Paliperidone extended-release tablets in patients with recently diagnosed schizophrenia

Original Article

Paliperidone extended-release tablets in patientswith recently diagnosed schizophreniaeip_165 64..78

Carla M. Canuso,1 Cynthia A. Bossie,1 Joan Amatniek,1 Ibrahim Turkoz,1 Gahan Pandina2 andBarbara Cornblatt3

1Ortho-McNeil Janssen Scientific Affairs,LLC, Titusville New Jersey 2PharmaceuticalResearch and Development, Johnson &Johnson, Titusville, New Jersey, and3Zucker Hillside Hospital, Glen Oaks, NewYork, USA

Corresponding author: Dr. Carla M.Canuso, Ortho-McNeil Janssen ScientificAffairs, LLC, 1125 Trenton-HarbourtonRoad, Titusville, NJ 08560-0200, USA.Email: [email protected]

Received 30 April 2009; accepted 26November 2009

Abstract

Aim: Effective early and persistentantipsychotic treatment in recentlydiagnosed schizophrenia may posi-tively impact long-term outcomes.Paliperidone extended-release (ER)was assessed in this population.

Methods: Post hoc analysis of pooleddata from three 6-week, double-blind(DB), placebo-controlled, and three1-year open-label (OL) studies of pali-peridone ER in schizophreniapatients. Data stratified by time sincediagnosis (�3 vs. >3 years).

Results: At DB (n = 1193) and OLbaselines (n = 744), 259 (21.9%) and188 (25.3%) patients were diagnosed�3 years. At DB end point, bothpopulations improved with paliperi-done ER versus placebo on Positiveand Negative Syndrome Scale(PANSS) total, Clinical GlobalImpressions–Severity and Personaland Social Performance (PSP) scalescores (all P < 0.05). At OL end point,there were significant improvements

from DB baseline in both populationson these scales (P < 0.0001), withgreater improvement in the �3-yearpopulation on PANSS total (P < 0.001)and PSP (P < 0.001) scores. During DBtreatment, only the �3-year popula-tion reported adverse events (AEs) in�5% (placebo-adjusted rate) of sub-jects receiving paliperidone ER:akathisia, extrapyramidal disordernot otherwise specified and somno-lence. During OL treatment, akathisiaand somnolence occurred more fre-quently (�5%) in the �3- versus>3-year population. OL studycompletion rates were 51.1% in�3-year, and 48.2% in >3-yearsubjects.

Conclusions: Paliperidone ER signifi-cantly improved symptoms and func-tioning in schizophrenia patients,regardless of time since diagnosis.Recently diagnosed patients who con-tinued treatment exhibited greatersymptom reduction and functionalbenefit over the long term. Resultsalso suggest that these patients maybe more susceptible to certain AEs.

Key words: paliperidone ER, schizophrenia, treatment outcome.

INTRODUCTION

The early course of schizophrenia typically includesa prodromal phase characterized by non-specificsymptoms and behaviours; a formal onset/deteriorative stage with active psychosis, cognitiveimpairment, negative symptoms and social deficits;and a period of several years following the initialepisode that often includes repeated episodes ofpsychosis with a progressive increase in residualsymptoms and functional decline.1,2 There is generalagreement that, approximately 5 years after the

initial psychotic episode, patients enter a chronic,but relatively more stable phase with no markedfurther decline in functioning or increase in residualsymptoms.2–4

The first years following the onset of fully mani-fested disease are considered particularly critical fortreatment.5 It is hypothesized that antipsychotictreatment interrupts, at least to a degree, the pre-cipitous functional decline that otherwise occursduring this period.4,6,7 Evidence for the benefit ofearly treatment is found in studies that have exam-ined the duration of active psychotic symptoms

Early Intervention in Psychiatry 2010; 4: 64–78 doi:10.1111/j.1751-7893.2010.00165.x

© 2010 Blackwell Publishing Asia Pty Ltd64

before treatment is first initiated: patients with ashorter duration of untreated psychosis have abetter initial treatment response and long-termprognosis than patients in whom treatment isdelayed.2,7–9 Because of a combination of factorsincluding those related to the illness and to toler-ability, however, patients with early illness fre-quently discontinue treatment, thus puttingthemselves at risk for poorer long-termoutcomes.10–12 Therefore, a treatment regimen that isboth effective and well tolerated is particularlyimportant for patients at early stages of the illness.

Paliperidone extended-release (ER (Invega)) is anatypical antipsychotic agent that uses OROS tech-nology to deliver a therapeutic dose with lessplasma level variability than immediate-release for-mulations.13 More constant drug plasma levels maycontribute to improved tolerability and a more con-sistent clinical response. In double-blind (DB)placebo-controlled studies, paliperidone ER wasefficacious and well tolerated in patients withschizophrenia, and was associated with a delay insymptom relapse in stable patients.14–18 These trialsinvolved patients who had been diagnosed withschizophrenia for at least 1 year, and included asubpopulation who had been diagnosed recently(i.e. between 1 and 3 years). To examine the effectsof paliperidone ER in subjects who were recentlydiagnosed, a post hoc analysis of these trialsassessed whether paliperidone ER would be moreeffective than placebo in patients with recently diag-nosed illness, and if symptoms and functioningwould improve more at 1 year in the populationdiagnosed for �3 years than those diagnosed for>3 years.

