Division of Psychiatry, University of Bristol, UK
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook, NY, USA
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
Indian Council of Medical Research, Ansari Nagar, New Delhi, and WHO Centre for Research and Training in Mental Health, Agra, India
WHO Collaborating Centre, Sofia, Bulgaria
Department of Social Psychiatry, University Hospital Groningen, The Netherlands
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
University of Rochester, Rochester, NY, USA
Division of Mental Health, World Health Organization, Geneva, Switzerland
Department of Psychiatry, University of Hong Kong, Hong Kong
Department of Psychiatry, Universidad del Valle, Cali, Colombia
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Department of Psychology, University of Hawaii, Honolulu, HI, USA
Department of Neuropsychiatry, Nagasaki University School of Medicine, Nagasaki, Japan
Division of Mental Health, World Health Organization, Geneva, Switzerland
Institute of Mental Health, Beijing Medical University, Beijing, China
Psychiatric Demography Unit, Prague Psychiatric Centre, Prague, Czech Republic
Schizophrenia Research Foundation, Madras, India
Research Centre for Mental Health, Russian Academy of Medical Sciences, Moscow, Russia
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
St Loman's Hospital and the Health Research Board, Dublin, Ireland
Department of Psychiatry, Graduate School of Behavioural and Cognitive Neurosciences, Groningen, The Netherlands
Correspondence: Professor G. Harrison, Division of Psychiatry, University of Bristol, 41 St Michael's Hill, Bristol BS2 8DZ, UK. Tel: 0117 928 7768; Fax: 0117 925 9709; e-mail: G.Harrison{at}bristol.ac.uk
Declaration of interest Funded by the Laureate Foundation, the World Health Organization and the participating centres (see Acknowledgements).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To describe long-term outcome in 18 diverse treated incidence and prevalence cohorts. To compare mortality, 15- and 25-year illness trajectory and the predictive strength of selected baseline and short-term course variables.
Method Historic prospective study. Standardised assessments of course and outcome.
Results About 75% traced. About 50% of surviving cases had favourable outcomes, but there was marked heterogeneity across geographic centres. In regression models, early (2-year) course patterns were the strongest predictor of 15-year outcome, but recovery varied by location; 16% of early unremitting cases achieved late-phase recovery.
Conclusions A significant proportion of treated incident cases of schizophrenia achieve favourable long-term outcome. Sociocultural conditions appear to modify long-term course. Early intervention programmes focused on social as well as pharmacological treatments may realise longer-term gains.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Building upon earlier groundwork, the recently completed International Study of Schizophrenia (ISoS), coordinated by the World Health Organization (WHO), attempted to address these and related problems in a long-term follow-up study of 14 culturally diverse treated incidence cohorts and four prevalence cohorts, totalling 1633 subjects. Reported here are: crude and adjusted mortality (standardised mortality ratios; SMRs); 15- and 25-year cross-sectional outcomes for symptoms, disability and resource utilisation; longitudinal patterning of aggregated 15-year course data for first-episode cases and assessment of a late recovery effect; and (for a selected group of incidence cohorts) the predictive strength of selected baseline, centre and short-term (2-year) outcome variables. Comprehensive analyses and centre-specific reports will appear in the collaborative report on ISoS (Hopper et al, 2001). The investigators have also agreed to post the relevant research data on the internet (see http://www.csipmh.rfmh.org/isos.htm).
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Study cohorts
The International Study of Schizophrenia builds upon the results of earlier
studies. The International Pilot Study of Schizophrenia (IPSS;
WHO, 1973) reported better 2-
and 5-year outcomes for patients in developing centres. This
finding was reinforced in the subsequent Determinants of Outcome of Severe
Mental Disorders (DOSMeD) study (Jablensky
et al, 1992), which traced treated incidence cohorts in
geographically defined areas, using standardised methods of case finding and
diagnosis. A third WHO study, the Assessment and Reduction of Psychiatric
Disability (RAPyD; Wiersma, 1996), identified a further set of treated
incidence case groups assembled from diverse catchment areas. These three
cohorts offered a unique opportunity to carry out 15-year (DOSMeD, RAPyD) and
25-year (IPSS) follow-up studies. The cultural diversity of the sample was
further enhanced by adding two incidence case groups and one prevalence case
group to the field research centres (FRCs) recruited from the earlier studies
(12 from DOSMeD and RAPyD, three from IPSS).
Table 1 lists the 14 treated incidence cohorts and four prevalence cohorts, totalling 1633 subjects. The treated incidence case group of 1171 subjects included 766 DOSMeD subjects, defined as "cases in the early stages of the illness, evaluated as closely as possible to the point of their first contact with any service or helping agency" (Jablensky et al, 1992); 205 RAPyD subjects, selected by screening administrative records for recent onset of non-affective psychotic disorder; 200 additional subjects, including 100 subjects in the Hong Kong FRC randomly selected through a record review of first admissions for schizophrenia in clinics serving a defined catchment area, and 100 subjects in Madras, who earlier met Feighner criteria for schizophrenia (Thara & Eaton, 1996).
|
The prevalence case group included 373 cases from three centres from the original IPSS and 89 subjects from Beijing, who had met criteria for schizophrenia in a community epidemiological survey (Shen et al, 1986).
