ORIGINAL INVESTIGATION

Effectiveness of maintenance treatments with atypicaland typical antipsychotics in stable schizophreniawith early stage: 1-year naturalistic study

Xiaofeng Guo & Maosheng Fang & Jinguo Zhai & Bo Wang & Chuanyue Wang & Bin Hu &

Xueli Sun & Luxian Lv & Zheng Lu & Cui Ma & Tiansheng Guo & Shiping Xie &

Elizabeth W. Twamley & Hua Jin & Jingping Zhao

Received: 16 November 2010 /Accepted: 18 February 2011 /Published online: 3 March 2011# Springer-Verlag 2011

AbstractRationale The relative effectiveness of the atypical anti-psychotic drugs and conventional agents in patients withearly-stage schizophrenia has not been comprehensivelydetermined.Objectives The aim of our study was to evaluate theefficacy and safety of seven antipsychotic drugs for themaintenance treatment in patients with early-stageschizophrenia.

Methods In a 12-month open-label, prospective observa-tional, multicenter study, 1,133 subjects with schizo-phrenia or schizophreniform disorder within 5 years ofonset were monotherapy with chlorpromazine, sulpiride,clozapine, risperidone, olanzapine, quetiapine, or aripi-prazole. The primary measure was the rate of treatmentdiscontinuation for any reason. Secondary outcomesincluded measures for clinical and functional outcomesand tolerability.

Clinical Trials.gov Identifier: NCT00654576

Guo and Fang contributed equally to the study.

X. Guo :M. Fang : J. Zhai : J. Zhao (*)Institute of Mental Health, the Second Xiangya Hospital,Central South University,139 Renmin Middle Road,Changsha 410011 Hunan, People’s Republic of Chinae-mail: fengcsu@yahoo.com.cn

M. FangMental Health Center, Tongji Medical College of HuazhongUniversity of Science and Technology,Wuhan, China

B. WangChongqing Mental Health Center,Chongqing, China

C. WangBeijing Anding Hospital Affiliated to Capital Medical University,Beijing, China

B. HuPsychiatric Hospital of Jiangxi Province,Nanchang, China

X. SunMental Health Center of West China Hospital, Sichuan University,Chengdu, China

L. LvMental Hospital of Henan Province,Xinxiang, China

Z. LuShanghai Mental Health Center,Shanghai, China

C. MaGuangzhou Brain Hospital,Guangzhou, China

T. GuoHunan Brain Hospital,Changsha, China

S. XieNanjing Brain Hospital, Nanjing Medical University,Nanjing, China

E. W. Twamley :H. JinDepartment of Psychiatry, University of California,San Diego, USA

Psychopharmacology (2011) 216:475–484DOI 10.1007/s00213-011-2242-3

Results The percentage of patients discontinued treatmentwithin 12 months was 41.4% for chlorpromazine, 39.5% forsulpiride, 36.7% for clozapine, 40.2% for risperidone, 39.6%for olanzapine, 46.9% for quetiapine, and 40.2% for aripipra-zole, a nonsignificant difference (p=0.717); there were nosignificant differences among these seven treatments ondiscontinuation due to relapse, intolerability, patient decision,or nonadherence (all p values≥0.260). Extrapyramidalsymptoms were more prominent in chlorpromazine andsulpiride treatment groups. Anticholinergic side effects weremost common with clozapine and chlorpromazine. Weightgain was most common with olanzapine and clozapine.Conclusions The efficacy of seven antipsychotic medica-tions for the maintenance treatment appeared similar inearly-stage schizophrenia. With regard to the high dropoutrate and side effects, special programs are needed to keepefficacy and safety of antipsychotics maintenance treatmentfor schizophrenia with early stage

Keywords Antipsychotic . Schizophrenia . Safety

Introduction

Treatment of schizophrenia usually involves the long-termadministration of antipsychotic drugs. However, long-termtherapy with antipsychotics is generally associated with thelack of efficacy, poor patient compliance, and a range ofadverse effects including acute extrapyramidal symptoms,tardive dyskinesia, weight gain, and sedation. Theseadverse effects can interfere with long-term adherence tomaintenance drug therapy (Lieberman et al. 2003a).Atypical antipsychotic drugs have been proven lower riskof extrapyramidal symptoms, but higher risk of metabolicadverse events (Marder et al. 2003;Leucht et al. 2009a, b).The effectiveness of long-term therapy with typical andatypical antipsychotics in schizophrenia is not well under-stood, but some recent studies had sought to provideobjective evidence in real-world settings. One studycomparing haloperidol and risperidone in stable outpatientsfound advantages in preventing relapse for risperidone(Csernansky et al. 2002). The Schizophrenia OutpatientHealth Outcomes study shows that patients on clozapineand olanzapine have a lower risk of relapse and patients onolanzapine have a higher chance of remission than typicalantipsychotics (Haro et al. 2006). Results of the ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE)have been found no differences in drug discontinuationrates between typical and atypical drug in chronic schizo-phrenia patients (Lieberman et al. 2005). Comparison ofatypicals in first episode of psychosis found atypicalantipsychotics (quetiapine, risperidone, and olanzapine)had equal effectiveness in first episode schizophrenia

(McEvoy et al. 2007). The new result of European First-Episode Schizophrenia Trial showed all atypical antipsy-chotics better than haloperidol in loss of retention on drug(Kahn et al. 2008).

