Asian Journal of Psychiatry 14 (2015) 3–12

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Asian Journal of Psychiatry

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Review

Course and Outcome of Schizophrenia in Asian Countries:

Review of Research in the Past Three Decades
Bharath Holla, Jagadisha Thirthalli *
Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore

A R T I C L E I N F O A B S T R A C T

Article history: Considerable variation has been observed in the course and outcome of schizophrenia. With regard to
Received 7 October 2014 epidemiology of schizophrenia, papers from different Asian countries have reported findings which are
Received in revised form 5 January 2015 in contrast with literature from the western countries. In this background we undertook a narrative
Accepted 18 January 2015
review of literature regarding course and outcome of schizophrenia in Asian countries. We conducted
Medline search for English-language papers on long-term course and outcome of schizophrenia
Keywords: conducted in Asia in the past 3 decades. We also reviewed data pertaining to Asian countries from the
Schizophrenia
World Health Organization’s International Study of Schizophrenia (ISoS). In addition to ISoS, we
Asia
Course
retrieved 14 reports from 9 Asian countries. While ISoS used comparable methodology across the
Outcome countries, non-ISoS studies differed substantially in their aims, sampling, follow-up rates and
Mortality assessment tools used for studying the course and outcome. Overall, the percentage of patients who
experienced clinical and functional outcome in the Asian countries were largely comparable to those in
the western studies. We observed significant variations in the long-term outcome and mortality in
schizophrenia even among the Asian countries. In conclusion, there is substantial variation in the long-
term course and outcome and mortality across different Asian countries. The reason for this remains
unexplored. Cross-national studies exploring biological and cultural explanations for this variation may
provide clues, which may have heuristic, translational and public-health significance.
ß 2015 Elsevier B.V. All rights reserved.

Contents

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. ISoS centres (Tables 1 and 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2. Non-ISoS studies (Tables 3 and 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.3. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.4. Substance use comorbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.5. Predictors of outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.1. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.2. Substance use comorbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.3. Antipsychotic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.4. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

* Corresponding author. Additional Professor, Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India.
Tel.: +918026995350; fax: +918026564830.
E-mail address: jagatth@yahoo.com (J. Thirthalli).

