remission in schizophrenia: one-year italian prospective study of risperidone long-acting injectable...

human psychopharmacology

Hum. Psychopharmacol Clin Exp 2009; 24: 574–583.

Published online in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/hup.1067

Remission in schizophrenia: one-year Italian prospective study ofrisperidone long-acting injectable (RLAI) in patients withschizophrenia or schizoaffective disordery

Alessandro Rossi1*, Anna Bagala2, Vincenzo Del Curatolo3, Francesco Scapati4,Micaela Maria Bernareggi5z and Maria Grazia Giustra5x on behalf of the Risperidone Long-Acting TrialInvestigators (R-LAI)

1Department of Experimental Medicine, University of L’Aquila, Italy2Mental Health Department, Palmi, Reggio Calabria, Italy3Mental Health Department, Barletta, Bari, Italy4Mental Health Department, Taranto, Italy5Medical Affairs, Janssen-Cilag SpA, Cologno Monzese, Milano, Italy

Objectives To evaluate the maintenance of efficacy of risperidone long-acting injectable (RLAI) in stable patients with schizophrenia orschizoaffective disorders. The prevalence of patients who met standardized remission criteria will be also evaluated as well as the predictorsfactors of remission according to psychopathological, psychosocial and subjective correlates.Methods 52-week, open-label prospective trial in 347 stable patients switching directly to RLAI from any previous antipsychotic treatment.Results One year of treatment was completed by 70% of patients. Positive and Negative Syndrome Scale (PANSS) total and subscale,Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) scores improved from baseline at each assessment visit(p< 0.001, p< 0.001 and p< 0.05, respectively). Drug Attitude Inventory 30 (DAI30) scores improved significantly from month 3 onwards.32% of patients met sustained remission at week 52. In a logistic regression model less severe positive and negative PANSS scores at baselinepredicted remission (p< 0.001). RLAI treatment was well tolerated: one-third of patients reported mild to moderate adverse events (AEs).Eleven patients (3.2%) discontinued treatment due to an AE. No significant weight gain (p¼ 0.093) was reported.Conclusions RLAI treatment up to one year improved symptoms and global functioning versus baseline, indicating that an established andaccepted antipsychotic therapy can enable patients with schizophrenia to achieve and maintain remission. Copyright # 2009 John Wiley &Sons, Ltd.

key words—schizophrenia; antipsychotics; long-acting; remission; PANSS; DAI30

INTRODUCTION

Pharmacotherapy for schizophrenia and related dis-orders is well established in clinical psychiatry andoffers considerable benefit in controlling symptomsand preventing relapse (Lehman et al., 2004). Short-term efficacy and relapse-prevention studies have thevalue to establish a quantitative aspect of pharmacotherapy

*Correspondence to: Prof. A. Rossi, Department of Experimental Medi-cine, University of L’Aquila, Coppito II, 67100 L’Aquila (Italy). Tel: þ39-0862-433602. Fax: þ39-0862-433602.E-mail: [email protected] other authors state that no potential conflicts do exist.zClinical Research Manager for the Global Clinical Operation- MedicalAffairs Operations of Janssen Cilag ItalyxMedical Affairs Manager for the Medical Affairs Department of JanssenCilag Italy.

Copyright # 2009 John Wiley & Sons, Ltd.

related mainly to efficacy and safety (Kane et al., 2003;Honer et al., 2007).Although longitudinal studies continue to point to a

large number of patients who experience improve-ments in their condition over time (Davidson et al.,2008), few studies have addressed the issue of remission.The goals of treatment during the stable phase are toensure that symptoms remission or control is sustained,the patient’s level of functioning and quality of life aremaintained or improved, and relapses are preventedand, if they occur, are effectively treated. There is gro-wing attention to the issue of remission in psychiatry(Kupfer, 1991; Ballenger, 2001) and more recently inschizophrenia (Andreasen et al., 2005; Leucht et al.,2007) as a critical component of recovery. In anaturalistic cohort, 29% of patients with a diagnosis ofschizophrenia or schizoaffective disorder in different

Received 23 March 2009

Accepted 29 July 2009

remission in schizophrenia with risperidone lai 575

treatment settings met the criteria for remission atstudy endpoint. These patients showed better globalfunctioning and insight than those who did not meet thecriteria (De Hert et al., 2007). Analyses of trial datausing the remission criteria indicate that remission mayrepresent a meaningful clinical target (Lasser et al.,2005; Sethuraman et al., 2005).To further address this issue, we studied the pattern

of symptoms related to remission in a population ofpatients with schizophrenia or schizoaffective disorderwho were switched to risperidone long-acting inject-able (RLAI). RLAI is the first atypical antipsychotic tobecome available in long-term injectable form and haswell-proven efficacy, safety and tolerability (Fleisch-hacker et al., 2003; Kane et al., 2003).This prospective trial followed a cohort of patients

who were switched to RLAI. The primary aim was toinvestigate the maintenance of antipsychotic efficacyand safety of RLAI injected every 2 weeks over aperiod of 52 weeks. The secondary aim was toinvestigate prospectively the prevalence of patientswho met standardized remission criteria (Andreasenet al., 2005) and the psychopathological, psychosocialand subjective predictors of achieving remission.

