Effect of antipsychotic medication alone vs combined with psychosocial intervention on outcomes of early-stage schizophrenia: A randomized, 1-year study.

Abstract

Antipsychotic drugs are limited in their ability to improve the overall outcome of schizophrenia. Adding psychosocial treatment may produce greater improvement in functional outcome than does medication treatment alone.
To evaluate the effectiveness of antipsychotic medication alone vs combined with psychosocial intervention on outcomes of early-stage schizophrenia.
Randomized controlled trial.
Ten clinical sites in China.
Clinical sample of 1268 patients with early-stage schizophrenia treated from January 1, 2005, through October 31, 2007. Intervention Patients were randomly assigned to receive antipsychotic medication treatment only or antipsychotic medication plus 12 months of psychosocial intervention consisting of psychoeducation, family intervention, skills training, and cognitive behavior therapy administered during 48 group sessions.
The rate of treatment discontinuation or change due to any cause, relapse or remission, and assessments of insight, treatment adherence, quality of life, and social functioning.
The rates of treatment discontinuation or change due to any cause were 32.8% in the combined treatment group and 46.8% in the medication-alone group. Comparisons with medication treatment alone showed lower risk of any-cause discontinuation with combined treatment (hazard ratio, 0.62; 95% confidence interval, 0.52-0.74; P < .001) and lower risk of relapse with combined treatment (0.57; 0.44-0.74; P < .001). The combined treatment group exhibited greater improvement in insight (P < .001), social functioning (P = .002), activities of daily living (P < .001), and 4 domains of quality of life as measured by the Medical Outcomes Study 36-Item Short Form Health Survey (all P < or = .02). Furthermore, a significantly higher proportion of patients receiving combined treatment obtained employment or accessed education (P = .001).
Compared with those receiving medication only, patients with early-stage schizophrenia receiving medication and psychosocial intervention have a lower rate of treatment discontinuation or change, a lower risk of relapse, and improved insight, quality of life, and social functioning.
clinicaltrials.gov Identifier: NCT00654576.

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ORIGINAL ARTICLE
Effect of Antipsychotic Medication Alone
vs Combined With Psychosocial Intervention
on Outcomes of Early-Stage Schizophrenia
A Randomized, 1-Year Study
Xiaofeng Guo, MD; Jinguo Zhai, MD; Zhening Liu, MD; Maosheng Fang, MD; Bo Wang, MD; Chuanyue Wang, MD;
Bin Hu, MD; Xueli Sun, MD; Luxian Lv, MD; Zheng Lu, MD; Cui Ma, MD; Xiaolin He, MD; Tiansheng Guo, MD;
Shiping Xie, MD; Renrong Wu, MD; Zhimin Xue, MD; Jindong Chen, MD; Elizabeth W. Twamley, PhD;
Hua Jin, MD; Jingping Zhao, MD, PhD
Context: Antipsychotic drugs are limited in their abil-
itytoimprovetheoveralloutcomeofschizophrenia.Add-
ingpsychosocialtreatmentmayproducegreaterimprove-
ment in functional outcome than does medication
treatment alone.
Objective: To evaluate the effectiveness of antipsy-
chotic medication alone vs combined with psychosocial
intervention on outcomes of early-stage schizophrenia.
Design: Randomized controlled trial.
Setting: Ten clinical sites in China.
Participants:Clinicalsampleof1268patientswithearly-
stageschizophreniatreatedfromJanuary1,2005,through
October 31, 2007.
Intervention: Patients were randomly assigned to re-
ceive antipsychotic medication treatment only or anti-
psychoticmedicationplus12monthsofpsychosocialin-
tervention consisting of psychoeducation, family
intervention, skills training, and cognitive behavior
therapy administered during 48 group sessions.
Main Outcome Measures: The rate of treatment dis-
continuation or change due to any cause, relapse or re-
mission, and assessments of insight, treatment adher-
ence, quality of life, and social functioning.