http://dx.doi.org/10.1016/j.ajp.2015.01.001
1876-2018/ß 2015 Elsevier B.V. All rights reserved.
4 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12
1. Background
Kraepelin described dementia precox as a disorder character-
ized by a chronic, progressive course with minimal chances of
clinical improvement (Kraepelin, 1899). Since then, course and
outcome of this disorder, which later came to be popularly known
as schizophrenia, has drawn considerable research interest. In fact,
in an influential systematic review and meta-analysis conducted
2 decades ago (Hegarty et al., 1994), the authors identified
320 studies that met their fairly stringent inclusion criteria. This
and other reviews (McGlashan, 1988; Stephens, 1978) have
indicated that the outcome of schizophrenia is not uniformly
poor; it is rather highly heterogeneous, and, on an average,
substantially high proportion of persons who receive a diagnosis of
schizophrenia experience reasonably good clinical and functional
outcome. The heterogeneity stems from several sources: nature of
sampling, criteria used to diagnose schizophrenia, use of modern
treatment, particularly antipsychotic medications, provision of
psychiatric services, etc.
In the World Health Organization (WHO) follow up studies –
International Pilot Study of Schizophrenia (IPSS) (WHO, 1979),
Determinants of Outcome of Severe Mental Disorder (DOSMeD)
(Jablensky et al., 1992) and International Study of Schizophrenia
(ISoS) (Harrison et al., 2001) – another important factor influencing
the course and outcome was noticed–patients belonging to the
‘developing’ countries had more favorable overall outcome than
those in the ‘developed’ countries. The reason for this differential
outcome has not been studied well. What is it in the developing
countries that could favourably influence the course and outcome?
A number of hypotheses have been put forth, but these have
remain untested. Differences in the level of industrialization,
urbanization, social support, family structure, expressed emotions,
explanatory model for causation of the illness, societal challenges,
etc., have been proposed to explain the differential outcome.
Though countries were divided as ‘developed’ and ‘developing’ on
economic status, it is not clear as to whether the economic status
per se could be responsible for the differential outcomes. The
differences observed may be better described as ‘regional’
differences, which encompass differences due to racial (genetic)
environmental and sociocultural differences. Indeed, even within
the ‘developed’ and ‘developing’ countries included in the WHO
studies, substantial differences have been noted (Cohen et al.,
2008).
Studies from several Asian countries have documented many
findings, which are in contrast to that of the rest of the world. For
instance, prevalence of schizophrenia has been reported to be more
in women than in men in Chinese studies (Cooper et al., 1996).
Studies from India (Gangadhar et al., 2002; Murthy et al., 1998;
Venkatesh et al., 2008) and Pakistan (Naqvi et al., 2005) have failed
to find earlier age of onset of schizophrenia that is so well
replicated elsewhere (Hafner et al., 1993). Substance use
comorbidity, which can adversely influence the course and
outcome of schizophrenia (Volkow, 2009), is found to be lower
in India (Chand et al., 2014; Isaac et al., 2007); this reflects a fairly
low occurrence of substance use and psychiatric disorders in many
Asian countries (Thirthalli et al., 2012). Similarly, family expressed
emotions, which also can adversely influence the course of
schizophrenia is found to be lower in Indian families than in
some of the western countries (Leff et al., 1990). There is an
argument that repeated exposure to severe famines have possibly
eliminated severest forms of schizophrenia and there is a natural
selection in the favour of milder forms of schizophrenia in some
Asian countries (Thirthalli and Jain, 2009). A recent study has also
found that the proportion of patients who had longer than
6 months of prodrome was less than 10% (Kare et al., 2009) in
contrast to the typical course of prodrome described in text books
(Sadock, 2000). With several studies showing that different
dimensions of schizophrenia are different in the Asian countries,
it is of interest to see if course and outcome of schizophrenia is
different in these countries.
2. Methods
In this narrative review, we attempt to provide an overview of
the past three decades of research studies on course and outcome
of schizophrenia in Asian countries. We conducted Medline search
using the following combinations of keywords: ‘schizophrenia’,
‘psychosis’, ‘outcome’, ‘course’, ‘follow-up’, ‘Asia’ along with names
of individual Asian countries. We further conducted author
searches and used cross-references from the identified research
reports. Papers published in English language, presenting results of
research conducted in an Asian country since 1980 were reviewed if
the follow-up period was at least 2 years. We reviewed only such
follow-up studies, where either clinical/functional outcomes and/or
mortality were reported (i.e., we did not review papers where other
outcomes like stigma, quality of life, medication adherence, etc., were
studied) In addition, we also reviewed data of Asian centres from the
World Health Organization’s (WHO) influential ISoS project. The
ISoS is a transcultural investigation coordinated by the WHO in
18 centres in 14 countries. It included cohorts from three earlier
WHO studies, the IPSS (WHO, 1979), DOSMeD (Jablensky et al.,
1992), Reduction and Assessment of Psychiatric Disability
(RAPyD) (Wiersma et al., 1996) and three other centres not
involved in these three studies. For this review, if more than one
paper was published from a cohort, then we considered the data
from the longest follow-up period; we also reviewed significant
results from other related papers from those studies.
We reviewed each study specifically with regard to the following
characteristics: primary aim of the study, method of sampling,
number of subjects included in the original cohort, percentage of
subjects whose data was considered for outcome analysis, system
and method of diagnosis, tools used for assessing clinical, functional,
course-related and overall outcomes and mortality. Predictors of
outcome were also reviewed. We specifically reviewed the papers
for data on substance use comorbidity because of the following
reasons: (a) it is known to adversely affect the outcome of
schizophrenia (Volkow, 2009); (b) earlier long-term studies of
schizophrenia have not specifically examined its influence on the
course and outcome of schizophrenia and (c) substance use
comorbidity is relatively lower in the Asian countries (Chand
et al., 2014). Finally, we carefully examined the treatment details,
which could influence the course and outcome of schizophrenia.
3. Results
In addition to ISoS, we retrieved 14 studies which met our
inclusion criteria. ISoS employed uniform method of assessing the
course and outcome of the included cohorts, though the individual
cohorts themselves were formed using substantially different
methods. Hence, it would be useful to consider the results of all
ISoS cohorts and non-ISoS cohorts separately. The results of the
ISoS and non-ISoS studies are shown in Tables 1 and 2 and
Tables 3 and 4 respectively.
3.1. ISoS centres (Tables 1 and 2)
There were seven Asian sites in the ISoS, including four from
India. The samples included community-dwelling patients, inpa-
tients and outpatients with recent onset schizophrenia. The
duration of follow-up ranged from 12 years to 26 years – centres
from the DOSMeD study had 15 years of follow-up. There were
wide variations in the percentage of the original cohort that was
 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12 5

Table 1
Details of cohorts in the International Study of Schizophrenia (ISoS; see text for details).

Location Sampling details Original % followed-up Duration of Males:

cohort (n) follow up (yr) Females (%)

Prevalence cohortsa
Agra, India Outpatients of mental hospital; 15-45 ears of age, 138 43.5 26 64:36
<5yr duration of illness
Beijing, China Random sampling from an urban area 89 65.2 12 50:50
b
Incidence cohorts
Chandigarh-rural, India Incidence cases: symptoms within 12 months and 55 50.7 15 50:50
treatment seeking at any place within 3 months.
Chandigarh-urban, India Incidence cases: symptoms within 12 months and 148 69.1 15 59:41
treatment seeking at any place within 3 months.
Nagasaki, Japan Incidence cases: symptoms within 12 months and 111 50.5 15 57:43
treatment seeking at any place within 3 months.
Hong-Kong, China Randomly selected from a pool of recent-onset 100 70 15 51:49
schizophrenia patients
Madras# (Chennai), India Consecutive outpatients with <2 years of illness 100 77 15 50:50
a
From the original International Pilot Study of Schizophrenia (IPSS) (WHO, 1979).
b
From the original Determinants of Outcome of Severe Mental Disorder (DOSMeD) (Jablensky et al., 1992).
# 25-year follow-up of this cohort has been published elsewhere (Rangaswamy, 2012); however, we have considered only the 15-year outcome for this paper because it
formed part of the ISoS and thus, the findings of this cohort can be readily compared with results of other cohorts of ISoS.