METHODS

Study design

This 52-week, prospective, open-label, single-arm studywas conducted at 47 sites in Italy betweenJanuary 2005 and April 2007. Patients with schizo-phrenia or schizoaffective disorder who were receivingtreatment with any antipsychotic medication and whorequired a long-term antipsychotic therapy wereswitched directly to RLAI without an oral risperidonerun-in. They were not to be considered either optimallytreated or symptom-free. Patients were either out-patients or living in residential structures at the time ofthe enrolment as well as throughout the study.The trial was performed in accordance with the

guidelines of the International Conference on Harmo-nization for Good Clinical Practice as stipulated in theDeclaration of Helsinki. Local Ethics Committees approvalwas obtained at each of the participating study sites.

Patient characteristics

A total of 347 patients, aged 18 years or older, withschizophrenia or schizoaffective disorder according tothe Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition (DSM-IV) (APA, 1994) and


who required long-term antipsychotic therapy wereeligible for inclusion. At the time of recruitment, allpatients were symptomatically stable and had beentaking the same dose of antipsychotic agents for at leastone month before the baseline visit. Patients wereconsidered stable if there had been no appreciablechange in symptoms over the previous month, regard-less of the severity of their symptoms.Patients who had received clozapine during the pre-

vious 3 months, who had participated in an investiga-tional drug trial in the previous 30 days, or who hadpreviously been shown to be either intolerant or non-responsive to risperidone therapy were excluded. Otherexclusion criteria included the presence of a seriousunstable medical condition, such as a history or currentsymptoms of tardive dyskinesia or a history ofneuroleptic malignant syndrome. Pregnant or breast-feeding patients were also ineligible, and all otherfemale patients of childbearing potential who did notuse adequate contraception were excluded.All patients or their legal representatives provided

their written informed consent prior to enrolment in thestudy.Three hundred and forty seven patients were

included in the study and received at least one doseof RLAI (safety population), whereas 326 had at leastone post-baseline efficacy evaluation intention-to-treat(ITT) population. Overall, 243 patients (70%) com-pleted the 52-week study period in accordance with thestudy protocol (per-protocol (PP) population, i.e.treatment completers).All these patients were in charge to the local unit on

the Mental Health Centre who followed up the patientswithin the local community program as established bythe National Mental Health Care Service guidelines.The patients were contacted each month.The most common reason for discontinuation of RLAI

treatment was withdrawal of consent (15.6%, Table 1).Of the 347 patients, the majority (61.9%) were male.

Mean� SD age was 44.2� 11.4 years. On the basis ofDSM-IV criteria, patients were diagnosed withschizophrenia (n¼ 260; 74.9%) or schizoaffectivedisorder (n¼ 87; 25.1%). The mean age at first onsetof symptoms was 26.9� 9.4 years and mean age at firstantipsychotic treatment was 28.6� 9.5 years. Patientshad an average of 4.6� 5.9 hospitalizations over aperiod of 6 months prior to inclusion in the study. Thedemographic characteristics of the PP population werecomparable to those of the overall population.The demographic and clinical characteristics of

schizophrenic patients were comparable to those ofschizoaffective patients but the former had baselinehigher negative symptoms (t-test: p< 0.02).

Hum. Psychopharmacol Clin Exp 2009; 24: 574–583.DOI: 10.1002/hup

Table 1. Reasons for discontinuation of RLAI treatment

N %

Total number of subjects 347 100Completed 52-week treatment (PP) 243 70.0Discontinued 104 30.0Reasons for discontinuationWithdrawal of consent 54 15.6Adverse event 11 3.2Patients lost to follow-up 11 3.2Insufficient response 10 2.9Non-compliance 10 2.9Death 1 0.3Other 7 2.0

PP: Per Protocol Population.

576 a. rossi ET AL.

More than the half of the 347 patients were onantipsychotic monotherapy at baseline (n¼ 201;57.9%). The most common antipsychotic medicationswere risperidone (n¼ 71; 35.3%).The choice of previous antipsychotic reflected

clinical judgement only. Insofar as we are unable toverify the impact of different antipsychotic amongpolitherapy patients on outcome measure, monother-apy patients (i.e. risperidone vs. conventional neuro-leptics) were contrasted. No significant differencebetween completers and discontinued patients wereobserved in relation to their previous antipsychotictherapy (x2 p ns).At the onset of RLAI treatment, the vast majority

(97.1%) of patients received 25mg as the initial dose,whereas the remainder received 37.5mg. At theendpoint, 41.2% of patients were receiving the25mg dose, whereas 30.0% and 28.8% were receiving37.5mg and 50mg, respectively. The modal dose ateach visit was 25mg. During the 52-week study periodexcluding the first 3 weeks, 23.3% of patients receivedoral risperidone supplementation at a mean dose of2.1� 0.1mg and for a mean duration of 46.0� 5.1days. This supplementation was given to manage abrief burst of symptoms.