Results:Theratesoftreatmentdiscontinuationorchange
due to any cause were 32.8% in the combined treatment
group and 46.8% in the medication-alone group. Com-
parisonswithmedicationtreatmentaloneshowedlower
risk of any-cause discontinuation with combined treat-
ment(hazardratio,0.62;95%confidenceinterval,0.52-
0.74; P?.001) and lower risk of relapse with combined
treatment(0.57;0.44-0.74;P?.001).Thecombinedtreat-
ment group exhibited greater improvement in insight
(P?.001),socialfunctioning(P=.002),activitiesofdaily
living(P?.001),and4domainsofqualityoflifeasmea-
suredbytheMedicalOutcomesStudy36-ItemShortForm
Health Survey (all P?.02). Furthermore, a significantly
higher proportion of patients receiving combined treat-
ment obtained employment or accessed education
(P=.001).
Conclusion: Compared with those receiving medica-
tiononly,patientswithearly-stageschizophreniareceiv-
ingmedicationandpsychosocialinterventionhavealower
rateoftreatmentdiscontinuationorchange,alowerrisk
of relapse, and improved insight, quality of life, and so-
cial functioning.
Trial Registration: clinicaltrials.gov Identifier:
NCT00654576
Arch Gen Psychiatry. 2010;67(9):895-904
A
nia.1,2However,long-termtherapywithan-
tipsychotics is associated with a range of
adverseeffects,pooradherence,andhigh
rates of medication discontinuation.2-4
Most patients, even those with a good re-
sponse to medication, continue to expe-
rience disabling residual symptoms, im-
NTIPSYCHOTIC DRUGS HAVE
been shown to be effec-
tive against psychotic
symptoms, and they are
now the mainstay of
therapy for patients with schizophre-
pairedsocialandoccupationalfunctioning,
and a high risk of relapse. Certain psy-
chosocial treatments have been shown to
havebeneficialeffectsonclinicalandfunc-
tionaloutcomes.5-9Forinstance,familyin-
tervention reduces relapse rate,5cogni-
tive behavior therapy reduces positive
symptoms,5,8andsocialskillstrainingim-
provessocialcompetence.7Thecombina-
tion of pharmacotherapy and psychoso-
cial intervention has been recommended
for treatment of schizophrenia by prac-
ticeguidelinesforpsychiatrists.10Psycho-
Author Affiliations are listed at
the end of this article.
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socialinterventionscanbebestimplementedwhenacute
symptomshavebeenreducedandthepatientcanbesuc-
cessfully engaged in treatment. The goals of interven-
tion are to reduce stress on the patient, provide support
to minimize the likelihood of relapse, enhance the pa-
tient’s adaptation to life in the community, and facili-
tate continued reduction in symptoms and consoli-
dation of remission.10However, the effectiveness of
psychosocial intervention approaches has been consid-
ered separately. Each intervention has been directed
toward one of the components of the problem: the pa-
tient’s symptoms, relapse, or social skills. Few compre-
hensivepsychosocialinterventionpackageshavebeende-
velopedthatcanaddressseveralproblemssimultaneously
in schizophrenia.
Early illness course is an important predictive factor
forthelong-termoutcome;interventionduringthiscriti-
cal period is considered important.11As with the pub-
lishedliteratureonchronicschizophreniatreatment,stud-
iesoffirst-episodeandearlyschizophreniasampleshave
shown that they benefit from medication management
integratedwithavarietyofpsychosocialtreatments.For
example, the OPUS trial used an intensive early-
intervention approach combining assertive community
treatment,familypsychoeducation,andsocialskillstrain-
ing, with positive effects on hospitalization rates, living
independence, symptom severity, and family bur-
den.12,13Integratedtreatmentwithmedication,skillstrain-
ing, and cognitive behavior therapy is another approach
thathasbeenused,withpositiveeffectsonsymptomse-
verity.14Finally,medicationhasalsobeenintegratedwith
cognitive behavior therapy, family support, and voca-
tionalservices,withpositiveeffectsonhospitalreadmis-
sion, functioning, and medication adherence.15,16
In this article, we report on the Antipsychotic Com-
bination With Psychosocial Intervention on the Out-
comeofSchizophreniaStudy(fundedbytheMinistryof
ScienceandTechnologyofChina),a1-yearrandomized
clinical trial that tested the effect of medication com-
bined with a group psychosocial intervention vs medi-
cationtreatmentaloneonoutcomesofpatientswithearly-
stageschizophrenia.17Theoutcomesmeasuredincluded
the rate of treatment discontinuation or change due to
any cause, relapse or remission, and assessments of in-
sight,treatmentadherence,qualityoflife,andsocialfunc-
tioning.Wehypothesizedthatcombinedmedicationand
comprehensive psychosocial treatment would result in
lower rates of treatment discontinuation or relapse than
would medication treatment alone, which would reflect
variations in efficacy, insight and adherence, quality of
life, social outcome, and adverse effects.