followed up across the centres; on an average, it was lower in
centres from India. ISoS study used an array of clinical, functioning
and global outcomes based on several assessment tools (see
footnote to Table 2); we have highlighted only few selected
outcomes here. The reader is referred to the source book of the
study (Hopper et al., 2007) for other details.
In terms of clinical outcome, about 50% of patients were never
psychotic in the last 2 years of follow-up across all the centres
(Harrison et al., 2001) of this trans-continental study. Among the Asian
countries, all three Indian sites had nearly more than 60% patients, who
were free of psychosis in the past 2 years. In contrast, the non-Indian
sites (Beijing, Nagasaki and Hong-kong) had substantially less

Table 2
Findings of International Study of Schizophrenia (ISoS; see text for details):.

Location Course and clinical Social-occupational Overall outcome Mortality Treatment details Co-morbidity Predictors
outcome outcome

Prevalence cohortsa
Agra, India 63% not psychotic; 60% best; 20% each 18% better; 23% same; 31.2% 63% never; 25.9% Though NR
13.3% continuously fair and poor 8.2 worse; 35% other (SMR = 1.86*) sometimes 11.1% studied,
psychotic; 23.7% other most times on AP not used
in analysis;
details not
available
Beijing, China 34.5% not psychotic; 25% best; 8.3% 48.3% better; 12.1% 22.5%; 8.6% never; 51.7% NR Females
51.7% continuously fair; 66.6% poor same; 25.9% worse; SMR = 2.97* sometimes; 39.7% had poorer
psychotic; 13.8% other 13.8 other most times on outcome
AP

Incidence cohortsb
Chandigarh-rural, 71.1% not psychotic; 71% best; 19.4% 57.9% better; 18.4% 18.2%; 5.3% never; 89.5% NR NR
India 7.9% continously fair; 9.6% poor same; 5.3% worse; SMR = 3.2* sometimes; 5.3%
psychotic; 11% other 18.4% other most times on AP
Chandigarh-urban, 63.8% not psychotic; 63.2% best; 28.7% better; 27.5% 6.3%; 53% sometimes; 27% NR NR
India 18.8% continously 26.5% fair; 10.3 same; 8.8% worse; SMR = 1.8* most times on AP;
psychotic 17.4% others poor 35% other 20% unknown
Nagasaki, Japan 25% not psychotic; 25% best; 16.1% 35.1% better; 31.6% 6.3%; 14% sometimes and NR NR
55.4% continuously fair; 58.9% poor same; 33.3% worse SMR = 5.71% 86% most times on
psychotic; 19.6% AP
others
Hong-Kong, China 43.5% not psychotic; 62.3& best; 46.4% better; 26.1% 11%; 4.3% sometimes and NR NR
36.2% continuously 21.9% fair; same; 27.5% worse SMR = 5.7* 95.7% most times on
psychotic; 20.3% 15.7% poor AP
others
Madras (Chennai), 61% not psychotic; 46.7% best; 17.3% 72.8% better; 16.9% 9%; SMR = 1.9 42.9% sometimes NR NR
India 18.2% continuously fairl; 36% poor same; 10.4% worse and 57.1% most
psychotic; 20.8% other times on AP

The assessment tools used were uniform across all the centres. These included the Present State Examination (PSE; Cooper et al., 1996), Diagnostic Schedule Scoresheet (DSS;
developed for this study), which records study team’s consensus diagnosis according to DSM-III-R or ICD-10; Scale for the Assessment of Negative symptoms (SANS;
Andreasen et al 1989); Disability Assessment Schedule (DAS); Substance Abuse Schedule (SAS developed for this study); Life-Chart Schedule (LCS; Harding et al), Broad Rating
Schedule (BRS; developed for this study).
a
From the original International Pilot Study of Schizophrenia (IPSS) (WHO, 1979).
b
From the original Determinants of Outcome of Severe Mental Disorder (DOSMeD) (Jablensky et al., 1992).
*
p < 0.05.
6 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12

Table 3
Details of cohorts in the non-ISoS studies (See text for details).

Author/Year/Location Aim Samplinga,b,c Original Sample Follow up M:F Dia-gnosis

sample followed dura-tion
up (%) (yrs)