Trial medication

Risperidone long-acting injectable (RISPERDAL1

prolonged-release powder and solvent for suspensionfor intramuscular injection, Cilag AG, Schaffhausen,Switzerland) was administered by intramuscular(gluteal) injection every 2 weeks, at a startingrecommended dose of 25mg, which could be higher(37.5 or 50mg) in case of persistence of symptoms or ifthe patient was known to respond only to higherdosages of antipsychotics.According to the patient’s symptoms and response to

treatment, the dosage could be adjusted or, if necessary,


increased 4 weeks after treatment but not earlier than2 weeks after the previous injection. Tolerability of oralrisperidone should be investigated before the firstinjection of RLAI in patients with no history ofprevious risperidone use by administering two 1mgrisperidone tablets once daily for 2 days.Patients were switched from their previous anti-

psychotic agent(s) directly to RLAI without an oralrisperidone run in. When switching from an oralantipsychotic, the agent was administered at the samedose for 21 days after the first injection of RLAI, andthen stopped or tapered off over 3 days. If the switchingwas from conventional depot neuroleptics, the RLAItreatment regimen was as follows: one injection ofdepot neuroleptic 7 days before and 7 days after thefirst RLAI dose, if the patient received medicationevery 2 weeks. If the interval of the depot neurolepticwas every 3 weeks, patients were injected 21 daysbefore the first RLAI injection, plus a final injection ofdepot agent into the other buttock on the same day asthe first RLAI injection. Finally, patients received afinal depot dose 7 days before the first RLAI injection ifthe interval of administration of the conventional depotwas every 4 weeks.Temporary oral supplementation with risperidone

(1–2mg/day) was permitted when considered necess-ary by the investigator to treat breakthrough psychosis,and also for up to 21 days following an increase in thedose of RLAI if an immediate clinical effect wasneeded. Patients could receive other psychotropicmedication that had been initiated before the trial forother reasons (e.g. sleep induction or sedation).Anticholinergic medication was allowed up to

8 weeks past baseline with a gradual tapering. Finally,benzodiazepines could be used as rescue medicationfor a short period (45.8% of patients (n¼ 159) takingthese during the 52 weeks of the study).

Outcome measures

Efficacy. All efficacy assessments were performed atbaseline and after 4, 12, 26, 38 and 52 weeks oftreatment with RLAI.Symptom severity was assessed using the Positive

and Negative Syndrome Scale (PANSS) (Kay, 1991;Pancheri et al., 1995). Total, positive, negative, generalpsychopathology PANSS scales and PANSS cognitivecluster score were evaluated as reported by Daneluzzoet al. (2002) and by Ehmann et al. (2004). The ClinicalGlobal Impression-Severity (CGI-S) scale (Guy, 1976)was used to assess patient condition at baseline and theCGI-Change score was used at all other time points.Changes in functioning from baseline were recorded



using the Global Assessment of Functioning (GAF)scale (Endicott et al., 1976). Personal attitude towardsRLAI treatment was rated by a subjective question-naire, the Drug Attitude Inventory 30 (DAI30) (Rossiet al., 2001).

Safety and tolerability

All adverse events (AEs), including any serious AEsthat occurred from the first up to the last trial-specificprocedure were recorded. Changes in weight and bodymass index (BMI) were also recorded at baseline and atall trial time points.

Statistical analysis

All patients who received at least one dose of RLAIwere included in the safety analysis (safety popu-lation). All patients who received at least one dose ofRLAI and completed at least one post-baseline efficacyassessment were included in the intention-to-treat(ITT) population and analysed for the primary efficacyparameter using a last-observation-carried-forward(LOCF) approach with respect to endpoint visits.Demographic characteristics were analysed usingdescriptive statistics. Patients in the ITT populationwho completed the study according to study protocol(i.e. completers) were included in the PP population.The primary efficacy measure (i.e. PANSS total and

subscales score change from baseline to endpoint) wasanalysed for the ITT and PP populations.Secondary efficacy measures (i.e. CGI-C, GAF and