METHODS

This post hoc analysis examined the effects of pali-peridone ER by time since diagnosis (�3 vs. >3 years)in patients with schizophrenia experiencing anacute exacerbation of symptoms. Pooled data fromthree pivotal trials of paliperidone ER (multicentre,DB, randomized, placebo-controlled, parallel-group, 6-week studies) and their open-label (OL)1-year extensions served as the database for thisanalysis (PALI-SCH-303 (CR003379), PALI-SCH-304(CR004378) and PALI-SCH-305 (CR004375)).14–16,18,19

Original trial inclusion criteria required that subjectsbe diagnosed �1 year prior to entry. These studieshad similar populations and study designs, with thesame entry criteria, efficacy variables, rating guide-lines, rater training procedures and time-points, andwere conducted in accordance with current Interna-

tional Conference on Harmonization–Good ClinicalPractice guidelines and the Declaration of Helsinki.20

Independent ethics committees or institutionalreview boards approved the final study protocolbefore study initiation. Each subject providedwritten consent according to local requirementsafter receiving a full description of the study.Efficacy and safety findings have been reportedelsewhere.14–16,18,19

Participants

Participants were male or female, �18 years of age,with a Diagnostic and Statistical Manual of MentalDisorders, 4th edition (DSM-IV) diagnosis of schizo-phrenia for �1 year. Subjects had to have beenexperiencing active symptoms at the time of enroll-ment, with a Positive and Negative Syndrome Scale(PANSS) total score of 70–120 points at screeningand baseline, and to have agreed to voluntary hos-pitalization for at least 14 days. Key exclusion crite-ria included: poor general health or chronic healthconditions; an Axis I diagnosis other than schizo-phrenia; a DSM-IV diagnosis of substance depen-dence within 6 months before screening or ifdeemed at significant risk of suicide or violentbehaviour. Subjects were also excluded if they hadpreviously demonstrated a lack of response to ris-peridone. Patients who completed a DB study ordiscontinued because of lack of efficacy after at least21 days of DB treatment were eligible to enter an OLtreatment study.

Treatment

Pre-study medications were discontinued at screen-ing, which was within 5 days before randomization(baseline). Subjects included in this analysisreceived fixed doses of paliperidone ER (3, 6, 9 or12 mg day-1, reflecting the recommended doserange) or placebo during the DB studies.

OL treatment with paliperidone ER was initiatedat 9 mg day-1 for all patients irrespective of DB studyarm assignment. The dosage was flexible in that itcould be increased (to a maximum of 12 mg day-1)or decreased on a patient-to-patient basis, as perclinical judgement.

Measures

Efficacy measures included the PANSS total score21

and PANSS factor scores for positive symptoms,negative symptoms, anxiety/depression, disorga-nized thoughts and uncontrolled hostility/excitement as described by Marder et al.22 A global

C. M. Canuso et al.

© 2010 Blackwell Publishing Asia Pty Ltd 65

evaluation of the patient’s condition was assessedby the Clinical Global Impressions–Severity scale(CGI-S),23 a 7-point scale that rates overall clinicalstatus from 1 (not ill) to 7 (extremely severe). ThePersonal and Social Performance (PSP) scale24

evaluated four domains of functioning: sociallyuseful activities (including work and study), per-sonal and social relationships, self-care and disturb-ing and aggressive behaviours. Ratings of 71–100indicate good functioning, with only mild difficul-ties; ratings of 31–70 indicate variable degrees offunctioning; and ratings of 0–30 indicate poor func-tioning that requires the patient to receive intensivesupport or supervision.24 Safety and tolerabilitywere assessed via adverse event (AE) reporting,including monitoring for the incidence of extrapy-ramidal symptom (EPS)-related AEs (tremor, dysto-nia, hyperkinesia, Parkinsonism and dyskinesia).Movement disorders were assessed at days 0, 14 and42 using the Simpson–Angus Scale (SAS),25 BarnesAkathisia Rating Scale (BAS)26 and the AbnormalInvoluntary Movement Scale (AIMS),27 validatedand commonly used in clinical trials.

Analysis

In this post hoc analysis, efficacy outcomes in theDB studies were analysed using the intent-to-treat(ITT) analysis set, defined as all subjects who took atleast one dose of paliperidone ER or placebo, andhad one post-baseline efficacy assessment; safetywas analysed in all patients who took at least onedose of study medication. In the OL studies, efficacywas analysed in all subjects who received at leastone dose of OL study medication and had at leastone post-baseline efficacy assessment; safety wasanalysed in all patients who took at least one dose ofstudy medication. The �3- and >3-year populationsrandomized to paliperidone ER were comparedwith their respective placebo groups for the DBstudies. Data were pooled for paliperidone ER doses(3–12 mg day-1). For the OL studies, comparisonswere made within each population versus baseline,and between the �3- and >3-year populations. Fre-quencies, percentages and descriptive statisticswere used, as appropriate, to describedemographic/clinical characteristics, and efficacyand safety variables. Placebo adjustment for AEswas calculated by: % AEpaliperidone ER - % AEplacebo forAEs reported at a greater frequency with paliperi-done ER versus placebo. Outcome variables wereanalysed using a last-observation-carried-forward(LOCF) approach. Analysis of covariance (ANCOVA)models compared change scores for the paliperi-done ER group with placebo for continuous mea-

sures. The ANCOVA model included treatment andstudies as fixed design factors; the baseline score forthe analysed variable was used as a covariate.Within-population differences were evaluated usingpaired t-tests. Between-population differences forcategorical outcomes on the CGI-S were analysedusing the Cochran–Mantel–Haenszel (CMH) testadjusted for the study. In addition, the continuousmeasures were evaluated using repeated-measuresmixed-effects linear models including all observeddata points. The model included treatment, studiesand time (scheduled visit assessments) as fixed-effect design factors, and the interaction betweentime and treatment. No adjustments for multiplicitywere performed owing to the exploratory nature ofthe analysis. For the OL extensions, efficacy data arepresented for week 52 completers and using theLOCF approach. Effect sizes (the standardized meandifference) were used to compare efficacy in the�3-year population with the >3-year population.Population effect sizes (Hedges’s gu) were estimatedby averaging the effect size estimates from indi-vidual studies. The differences between two meanchanges from baseline to end point were divided byan unbiased estimator of the pooled populationvalue of the standard deviation.28