Chang WC et al/2011,12,
13/Hong Kong (EASY)
Kua J et al/2003/Singapore
Liu T et al/2014/China
Ran MS et al/2010/China
Verma S et
al/2012/Singapore (EPIP)
Yang J et al/2014/China
Johnson S et al/2012/
Vellore, India
Srivastava A et al/2009;
10/Mumbai, India
Suresh et al/2012/Rural
Karnataka, India
Verghese A
et al/1989/Chennai, Vellore,
Lucknow, India (SOFACOS)
Kurihara T et
al/2011/Indonesia
Marom S et al/2005/Israel
Ryu Y et al/2006/Japan
Haro MJ et al/2011/Korea,
Malaysia Taiwan
(W-SOHO)
To Investigate the rates and Community outreach— 700 77 3 52:48 ICD
predictors of symptomatic first episode 10
remission and recovery in schizophreniaa
first-episode ‘psychosis’
Assess the course of illness First admission in 1975 at 402 72% at 10yr; 10, 15,and 20 61:39 ICD 9
and to examine the variables mental hospital in 74% at 15yr;
that are useful predictors of Singaporeb 54% at 20yr
outcome.
To examine mortality among Randomly selected 2071 2071 97.5 4 56:44
those with disability due to from a national pool of ICD-10
schizophrenia patients with disability
due to schizophreniaa
To study work functioning All patients in six rural 510 72 10yrs 47:53 ICD-10
and its predictors rural area townships of Xinjin
County identified by key-
informant method a
To describe outcomes of early Community outreach– 1175 66 2 51:49 SCID
intervention programme first episode
schizophreniaa
To study the prevalence, Random cluster sampling, 30 70 30 57:43 CIDI ICD9, 10
natural course and prognosis prevalencea
in Jinuo people, (national
minority) every 10yrs since
1979
To study the relationship Outpatients with first 131 72.5 5 55:45 DSM-IV
between insight, explanatory contact with mental
models and outcome health professionalsb
Predictors of outcome after Patients hospitalized for 200 57 10 73:27 DSM-IV
‘10yrs of follow up first-episode in a private
hospital in Mumbai a
to study work-functioning of All patients with 236 85.1 4yrs (mean) 51:49 MINI: ICD-10
schizophrenia patients living schizophrenia in a rural
in a rural community in south community in South India
India (both treated and
untreated)c
To study factors affecting Consecutive outpatients 386 74.4 5 63.2:36.8 Feighner’s
course and outcome of with <2yrs of illnessa criteria
schizophrenia
clinical outcome of Consecutively admitted 59 72 17 63:37 DSM-III-R
schizophrenia and its first-episode patientsa
predictors
To study predictive value of Consecutive in-patientsa 114 95 7 Not DSM-III-R
expressed emotions for long- reported
term outcome.
To investigate the effects of Chronic institutionalized 94 83 2 65:35 ICD-10
deinstitutionalization and patients transferred to
evidence-based strategies for community-based
the treatment of mental facilitya
disorders among long-stay
patients after their discharge
To determine the frequency In/outpatients who were 1223 37.5 3 54:46 DSM
of symptom and functional initiating/changing IV/ICD 10
remission in outpatients in antipsychoticsc
different regions of the world

EPIP, Early Psychosis Intervention Programme; EASY, Early Assessment Service for Young People with Psychosis; SOFACOS, Study Of Factors Associated With Course and
Outcome of Schizophrenia; W-SOHO, Worldwide Schizophrenia Outpatient Health Outcomes; ICD, International Classification of Diseases (ICD); DSM, Diagnostic and
Statistical Manual of Mental Disorders
a
Community sample.
b
Hospital sample.
c
Mixed sample.

percentage of patients who were never psychotic in the past 2 years of
follow-up.
In terms of disability, among the ‘incidence’ cohorts, 40% of the
patients across all centres of ISoS had good or excellent global
functioning score on a modified version of the WHO Disability
Assessment Schedule (DAS) (Jablensky et al., 1980). The percent-
age of patients with good or excellent global functioning among all
Indian cohorts and also the Hong-Kong cohort were higher than
this; in Nagasaki only 25% had good or excellent functioning.
Among the ‘prevalence’ cohorts, across all centres of ISoS, nearly
50% had good or excellent functioning. It was 60% for Agra and only
25% for Beijing, Hong-Kong and Nagasaki. The results for global
evaluation of outcome was also similar: the proportion of patients,
whose overall course was classified as ‘worse’ was 10% or less
across the four Indian sites. In contrast, it was more than 25% in
other centres.
When mortality was examined with regard to standardized
mortality ratio (SMR), Nagasaki and Hong-Kong had the highest
Table 4
Findings of the non-ISoS studies (see text for details).

Author/Year/Loca-tion Outcome–measurement Outcome–results Mortality Treatment Co-morbidity Predictors

details
Clinical Functioning Overall Clinical Social- Overall
occupational

Chang WC et al/2011, CGI-S SOFAS CGI 58.8% achieved 23.7% achieved 17.4% met NA Medications & 6.5% ‘Substance Female sex, older age of
12,13/Hong symptomatic functional criteria for psychosocial; abuse’ onset, shorter DUP & early
Kong, China(EASY) remission (CGI-SCH remission (SOFAS both adherence symptom resolution
<3 on +ve and ve >60 and symptomatic details NA predicted symptomatic
symptom domains) employment/ and remission 3yr; (education,
education >12 functional onset-type, diagnosis and
months) remission substance use did not
and no predict outcome)
hospitalization
Liu T et al/2014/China NR NR NR NR NR NR 7.2%; medical:6%; NA NA (Age, education, marital
suicide:0.34%; status and income did not
others:0.8% predict mortality)
SMR = 10.17 &