DAI30 score change from baseline to week 52, andremission data) were analysed for the PP population.Three nonparametric tests were used for comparative

statistical analyses of efficacy measures: WilcoxonRank–Sum test, Wilcoxon Signed–Rank test andKruskal–Wallis test. A p< 0.05 was consideredstatistically significant.The PANSS scores at each visit were analysed (PP

population) to determine whether patients met thecriteria for remission as defined by the Remission inSchizophrenia Working Group (Andreasen et al.,2005). This definition requires the simultaneousattainment of a score of 3 (mild), 2 (minimal) or 1(absent) for at least 6 months for all of the followingsymptoms (PANSS items): delusions (P1); conceptdisorganization (P2); hallucinatory behaviour (P3);unusual thought content (G9) or mannerisms andposturing (G5); blunted affect (N1); passive/apatheticsocial withdrawal (N4) and lack of spontaneity andflow of conversation (N6). For visits up to week 26,only the severity criteria were applied, but both severity


and duration criteria were applied for subsequent visits(i.e. patients were considered to be ‘in remission’).A binary logistic regression model was used to test

the power of the predictors to estimate the remission.From the predictor variables the 8 PANSS remissionitems were removed.

RESULTS

Efficacy

The mean change from baseline to endpoint in thePANSS total score was reduced significantly(p< 0.001) at week 52 and at the endpoint. Table 2shows values at baseline and at each time point in thetwo analysed populations (ITT and PP). A significantimprovement was seen as early as week 4 of treatmentwith RLAI, and further improvements were observedwith continued treatment throughout the one-yearstudy period (Table 2). Significant improvements frombaseline to endpoint were observed in all the subscoresfor the PANSS positive, negative, general psycho-pathology subscales and in the PANSS cognitivecluster score (Table 2).When patients who completed the 52-week study

period (PP population; PANSS data for 12 patientswere not available at all time points and thereforeexcluded from analysis) were stratified on the basis oftheir improvement in PANSS total score from baselineto week 52, 57.6% (n¼ 133) had� 20% improvement.Of these patients, 16% (n¼ 37) showed� 30%improvement, 6.1% (n¼ 4) had� 40% improvementand 5.6% (n¼ 13) achieved� 50% improvement.No differences in the extent of improvement in the

PANSS total score from baseline to week 52 wereobserved among treatment completers (PP population)taking 25, 37.5 or 50mg of RLAI as final doses(Figure 1A), although these groups had significantlydifferent (p¼ 0.012) baseline PANSS total scores(Figure 1B).At baseline, 46.5% of patients (n¼ 113, PP

population) were considered to be ‘moderately ill’according to the CGI-S. The percentage of patientswho experienced any degree of improvement accord-ing to the CGI-Change between assessment visitsincreased significantly from 34.8% (V2-V1) to 65.8%(V6-V5) (x2 Test, p< 0.05). Psychosocial functioningas measured by GAF improved significantly frombaseline (49.1� 11.2) to week 52 (58.9� 13.3; PPpopulation, p< 0.001).There was an overall improvement in the personal

attitude towards medication during treatment withRLAI, as demonstrated by the significant increase


Table 2. PANSS total and subscale scoresa and PANSS cognitive cluster score at each time point

Baseline 4 weeks 12 weeks 26 weeks 38 weeks 52 weeks Endpoint

Subscales ITT (n¼ 326) (n¼ 326) (n¼ 298) (n¼ 265) (n¼ 248) (n¼ 231) (n¼ 326)PP (n¼ 243) (n¼ 242) (n¼ 239) (n¼ 236) (n¼ 232) (n¼ 231) (n¼ 242)

Positive ITT 17.9� 6.3 16.9� 6.4b 15.7� 6.0b 15.5� 6.5b 14.8� 5.9b 13.7� 5.7b 14.5� 6.3b

PP 18.0� 6.1 17.3� 6.4b 16.0� 6.1b 15.5� 6.4b 14.6� 5.7b 13.7� 5.7b 13.9� 6.0b

Negative ITT 24.4� 8.0 23.4� 8.0b 22.5� 7.8b 22.1� 7.4b 21.1� 7.5b 19.9� 7.4b 20.3� 7.7b

PP 25.2� 7.8 24.2� 7.6b 23.0� 7.6b 22.1� 7.5b 20.9� 7.4b 19.9� 7.4b 20.1� 7.3b

Cognitive ITT 21.2� 6.9 20.3� 6.8b 19.4� 6.5b 19.2� 6.7b 18.4� 6.5b 17.4� 6.5b 17.9� 6.8b

PP 21.6� 6.7 20.9� 6.5b 19.8� 6.4b 19.2� 6.6b 18.2� 6.3b 17.4� 6.5b 17.6� 6.5b

General ITT 44.9� 11.9 42.7� 12.3b 40.6� 11.7b 40.0� 12.8b 38.2� 12.1b 36.1� 12.2b 37.6� 12.7b

PP 45.2� 11.8 43.6� 12.2b 40.9� 11.7b 40.0� 12.9b 37.7� 12.0b 36.1� 12.2b 36.6� 12.4b

Total ITT 87.2� 22.5 83.0� 23.3b 78.8� 22.3b 77.6� 23.8b 74.1� 22.9b 69.6� 22.9b 72.5� 24.1b

PP 88.4� 22.1 85.1� 22.8b 79.9� 22.1b 77.6� 23.9b 73.2� 22.5b 69.6� 22.9b 70.6� 23.1b

PANSS¼Positive and Negative Syndrome Scale.ITT¼ Intention To Treat population.PP¼Per Protocol Population.aScores are expressed as mean�SD.bWilcoxon Signed–Rank Test, p< 0.001, shifts versus baseline.