METHODS
PARTICIPANTS
The study was conducted between January 1, 2005, and Oc-
tober 31, 2007, at 10 clinical sites in China (6 university clin-
ics and 4 province mental health agencies). All patients were
enrolled from outpatient psychiatric clinics and were under
maintenance treatment. Eligible patients were those 16 to 50
years of age who met the following enrollment criteria: (1)
DSM-IV diagnosis of schizophrenia or schizophreniform dis-
order within the past 5 years, as determined by the Structured
Clinical Interview for DSM-IV Axis I Disorders–Clinician Ver-
sion18administered by study investigators or trained staff; (2)
living with family members who could be involved in the pa-
tient’scare;(3)PositiveandNegativeSyndromeScale(PANSS)19
total score of 60 or less; (4) receiving maintenance treatment
with one of the following 7 oral antipsychotics: chlorproma-
zine hydrochloride, sulpiride, clozapine, risperidone, olanza-
pine, quetiapine fumarate, or aripiprazole. We selected these
7 antipsychotics because more than 90% of schizophrenic pa-
tients in China were prescribed one of these antipsychotics.20
Patients were excluded if they were (1) prescribed 2 or more
antipsychoticsorlong-actinginjectableantipsychotics,(2)par-
ticipating in other therapy programs, (3) pregnant or breast-
feeding,or(4)diagnosedashavingaseriousandunstablemedi-
cal condition. This study was approved by the institutional
review board at each site, and written informed consent was
obtained from the patients or their legal guardians.
PROCEDURE
After baseline assessment, participants were randomly as-
signedtoreceivecombinedmedicationandpsychosocialtreat-
ment or medication treatment alone and were monitored for
up to 12 months or until medication treatment was discontin-
ued for any reason. Group assignment was based on a 1:1 ran-
domization scheme balanced by sites and medication pre-
scribed. All medication visits and interventions took place in
the outpatient psychiatric clinics in these participating insti-
tutes.Membersofbothstudygroupscametomedicationman-
agementvisitsonceamonth,andthetherapywasgivenonthe
same day for the combined treatment group. The family mem-
bers had to bring the patient to each appointment, regardless
oftreatmentgroup.Allpatientsandtheirfamilymembersfrom
both study groups came to the clinic once a month and re-
ceived the same compensation for participating in the study.
Notransportation,outreach,orotherlogisticsupportswerepro-
vided by this study. In both groups, patients and family mem-
bers could ask medication- or treatment-related questions of
the treating clinicians during their 30-minute visit as standard
of outpatient care for medication management. To better keep
theassessorsandcliniciansblinded,thepsychotherapyrooms,
clinicians’offices,andassessors’officeswereisolatedfromeach
other; patients and family members were reminded at enroll-
ment and follow-up visits not to discuss treatment assignment
with their clinicians and assessors; and investigators and staff
were restricted in the discussion of patients within research
teams.Furtherdetailaboutthestudyrationale,design,andmeth-
ods have been described previously.17
INTERVENTIONS
Pharmacotherapy
Becauseallpatientswerereceivingmaintenancetreatment,we
encouragedclinicianstotrytokeeppatientsonthesamemedi-
cation regimen for 3 to 6 months to gauge treatment efficacy
andminimizeearlydiscontinuation.However,medicationscould
be changed at any time during the course of the study if the
change was clinically warranted. If a patient’s medication was
stopped or switched, patients were classified as discontinued
and were terminated from the study. No further assessments
were required for these patients. Mood stabilizers, benzodiaz-
epines,antidepressants,andanticholinergicmedicationswere
permitted, and daily doses of all medications were recorded
throughout the study.