B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12

12.42 for men &
women
Ran MS et al/2010/ NR Interview NR NR 27.3% had full- NR 19.6%; suicide:4.2%; ‘‘once treated’’ vs. NA Work history and
China about their time work; 49.7% other causes: 15.4% ‘‘never treated’’ disability at baseline
work status had part-time predicted work status;
work; 23% had no (Age, sex, education, age of
work onset, duration of illness,
treatment status did not
influence outcome)
Yang J et al/2014/China PANSS, CGI NR NR After 30yr: 18.87% NR NR 23.3%; suicide:6.6%; Only one patient NA Longer duration associated
achieved remission, Medical/ was receiving with poorer outcome (No
62.26% had accidental:16.6% antipsychotics other predictors studied)
deteriorated or had at 30yr follow up.
residual symptoms
Verma S et al/2012/ PANSS GAF NR 54.1% achieved 58.4% of patients 29.4% met Nil Comprehensive Excluded Female sex, shorter DUP,
Singapore, (EPIP) remission achieved criteria for treatment with substance fewer negative symptoms
significant both pharmacological abuse at baseline and early
functional symptomatic and psychosocial response at 3 months were
remission and interventions found to be significant
functional factors associated with
remission both symptomatic and
functional remission as
well as recovery at 2yr.
(Malay ethnicity was
associated with poor
functional remission &
Other ethnicity was
associated with poor
recovery as compared to
Chinese ethnicity)
Kua J et al/2003/ 1. Good: patient not 10yr: 35% poor 66% had 14.6%; suicide:9.7%; 44–48% were not NA Shorter illness
Singapore receiving treatment, well functioning; fair to others:4.9%; Suicide on treatment at duration and male
and working. 15yr: 38% poor good about 60 times higher different points in gender associated with
2. Fair: patient not functioning outcome and death about time better outcome;
receiving treatment and 20yr: 35% poor through-out 10 times higher than (Race, family history,
not working, or receiving functioning; the study general population education, marital
out-patient treatment and 10yr: 45% period status at presentation,
working. unemployed; premorbid Personality
3. Poor: patient receiving 15yr: 52% did not predict
treatment and not unemployed; outcome)
working, or receiving in- 20yr: 53%
patient treatment. unemployed
Global Assessment Scale,

7
 8
Table 4 (Continued )

Author/Year/Loca-tion Outcome–measurement Outcome–results Mortality Treatment Co-morbidity Predictors

details
Clinical Functioning Overall Clinical Social- Overall
occupational

Johnson S et al/2012/ BPRS, PANSS WHODAS NR 68% remitted; 24% had Median WHODAS NR 3.8% 25.3% regular on NA Higher insight & having
Vellore, India at least one additional score 8 medication non-medical explanatory
psychotic episode model associated with
remission;
Srivastava A et al/2009; PANSS GAF CGI 100% had PANSS 61.7% had GAF >80 61% had NA 80% adherence to NA Hard to interpret because
‘10/Mumbai, India positive score <21; CGI <2 treatment ensured of insufficient data
88% had PANSS analysis
negative score <21
Suresh et al/2012/Rural PANSS IDEAS NR NR 60% of patients had NR 6.5%; 90% treated with NR Medication adherence;
Karnataka, India mild/no disability Suicide:3.6%; antipsychotics; sociodemographic details;
in work Others:2.9% 74% had good psychopathology
adherence
Verghese A et al/1989/ PSE PPHS PPHS 64% in remission; 6% 61% had 27%-very 8.2% 85% had 8% had alcohol Treatment adherence,
Chennai, Vellore, continuous psychosis; occupational favourable; good/moderate abuse dangerous behaviour,
Lucknow, India 30% other impairment 40%- adherence on change in SES, delusion of

B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12

(SOFACOS) favourable; typical persectution, agitation
31% antipsychotics explained 22% variance
intermediate;
1.7%
unfavourable
outcome
Kurihara T et al/2011/ PANSS Interview on work, NR 19 (32.2%) had cross- NR Combined 25.4%; None with No medical Shorter DUP predicted
Indonesia Independent living sectional symptomatic remission Physical disease/ combined comorbidity both remission and
and peer relationship. remission (symptomatic accident:24%; remission and at intake mortality; (age, sex,
& functional): Suicide:1.6% 41.4% without education, marital status,
23.7% remission were premorbid functioning
on treatment and age at onset did not
predict either)
Marom S et al/2005/ Time to, number NR NR 66.9% had re- NR NR 3.5% Only data on Excluded High criticism was
Israel and duration of admission compliance at substance associated with higher
IP care baseline and not abuse rates of readmissions and
for the follow-up & longer hospital stay
duration
Ryu Y et al/2006/Japan PANSS, SAI GAF, REHAB, SFS NR Significant Significant Successful 2%; 1% each by suicide Comprehensive NA NR
improvement in improvement in community and accident medical and
PANSS scores. No many items of tenure: 76.9%, psychosocial
categories given; REHAB and SFS; no Hospitalization management
significant categories given due to physical provided to all
deterioration on SAI; illness 15.4%
no categories given and psychiatric
exacerbations:
5.1%
Haro MJ et al/2011/ CGI-SCH (a) Occupational NR 84.4% achieved clinical 24.6% achieved NR NA All patients Alcohol misuse: Baseline social
Korea, Malaysia status (b) Living remission functional received treatment 3.8%, Other functioning, being female
Taiwan (W-SOHO) arrangement (c) remission substance and previously untreated
Social interactions misuse: 3.1% were consistent predictors
of remission across
regions. Particularly
alcohol misuse had a lower
likelihood of achieving
clinical remission in east
Asia