RESULTS

Populations

Among a total of 1193 randomized ITT patients inthe three individual studies, 259 (21.9%) wererecently diagnosed (dose groups: paliperidone ER3 mg, n = 32; 6 mg, n = 42; 9 mg, n = 68; 12 mg,n = 47; placebo, n = 70). Nine patients wereexcluded because no information was available ondate of diagnosis. Two patients (0.8%) had beendiagnosed within a year, 175 (67.6%) had been diag-nosed between 1 and 2 years, and 82 (31.7%) hadbeen diagnosed between 2 and 3 years. A total of 925patients were in the >3-year population (dosegroups: paliperidone ER 3 mg, n = 89; 6 mg, n = 190;9 mg, n = 173; 12 mg, n = 193; placebo, n = 280)(Fig. 1). Significant differences between the �3- and>3-year populations included the mean duration ofschizophrenia from the point of diagnosis, whichwas approximately 2 and 15 years, respectively.Other significantly different parameters were meanage, mean age at diagnosis, racial distribution,schizophrenia subtype, number of prior hospital-izations and mean PANSS total score (Table 1).Baseline characteristics between the treatmentarms were similar within the �3-year population

Paliperidone ER in recent schizophrenia

66 © 2010 Blackwell Publishing Asia Pty Ltd

(paliperidone ER, n = 189; placebo, n = 70) andwithin the >3-year population (paliperidone ER,n = 645; placebo, n = 280; all P � 0.05) (Table 1). Six-week completion rates with paliperidone ER werecomparable in the �3- and >3-year populations.Lack of efficacy was the most common reason fordiscontinuation in all groups (Fig. 1).

A total of 188 patients in the �3 years population,and 556 in the >3-year population entered OL treat-ment. Characteristics at DB baseline for the �3- and>3-year populations eventually entering OL treat-ment were comparable to those in Table 1, indicat-ing that the �3- and >3-year populations thatentered both DB and OL studies were similar. Themean (SD) paliperidone ER dose was 9.6 (2.5)mg day-1 in the �3-year population, and 10.1 (2.3)mg day-1 in the >3-year population. One-yearcompletion rates were approximately 50% in bothpopulations, and the most common reason for dis-continuation was withdrawal of consent (Fig. 1).

Efficacy results from the 6-week DB studies

In both populations, treatment with paliperidoneER was associated with statistically significantimprovements compared with placebo for meanPANSS total and factor scores, CGI-S mean scoreand categorical ratings, and the mean PSP scalescore. For PSP categorical ratings, significantimprovement compared with placebo wasobserved only in the >3-year population(Tables 2,3). Effect-size 95% confidence intervals(CIs) overlapped on almost all measures,suggesting that there was no meaningful diff-erence in treatment effect between the twopopulations.

Results by dose group showed improvements inmean PANSS total scores at end point in the �3-yearpopulation were significant versus placebo in the 6,9 and 12 mg paliperidone ER dose groups. Inthose diagnosed for >3 years, PANSS total score

FIGURE 1. Patient flow diagram.

†Nine patients from the double-blind phase did not have information available to determine time since diagnosis.‡Patients who completed week 3 or more of the double-blind phase were eligible to enter open-label treatment.

C. M. Canuso et al.


TABL

E1.

Dou

ble-

blin

dba

selin

ech

arac

teri

stic

sin

the

�3-

and

>3-y

ear

popu

lati

ons

�3-

Year

popu

lati

on>3

-Yea

rpo

pula

tion

Palip

erid

one

ER(n

=18

9)Pl

aceb

o(n

=70

)To

tal(

n=

259)

Palip

erid

one

ER(n

=64

5)Pl

aceb

o(n

=28

0)To

tal(

n=

925)

Para

met

erM

ean

SDM

ean

SDM

ean

SDM

ean

SDM

ean

SDM

ean

SDA

ge(y

ears

)30

.59.

333

.111

.231

.29.

9*40

.210

.440

.510

.540

.310

.4A

geat

diag

nosi

s(y

ears

)28

.59.

431

.011

.229

.210

.0*

25.2

8.2

25.1

8.7

25.2

8.4

Mea

nPA

NSS

tota

lsco

re91

.711

.193

.69.

492

.210

.7**

94.0

11.9

93.9

12.2

94.0

12.0

N%

N%

N%

N%

N%

N%

Mal

ege

nder

125

66.1

4868

.617

366

.838

459

.518

265

.056

661

.2Ra

ce Cau

casi

an12

164

.043

61.4

164

63.3

*41

464

.217

361

.858

763

.5Bl

ack

2613

.811

15.7

3714

.314

722

.868

24.3

215

23.2

Asi

an16

8.5

811

.424

9.3

426.

520

7.1

626.

7O

ther

2613

.88

11.4

3413

.142

6.5

196.

861

6.6

Type

ofsc

hizo

phre

nia

Para

noid

161

85.2

5274

.321

382

.2**

522

80.9

228

81.4

750

81.1

Und

iffer

enti

ated

2312

.213

18.6

3613

.975

11.6

3612

.911

112

.0D

isor

gani

zed

52.

65

7.1

103.

927

4.2

93.

236

3.9

Resi

dual

00

00

00

172.

67

2.5

242.

6C

atat

onic

00

00

00

40.

60

04

0.4

Prio

ran

tips

ycho

tic

use

166

87.8

5882

.922

486

.553

182

.323

182

.576

282

.4Pr

ior

hosp

ital

izat

ion

036

19.1

1622

.952

20.1

*67

10.4

258.

992

10.0

157

30.2

2840

.085

32.8

121

18.8

6021

.418

119

.62

4021

.213

18.6

5320

.510

115

.743

15.4

144

15.6

331

16.4

912

.940

15.4

104

16.1

3813

.614

215

.4�

425

3.2

45.