Schizophrenic patients require long-term antipsychoticmaintenance treatment, but studies of maintenance treat-ment with antipsychotic drugs in the early stage of stableschizophrenia are scarce, especially some typical antipsy-chotics (e.g., chlorpromazine and sulpiride) and clozapineused widely in developing countries(Si et al. 2004; Mao etal. 2007). Patients with early-stage schizophrenia are likelyto be more sensitive to drugs than are those with chronicones. Moreover, trials of drugs in chronic patients wereusually conducted in highly selected samples, so findingshave no external validity.

We undertook an open-label, prospective observational,multicenter study to determine if any of seven antipsychotics(chlorpromazine hydrochloride, sulpiride, clozapine, risper-idone, olanzapine, quetiapine fumarate, and aripiprazole)maintenance treatment was more effective in stable out-patients with schizophrenia or schizophreniform disorder, andwhether atypical antipsychotics had an advantage over typicalantipsychotics. We selected these antipsychotics because over90% of schizophrenia patients in China were prescribed oneof these antipsychotics (Si et al. 2004).

Methods

Participants

The study was conducted between January 2005 andOctober 2007 at ten clinical sites in China (six universityclinics and four province mental health agencies). Studyparticipants were enrolled from outpatient psychiatricclinics and included in the study if they met the followingcriteria: (1) were age 16–50 years; (2) met the Diagnosticand Statistical Manual, Fourth Edition (DSM-IV) criteriafor schizophrenia or schizophreniform disorder within thepast five years, as assessed with the Structured ClinicalInterview for DSM-IV, Research Version; (3) lived withfamily members who could be involved in the patients’care; (4) had relatively stable improvement (Positive andNegative Syndrome Scale (PANSS) (Kay et al. 1987) totalscores were≤60); (5) treated with only one of the followingseven oral antipsychotics: chlorpromazine, sulpiride, cloza-pine, risperidone, olanzapine, quetiapine, or aripiprazole forat least 8 weeks, provided that the dose had remained stableduring the 4 weeks before screening. Patients wereexcluded if they were: (1) prescribed two or moreantipsychotics or long-acting injectable antipsychotics; (2)had treatment-refractory illness according to Kane’s criteria(Kane et al. 1988), as evidenced by continued psychosis

476 Psychopharmacology (2011) 216:475–484

despite two previous trials of conventional neuroleptics atdosages of at least 1,000 mg of chlorpromazine equivalentsa day for at least 6 weeks; (3) pregnant or breastfeeding; (4)diagnosed with a serious and unstable medical condition; or(5)participating in other therapy programs.

Study design

This was a 12-month open-label, naturalistic, flexible-dose,multicenter study of antipsychotic medications used fortreatment of early course of schizophrenia. Patients initiatedor switched to one of study antipsychotic drugs beforescreening were potential candidates for the study. If patientsentered a stabilization period and met our study criteria,they were invited to participate in this 12-month mainte-nance treatment study.

The study was approved by the institutional reviewboard at each site, and a written informed consent wasobtained from the patients and their legal guardians.

Interventions

Since all patients were on maintenance treatment, weencouraged clinicians to try to keep patients on the samemedication for 3 to 6 months in order to gauge treatmentefficacy and minimize early discontinuation. However,medications could be changed at any time during thecourse of the study if the change was clinically warranted.If a patient’s medication was stopped or switched, patientswere classified as discontinued and terminated from thestudy. No further assessments were required for thesepatients. During the 12-month follow-up study, the dailydoses of antipsychotics was set: chlorpromazine hydrochlo-ride 200 to 800 mg, sulpiride 200 to 1,200 mg, clozapine100 to 450 mg, risperidone 1.5 to 6 mg, olanzapine 5 to20 mg, quetiapine fumarate 200 to 750 mg, and aripiprazole5 to 30 mg. Mood stabilizers, benzodiazepines, antidepres-sants, and anticholinergic medications were permitted, anddaily doses of all medications were recorded throughout thestudy.

Outcome measures

All subjects were assessed monthly by the study psychia-trists and every 2 weeks by a research assistant who hadinstructions to contact the psychiatrist if medicationdiscontinuation, relapse or other problems were suspected.The primary outcome measure was rate of treatmentdiscontinuation or change and time to treatment discontin-uation. Our criteria for treatment discontinuation or changewere somewhat broader than those of the CATIE study(Lieberman et al. 2005) and included: (1) clinical relapse/hospital admission, (2) patient’s refusal or lost to follow-up,

(3) noncompliance or changing initial antipsychotic, and (4)intolerability. When investigators recorded more than onereason for discontinuation, we ranked the reasons: clinicalrelapse/hospital admission, intolerability, noncompliance orchanging initial antipsychotic, and other reasons.

Clinical relapse was defined by any one of the following(Csernansky et al. 2002): (1) psychiatric hospitalization, (2)an increase in the level of psychiatric care (e.g., from clinicvisits to day treatment) and a 25% or more increase in thePANSS total score (or 10 points if the initial score was 40or less), (3) a Clinical Global Impressions (CGI) Scalescore of “much worse” or “very much worse” (Guy 1976a),(4) deliberate self-injury, (5) emergence of clinicallysignificant suicidal or homicidal ideation, or (6) violentbehavior resulting in significant injury to another person orsignificant property damage.

