data are also limited, and consist chiefly 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 sufficient 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 fluoxetine, and quetiapine) and treatment- resistant major depression (aripiprazole, olanzapine, and quetiapine as adjuncts to antidepressants) [91–95]. 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 efficacy of all reviewed agents for the treat-ment of major depression or the depressive phase of bipolar I dis-order is being actively investigated. Significantly 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 [99–101]. 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 significant weight gain, hyperglycemia and new-onset Type 2 diabetes, and atherogenic hyperlipidoses [103]. The efficacy 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 benefit and adverse effects under antipsychotic treatment will be an additional research focus. Currently, no genetic or biological response predictors are yet sufficiently 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 efficacy response and risk markers for QT interval prolongation [35,104,105]. These analyses uncovered several DNA polymorphisms that were significantly associated with clini-cal response and QT prolongation in iloperidone-treated patients [104–106]. 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


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 disclosureWV Bobo has received grant/research support from Cephalon, Inc. and previously served on speaker bureaus for Janssen Pharmaceutica and Pfizer, Inc. This work was supported, in part, by NIMH grant MH087747. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict 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-HT2A and D2 receptors; however, they display variable affinity 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 profiles 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 profile, ease of use, patient acceptability and potential for drug–drug interactions.

ReferencesPapers of special note have been highlighted as:• of interest

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204 Latuda [prescribing information]. Sunovion Pharmaceuticals, Marlborough, MA, USA (2010). www.latuda.com/LatudaPrescribingInformation.pdf

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Critical Apprasal of Newly Approved Drugs Used to Treat Schizophrenia

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