578 a. rossi ET AL.

versus baseline in DAI30 total scores observed atweek 12 and thereafter up to week 52 (baseline, n¼215, 42.6� 5.1; week 12, n¼ 199, 43.7� 5.1; week52, n¼ 180, 43.7� 5.5; PP population, p< 0.05). Thisimprovement was also observed in both Attitudetowards Medication (baseline, 18.7� 2.5; week 12,n¼ 199, 19.1� 2.4; week 52, 19.2� 2.6; PP population,p< 0.05) and Subjective Response DAI30 scores(baseline, 23.9� 3.2; week 12, n¼ 199, 24.6� 3.2;week 52, 24.5� 3.5; PP population, p< 0.05).In the PP population (n¼ 243), the PANSS severity

criteria for remission, measured at each time point,were met by 35 patients (14.4%) at baseline and by 110patients (45.3%) at week 52 (Figure 2). Additionally,22 of 35 patients (62.9%) who met the severity criteria

Figure 1. Improvement of symptoms when patients were stratified according to thnot differ significantly between patients taking different final RLAI doses (Kruskalbetween patients taking different final RLAI doses (Kruskal–Wallis test; p¼ 0.0


at baseline also met them at week 52. The number ofpatients who met sustained remission (both severityand duration criteria) increased from 22 (9.1%) atweek 26 to 77 (31.7%) at week 52 (Figure 2). Of the208 patients who did not meet the severity criteria atbaseline, 88 (42%) met them at week 52, and 55(26.4%) reached and maintained sustained remission(both severity and duration) at week 52.Treatment completers (PP population) who remitted

during the study had significantly lower baselinePANSS total scores than did non-remitted patients(Wilcoxon Rank–Sum Test, z¼�6.9, p< 0.001;Table 3). In the Table 3 are reported the clinicalfindings of remitted patients compared with non-remitted patients that showed a worse baseline clinical

e final RLAI dose (25, 37.5, or 50mg). A, Change in PANSS total scores did–Wallis test; p> 0.05). B, Baseline PANSS total scores differed significantly12)


Figure 2. Percentage of patients (PP population n¼ 243) who met remission criteria at each time point. The number of patients who met severity criteria orwho met both severity and duration criteria at each time point is indicated above each bar


profile. The difference in baseline CGI-S and GAFscores between groups was statistically significant(Wilcoxon Rank–Sum Test, p< 0.001) with moresevere scores in the non-remitting population (Table 3).Baseline DAI30 scores did not differ between groups,although the change in DAI30 scores (i.e. frombaseline to week 52) was significantly (p< 0.05)greater among remitted patients versus non-remittedpatients (Table 3).In a logistic regression model, baseline PANSS posi-

tive and negative scores were the strongest predictivefactors for remission, representing 13% and 14%,respectively, of the explained variance (p< 0.001)with less severe scores predicting remission (Table 4).

Table 3. PANSS, CGI-S, GAF and total DAI30 scores at baseline andDAI30 change between baseline and week 52 in remitted patients versusnon-remitted patientsa (PP population)

bNon-remittedpatients (n¼ 166)

Remittedpatients (n¼ 77)

PANSS Total 94.7� 19.6 74.6� 20.9d

PANSS Positive 19.5� 5.5 14.8� 6.2d

PANSS Negative 27.5� 6.9 20.2� 7.4d

PANSS Cognitivecluster score

23.1� 6.2 18.3� 6.7d

PANSS Insight item G12 3.5� 1.5 2.8� 1.4d

PANSS GeneralPsychopathology

47.7� 11.5 39.6� 10.5d

CGI-S 4.7� 0.8 4.3� 0.9d

GAF 46.5� 10.2 54.6� 11.4d

DAI30 Total 42.5� 5.0 (n¼ 152) 43.0� 5.5 (n¼ 63)DAI30 changec 0.51� 4.9 (n¼ 115) 2.70� 5.3 (n¼ 53)e

aData are expressed as mean�SD.b110 patients out of 166 at the end of 52 weeks reached severity remissioncriteria only, but not duration. The examination of the variables assessed forthis group showed intermediated values between ‘remitted’ (i.e. betterprofile) and ‘non-remitted’ (n¼ 56) with worse profile (ANOVA Krus-kal–Wallis analysis).cDAI30 change¼ from baseline to week 52.dWilcoxon Rank–Sum Test, p< 0.001 versus non-remitted patients.eWilcoxon Rank–Sum Test, p< 0.05 versus non-remitted patients.