Secondary outcomes further assessed treatment effec-tiveness by measuring symptom severity (PANSS) andCGI, insight (Insight and Treatment Attitudes Question-naire (ITAQ) McEvoy et al. 1989), treatment adherence(appointment compliance), and social function on theGlobal Assessment Scale (GAS) Guy 1976b; Endicott etal. 1976).The physical examination and the effect ofantipsychotic treatment on weight gain were recordedregularly. The tolerability and adverse events was assessedby Treatment Emergent Symptom Scale (Guy 1976c) andthe Simpson–Angus Extrapyramidal Signs Scale (Simpsonand Angus 1970).

Data collected at baseline and after 3, 6, 9, and12 months of study participation, as well as thetreatment discontinuation.

All interviewers trained and received reassessments ofinter-rater reliability based on videotaped demonstrationinterviews. Agreement among the raters was high for thePANSS, CGI (Pearson’s correlation coefficient=0.78 to0.86) at baseline, and every 6 months.

Statistical analyses

All analyses were conducted with the Statistical Packagefor Social Sciences, version 15.0 (SPSS Inc, Chicago,Illinois). Assuming a treatment discontinuation rate at12-month follow-up, of 50% in patients receiving first-generation antipsychotic drugs and 40% in patients receiv-ing second-generation antipsychotic drugs, 136 patients pertreatment group were needed, on the basis of a two-tailedtest with α=5% and 1-β=80%. Therefore, we planned toenroll 150 patients per group. The seven treatment regimenswere compared at baseline for continuous parameters with asix degree of freedom analysis of variance (ANOVA) test.Groups were compared for baseline categorical outcomeswith Pearson’s Chi-square (χ2) test, Kruskal–Wallis H test,or Fisher’s exact test.

Psychopharmacology (2011) 216:475–484 477

The primary outcome measure was analyzed usingPearson’s χ2 test and Kaplan–Meier survival analysis(comparing the treatment groups with a log-rank test),considering all eligible patients.

The continuous (secondary) outcome measures used theintention-to-treat population included all eligible patientswith at least one follow-up test. Missing data of patientsdiscontinuing were replaced by the last-observation carried-forward. Changes within groups were analyzed usingWithin-sample t tests (paired t tests). Treatment regimenswere compared for change from baseline for PANSS, CGI-S, ITAQ, and GAS total scores at 12 months using ananalysis of covariance (ANCOVA) with adjustment for thebaseline value. Other categorical outcomes were comparedwith the use of Pearson’s χ2 test or Fisher’s exact test.

Partitions of χ2 methods were performed comparing thedata between each treatment group if overall χ2 p valuewere more than 0.05. We adjusted the alpha levels in thefollowing way, α*=α/[k(k-1)/2+1]=0.05/[7*(7–1)/2+1]=0.0023, according to Brunden (Brunden 1972) and Bortz(Bortz et al. 1990).

Results

Patients disposition and baseline characteristics

A total of 1,661 potentially eligible subjects were screened.Of these subjects, 1,133 patients completed the baselineassessment (Fig. 1).

The mean age of eligible subjects was 26.1 years(SD, 7.7), 45.6% were female, and most patients had adiagnosis of schizophrenia (85.0%; Table 1). There wereno significant differences among treatment groups in age,sex, education, marital status, diagnostic composition,number of episodes, duration of illness, psychopathologyscores, or duration of study drug treatment beforescreening (all p values≥0.059). Differences in socio-economic status among groups was found (p<0.001).

Discontinuation of treatment

Discontinuation outcomes were presented in Table 2.Four hundred fifty-nine of the 1,133 patients (40.5%)discontinued treatment before completion of the study.The mean treatment duration was 8.9 months, whichcorresponds to an average of 75% of the maximumpossible participation time. The percentage of patientsdiscontinued treatment for any cause within 12 monthswas 41.4% for chlorpromazine, 39.5% for sulpiride,36.7% for clozapine, 40.2% for risperidone, 39.6% forolanzapine, 46.9% for quetiapine, and 40.2% for aripipra-zole, a nonsignificant difference (p=0.717). The time todiscontinuation for any reason using the log-rank testshowed no difference between groups (p=0.667).

Compliance, insight, efficacy, and social function

The proportion of visit “always or almost always” adherancewas 60.9% for chlorpromazine (n=92), 67.3% for sulpiride

Chlorpromazine

N=169

Sulpiride

N=162

Clozapine

N=177

Discontinued, N=65

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=7

Discontinued, N=64

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other,

Discontinued, N=70

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=7

Completed study

N=99

Completed study

N=98

Completed study

N=112

Screened N=1661

Baseline N=1133

Excluded Did not meet study criteria N=304

Refused to participate

Had other reasons

Risperidone

N=199

Olanzapine

N=149

Quetiapine

N=145

Aripiprazole

N=132

Discontinued, N=80

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=7

Discontinued, N=59

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=6

Discontinued, N=68

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=6

Discontinued, N=53

Relapse,

Patient decision or lost

to follow-up,

Intolerability,

Other, N=4

Completed study

N=119

Completed study

N=90

Completed study

N=79

Completed study

N=77

N=37

N=20

N=6

N=35

N=19

N=4

N=6

N=27

N=23

N=8

N=35

N=26

N=12

N=23

N=20

N=10 N=6

N=21

N=35 N=22

N=22

N=5

N=132

N=92

N=528

Fig. 1 Flow diagram for 12-month follow-up

478 Psychopharmacology (2011) 216:475–484

(n=101), 63.3% for clozapine (n=100), 62.2% for risper-idone (n=115), 62.6% for olanzapine (n=87), 57.6% forquetiapine (n=72), and 62.0% for aripiprazole (n=75), therewas no significant difference between treatment groups (χ2=3.823, p=0.701).