EPIP, Early Psychosis Intervention Programme; EASY, Early Assessment Service for Young People with Psychosis; SOFACOS, Study Of Factors Associated With Course and Outcome of Schizophrenia; W-SOHO, Worldwide Schizophrenia
Outpatient Health Outcomes; PANSS, Positive and Negative Syndrome Scale(Kay et al., 1987); PSE, Present State Examination; PPHS, Psychiatry and Personal History Schedule; GAF, Global Assessment of Function (APA, 1994); CGI-
SCH, Clinical Global Impression-Schizophrenia (Haro et al., 2003); CGI-S, Clinical Global Impression-Severity (Guy, 1976); SAI, Schedule of Assessment of Insight (David, 1990); REHAB, Rehabilitation Evaluation Hall and Baker (Baker
and Hall, 1988); SFS, Social Functioning Scale (Birchwood et al., 1990); SOFAS, Social Occupational Functioning Assessment Scale (APA, 1994); BPRS, Brief Psychiatric Rating Scale (Overall and Gorham, 1962); WHODAS, WHO
Disability Assessment Schedule; IDEAS, Indian Disability Evaluation and Assessment Scale; NA, Not Available; NR, Not Reported
 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12
SMRs across all ISOS centres: 5.71 and 5.76 respectively; all Indian
centres except Chandigarh rural had SMRs less than 2.
Nearly all, or most patients across all the centres were on
antipsychotics for some time or most of the time throughout the follow
up period. However, in Agra, nearly 63% were never on antipsychotics.
Predictors of outcome were not reported separately for the Asian
centres. Moreover, though ISoS had a tool to assess substance use
among patients with schizophrenia, we were unable to find any
analysis regarding this important determinant of outcome.
3.2. Non-ISoS studies (Tables 3 and 4)
Studies varied in their specific aims: while a few studies had
specific aims of examining the course and outcome of schizophrenia,
several studies had recorded outcome as part of some other research
agenda, including examining the effect of early intervention
programmes (Chang et al., 2012; Verma et al., 2012), deinstitution-
alization (Ryu et al., 2006), expressed emotions (Marom et al., 2005),
treatment response (Haro et al., 2011), insight (Johnson et al., 2012)
etc., on the outcome. While (Liu et al., 2014) focused exclusively on
mortality, (Suresh et al., 2012) focused exclusively on work-
functioning. The variations in outcome of subjects across the studies
could be a function of such variable research agenda.
Generally, there was a slight male preponderance in all cohorts.
There was a mix of community-based, clinic (outpatient) – based
and inpatient cohorts (See footnote to Table 3). Eyeballing of the
results suggest that outpatient and community samples had
overall better outcomes. Striking exceptions to this observation are
(a) (Yang et al., 2013) cohort, in which only about 18% of a
community-dwelling patients had remission – most of them were
not on any treatment for nearly 30 years of their follow-up and (b)
(Shrivastava et al., 2010) cohort, where nearly all patients showed
clinical remission after 10 years of follow-up – all were on
continuous treatment for about 80% of the follow-up period.
In contrast to ISoS study, the non-ISoS studies varied widely in
their method of assessing clinical, functional and overall out-
comes: most commonly used tool for symptoms was the Positive
and Negative Syndrome Scale, (PANSS) (Kay et al., 1987); tools
used for assessing functioning were more varied – a few studies did
not even specify the tools for assessing functioning (Kua et al.,
2003; Marom et al., 2005). Such variations in assessment tools
makes comparison across different cohorts difficult–any interpre-
tation of similar or differential outcomes across the cohorts should
be made in this background.
Most studies were successful in following up about three-
quarters of their original cohorts through the follow-up period
ranging from 2 years to 30 years. While this could have influenced
the results, close examination of reasons for loss to follow up
suggests apparently extraneous causes like migration, inability to
trace, change of diagnosis, etc. The extent to which such factors
would influence the outcome of schizophrenia is debatable.
Most studies used different definitions of clinical remission and
reported remission in majority of their cohorts (54%–100%). In
contrast, improvement in functioning was achieved by slightly less
percentage of patients – in almost all studies, percentage of
patients with functional improvement, especially in the field of
work/occupational functioning, was less than those with clinical
remission. Not surprisingly, when combined improvement in
symptoms and functionality was considered, the percentage of
patients reporting improvement fell even further.
3.3. Mortality
Nearly all studies provided data on the percentage of patients
who died during the follow-up period. However, unlike in ISoS,
none of the studies provided comparison with mortality among the
9
general population except (Liu et al., 2014). This poses problems in
interpreting the mortality figures. Nevertheless, substantial
percent of patients had died at fairly young age. Generally, deaths
due to non-suicidal causes were commoner than suicide, though
some exceptions where there (Kua et al., 2003; Suresh et al., 2012).
Liu et al. (2014) reported very high rates of mortality among
schizophrenia patients with SMRs of 10.17 and 12.42 for men and
women respectively. For some age group of patients like 18–29
years, the SMR was as high as 75.02 and 239.26 for men and
women respectively. These SMRs are considerably higher than
those reported for the ISoS cohorts.
3.4. Substance use comorbidity
Many studies do not mention the rates of substance use
comorbidity among their cohorts; a few excluded those with
substance use comorbidity. (Chang et al., 2012) reported 6.5%
comorbidity with ‘substance abuse’; (Verghese et al., 1989)