This means that even removing ‘PANSS remissioncriteria’ from the prediction, severity of symptoms stillhave a role in the remission prediction.A total of ten patients (2.9%) discontinued RLAI

treatment due to insufficient response. Half of thesepatients were receiving the 37.5mg dose at the time ofleaving the trial, while the remainder were receivingthe 50mg dose.

Safety and tolerability

A total of 347 patients were treated and included in thesafety analysis. Treatment with RLAI was welltolerated: 30.2% of patients experienced one or moretreatment-emergent AEs during the 52-week treatmentperiod. The majority of these events were considered tobe mild (51.9%) or moderate (37.7%) in severity, and81.0% of these events required no change in studytreatment. Table 5 lists the most frequently reportedtreatment-emergent AEs that occurred in� 5% ofpatients. Treatment-emergent endocrine-related AEswere reported by 18 patients (7.7%; mainly amenor-rhea, galactorrhea and impotence). Only 11 patients(3.2%) discontinued treatment due to a reportedtreatment-emergent adverse event, with extrapyrami-dal symptoms (4/11) as the most frequently reportedreason for discontinuation.Four per cent of patients (n¼ 14) were hospitalized

due to a psychotic exacerbation during one-year followup.One patient died during the study due to suicide,

which was considered by the investigator to beunrelated to treatment with RLAI. This patient hadreceived 4 injections of the 25mg dose before death.There were no clinically significant changes in vitalsigns over the 52-week study period. Overall, there wasno significant increase in mean body weight from


Table 4. Predictive factors for remission by a logistic regression

Regression Model

Predictors b S.E. Wald df Sig. Exp(B)

95% CI for Exp (B)

lower upper

PANSS Positive (baseline) �.193 .065 8.784 1 .003 .824 .725 .937PANSS Negative (baseline) �.210 .060 12.348 1 .000 .811 .721 .911

aSex �.542 .382 2.008 1 .156 .582 .275 1.231PANSS General Psychopathology (baseline) .023 .029 .659 1 .417 1.024 .968 1.083DAI30 (baseline) �.025 .037 .463 1 .496 .975 .907 1.049Age (years) �.023 .021 1.209 1 .271 .977 .939 1.018GAF (baseline) .030 .027 1.251 1 .263 1.030 .978 1.085Age onset first symptoms (years) .010 .022 .218 1 .640 1.010 .968 1.054CGI-C (baseline) �.064 .293 .048 1 .826 .938 .528 1.666

Binomial Logistic Regression used to model the value of a dependent variable ‘Remission’ based on its relationship to predictors.The regression model explained cumulatively 35% of the variation.Considering the diagnosis as variable of stratification in the Binomial Logistic Regression significative differences were not observed between the two groups(schizophrenic vs. schizoaffective patients).S.E.: standard error.aDummy variable: male gender was scored 1

Table 5. Treatment-emergent adverse events occurring in � 5% ofpatients

N %

Any adverse event 105 30.2Exacerbation of disease 23 9.9Endocrine-related 18 7.7Extrapyramidal symptoms 17 7.3Insomnia 14 6.0Cardiovascular disorders 13 5.6Respiratory disorders 13 5.6Mood disorders 12 5.1

580 a. rossi ET AL.

baseline (81.3� 16.1 kg) to week 52 (82.1� 16.5 kg,paired t-test; p¼ 0.093) and in mean BMI(28.7� 5.5 kg/m2 vs. 28.9� 5.4 kg/m2; p¼ 0.102). Aweight increase of greater than or equal to 5% wasobserved in 15.3%of patients.

DISCUSSION

The main finding of this clinical trial is that one-yeartreatment with RLAI is associated with sustainedantipsychotic efficacy and also with a reduction in theseverity of symptoms, as demonstrated by the signi-ficant improvements in PANSS total and subscalesscores, CGI-S and -C scores and psychosocial variablessuch as patients’ overall functional capacity andtreatment choice acceptance as assessed by physiciansin the GAF and by patients in the DAI-30 ques-tionnaire. These results are further supported by thehigh completion rate (70%) and the very low (3.2%)dropout rate due to AEs.Furthermore, these improvements were obtained

without treating patients with the highest available


RLAI dose. Indeed, at the treatment endpoint, morethan 70% of patients were receiving the 25 or 37.5mgdose. At the end of our study, there were no differencesin the degree of PANSS improvement among thosetaking 25, 37.5 or 50mg doses, each group represent-ing about one-third of all patients studied. Although wedid not evaluate the response per dose per baselinePANSS subgroup, it could be suggested that at leastone-third of patients did not need an increase in theirdrug regimen to obtain a satisfactory response, andonly one-third of patients needed the 50mg dose toreach a similar response. In so far as these groupsdiffered in their baseline PANSS score, it isconceivable that patients with more severe symptomsat baseline (i.e. higher baseline total PANSS score)needed a higher drug dosage to achieve improvementssimilar to those attained by patients with better baselinePANSS scores.Beyond the maintenance of antipsychotic efficacy