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Psychosocial Intervention
Patients assigned to the combined treatment group received
medication treatment and were enrolled in a psychosocial in-
terventionprogram.Thepsychosocialinterventionstrictlyfol-
lowed a detailed treatment manual designed by the principal
investigators (Drs X. Guo, Liu, and Zhao) and included 4 evi-
dence-based practices: psychoeducation, family intervention,
skills training, and cognitive behavior therapy.21Participants
receiving psychosocial intervention were seen 12 times (once
per month for 12 months), receiving each of the 4 group treat-
mentsonthesameday,foratotalof48one-hoursessions(see
Table 1 for topics covered). A lunch break and 2 half-hour
breaks were provided to maintain engagement and attention.
We designed this comprehensive psychosocial intervention to
be delivered on the same day once a month mainly owing to
the care structure in China, the potential time and cost bur-
den to patients and their family members, and the feasibility
ofadoptionbyothercaresettings.InChina,mostpatientswith
schizophrenia live with their family members because of lim-
ited social welfare for severely mentally ill patients. Many of
these family members also work full time, so it is not conve-
nient for them to take time off every week and bring the pa-
tients for therapy. In addition, all our psychosocial interven-
tionsweregroupbased,sohavingmanypatientsandtheirfamily
members come in once a week at the same time was not fea-
sible or practical. Weekly intervention visits also would have
increased the costs of transportation and therapist time, mak-
ingtheoverallcostofthepsychosocialinterventionhigher.Fi-
nally, psychosocial interventions have become more popular
inrecentdecadesinChina,butthenumberofwell-trainedthera-
pistsremainslimitedinmanyChinesepsychiatricsettings.More
frequent therapy sessions could be not only difficult for pa-
tients and family members but also hard for many psychiatric
settings to adopt.
Psychoeducation included teaching patients and care-
givers about the symptoms, treatment, and course of mental
illness and afforded patients and family members the oppor-
tunity to ask questions about psychiatric disorders and treat-
ment options. This group provided a forum in which to dis-
cussconcernsandobtainsupportfromthegrouptoreducethe
stigma of mental illness. The purpose of psychoeducation was
toincreasepatients’andcaregivers’knowledgeandunderstand-
ing of the illness and treatment.22-24
Familyinterventionincludeddevelopingcollaborationwith
thefamily,socializingaboutnon–illness-relatedtopics,monthly
updates on each family’s situation, enhancing family commu-
nication,teachingpatientsandtheirfamiliestocopewithstress-
ful situations and the illness, and teaching patients and their
families to detect signs of relapse and intervene in crises.22,25,26
Skills training included modules on medication manage-
mentandsymptomself-management,dealingwithstigma,so-
cial problem solving, and independent living skills. The train-
ingincludedteachingcomplexinterpersonalskillsbybreaking
down the targeted behaviors into component steps and sys-
tematically using modeling, behavioral rehearsal, positive and
corrective feedback, and in vivo practice to shape the acquisi-
tion and generalization of skills.7,27-29
Cognitive behavior therapy involved treatment of auditory
hallucinations,delusions,andassociatedsymptomsandprob-
lems (ie, anxiety, depression, and self-esteem); prevention of
relapse; and enhancement of medication adherence. Treat-
ment included an assessment and engagement phase, educa-
tion,andbuildingatherapeuticalliance;functionalanalysisof
Table 1. Content of Monthly Psychosocial Treatment Sessions
Month Psychoeducation TopicsFamily Intervention TopicsSkills Training TopicsCognitive Behavior Therapy Topics
1 Introduction into program;
discussion of goals and
questions
What is schizophrenia?