reported 8% ‘alcohol abuse’ and (Haro et al., 2011) reported 3.8%
and 3.1% patients with ‘alcohol misuse’ and ‘substance misuse’
respectively. The papers are not clear about the time course of
comorbidity – whether these were life-time diagnoses or current
diagnoses.
3.5. Predictors of outcome
While ISoS report (Hopper et al., 2007) has provided important
predictors of long-term outcome, analysis of predictors is not
available for any individual centres, including the Asian ones. As
with other issues, there was high degree of variation in the
predictors of outcome across different non-ISoS centres. Never-
theless, several good prognostic indicators were consistently seen.
These included female gender, shorter duration of illness, better
baseline status, shorter duration of untreated illness, and early
treatment response and treatment adherence.
4. Discussion
In this paper, we reviewed studies on course and outcome of
schizophrenia in Asian countries. We reviewed studies examining
clinical/functional outcomes and/or mortality data in cohorts of
schizophrenia patients recruited in diverse settings and followed
up for a minimum of 2 years. We found wide variations in the
course and clinical and functional outcome of patients across
different cohorts in Asia.
As discussed in the methods and results section, we reviewed
the ISoS and non-ISoS studies separately. Though ISoS cohorts were
different insofar as the settings from which they were initiated, the
outcome measures were uniform and to this extent, the results
could be compared across the centres. However, the non-ISoS
studies varied widely in their settings, follow-up duration,
percentage of followed-up patients, measurement of outcome,
assessment of predictors of outcome, etc., which make comparison
across different cohort hard. Because of this, firm inferences
regarding cross-national comparisons can be made only from the
ISoS report. It was interesting to note that the outcome was better
in the Indian centres than in non-Indian centres. From this review
it is not possible to speculate the plausible explanation for this.
Clearly, the ‘developing’ vs. ‘developed’ country classification
would not be relevant here, as Beijing as well as all the Indian
centres were classified as from ‘developing’ countries; the status of
Hong-Kong in this regard is debated (Hopper and Wanderling,
2000). Many researchers have suggested that involvement of the
families in the care of schizophrenia patients may explain the
better outcome of the disorder (Nunley, 1998; Wig et al., 1987). In
the absence of concrete information about the involvement of
10 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12
family members in other centres, the assumption that this variable
could explain the differential outcome remains extremely conjec-
tural. Unfortunately, this issue of differential outcome of schizo-
phrenia across different regions remains unexplained.
Notwithstanding these regional variations, in both ISoS and
non-ISoS cohorts of schizophrenia patients in Asia the overall
outcomes are largely comparable to other long-term studies,
including (Bleuler, 1978; Ciompi and Müller, 1976; Huber et al.,
1975; Tsuang et al., 1979)
4.1. Mortality
Mortality is an important outcome in any medication condition.
Mortality in schizophrenia is assuming greater importance
recently, with studies systematically suggesting that the relatively
excessive mortality among schizophrenia patients vis-à-vis the
general population is increasing over the past decades (McGrath
et al., 2008; Saha et al., 2007). We specifically examined the issue of
mortality in all the reviewed studies. All ISoS centres had data on
SMRs. Consistent with better clinical and functional outcomes in
the Indian centres, SMR was generally lower in three of the four
Indian centres. While many non-ISoS studies provided definitive
data on mortality, the interpretation of this is seriously constrained
by the lack of comparison with mortality among the general
populations in the reports. Fewer studies had reported causes of
mortality: in many centres (Kurihara et al., 2011; Liu et al., 2014;
Ran et al., 2011) causes of death other than suicide were commoner
than suicidal deaths. However, in the absence of cause-specific
SMRs, interpretation of this differential rate of mortality due to
suicidal and non-suicidal causes is limited. For instance, in (Kua
et al., 2003), the percentage of patients dying due to suicide was
9.7% and those due to other causes was 4.9%. However, when
compared with general population figures, suicide rates were
as high as 80-times greater and non-suicidal deaths were about 10-
times greater in schizophrenia patients for the respective age-
groups. Only one study provided SMRs for different age- and sex-
groups of patients (Liu et al., 2014). SMR for men and women were
respectively 10.17 and 12.42, higher than all centres across ISoS.
Plausible explanation for this unusually high SMR is the fact that
the cohort consisted of only such patients who had substantial
disability–schizophrenia patients with milder form of illness (i.e.,
without disability) were not part of this cohort. Three studies had
relatively long durations of follow-up, viz., Kua et al. (20 years),
Yang et al. (30 years), and Kurihara et al. (17 years). Percentages of
patients committing suicide in these studies – 9.7%, 6% and 1.6%
respectively – were notably much lower than the 14–22% Twenty
year suicide rate reported in the literature from the western
countries.
4.2. Substance use comorbidity
Substance use comorbidity is well known to influence several
short-term outcomes of schizophrenia. It is surprising that there is
relative lack of literature on its influence on the long-term
outcome. We attempted to review this issue in the Asian
schizophrenia cohorts. Though ISoS centres had substance abuse
schedule among their assessment tools, we could not find data on