The results of the PANSS, CGI-S, ITAQ, and GASanalyses were presented in Table 3. Using a within-sample ttest for change on the PANSS, CGI-S, ITAQ, and GAS

score from baseline, all of treatments were associated withsignificant improvement at 12 months (all p values<0.01).

The PANSS, CGI-S, and ITAQ total score changes at12 months showed no significant differences amongtreatment groups using ANCOVA (p values≥0.054). Thechange of GAS score from baseline to 12 months werehigher in clozapine, risperdone, and aripiprazole group thanchlorpromazine group (p values≤0.001).

Table 1 Baseline demographic and clinical characteristics of all eligible patients

Sample characteristics Treatment groups

Chlorpromazine(N=169)

Sulpiride(N=162)

Clozapine(N=177)

Risperidone(N=199)

Olanzapine(N=149)

Quetiapine(N=145)

Aripiprazole(N=132)

p

Age (mean (SD), year) 27.3 (7.7) 25.6 (7.4) 25.6 (7.2) 26.3 (7.8) 25.5 (7.3) 26.2 (8.1) 26.0 (8.2) 0.337

Gender (female, N (%)) 83 (49.1) 80 (49.4) 71 (40.1) 90 (45.2) 63 (42.3) 68 (46.9) 62 (47.0) 0.571

Education (less than highschool, N (%))

40 (23.7) 42 (25.9) 46 (26.0) 60 (30.2) 36 (24.2) 35 (24.1) 41 (31.1) 0.629

Marital status (N (%)) 0.703

Married 43 (25.4) 48 (29.6) 42 (23.7) 57 (28.6) 37 (24.8) 39 (26.9) 31 (23.5)

Never married 115 (68.0) 107 (66.0) 121 (68.4) 131 (65.8) 106 (71.1) 101 (69.7) 97 (73.5)

Widowed, divorced, orseparated

11 (6.5) 7 (4.3) 14 (7.9) 11 (5.5) 6 (4.0) 5 (3.4) 4 (3.0)

Socio-economic status (N (%)) <0.001

Bad 55 (32.5) 43 (26.5) 33 (18.6) 18 (9.0) 7 (4.7) 4 (2.8) 16 (12.1)

Good 102 (60.4) 106 (65.4) 113 (63.8) 129 (64.8) 75 (50.3) 84 (57.9) 89 (67.4)

Very good 12 (7.1) 13 (8.0) 31 (17.5) 52 (26.1) 67 (45.0) 57 (39.3) 27 (20.5)

DSM-IV diagnosis (N (%)) 0.408

Schizophrenia 149 (88.2) 137 (84.6) 155 (87.6) 173 (86.9) 123 (82.6) 119 (82.1) 107 (81.1)

Schizophreniform disorder 20 (11.8) 25 (15.4) 22 (12.4) 26 (13.1) 26 (17.4) 26 (17.9) 25 (18.9)

Number of episodes 1.7 (0.9) 1.7 (0.9) 1.7 (1.0) 1.5 (0.8) 1.5 (0.8) 1.5 (0.8) 1.6 (1.0) 0.095

Duration of schizophrenia(mean (SD), months)

20.5 (19.7) 23.7 (19.6) 25.6 (19.0) 23.6 (18.5) 20.1 (19.0) 22.7 (20.4) 20.7 (19.5) 0.085

PANSS total score(mean(SD))

45.5 (13.3) 45.3 (14.2) 45.3 (11.0) 44.2 (11.6) 42.2 (11.8) 43.0 (11.2) 46.1 (12.4) 0.063

CGI-S score (mean (SD)) 2.5 (1.2) 2.7 (1.4) 2.6 (1.2) 2.4 (1.1) 2.4 (0.9) 2.5 (1.0) 2.7 (1.3) 0.123

ITAQ score (mean (SD)) 12.2 (5.0) 13.0 (5.5) 12.7 (5.7) 12.3 (5.5) 12.8 (5.2) 13.0 (5.4) 12.4 (6.0) 0.766

GAS score (mean (SD)) 75.8 (9.7) 75.1 (11.5) 73.9 (11.2) 74.6 (12.3) 74.0 (11.1) 75.0 (10.6) 72.4 (11.2) 0.059

Study drug dose(mean (SD), mg/d)

334.7 (140.3) 724.3 (252.0) 266.5 (112.3) 3.6 (1.3) 12.1 (5.2) 516.8 (234.5) 18.6 (7.5) N/A

Duration of study drugtreatment beforescreening (mean (SD),weeks)

11.3 (2.5) 11.4 (2.5) 11.2 (2.5) 11.1 (3.1) 11.7 (2.3) 11.7 (2.4) 11.4 (2.0) 0.302