Introduction into program; discussion
of goals and questions
Medication management 1:
identifying benefits of
antipsychotic medication
Medication management 2:
self-administration and
evaluation of medication
Developing therapeutic alliance
2 Role of family in schizophrenia
Using the “ABC Model” to find
connections between activating
events, beliefs, and
consequences
Intervening with auditory
hallucinations (voices)
3 Causal and triggering factorsRelatives sharing experiences of
caring for patients
Medication management 3:
adverse effects of
antipsychotic medication
Symptom management 1:
identifying warning signs
of relapse
Symptom management 2:
developing relapse
prevention plan
Verbal and nonverbal
communication
Verbal and nonverbal
communication
4 Description of various
symptoms
Coping strategies: identifying,
describing, clarifying, and teaching
coping strategies used by families
Coping strategies: identifying,
describing, clarifying, and teaching
coping strategies used by families
Helping families with problem solving
Intervening with auditory
hallucinations (voices)
5Patients’ concepts of illness
and vulnerability-stress-
coping model
Course and outcome
Intervening with delusions
6 Intervening with delusions
7Treatment recommendations
concerning
pharmacotherapy
Risks associated with
treatment withdrawal
Helping families with problem
solving.
Intervening with anxiety,
depression, and self-esteem
issues
Intervening with anxiety,
depression, and self-esteem
issues
Relapse prevention
8 Family communicationLearning and practicing
problem-solving skills
9Early detection of relapse Family communication Learning and practicing
problem-solving skills
Job-finding skills 10Pregnancy and genetic
counseling
Discussion of open
questions
Final session: review
of content
Behavior managementRelapse prevention
11Behavior management Independent living skillsEnhancing medication adherence
12 Final session: review of contentIndependent living skills Enhancing medication adherence
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keysymptoms,leadingtoformulationofaproblemlist;devel-
opment of a normalizing rationale for the patients’ psychotic
experiences;andexplorationandenhancementofcopingstrat-
egies.Concomitantaffectivesymptomswereaddressedbymeans
of relaxation training.30,31
Therapists who had at least 2 years of clinical experience
after earning an MD or PhD or at least 5 years of experience
after earning a masters degree in clinical psychology delivered
the psychosocial intervention. They attended training work-
shopsuntiltheyhadmasteredalltreatmentprocedures.Treat-
ment fidelity was maintained by having the therapists’ super-
visors assess adherence to the treatment manual after each
monthly session by reviewing videotapes.
OUTCOME ASSESSMENTS
All subjects were assessed monthly by the study psychiatrists
and every 2 weeks by a research assistant who had instruc-
tions to contact the psychiatrist if medication discontinua-
tion, relapse, or other problems were suspected. The psychia-
trists assessed patients mainly for medication management
purposes,evaluatingforclinicalresponsetomedications,medi-
cation adherence, and major adverse effects. The research as-
sistantsassessedpatients,patients’caregivers,andothersources
every 2 weeks by telephone for any hospitalizations, relapses,
or other causes of treatment discontinuation. The research as-
sistants also administered the symptom and functioning rat-
ingscalesatscheduledintervals.Theprimarymeasurewasrate
of treatment discontinuation or change and time to treatment
discontinuation.Onceapatientdiscontinuedthestudy,nofur-
therassessmentswerecompleted.Ourcriteriafortreatmentdis-
continuation or change were somewhat broader than those of
the Clinical Antipsychotic Trials of Intervention Effectiveness
study2andincluded(1)clinicalrelapse/hospitaladmission;(2)
loss to follow-up or patient’s refusal; (3) nonadherence, de-
fined as taking less than 70% of prescribed medications, de-
tected by either the treating psychiatrist or research assistants
duringfollow-upassessments;(4)changingorstoppingofthe
initial antipsychotic medication by physician or patient re-
quest; and (5) intolerability, defined as severe adverse effects
that caused the treating psychiatrists to stop the medication.
Clinical relapse was defined by any one of the following32:
(1) psychiatric hospitalization; (2) an increase in the level of
psychiatric care (eg, from clinic visits to day treatment) and a
25% or more increase in the PANSS total score (or 10 points if
the initial score was ?40); (3) a Clinical Global Impressions
Scale score of “much worse” or “very much worse”33(pp218-222);
(4) deliberate self-injury; (5) emergence of clinically signifi-
cant suicidal or homicidal ideation; or (6) violent behavior re-
sultinginsignificantinjurytoanotherpersonorsignificantprop-
erty damage.