729

11.2

252

39.1

114

40.7

366

39.6

Base

line

CG

I-S

Not

ill0

00

00

00

00

00

0Ve

rym

ild1

0.5

00

10.

40

01

0.4

10.

1M

ild6

3.2

22.

98

3.1

121.

95

1.8

171.

8M

oder

ate

7640

.231

44.3

107

41.3

246

38.1

107

38.2

353

38.2

Mar

ked

8444

.432

45.7

116

44.8

303

47.0

138

49.3

441

47.7

Seve

re22

11.6

57.

127

10.4

8212

.729

10.4

111

12.0

Extr

emel

yse

vere

00

00

00.

02

0.3

00

20.

2

*P<

0.00

1;**

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;�

3-ye

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tion

vers

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tion

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valu

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uous

vari

able

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edby

anal

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ce;

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asus

edfo

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rica

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ues.

CG

I-S,

Clin

ical

Glo

balI

mpr

essi

ons–

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rity

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,ex

tend

ed-r

elea

se;

PAN

SS,

Posi

tive

and

Neg

ativ

eSy

ndro

me

Scal

e.



TABL

E2.

Dou

ble-

blin

dre

sult

s:cl

inic

alan

dfu

ncti

onal

mea

sure

s

Para

met

er�

3-Ye

arpo

pula

tion

>3-Y

ear

popu

lati

on

Palip

erid

one

ER(n

=18

9)Pl

aceb

o(n

=70

)P

Effe

ctsi

ze†

95%

CI,

Low

erPa

liper

idon

eER

(n=

645)

Plac

ebo

(n=

280)

PEf

fect

size

†95

%C

I,Lo

wer

Mea

nSD

Mea

nSD

Hig

her

Mea

nSD

Mea

nSD

Hig

her

PAN

SSto

tal

Base

line

91.7

11.1

93.6

9.4

94.0

11.9

93.9

12.2

Cha

nge

aten

dpo

int

-18.

319

.5-8

.921

.1<0

.001

-0.4

7-0

.74

-17.

520

.9-3

.822

.1<0

.001

-0.6

5-0

.79

-0.1

9-0

.50

CG

I-S

rati

ngBa

selin

e4.

60.

84.

60.

74.

70.

74.

70.

7C

hang

eat

end

poin

t-0

.91.

2-0

.41.

20.

012

-0.3

7-0

.65

-0.9

1.1

-0.2

1.1

<0.0

01-0

.61

-0.7

6-0

.10

-0.4

7PS

Psc

ale

tota

lsco

reBa

selin

e50

.313

.650

.513

.946

.614

.146

.713

.7C

hang

eat

end

poin

t8.

714

.63.

313

.90.

018

0.37

0.09

8.6

15.2

-0.2

15.3

<0.0

010.

580.

430.

660.

73N

%N

%P

N%

N%

PPS

Pca

tego

rica

lrat

ings

‡Ba

selin

e0.

838

0.59

8G

ood

115.

85

7.1

314.

910

3.6

Vari

able

161

85.2

6085

.751

780

.923

183

.4Po

or17

9.0

57.

191

14.2

3613

.0En

dpo

int§

0.17

2<0

.001

Goo

d48

26.7

1015

.623

239

.162

24.5

Vari

able

123

68.3

4976

.631

553

.013

955

.0Po

or9

5.0

57.

847

7.9

5220

.6

†Eff

ect

size

sw

ere

calc

ulat

edby

Hed

ges’

sg u

.‡P

valu

esar

efo

rth

edi

stri

buti

onof

PSP

cate

gori

es.

§Num

bers

ofsu

bjec

tsat

end

poin

t:pl

aceb

o,n

=64

;pa

liper

idon

eER

,n

=18

0.C

GI-

S,C

linic

alG

loba

lIm

pres

sion

s-Se

veri

ty;

ER,

exte

nded

-rel

ease

;PA

NSS

,Po

siti

vean

dN

egat

ive

Synd

rom

eSc

ale;

PSP,

Pers

onal

and

Soci

alPe

rfor

man

ce.

C. M. Canuso et al.


TABL

E3.

Dou

ble-

blin

dre

sult

s:Po

siti

vean

dN

egat

ive

Synd

rom

eSc

ale

(PA

NSS

)fa

ctor

scor

es

PAN

SSfa

ctor

scor

e�

3-Ye

arpo

pula

tion

>3-Y

ear

popu

lati

on

Palip

erid

one

ER(n

=18

9)Pl

aceb

o(n

=70

)P

Effe

ctsi

ze†

95%

CI

Low

erPa

liper

idon

eER

(n=

645)

Plac

ebo

(n=

280)

PEf

fect

size

†95

%C

ILo

wer

Mea

nSD

Mea

nSD

Hig

her

Mea

nSD

Mea

nSD

Hig

her

Posi

tive

sym

ptom

sBa

selin

e27

.45.

127

.34.

227

.84.

927

.94.

6C

hang

eat

end

poin

t-6

.76.

8-3

.77.

50.

002

-0.3

2-0

.60

-6.1

7.0

-2.0

6.8

<0.0

01-0

.55

-0.6

9-0

.05

-0.4

0N

egat

ive

sym

ptom

sBa

selin

e22

.95.

123

.25.

123

.35.

423

.05.

2C

hang

eat

end

poin

t-4

.25.

0-1

.85.

2<0

.001

-0.3

3-0

.61

-4.1

5.9

-1.2

6.2

<0.0

01-0

.40

-0.5

4-0

.06

-0.2

6A

nxie

ty/d

epre

ssio

nBa

selin

e11

.53.

212

.23.

111

.53.

211

.63.

3C

hang

eat

end

poin

t-2

.43.

9-1

.23.