and safety, the achievement of remission is considereda more stringent outcome measure. Recently, an expertconsensus definition of remission in schizophrenia wasproposed along with specific operational criteria for theattainment of remission. (Andreasen et al., 2005).In our study, we report that of the 208 patients who

did not meet the severity criteria for remission atbaseline, 26% achieved the severity and durationcriteria at the end of the 52-week study period. This isin line with Lasser et al. (2005) who showed that 21%of non-remitted patients at baseline were able toachieve symptom remission for at least 6 months aftertreatment with RLAI. Moreover, our data collectedprospectively showed that one-third (32%) of patientswho completed the 52-week study period reached and



maintained remission over a one-year treatment periodwith RLAI and this is slightly different from studies byKissling et al. (2005) and Helldin et al. (2007). Anexplanation for this difference may be that our sampleis more severely ill which is indicated by the high rateof admissions in the last 6 months before inclusion andby higher PANSS total score at baseline. A muchhigher remission rate (64%) has been recently reportedby Emsley et al. (2008a; 2008b) in a 2-year prospectivetrial in first-episode schizophrenia patients. One reasonproposed by Emsley et al. for this finding is that earlypsychotic subjects are known to respond morefavourably to antipsychotic treatment.In our study, baseline PANSS positive and negative

scores were the best predictors of remission (i.e. lesssevere scores predicted higher remission). This is notan unexpected finding as Docherty et al. (2007) using asimilar model also showed that lower CGI severityscores predicted remission. Indeed, comparison ofbaseline characteristics between remitters and non-remitters revealed that patients with less severity in abroad range of clinical features at baseline, such assymptoms, health status and functionality, were morelikely to reach remission.In so far as we removed ‘PANSS remission criteria’

from the predictors, severity of symptoms still have arole in the remission prediction. Because factoranalysis demonstrates that several symptoms domainsare correlated, this is a not surprising finding. Howeverthis finding add some evidence to the ‘a prioriconstruct’ of remission of the Andreasen et al.(2005): if the 8 proposed items for ‘RemissionCriteria’ could be an innovative approach to facilitateresearch and treatment, severity of symptom as a wholehave also to be taken into account.Furthermore, we report an overall improvement in

the personal attitude towards medication, as demon-strated by the significant increase in DAI30 total scorewith RLAI treatment from month 3 onwards. Thispattern of improvement was also confirmed in bothAttitude towards Medication and Subjective ResponseDAI30 subscale scores. DAI30 change correlatedsignificantly with GAF and PANSS positive changes,suggesting that robust clinical improvement canmodify personal opinion about therapy and this inturn may motivate patients to continue treatment.Indeed, remitted patients had a significantly greaterchange in DAI30 scores compared with non-remitters.These results are in agreement with those of Dochertyet al. (2007) where the substantial improvement inpatient-rated drug attitude can be viewed as supportingthe validity of the remission criteria and as a relevantmeasure of moving toward a state of wellness.


A further relevant finding is the good tolerabilityprofile of RLAI. Only 3.2% of patients withdrew fromthe study due to an adverse event, which is in line withthe 3% rate reported in a 12-month study by Kisslinget al. (2005). Furthermore, in our study, one-third ofpatients experienced one or more adverse event duringthe 52-week treatment period. This compares favour-ably with adverse event rates of 69–72% reportedpreviously in similar trials (Kissling et al., 2005; Llorcaet al., 2008).Additionally, no significant weight gain (mean

increase 0.8 kg, p¼ 0.093) was seen after one yearof RLAI treatment, although a possible explanation forthe less-than-expected weight gain could be that a largenumber of patients had experienced most of theirweight gain due to prior medication before switching toRLAI. However, the significant mean weight gains of0.9, 1.4 and 1.0 kg reported, respectively, by Molleret al. (2005), Kissling et al. (2005) and Llorca et al.(2008) insimilar patient populations and study designsunderline the benefit of our positive findings. Lastly,movement disorders were reported as a treatment-emergent adverse event by 7.3% patients. Togetherthese results underscore the low discontinuation rate at12 months, which are consistent with the rates of 30%reported by Kissling et al. (2005) and Llorca et al.(2008). The good tolerability and safety profile ofRLAI may lead to better compliance with therapy andreduced risk of relapse.