Secondary outcomes further assessed treatment effective-
ness by measuring symptom severity (PANSS), insight (In-
sightandTreatmentAttitudesQuestionnaire[ITAQ]),34treat-
ment adherence (appointment adherence), quality of life
(Medical Outcomes Study 36-Item Short Form Health Survey
[SF-36]),35,36and social functioning on the Global Assessment
Scale(GAS)37andtheActivitiesofDailyLivingScale(ADL).38,39
The SF-36 consists of 8 domains that assess bodily pain, gen-
eral health, general mental health, physical functioning, role-
emotional, role-physical, social functioning, and vitality. The
GAS is a single-item rating scale for evaluation of overall pa-
tient functioning.37The 14-item independent ADL assesses a
person’sabilitytoperformbasic(eg,dressing,walking,andbath-
ing) and instrumental (eg, using a telephone, doing laundry,
and handling finances) activities of daily living.38,39This scale
has been widely used and has demonstrated validity in studies
ofmedicallyillanddementiapopulationsinChina.40,41Therate
of obtained work or education during the 12 months was also
usedtoassessrolefunctioningandcommunityintegration.The
physical examination and the effect of antipsychotic treat-
ment on weight gain were recorded regularly. The Treatment
EmergentSymptomScale33(pp341-350)wasusedformonitoringad-
verse effects.
All interviewers trained and received reassessments of in-
terraterreliabilityonthebasisofvideotapeddemonstrationin-
terviews.AgreementamongtheraterswashighforthePANSS,
ITAQ, GAS, and ADL (Pearson correlation coefficient, 0.78-
0.86) at baseline and every 6 months.
STATISTICAL ANALYSIS
Analyseswereperformedaccordingtotheintention-to-treatprin-
ciple.Randomizedpatientswhohadatleast1assessmentdur-
ing treatment made up the intention-to-treat population. The
sample sizes were selected to make possible the detection of a
15% difference in discontinuation rates after 1 year with 85%
power and a 2-tailed ? level of significance of .05.
Baselinecharacteristicswerecomparedbetweenthe2groups
by analysis of variance, Pearson ?2test, or Fisher exact test, as
appropriate. We used Kaplan-Meier survival curves to esti-
mate the time to discontinuation of treatment in the sample.
Factors associated with treatment discontinuation were deter-
mined by multivariate analysis using a Cox proportional haz-
ards model with stepwise reduction and a log-rank test with
control for site.42Data were presented as hazard ratios (HRs)
and 95% confidence intervals (CIs). Time course and treat-
ment differences for change in the PANSS, ITAQ, SF-36 do-
mainscores,GAS,andADLwereanalyzedbymeansofamixed-
effects model for repeated-measures analyses with effects of
treatment, time, and treatment?time interaction with unre-
strictedcovarianceofbaselinescores.43Timewasclassifiedinto
months (baseline and 3, 6, 9, and 12 months). Other categori-
cal outcomes (including data regarding adverse events) were
compared with the use of Pearson ?2test or Fisher exact test.
All statistical tests were 2-tailed.
RESULTS
DISPOSITION AND BASELINE
CHARACTERISTICS OF PATIENTS
Atotalof1563potentiallyeligiblesubjectswerescreened.
Of these subjects, 1268 patients completed the baseline
assessmentandunderwentrandomization;633wereas-
signedtoreceiveantipsychoticscombinedwithpsycho-
social intervention (of whom 29 refused the psychoso-
cial intervention and were excluded from analysis) and
635 to receive antipsychotics alone. Overall, 744 pa-
tients (60.0%) completed the 1-year follow-up: 406
(67.2%) in the combined intervention group and 338
(53.2%) in the antipsychotics-alone group (Figure 1).
There were no significant differences between study
groups with respect to baseline demographic and clini-
cal characteristics. The mean age was 26 years; 55.0% of
the patients were male and most patients (84.6%) had a
diagnosis of schizophrenia (Table 2).