Simpson–Angus: EPS meanscore (mean (SD))

0.2 (0.3) 0.1 (0.2) 0.1 (0.2) 0.1 (0.2) 0.1 (0.2) 0.1 (0.2) 0.1 (0.1) <0.001

Weight (mean (SD), lb) 135.9 (25.2) 132.2 (21.1) 140.6 (21.8) 138.4 (22.4) 140.7 (22.7) 136.5 (21.3) 134.5 (24.4) 0.009

Body mass index(mean (SD), kg/m2)

22.7 (3.5) 22.0 (3.5) 23.0 (3.3) 22.9 (3.4) 23.4 (3.5) 22.7 (3.2) 22.3 (3.6) 0.018

Data are presented as mean (SD) unless otherwise indicated. Percentages may not sum up to 100 because of rounding

DSM-IV the Diagnostic and Statistical Manual, Fourth Edition, PANSS Positive and Negative Syndrome Scale, CGI-S Clinical Global ImpressionsSeverity of Illness Rating Scale, EPS extrapyramidal symptoms, ITAQ Insight and Treatment Attitudes Questionnaire, GAS the Global AssessmentScale, N/A not applicable

Psychopharmacology (2011) 216:475–484 479

Table 2 Frequencies and reasons for treatment discontinuation of treatment groups during 12-month follow-up

Frequencies and reasons Chlorpromazine(N=169)

Sulpiride(N=162)

Clozapine(N=177)

Risperidone(N=199)

Olanzapine(N=149)

Quetiapine(N=145)

Aripiprazole(N=132)

p

Discontinuation for any cause 70 (41.4) 64 (39.5) 65 (36.7) 80 (40.2) 59 (39.6) 68 (46.9) 53 (40.2) 0.717

Due to relapse 37 (21.9) 35 (21.6) 27 (15.3) 35 (17.6) 23 (15.4) 35 (24.1) 22 (16.7) 0.260

Due to intolerability 6 (3.6) 4 (2.5) 8 (4.5) 12 (6.0) 10 (6.7) 6 (4.1) 5 (3.8) 0.558

Due to patient decision or lostto follow-up

20 (11.8) 19 (11.7) 23 (13.0) 26 (13.1) 20 (13.4) 21 (14.5) 22 (16.7) 0.905

Due to nonadherence orchanging initialantipsychotic

7 (4.1) 6 (3.7) 7 (4.0) 7 (3.5) 6 (4.0) 6 (4.1) 4 (3.0) 0.999

Kaplan–Meier estimated timeto treatment discontinuation(25% percentile (95%CI),months)

6.0 (3.3–7.7) 6.0 (3.3–7.7) 6.0 (3.8–8.2) 6.0 (3.3–7.7) 6.0 (3.1–7.9) 4.0 (2.7–5.3) 6.0 (3.7–7.3) 0.667

Treatment duration (mean(SD), months)

8.9 (3.8) 9.0 (3.7) 9.2 (3.7) 9.0 (3.7) 8.8 (3.9) 8.4 (4.2) 9.0 (3.8) 0.597

Readmission to psychiatryhospital

20 (11.8) 14 (8.6) 14 (7.9) 19 (9.5) 10 (6.7) 18 (12.4) 7 (5.3) 0.300

Data shown as number (percentage) of patients experiencing events unless otherwise indicated. Group differences are based on a six df test of themain effect of treatment in an ANOVA for duration, from a Chi-squared test for categorical outcomes, and from a log-rank test for time todiscontinuation

CI confidence interval

Table 3 Intent-to-treat sample: symptom, insight, and social function of treatment groups during 12-month follow-up

Chlorpromazine (N=151) Sulpiride(N=150)

Clozapine(N=158)

Risperidone(N=185)

Olanzapine(N=139)

Quetiapine(N=125)

Aripiprazole(N=121)

pa

PANSS score (mean (SD))

Baseline 45.1 (13.1) 44.6 (13.7) 45.0 (10.9) 44.0 (11.8) 42.3 (11.4) 42.2 (11.3) 45.6 (12.6) 0.057

Endpoint 42.6 (15.3) 39.7 (12.1) 40.1 (11.4) 38.1 (8.9) 36.8 (8.5) 40.2 (13.4) 38.9 (12.9) <0.001

Mean (SE) change −2.5 (1.5) −4.9 (1.2) −4.9 (1.0) −5.9 (1.0) −5.5 (0.9) −2.0 (1.1) −6.7 (1.2) 0.068

CGI-S score (mean (SD))

Baseline 2.5 (1.2) 2.7 (1.4) 2.6 (1.2) 2.4 (1.1) 2.3 (1.0) 2.5 (1.1) 2.7 (1.3) 0.105

Endpoint 2.2 (1.3) 1.9 (1.2) 2.1 (1.2) 1.9 (1.0) 1.7 (1.0) 2.0 (1.2) 1.8 (1.2) 0.005

Mean (SE) change −0.3 (0.1) −0.8 (0.1) −0.6 (0.1) −0.5 (0.1) −0.6 (0.1) −0.5 (0.1) −0.8 (0.1) 0.054

ITAQ score (mean (SD))