CONCLUSIONS

Despite limitation of the open-label design of thisstudy, we report a similar improvement in efficacy witha good safety profile to that reported in previously RCTprogramme involving over 2000 psychotic patientstreated with RLAI (Kane et al., 2003; Chue et al., 2005;Keks et al., 2007).Our result supports that remission is an achievable

condition for a significant portion of the patientpopulation with schizophrenia. Our results add anaturalistic perspective to previously reported data (DeHert et al., 2007). Other clinical factors leading to non-remission and likely to a more severe clinical pictureshould be further explored as potential therapeutictargets. For example, continuing treatment and follow-up beyond the one-year period could lead to increasedremission and possibly other additional benefits. Inlight of the high rate of medication discontinuation of74% reported in the CATIE study at 18 months(Lieberman et al., 2005), our 70% completion rate afterone year of treatment with a long-acting injectable drug


582 a. rossi ET AL.

is encouraging. As a practical point, the clinician iswell advised to consider with care whether the patientshould continue or switch treatment regimens (Daviset al., 2006). As continuing treatment for up to one yearproduces a slight but constant improvement, carefulobservation of an active treatment may be a wiserapproach than an urgent pressure to switch.The aim of our study was to apply the Andresean

remission criteria in a prospective way. The discussionof the Andreasen criteria is beyond the scope of thepresent paper and in any case the scientific literaturereports a favourable acceptance of the above men-tioned criteria (Van Os et al., 2006) even though withsome criticism (Remington and Kapur, 2005).Of course this is not the solution to all problems in

this area but ‘ . . . acceptance, refinement and use ofthese criteria should help to facilitate comparisons ofeffectiveness across the range of available therapeuticoptions . . .’ (from Andreasen et al., 2005).

ACKNOWLEDGEMENTS

R-LAI investigators:Dr G. Bertolazzi, SPDC Isola della Scala (VR); Dr P.

Bianco, CSM (AV); Dr G. Biffi, CPS Bonate Sotto (BG);Prof. F. Bogetto, CSM ASL 01 (TO); Dr ssa D. Caporale,DSM ASL 5 Collegno Grugliasco (TO); Dr N. Capozza,CSM (KR); Dr R. Cappuccio, CSM S. Antimo (NA); Dr M.Carbone, CSM (SA); Dr A. Contu, CSM ASL 6 Sanluri(CA); Dr G. Corlito, DSM (GR); Dr A. Cucciniello, CSMASLNA 2Mugnano di Napoli (NA); Dr ssa A. Cumin, CSM(RI); Dr P. De Iorio, SPDC (PE); Dr M. De Vito, CSM42–43Mondragone (CE); Dr V. Del Curatolo, CSM Barletta (BA);Dr W. Di Munzio, CSM Inferiore (SA); Dr A. Erlicher,Psichiatria 1 Ospedale Niguarda (MI); Dr ssa A. Ferraro,DSM (TR); Dr B. Forti, CSM (BL); Dr ssa F.F. Foti, CSMPalmi (RC); Dr P. Galimberti, CSM ASL Roma G (RM); Drssa O. Gambini, SPDC S. Paolo (MI); Dr G. Giardina, CSM(TA); Dr M. Grignani, SPDC A.O. di (PG); Dr ssa O. Grillo,CSM Novi Ligure (AL); Dr G. Interlandi, DSM Caltagirone(CT); Dr ssa C. Ionio, CSM (RA); Dr L. Lalicata, CSMCanicattı (AG); Dr V. Maffei, CSM (BA); Dr G. Malara,SPDC Ospedali Riuniti (RC); Dr E. Marchi, DSM (LU); DrC. Munizza, SPDC Ospedale Giovanni Bosco (TO); Dr G.Nuvoli, U.O. Salute Mentale 5 ASL 3 (GE); Dr R. Parravani,CSMASL Roma B (RM); Dr A. Pezzoli, DSMASL BO SudCasalecchio di Reno (BO); Dr E. Pirfo, DSM OspedaleAmedeo di Savoia (TO); Dr ssa V. Quattrocchi, DSMEmpoli (FI); Dr F. Ramaciotti, DSM Canareggio (VE);Dr E. Re Psichiatria 2 Ospedale Niguarda (MI); Dr G.Reggiani, CSM Gatteo (FC); Dr O. Rinaldi e Prof. A. Rossi,Centro Coordinatore, Unita Operativa Psicologia, Villa Ser-ena, Citta S. Angelo (PE); Dr A. Sbardella, SPDC OspedaleS. Filippo Neri (RM);Dr F. Selvaggio, CSM Gravina diCatania (CT); Dr S. Tagliamonte, CSM di Catanzaro Lido


(CZ); Dr ssa A.L. Todeschini, CSM Schio (VI); Dr R.Venanzini, DSM Fano (PS); Prof. S. Vender, Ospedale S.Macchi (VA).The study was sponsored by Janssen-Cilag Spa Medical

Affairs ItalyAlessandro Rossi has received grants or honoraria as a

consultant from Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Innova Pharma, Pfizer, Sanofi, Shering-Plough.

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