this in their reports. Among the non-ISoS studies, very few studies
examined substance use comorbidity. Consistent with a previous
review (Thirthalli et al., 2012), the proportion of patients with
substance abuse in the Asian centres, in the few cohorts where it
was studied, was less than 8%, much less than some of the western
studies (Barnes et al., 2006; Cantwell et al., 1999). Plausibly owing
to this, the influence of substance use comorbidity on the course
and outcome of schizophrenia was not studied in any of the
reports.
4.3. Antipsychotic treatment
Treatment with antipsychotics is recommended for preventing
relapse in multi-episode patients, PORT guidelines 2009, (Kreyen-
buhl et al., 2010) and only about 10–15% of patients with
schizophrenia are expected to remain free of relapses after the
first episode, APA practice guidelines 2004 (APA, 2004). In this
background, we reviewed the effect of continuation of antipsy-
chotics on the long-term outcome of schizophrenia. Different
cohorts had variable proportion of patients on antipsychotics for
variable periods of time in both ISoS and non-ISoS cohorts.
Unfortunately, the issue of adherence to antipsychotic medications
and outcome was not examined in most studies. Overall, across
ISoS and non-ISoS study, there was no consistent trend in terms of
percentage of patients on medications and percentage of patients
with good outcome. The review revealed two extreme examples:
in ISoS–Agra centre 63% of patients never received treatment and
in (Yang et al., 2013) cohort, nearly none received antipsychotics
through the follow-up period. While in Agra cohort majority were
free of psychosis at the end of 26 years of follow-up, most patients
had substantial deterioration in the Chinese cohort. The question
about treatment continuation was complicated by the fact that a
substantial proportion of patients in (Kua et al., 2003) study were
considered to have best outcome precisely since they were not
receiving antipsychotics. While antipsychotics are the standard of
care for acute schizophrenia in the modern day psychiatric
practice, it is possible that a substantial proportion of patients
may remain free of psychotic symptoms despite not being on
antipsychotics.
4.4. Limitations
The findings of this review need to be considered with a few
caveats. (1) We did not conduct a systematic review; narrative
reviews like ours may have inherent limitations in terms of
objectivity of inclusion of studies and results. Studies in the field
of long-term outcome in schizophrenia in Asia were very varied in
terms of their aims, study designs and methods, and could not yield
themselves to a systematic review. (2) We searched only English
language studies from one source. We could have missed out on
many Asian-language studies. (3) We could find long-term studies
on schizophrenia from only 9 of the 48 Asian countries–evidently,
the findings cannot be generalized to a large number of unrepre-
sented countries. (4) Though we set out to examine course as well as
outcome of schizophrenia, we could comment on the ‘course’ only in
ISoS centres [The ISoS (Hopper et al., 2007) has a number of other
outcome measures, interested readers are referred to this source];
from among the non-ISoS centres none of the studies had presented
data on the course of schizophrenia; they were rather focused on
outcomes at different points in time. (5) A number of studies in the
past few decades have highlighted the fact that medical comorbid-
ities are substantially higher among schizophrenia patients than in
the general population (Carney et al., 2006; Schoepf et al., 2014).
Studies reviewed in this paper did not systematically examine this
important aspect of course and outcome.
5. Conclusions
In Asian countries, overall, about 60% of patients with
schizophrenia show substantial clinical improvement and slightly
less percentage of patients show functional improvement. These
are consistent with findings from other long-term studies
conducted elsewhere in the world. Mortality among schizophrenia
patients relative to that of the general population is relatively less
in some Asian countries. However, variations in different outcomes
found across countries within Asia is largely similar to that found
 B. Holla, J. Thirthalli / Asian Journal of Psychiatry 14 (2015) 3–12
across different countries in the WHO studies. One obvious reason
for this is variations across individual studies in terms of their
scope and methodologies. However, the ISoS study, which used
comparable methods of investigation, found substantial variation.
Sadly, at this stage there is very little research evidence to
understand these variations. There is substantial evidence that a
diverse set of socio-environmental and cultural variables interact
with physiologic pathways related to psychological stress in
influencing the expression of psychosis (Howes and Kapur, 2009).
As van Os et al. (van Os et al., 2008) have elucidated, studies
examining the interaction between genetic and complex environ-
mental factors would have to necessarily involve researchers from
diverse disciplines. These should include researchers from cultural
anthropology, epidemiology, psychology, psychiatry, neurosci-
ence, neuroimaging, pharmacology, biostatistics, and genetics.
Measures of course and outcome should also move from clinical to
more real-life outcomes such as role-functioning, work-function-
ing, quality of life, stigma and caregiver burden. Finally, there is an
emerging interest in studying physical comorbidities such as
cardiovascular conditions, diabetes mellitus, metabolic syndrome
and cancer as measures of course and outcome of schizophrenia.
Future studies should systematically explore this important
dimension of long-term outcome of schizophrenia.
Conflict of interests
None
Acknowledgements
None
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