Baseline 12.3 (5.1) 13.3 (5.4) 12.7 (5.6) 12.4 (5.5) 12.9 (5.3) 13.1 (5.3) 12.5 (5.9) 0.706

Endpoint 15.6 (5.6) 16.6 (5.8) 16.8 (6.0) 16.2 (6.1) 16.9 (5.4) 16.4 (6.0) 16.2 (5.8) 0.589

Mean (SE) change 3.3 (0.5) 3.3 (0.5) 4.1 (0.5) 3.8 (0.5) 3.9 (0.5) 3.3 (0.6) 3.7 (0.6) 0.884

GAS score (mean (SD))

Baseline 75.2 (9.9) 75.3 (11.6) 73.5 (11.1) 74.7 (12.3) 74.0 (11.0) 74.0 (10.8) 72.0 (11.1) 0.224

Endpoint 76.4 (11.0) 79.1 (12.8) 78.8 (11.1) 81.0 (11.0) 78.9 (10.3) 78.6 (12.0) 78.7 (10.3) 0.027

Mean (SE) change 1.2 (0.9) 3.8 (0.9) 5.2 (0.9) 6.3 (0.8) 4.8 (0.7) 4.5 (0.9) 6.7 (1.0) <0.001b

Changes from baseline to endpoint within group based on within-sample t test are significant for PANSS total score, ITAQ score, and GAS score(all p values <0.01) in seven treatment groups

PANSS Positive and Negative Syndrome Scale, CGI-S Clinical Global Impressions Severity of Illness Rating Scale, ITAQ Insight and TreatmentAttitudes Questionnaire, GAS the Global Assessment Scalea p values are from a six df test of treatment based on ANOVA for baseline and ANCOVA for endpoint and change from baseline, adjusting forbaseline valueb Chlorpromazine vs clozapine, p=0.001; chlorpromazine vs risperidone, p<0.001; chlorpromazine vs aripiprazole, p<0.001

480 Psychopharmacology (2011) 216:475–484

Safety and tolerability

The incidence of at least one adverse event was lowest forariprprazole and highest for clozapine (72.0% vs. 91.0%;Table 4). The most frequent adverse events were anticholi-nergic side effects (dry mouth, constipation, and urinaryhestitancy), which were most common with clozapine (65.5%)and chlorpromazine (54.4%), lower for olanzapine (32.9%)

and aripiprazole (30.3%). Extrapyramidal side effects werehigher in chlorpromazine (42.0%) and sulpiride (41.4%) thanclozapine (8.5%), olanzapine (10.7%), quetapine (13.1%) andariprazole (24.2%), and higher in risperdone than clozapine,olanzapine and quetapine. The occurrence of sedation inpatients taking clozapine (47.5%), olazapine (41.6%), andquetiapine (41.4%) was higher than that in those takingrisperidone (24.1%) or aripiprazole (16.7%).

Table 4 Presence of adverse events associated with seven antipsychotics and concomitant medication during 12-month follow-up

Chlorpromazine(N=169)

Sulpiride(N=162)

Clozapine(N=177)

Risperidone(N=199)

Olanzapine(N=149)

Quetiapine(N=145)

Aripiprazole(N=132)

Overallp value

Adverse events

Hypersomnia and sleepinessa 57 (33.7) 46 (28.4) 84 (47.5) 48 (24.1) 62 (41.6) 60 (41.4) 22 (16.7) <0.001

Dry mouth, constipation, andurinary hestitancyb

92 (54.4) 80 (49.4) 116 (65.5) 84 (42.2) 49 (32.9) 55 (37.9) 40 (30.3) <0.001

Dizzinessc 27 (16.0) 16 (9.9) 28 (15.8) 25 (12.6) 10 (6.7) 22 (15.2) 9 (6.8) 0.026

Extrapyramidal symptomsd 71 (42.0) 67 (41.4) 15 (8.5) 65 (32.7) 16 (10.7) 19 (13.1) 32 (24.2) <0.001

Menstrual irregularitiese 12 (14.5) 15 (18.8) 12 (16.9) 20 (22.2) 10 (15.9) 7 (10.3) 5 (8.1) 0.247

Weight gain, >7%f 30 (17.8) 34 (21.0) 42 (23.7) 42 (21.1) 55 (36.9) 25 (17.2) 25 (18.9) 0.001

Weight gain from last to baselineobservation (mean (SE), lb)g

4.2 (0.8) 4.1 (1.0) 6.6 (1.0) 4.4 (0.9) 8.3 (1.0) 3.4 (1.1) 2.9 (1.1) 0.001

Change in blood glucose(mean (SE), mg/dl)

1.2 (1.2) 0.5 (1.2) 1.6 (1.3) 0.8 (1.5) 2.0 (1.5) 1.6 (1.3) 0.4 (1.6) 0.431

Change in corrected QT interval(mean (SE), ms)

5.5 (4.0) −0.4 (3.5) 0.7 (3.2) −2.5 (5.2) −5.4 (3.9) −3.9 (2.1) 0.2 (3.5) 0.337

Prolonged corrected QT interval 2 (1.1) 0 1 (0.6) 0 0 1 (0.7) 1 (18.9) 0.551

At least one adverse eventh 148 (87.6) 137 (84.6) 161 (91.0) 160 (80.4) 127 (85.2) 115 (79.3) 95 (72.0) <0.001