4<0

.001

-0.4

6-0

.74

-2.3

3.4

-0.9

4.1

<0.0

01-0

.48

-0.6

2-0

.18

-0.3

4D

isor

gani

zed

thou

ghts

Base

line

20.8

4.4

21.4

3.3

21.8

4.3

22.1

4.6

Cha

nge

aten

dpo

int

-3.5

4.6

-2.0

5.1

0.00

8-0

.43

-0.7

1-3

.55.

1-0

.65.

5<0

.001

-0.5

9-0

.73

-0.1

5-0

.45

Unc

ontr

olle

dho

stili

ty/

exci

tem

ent

Base

line

9.2

3.2

9.5

2.4

9.7

3.3

9.4

3.0

Cha

nge

aten

dpo

int

-1.5

4.2

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improvements versus placebo were significant ineach of the four paliperidone ER dose groups.

A mixed-model repeated-measures analysis, runas a sensitivity analysis, was consistent with theLOCF approach. The mean (SE) difference in PANSStotal score in the �3-year population (paliperidoneER minus placebo) at day 43 was –11.5 (2.8)(P < 0.0001). In the >3-year population, the meandifference in PANSS total score was -11.1 (1.5)(P < 0.0001). The mean (SE) difference in the CGI-Sscore was –0.4 (0.1) (P = 0.015) in the �3-year popu-lation, and -0.5 (0.1) (P < 0.0001) in the >3-yearpopulation. On the PSP, the mean difference was 2.0(2.5) (P = 0.432) in the �3-year population, and 4.9(1.3) (P < 0.001) in the >3-year population.

Safety results from the 6-week DB studies

In the �3-year population, at least one treatment-emergent AE was reported by 67.2% in the paliperi-done ER group, and 65.7% in the placebo group. Inthe >3-year population, AEs were reported by 72.2%and 66.8% with paliperidone ER and placebo,respectively. Common AEs (reported by �5% ofpatients in the paliperidone ER group) in the�3-year population were headache (11.1%), akathi-sia (10.6%), extrapyramidal disorder not otherwisespecified (7.4%), somnolence (7.4%), anxiety (6.9%),tachycardia (6.3%) and dizziness (5.8%); commonAEs in the >3-year population were headache(13.8%), insomnia (11.9%), tachycardia (6.8%),anxiety (6.2%), sinus tachycardia (5.9%) and akathi-sia (5.3%). After placebo adjustment (calculated by

subtracting the placebo AE rate from the AE ratewith paliperidone ER for AEs reported at a greaterfrequency with paliperidone ER), akathisia, extrapy-ramidal disorder not otherwise specified, somno-lence, hypertonia and dizziness were mostfrequently reported in the �3-year population;tachycardia was most frequent in the >3-year popu-lation (Table 4). Discontinuation rates due to AEswere similar across all groups (Fig. 1).

Rates of EPS-related AEs in the �3-year popula-tion were 24.9% with paliperidone ER and 10.0%with placebo; corresponding percentages in the>3-year population were 18.1% and 11.4% with pali-peridone ER and placebo, respectively. Mean move-ment disorder rating scale (SAS, BARS and AIMS)scores were low at baseline (<1) in both arms of bothpopulations. In the �3-year population, no signifi-cant differences were observed at end pointbetween active treatment and placebo on anymovement disorder scale. In the >3-year popula-tion, the end point mean SAS score with paliperi-done ER did not change from baseline, whereas itdecreased with placebo (mean (SD): –0.04 (0.2);P = 0.045 paliperidone ER vs. placebo). No statisti-cally significant differences between paliperidoneER and placebo were observed in change scores forthe BARS or AIMS in the >3-year population. Anti-cholinergic medications were used by 41 (21.7%)paliperidone ER- and 13 (18.6%) placebo-treatedpatients in the �3-year population and 123 (19.1%)paliperidone ER- and 44 (15.7%) placebo-treatedpatients in the >3-year population (P = 0.308between populations).

TABLE 4. Double-blind study period: placebo-adjusted treatment-emergent adverseevents that occurred in �5% of patients in the paliperidone ER treatment groups†

�3-Yearpopulation

>3-Yearpopulation

Adverse event %‡ %‡Akathisia 9.2 0.6Extrapyramidal disorder not otherwise specified 6.0 2.3Somnolence 6.0 NAHypertonia 4.8 NADizziness 4.4 0.1Headache 1.1 1.7Tachycardia 0.6 4.7Nausea 0.5 NASinus tachycardia NA 1.3Sedation NA 1.2

Adverse events (AEs) reported in �5% of patients treated with paliperidone ER in both the �3- and>3-year populations but were not a higher rate than placebo: agitation and anxiety.†Included AEs were reported at a higher rate with active versus placebo treatment.‡Placebo adjustment was calculated by: %AEpaliperidone ER - % AEplacebo.NA, not applicable (AE did not occur in �5% in the respective active-treatment group).

C. M. Canuso et al.


During DB treatment, five subjects in the�3-year population reported six AEs potentiallyrelated to prolactin, four (2.1%) subjects receivingpaliperidone ER reported anorgasmia, amenor-rhoea, erectile dysfunction, galactorrhoea andirregular menstruation, and 1 (1.4%) receivingplacebo reported sexual dysfunction. Seven sub-jects in the >3-year population reported seven AEspotentially related to prolactin, six (0.9%) subjectsreceiving paliperidone ER reported anorgasmia,loss of libido, amenorrhoea, breast discharge,galactorrhoea and gynaecomastia and one (0.4%)subjects receiving placebo reported erectile dys-function. Changes in prolactin levels at end pointare shown in Table 8.