Amongthe406combined-treatmentparticipantswho
completed the study, the mean (SD) number of sessions
attendedwas44.2(4.4)(92.1%ofthe48totalsessions),
whereas among the 198 combined-treatment partici-
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pantswhodiscontinuedorchangedtreatment,themean
number was 18.1 (4.9) (37.7% of total sessions).
RATES OF TREATMENT DISCONTINUATION
Fortypercentofpatientsinthefinalanalysis(495of1239)
discontinuedtheirtreatmentduringthe12-monthtreat-
ment period (32.8% of patients in the combined treat-
ment group and 46.8% of patients in the medication-
alonegroup).Thedifferencebetweengroupsintreatment
discontinuationforanycausewassignificant(HR,0.62;
95% CI, 0.52-0.74; P?.001) (Table 3 and Figure 2).
Relapses occurred in 14.6% of patients in the com-
binedtreatmentgroupand22.5%ofpatientsinthemedi-
cation-alonegroup.Theriskofrelapsewasloweramong
1563 Screened
295 Excluded
117
95
83
Did not meet study criteria
Refused to participate
Had other reasons
1268 Randomized
635 Assigned to medication
treatment
633
29
Assigned to combined
treatment
Refused psychosocial
intervention∗
198 (32.8%) Discontinued
88
71 Owing to loss to follow-up or
patients’ refusal
Owing to nonadherence
Owing to changing or stopping
medication
Owing to intolerability
17
17
5
Owing to clinical relapse
297 (46.8%) Discontinued
143
90Owing to loss to follow-up
or patients’ refusal
Owing to nonadherence
Owing to changing or stopping
medication
Owing to intolerability
36
19
9
Owing to clinical relapse
338 (53.2%) Completed 1-y
evaluation
406 (67.2%) Completed 1-y
evaluation
Figure 1. Study flowchart showing the numbers of patients screened for potential inclusion, the reasons for exclusions from randomization, and primary outcome
in 1-year follow-up. *These patients were excluded from the final analysis because their follow-up was not carried out.
Table 2. Baseline Demographic and Clinical Characteristics of Randomly Assigned Patientsa
Characteristic
Combined Treatment
(n=633)
Medication Treatment
(n=635)
Demographic
Age, y
Male, No. (%)
Marital status, No.(%)
Married
Previously marriedb
Never married
Education, y
Clinical
DSM-IV diagnosis, No. (%)
Schizophrenia
Schizophreniform disorder
PANSS total score
CGI severity score
Age at onset, y
Duration of schizophrenia, mo
Daily dose of antipsychotic agents, mg/total No. of patients
Chlorpromazine hydrochloride
Sulpiride
Clozapine
Risperidone
Olanzapine
Quetiapine fumarate
Aripiprazole
26.1 (25.5-26.8)
344 (54.3)
26.4 (25.7-27.0)
354 (55.7)
167 (26.4)
39 (6.2)
427 (67.5)
12.2 (11.9-12.5)
173 (27.2)
28 (4.4)
434 (68.3)
12.0 (11.7-12.3)
535 (84.5)
98 (15.5)
44.7 (43.7-45.7)
2.5 (2.4-2.6)
23.8 (23.2-24.4)
24.6 (23.0-26.3)
538 (84.7)
97 (15.3)
45.6 (44.5-46.7)
2.6 (2.5-2.7)
24.2 (23.4-24.6)
23.3 (21.7-24.9)
332.1 (305.0-359.2)/95
720.3 (673.2-767.4)/98
267.0 (244.0-290.0)/99
3.5 (3.3-3.7)/111
11.9 (10.9-12.9)/79
538.2 (490.2-586.2)/80
18.5 (16.9-20.1)/71
344.9 (319.0-370.8)/94
732.8 (683.2-782.4)/97
269.9 (246.7-293.1)/99
3.7 (3.4-3.9)/112
12.4 (11.1-13.7)/80
524.5 (467.3-581.7)/81
18.5 (16.6-20.4)/72
Abbreviations: PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impressions.
aData are presented as mean (95% confidence interval) unless otherwise indicated. Percentages may not sum to 100 because of rounding.
bThis category includes patients who were widowed, divorced, or separated.
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