Concomitant medications

Anticholinergicsi 70 (41.4) 59 (36.4) 7 (4.0) 60 (30.2) 11 (7.4) 15 (10.3) 29 (22.0) <0.001

Antidepressants 6 (3.6) 10 (6.2) 8 (4.5) 12 (6.0) 10 (6.7) 9 (6.2) 9 (6.8) 0.846

Anxiolytics 7 (4.1) 8 (4.9) 9 (5.1) 16 (8.0) 9 (6.0) 7 (4.8) 8 (6.1) 0.760

Lithium and anticonvulsants 2 (1.2) 2 (1.2) 2 (1.1) 4 (2.0) 2 (1.3) 4 (2.8) 3 (2.3) 0.889

Data shown as number (percentage) of patients experiencing events unless otherwise indicated. Partitions of χ2 methods were performed comparingthe data between each treatment group if overall χ2 p value were more than 0.05a Chlorpromazine vs aripiprazole, p=0.001; clozapine vs sulpiride, p<0.001; clozapine vs risperidone, p<0.001; clozapine vs aripiprazole, p<0.001;olanapine vs risperidone, p=0.001; olanapine vs aripiprazole, p<0.001; quetiapine vs risperidone, p=0.001; quetiapine vs aripiprazole, p<0.001b Chlorpromazine vs aripiprazole, p<0.001; chlorpromazine vs olanapine, p<0.001; sulpiride vs aripiprazole, p=0.001; clozapine vs risperidone,p<0.001; clozapine vs olanapine, p<0.001; clozapine vs quetiapine, p<0.001; clozapine vs aripiprazole, p<0.001c No p value <0.0023d The Simpson–Angus EPS scale score was ≥5 and/or anticholinergic medication was required; chlorpromazine vs clozapine, p<0.001;chlorpromazine vs olanapine, p<0.001; chlorpromazine vs quetiapine, p<0.001; chlorpromazine vs aripiprazole, p=0.001; sulpiride vs clozapine,p<0.001; sulpiride vs olanapine, p<0.001; sulpiride vs quetiapine, p<0.001; sulpiride vs aripiprazole, p=0.002; risperidone vs olanapine,p<0.001; risperidone vs quetiapine, p<0.001; risperidone vs clozapine, p<0.001e Percentages were based on the number female patients: 83 in the chlorpromazine group, 80 in the sulpiride group, 71 in the clozapine group, 90in the risperidone group, 63 in the olanzapine group, 68 in the quetiapine group, and 62 in the aripiprazole groupf Olanapine vs chlorpromazine, p<0.001; olanapine vs sulpiride, p=0.002; olanapine vs risperidone, p=0.001; olanapine vs quetiapine, p=0.001;olanapine vs aripiprazole, p=0.001g Post hoc pairwise comparisons between seven groups: olanapine vs chlorpromazine, p=0.004; olanapine vs sulpiride, p=0.003; olanapine vs risperidone,p=0.005; olanapine vs quetiapine, p=0.001; olanapine vs aripiprazole, p<0.001; clozapine vs quetiapine, p=0.027; clozapine vs aripiprazole, p=0.011h Chlorpromazine vs aripiprazole, p<0.001; clozapine vs aripiprazole, p<0.001; olanapine vs aripiprazole, p<0.001i Chlorpromazine vs clozapine, p<0.001; chlorpromazine vs olanapine, p<0.001; chlorpromazine vs quetiapine, p<0.001; chlorpromazine vsaripiprazole, p<0.001; sulpiride vs clozapine, p<0.001; sulpiride vs olanapine, p<0.001; sulpiride vs quetiapine, p<0.001; risperidone vsclozapine, p<0.001; risperidone vs olanapine, p<0.001; risperidone vs quetiapine, p<0.001; aripiprazole vs clozapine, p<0.001; aripiprazole vsolanapine, p<0.001

Psychopharmacology (2011) 216:475–484 481

Patients in the olanzapine group gained significantlymore weight compared with patients in the chlorpromazine,sulpiride, risperidone, quetiapine, and aripiprazole treat-ment group (all p values≤0.005). Patients in clozapinegroup gained significantly more weight compared withpatients in the quetiapine and aripiprazole treatment group(both p values≤0.027).

There were no significant differences among seven drugsat endpoint change in blood glucose (p=0.431). There wereno significant differences among seven drugs at endpointchange in corrected QT interval (p=0.337).

Anticholinergic drugs were added for a higher propor-tion of patients on chlorpromazine (41.4%) and sulpiride(36.4%) as compared with clozapine (4.0%), olanzapine(7.4%), quetiapine (10.3%), and aripiprazole (22.0%).

Discussion

This study reports a 1-year follow-up data in naturalisticgroup of patients stabilized on chlorpromazine, sulpiride,clozapine, risperidone, olanzapine, quetiapine, or aripipra-zole monotherapy. Treatment choice was at the discretion ofthe psychiatrists. The results presented here provide someimportant information on maintenance treatment of typicaland atypical antipsychotics in stable patients with early-stage schizophrenia in real-world settings. This studyshowed high rates of discontinuation and relatively shorttreatment duration for all antipsychotics studied and themost common reason for treatment discontinuation wasinefficacy (relapse) during the 1-year maintenance–treat-ment period. The typical antipsychotics and atypicalantipsychotics had no different in rates of discontinuation,which were similar in duration of treatment, and rates ofhospitalizations for an exacerbation of schizophrenia. Theseresults may be helpful in understanding the effectiveness ofantipsychotics in clinical practice, which though effective inacute period, have substantial limitations in their long-termtherapy in patients with early-stage schizophrenia. It is alsoimportant to note that the efficacy of typical antipsychoticand atypical antipsychotic may be similar in treatment ofpatients with early-stage schizophrenia.