No AEs related to weight increase were reported inthe �3-year population in either the paliperidone ERor placebo groups. Mean (SD) weight at baseline was72.7 (16.0) kg with paliperidone ER and 73.9 (20.1)with placebo. Patients in the paliperidone ER groupwho completed the DB phase (n = 116) had a mean(SE) weight increase of 1.7 (0.4) kg, whereas those inthe placebo group who completed the study (n = 37)experienced a mean gain of 0.4 (0.6) kg (P = 0.032paliperidone ER vs. placebo). At end point, the mean(SE) weight change was 1.0 (0.3) and 0.1 (0.4) kg,respectively (P = 0.050 paliperidone ER vs. placebo).In the >3-year population, an AE of ‘weightincreased’ was reported by 1.4% with paliperidoneER and 1.8% with placebo. The mean (SD) weight atbaseline was 77.0 (19.8) kg with paliperidone ER and

79.3 (19.9) kg with placebo. Patients in the paliperi-done ER group who completed the DB phase(n = 397) had a mean (SE) weight increase of 1.1 (0.2)kg, whereas those in the placebo group who com-pleted the study (n = 106) experienced a meanchange of -0.1 (0.4) kg (P = 0.003 paliperidone ER vs.placebo). Mean (SE) changes at end point were1.0 (0.1) and -0.5 (0.2) kg, respectively (P < 0.001paliperidone ER vs. placebo), in the >3-yearpopulation.

Efficacy results with 1-year OL treatment

Both �3- and >3-year populations experienced sta-tistically significant improvements on all clinical andfunctional measures from DB baseline to the week 52end point (completers and LOCF). However, signifi-cantly greater improvement was observed inrecently diagnosed patients versus those with moretime since diagnosis on most efficacy measures(Tables 5,6). Mean PANSS total scores were signifi-cantly improved for the �3-year population versus>3-year population in subjects (Fig. 2). For thosewho completed 1 year of OL treatment, mean (SD)PANSS scores were 50.7 (13.9) and 57.4 (15.4), respec-tively. PSP ratings of good functioning were given to77.4% of completers in the �3-year population, and48.2% in the >3-year population (P < 0.001 for thedistribution of PSP categories vs. >3-year popula-tion). Corresponding percentages at LOCF end pointwere approximately 52.2% and 32.2%, respectively

TABLE 5. Open-label results: clinical and functional measures

Parameter �3-Year population (n = 188) >3-Year population (n = 556) P

Mean SD/SE‡ Mean SD/SE‡

PANSS totalDouble-blind (DB)baseline

91.3 10.1 94.2 11.7 0.001

Change in completers† -42.2* 1.5 -36.5* 0.9 0.002Change at end point -32.3* 1.5 -26.7* 0.9 0.001

CGI-S ratingDB baseline 4.6 0.7 4.7 0.7 0.081Change in completers† -2.3* 0.1 -2.0* 0.1 0.002Change at end point -1.7* 0.1 -1.4* 0.1 0.004

PSP scale totalDB baseline 52.1 13.2 47.4 14.2 <0.0001Change in completers† 25.9* 1.4 20.6* 0.8 0.001Change at end point 18.8* 1.2 14.7* 0.7 0.003

*P < 0.0001 versus DB baseline.†The number of patients who completed 52 weeks of treatment were �3-year population, n = 93; >3-year population, n = 270.‡For baseline scores, unadjusted means and SDs were used. For change from baseline in completers and at end point, mean changes are least square meansand SEs, adjusted for group and DB baseline values.CGI-S, Clinical Global Impressions–Severity; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance.



(P < 0.001 for the distribution of PSP categories vs.>3-year population) (Fig. 3).

The mixed-model repeated-measures analysisalso found a significantly greater improvement inrecently diagnosed patients versus those with more

time since diagnosis, with mean (SE) differences atweek 52 (�3 years minus the >3-year population)for the PANSS total score (-5.2 (1.7) (P = 0.002)),CGI-S (-0.3 (0.1) (P = 0.001)) and PSP (4.1 (1.4)(P = 0.004)).

TABLE 6. Open-label results: Positive and Negative Syndrome Scale (PANSS) factor scores

Parameter �3-Year population (n = 188) >3-Year population (n = 556) P

Mean SD/SE‡ Mean SD/SE‡

PANSS positive symptomsDouble-blind (DB) baseline 27.1 4.7 27.6 4.8 0.247Change in completers† -14.1* 0.5 -12.1* 0.3 <0.001Change at end point -11.1* 0.5 -8.9* 0.3 <0.001

PANSS negative symptomsDB baseline 22.6 5.2 23.5 5.4 0.035Change in completers† -9.8* 0.5 -8.3* 0.3 0.010Change at end point -7.5* 0.4 -6.1* 0.2 0.004

PANSS anxiety/depressionDB baseline 11.7 3.2 11.4 3.1 0.176Change in completers† -5.1* 0.2 -4.9* 0.1 0.487Change at end point -3.9* 0.2 -3.7* 0.1 0.495

PANSS disorganized thoughtsDB baseline 20.7 4.0 22.2 4.1 <0.0001Change in completers† -8.9* 0.4 -7.7* 0.3 0.018Change at end point -7.1* 0.4 -5.6* 0.2 0.001

PANSS uncontrolled hostility/excitementDB baseline 9.1 2.7 9.5 3.0 0.118Change in completers† -4.1* 0.2 -3.7* 0.1 0.055Change at end point -2.9* 0.2 -2.3* 0.1 0.042

*P < 0.0001 versus DB baseline.†The number of patients who completed 52 weeks of treatment were �3-year population, n = 93; >3-year population, n = 270.‡For baseline scores, unadjusted means and SDs were used.For change from baseline in completers and at end point, mean changes were least square means and SEs, adjusted for group and DB baseline values.

FIGURE 2. Open-label results: categoricalratings on the Personal and SocialPerformance scale for the �3- and >3-yearpopulations.