Our study showed lower rates of treatment discontinu-ation comparing to previous studies (Csernansky et al.2002; Lieberman et al. 2005; Kinon et al. 2006). Onereason may be that in naturalistic studies and stabilizedpatients treatment discontinuation might be lower than in adouble-blinded trial and patients with acute exacerbated(Lieberman et al. 2005). Another reason could be thatfamily members are more involved in patients’ care inChina, similar to other Asian or developing countries. Thiskind of family involvement and support could furtherreduce medication discontinuation rates and subsequently

improve outcomes (Bertelsen et al. 2008). Our studyshowed ITAQ score and GAS score in all seven groupsimproved significantly from baseline to 12 months.

Inconsistent with previous study (Csernansky et al.2002; Lieberman et al. 2005; Haro et al. 2006; Kinon etal. 2006; Gaebel et al. 2007; Stroup et al. 2006, 2007;McEvoy et al. 2006; Chrzanowski et al. 2006; Kasper et al.2003; Dossenbach et al. 2005), the difference in rates oftreatment discontinuation between treatment groups wasnot significant in our trial. One factor may be is that we didnot use the similar selection of drugs as did other trials,notably, we used the low-potency first-generation drugchlorpromzine and sulpride which were widely used to treatschizophrenia in China. Low-potency first-generation anti-psychotic drugs might differ from the high-potency first-generation antipsychotic drugs, which are more likely thansecond-generation drugs to cause extrapyramidal symptoms(Martin et al. 2006). Another factor that may influence theresults is that patients who initiated different antipsychoticsat baseline had different in socio-economic status. Thenewer second-generation antipsychotics are relatively moreexpensive than first-generation antipsychotics and cloza-pine in China. Some of patients who took “cheap”antipsychotic drugs may have to continue their drugs eventhough they suffered from drug side effects or other reasonbecause drugs were paid by patients or their family inChina. However, we cannot rule out this factor that couldinfluence the results. Last, the doses of the medicationsused in this study may also have affected results. The dosesin this study were similar to those in other trials exceptolanzapine, but the mean modal dose of which (12.1 mg)was lower than CATIE (20.1 to 23.4 mg; Lieberman et al.2005; Stroup et al. 2006, 2007; McEvoy et al. 2006).

Although there were no significant differences in therates of discontinuation owing to intolerable side effects,advent events were differences between treatment groups.All drugs showed dose-related sedative potential, withclozapine, olazapine, and quetiapine showing higher ratesthan did risperidone and aripiprazole, which was consistentwith previously observations (Lieberman et al. 2005).Chlorpromazine, risperidone, and sulpiride were associatedwith greater extrapyramidal side effects than other antipsy-chotic drugs (Lieberman et al. 2003b). A small percentage ofpatients on clozapine, olanzapine, and quetiapine requiredconcomitant anticholinergic medication, whereas a significantminority of chlorpromazine, sulpiride, risperidone, andaripiprazole did need it. Risperidone may be one of the most“typical-like” of the atypical drugs due to its relatively higheraffinity for the dopamine receptor (Miyamoto et al. 2005). Asprevious studies (Leucht et al. 2009a; Lieberman et al. 2005;Stroup et al. 2009; Wu et al. 2006) have shown, we foundthat weight gain was most pronounced in patients takingolanzapine and clozapine.

482 Psychopharmacology (2011) 216:475–484

Our study was conducted in a variety of clinical settingsin which patients with schizophrenia are treated, whichwere intended to make the results widely applicable.However, several limitations should be considered whenreferring these results. Although observational studies canprovide valuable information on treatment outcomes, theyare also prone to selection and observer bias. We controlledfor selection bias by adjusting for baseline covariates whencomparing the differences between treatment groups.Observer bias could potentially influence the present resultsbecause our study was not blinded. However, observer biasis less when outcome reflected an objective outcome(medication maintenance/medication change) in clinicalpractice.

Conclusions

In summary, our study indicated that clinical efficacy wassimilar in chlorpromazine, sulpiride, clozapine, risperidone,olanzapine, quetiapine, and aripiprazole for maintenancetreatment of early-stage schizophrenia. Chlorpromazine,risperidone, and sulpiride were associated with greaterextrapyramidal symptoms; olazapine and clozapine wereassociated with greater weight gain. The differences in sideeffect profiles may be useful in matching early-stageschizophrenia patients with appropriate treatments. Thefindings from this study should be interpreted conserva-tively because of its limitations.

Acknowledgments This research was supported by the NationalKey Technologies R&D Program in the 10th 5-year-plan of China(grant no. 2004BA720A22), by the National Natural ScienceFoundation of China (grant no. 30630062 and 30900485), and bythe National Basic Research Program of China (grant no.2010CB529601).

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