C. M. Canuso et al.


Safety results with 1-year OL treatment

At least one treatment-emergent AE was reported by80.3% of patients in the �3-year population and in75.4% in the >3-year population. The incidence ofAEs (�5%) for both populations is listed in Table 7.There was one death during OL treatment (received6 mg paliperidone ER during the DB phase), a

suicide in a patient recently diagnosed that wasdetermined to be unrelated to study medication.Akathisia, somnolence and depression occurredmore frequently (�5%) in the �3- versus >3-yearpopulation.

EPS-related AEs were observed in 64 (34.0%)patients in the �3-year population, and in 130(23.4%) in the >3-year population. Mean ratings on

FIGURE 3. OL results: Positive and Negative Syndrome Scale total score for patients who entered the OL studies.

PANSS, Positive and Negative Syndrome Scale; DB, double-blind; OL, open-label. *P < 0.05 �3- versus >3-year population. **P < 0.002 �3- versus>3-year population.

TABLE 7. Open-label results: treatment-emergent adverse events (reported in �5% of either population)

Parameter �3-Year population (n = 188) >3-Year population (n = 556)

n % n %

Any adverse event 151 80.3 419 75.4Akathisia 35 18.6 51 9.2Headache 27 14.4 62 11.2Insomnia 26 13.8 73 13.1Somnolence 21 11.2 32 5.8Depression 20 10.6 34 6.1Anxiety 18 9.6 45 8.1Schizophrenia 16 8.5 36 6.5Extrapyramidal disorder not otherwise specified 14 7.5 34 6.1Tachycardia 14 7.5 33 5.9Psychotic disorder 14 7.5 47 8.5Weight increased 12 6.4 26 4.7Sinus tachycardia 10 5.3 23 4.1Nasopharyngitis 9 4.8 30 5.4Nausea 6 3.2 28 5.0



the SAS, BARS and AIMS rating scales did notchange at end point from DB baseline in the�3-year population; small but statistically signifi-cant mean (SD) decreases were observed in the>3-year population (SAS: -0.03 (0.2), P < 0.001;BARS: -0.15 (1.2), P = 0.005; AIMS: -0.21 (1.5),P = 0.002). Mean changes on movement disorderscales, however, were not significantly differentbetween the �3- and >3-year populations at the endof OL treatment. Anticholinergic medications wereused by 48 (25.5%) patients in the �3-year popula-tion and 129 (23.2%) in the >3-year population(P = 0.517).

During the OL extension, 14 (7.5%) subjects in the�3-year population reported 17 AEs potentiallyrelated to prolactin, including hyperprolactinemia(1), anorgasmia (2), decrease or loss of libido (2),amenorrhoea (5), irregular menstruation (3), galac-torrhoea (1), sexual dysfunction (1) and erectile dys-function (2). Twenty-eight (5.0%) subjects in the>3-year population reported 35 AEs potentiallyrelated to prolactin: hyperprolactinemia (2),decreased libido (1), amenorrhoea (9), breast painor tenderness (2), erectile dysfunction (4), galactor-rhoea (6), gynaecomastia (2), irregular menstrua-tion (5), oligomenorrhoea (1) and sexualdysfunction (3). End point changes in prolactinlevels are shown in Table 8.

Weight increase was reported as an AE by 6.4%and 4.7% in the �3- and >3-year populations,respectively. Mean (SE) weight increased signifi-cantly for both populations at end point from DBbaseline (P < 0.001): 2.1 (0.5) kg in the �3-yearpopulation and 1.9 (0.3) kg in >3-year population.Subjects in the �3-year population who completedOL treatment (n = 93) experienced a mean (SE) gainof 2.6 (0.7) kg. Subjects in the >3-year populationwho completed OL treatment (n = 269) experienced

a mean (SE) gain of 2.1 (0.4) kg. Mean weight gainbetween the two populations was not significantlydifferent for completers (P = 0.597) or at end point(P = 0.687).

DISCUSSION

In this post hoc analysis, patients with recently diag-nosed schizophrenia receiving paliperidone ERexperienced significant symptomatic and func-tional improvements at 6 weeks compared withplacebo. During OL treatment, the �3- and >3-yearpopulations both demonstrated improvement insymptoms and functioning, particularly with con-tinued treatment as observed in those who com-pleted the studies (Figs 2,3). Notably, the �3-yearpopulation experienced significantly greaterimprovements than those diagnosed for >3 years formost efficacy measures. In completers, the PANSStotal score was 51 in the �3-year population and 57in the >3-year population at the end of 1 year, high-lighting the importance of continued treatment.These data are consistent with published reportsshowing that recently diagnosed patients respondwell to treatment.29,30

Antipsychotic treatment during the early courseof schizophrenia appears to lessen the full expres-sion of disease.2,6,8,31 Such treatment would be ofparticular value if it not only improved symptoms,but also positively affected functioning.2–4 Further, ifpatients with early illness may be more likely to con-tinue the treatment and gain the benefits of sus-tained antipsychotic treatment, including a lowerrisk of relapse. Whereas patients with early illnessare notably likely to discontinue treatment,10–12 thecompletion rate during short- and long-term treat-ment in these studies was numerically higher in the

TABLE 8. Change in prolactin levels at end point

Prolactin (ng mL-1),change atend point

�3-Year population >3-Year population

Paliperidone ER Placebo Paliperidone ER Placebo

Double-blind results Mean SE Mean SE Mean SE Mean SEMale subjects 25.5* 3.7 1.2 6.0 24.2* 1.2 -2.9 1.6Female subjects 84.3* 8.7 -1.2 14.9 80.0* 5.0 -19.8 7.9

�3-Year population >3-Year population

Open-label results Mean SE Mean SEMale subjects 22.4 3.3 24.2 2.1Female subjects 68.4 13.2 68.5 7.0

*P � 0.001 versus placebo. Adjusted mean change from an analysis of covariance model includingbaseline, group and centre.

C. M. Canuso et al.


�3-year than the >3-year population (Fig. 1). Thehigh discontinuation rates associated with all antip-sychotics is an important limitation to treatmenteffectiveness. Completion rates were 62.4% and61.6% in the 6-week DB phase for the �3-and >3-year populations, respectively, and 51.1%and 48.2%, respectively, in the 1-year OL extension.These rates are consistent with those reported in6-week placebo-controlled studies of other atypicalantipsychotics in acutely ill populations,32–35 and inlong-term studies in both chronic schizophreniaand early illness.11,36

Preserving and/or enhancing functioning inrecently diagnosed patients is an important goal oftreatment. Whereas short-term functional improve-ments were generally similar in the �3- and >3-yearpopulations, improvement during OL treatmentwas significantly greater in the �3-year population.More than 75% of recently diagnosed patients whocompleted OL treatment were rated as having goodfunctioning, compared with approximately 50% inthe >3-year population. Improved functioning inrecently diagnosed 52-week completers was notlikely caused by differential dropout during OLtreatment, as those who completed treatment andthose who discontinued had similar mean (SD) PSPscores at entry into OL treatment (64.0 (14.6) and60.2 (14.3)). The adjusted mean increase in the PSPscore at end point in recently diagnosed patientswas 19 points, more than twice the 7–9 points sug-gested to reflect a clinically meaningful functionalimprovement,37,38 and approximately 4 pointshigher than that achieved by patients with a longertime since diagnosis. Taken together with PANSSdata, these results further highlight the potentialpositive impact of continued effective treatment inearly illness.

Patients early in the course of schizophrenia arereportedly more susceptible to AEs, particularlymovement disorders and somnolence.11,39,40 In boththe �3- and >3-year populations, paliperidone ERduring DB treatment was associated with a low inci-dence of AEs and an AE-related discontinuation ratelower than in placebo-treated subjects. Althoughmovement disorder rating scale scores did notdiscern a difference between the populations, therewere more reports of akathisia during both short-and long-term treatments in patients with earlyillness. A higher incidence of EPS during the firstyear of treatment in patients with first-episodeschizophrenia or schizoaffective disorder has beendemonstrated to be a significant factor in medica-tion discontinuation,10 and evidence indicates thatsensitivity to EPS is greater in younger populations,which represent a substantial proportion of subjects

with early illness.39,40 In our population of recentlydiagnosed patients, EPS-related symptoms did notappear to impact 1-year study completion in com-parison with the >3-year population. This data setfurther suggests that rates of AEs potentially relatedto prolactin were no higher with paliperidone ER inthe �3- and >3-year populations.

There are several limitations to the interpretationof these results. This was a post hoc analysis of trialsthat were not designed to study patients with earlyillness (duration of illness was not a randomizationfactor in the original studies). Therefore, other vari-ables may have accounted for the greater improve-ment observed in the early illness population. Theage at diagnosis between the �3- and >3-year popu-lations was different (29.2 vs. 25.2 years), forexample, and may have confounded treatment out-comes. Further, the long-term treatment data arefrom single-arm OL trials. The measure for earlyillness used in this study, time since diagnosis, waschosen as a proxy for early illness, as data were notcollected on duration of illness. It necessarily relieson historical information and is subject to recallbias.

A cutoff point of 3 years was selected based on theliterature as likely to identify a population ofpatients with early illness.5,11,41 It is recognized thatthe first 5 years after diagnosis is a crucial treatmentperiod that sets the parameters for long-term recov-ery and outcome.5 Prior researchers have usedcutoff points of 3–5 years to define early illnesspopulations.11,41 The early course of schizophrenia isquite difficult to study, and it is not easy to pinpointthe formal onset of the first psychotic episode,despite criteria for identifying the initial phases ofschizophrenia.1,42 Reports in the literature suggestthat a variable period, averaging about 1 year,43

occurs between the emergence of psychotic symp-toms and first contact between the patient and themental health-care system. Thus, ‘time since diag-nosis’ may underestimate the duration of illness forsome patients. The more conservative time frame of�3 years of diagnosis was selected to better specifyan early illness population. Because subjects in ourdatabase had to have been diagnosed with schizo-phrenia at least 1 year prior to screening, theseresults may not be generalizable to patients diag-nosed <1 year.

In this database, the mean age of the recentlydiagnosed subjects (31.2 years) was somewhat olderthan might be expected for patients experiencingearly illness. These ages, however, are consistentwith epidemiologic data indicating that first contactor first admission generally occurs between 25 and35 years of age,44 and these patients are typical of



those who are included in clinical trials. Eventhough this population was relatively chronic incomparison with a first-episode population, theadvantage of effective, prolonged treatment wasdemonstrable. It may be anticipated that such ben-efits would be even more evident in first-episodepatients.

Results from this analysis suggest that paliperi-done ER may significantly improve symptoms andoverall functioning, and is well tolerated in recentlydiagnosed patients with schizophrenia. Whereassymptomatic and functional improvements weresimilar in �3- and >3-year populations duringshort-term treatment, improvements after 1 year oftreatment appeared to be greater in recently diag-nosed patients than in those with more time sincediagnosis. Findings were consistent with the currentthinking in the literature that early, persistent andeffective long-term treatment may modify thecourse of disease. This hypothesis warrants furtherinvestigation.

ACKNOWLEDGEMENTS

The authors acknowledge Dr Mariana Ovnic andHelix Medical Communications for assisting withthe development and submission of this paper.CMC, CAB, JA and IT are full-time employees ofOrtho-McNeil Janssen Scientific Affairs, LLC, andare Johnson & Johnson stockholders. GP is a full-time employee of Johnson & Johnson Pharmaceuti-cal Research and Development, and is a Johnson &Johnson stockholder. BC is a consultant forXenoport. Funding was supported by Ortho-McNeilJanssen Scientific Affairs, LLC.

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Paliperidone extended-release tablets in patients with recently diagnosed schizophrenia