Table 1 also shows the distribution of living subjects (those with sufficient follow-up data for analysis), dead subjects, and those participants lost at follow-up (those with insufficient follow-up data for analysis).
Baseline diagnoses
The original IPSS and DOSMeD cohorts were identified before the widespread
use of operationalised diagnostic criteria such as ICD-10-DCR
(WHO, 1993) and DSM-IV
(American Psychiatric Association,
1994). For the IPSS, DOSMeD and RAPyD case groups, project
diagnoses were also made in terms of then-conventional criteria of ICD-8
(IPSS) or ICD-9 (DOSMeD and RAPyD) in accordance with the WHO glossary
(WHO, 1978). The newly added
case groups were identified through prior epidemiological studies (Beijing and
Madras both used the Present State Examination (PSE), and the latter employed
Feighner criteria) or by re-analysis of original case notes (Hong Kong).
Ideally, we would have wished to reassemble baseline and supplementary data for all ISoS cases and, blind to subsequent course and outcome, apply a diagnostic algorithm for one of the current operationalised research criteria. Resource constraints precluded such an exercise, however, and (apart from the three added centres) we decided to utilise the original project diagnosis made at baseline. In some FRCs, these were consensus diagnoses arrived at by two or more investigators; in others, diagnoses were made by an individual investigator without further review by a research team. The reliability of this process was investigated in the original DOSMeD study and found to be acceptable (Jablensky et al, 1992).
For ISoS, original ICD-8 or ICD-9 diagnoses were converted to ICD-10 diagnoses, as were case notes or project diagnoses provided by the three additional centres, using WHO cross-walk rules (WHO, 1994). This method provided the closest approximation to a standardised diagnostic system given the constraints of the study. For the descriptive analyses, study subjects in each of the groups were further divided into three analytical groups: schizophrenia only (F20.0-20.3; 20.5-20.9); psychotic disorders other than schizophrenia (F10.5, 22, 23, 24, 25, 28, 29, 30-34); and total psychoses (both groups combined).
Tracing exercise
The ISoS research was approved through local FRC ethics committees (or
their functional equivalents). Tracing methods varied considerably (and are
described in detail in centre reports;
Hopper et al, 2001),
but efforts generally began with the last known address and worked forward in
time, consulting clinical records, address directories, death registries,
primary care practitioners and family contacts. Tracing was facilitated in
those areas where psychiatric case registries were available or research
subjects had been followed clinically. Logistical obstacles could prove
formidable where communication facilities were primitive or in areas of high
residential mobility.
Follow-up assessments
Training and reliability
Most of the principal investigators had extensive experience of using the
PSE (and several other ISoS instruments) from prior IPSS, DOSMeD and RAPyD
studies. Two of the three added FRCs had also collected PSE data at baseline.
Because ISoS introduced new instruments and recruited some inexperienced
fieldworkers, training and reliability were approached systematically.
(Further details are available in Siegel
et al, 2001.)
The ISoS follow-up instruments were combined in a single package, accompanied by procedural guidance for local training and implementation in fieldwork exercises. The full package was introduced at three training seminars for principal investigators spread over 2 years. At each seminar, experienced users demonstrated the instruments. Training also made use of video-tapes and/or case vignettes.
Reliability was examined both within centre and between centres. Five centres also carried out a maintenance reliability check mid-way through their follow-up procedures. Within centres, the rater-observer method used live or videotaped interviews and had observers make independent ratings. Each FRC aimed to assess 10 patients, a target met in nine centres. Another completed ratings for five cases, and a centre with only a single clinician carried out a test-retest assessment. No reliability assessments were carried out in Moscow, Honolulu and Rochester, where single investigators made nearly all ratings. Mannheim and Cali did not carry out within-centre reliability exercises because their data collection had been completed through existing studies before ISoS formally began.
The between-centre reliability exercise used five videotapes of patients with a history of psychosis comparable to the ISoS incidence cases. Videotaped interviews were done in English with English-speaking subjects; the tapes were accompanied by interview transcripts and structured case vignettes that approximated case notes. Videotapes and vignettes were circulated for reliability assessments of the PSE, DAS and LCS. An average of 29 researchers rated each case. All but one centre assessed at least one tape; the majority, three or more.
Because measuring pairwise agreements between raters does not take into
account chance agreement, the statistic is commonly used. Low
variability for an item, however, may produce imprecision in the
statistic. We therefore devised a customised method for assessing interrater
reliability. We tested only items for which ratings were categorical and
defined a range of variability sufficient for reporting
. Variables
were considered to have insufficient variation if the percentage scoring
absent for that item approached 0 or 100% (i.e. 0-10% or
90-100%).
Analytical approach
Mortality
Cause of death was determined from available data at each centre (death
certificates, autopsies, etc). SMRs were calculated against a standard
population that depended upon the location of the centres. For all but three
centres in India, the standard was the corresponding national population; for
the Indian centres, it was the national population up to 1990 and the relevant
state-specific populations thereafter. For most countries, WHO mortality rates
were used (WHO, 1996),
although other sources were also used. Statistical significance of SMRs was
determined by the method of Breslow & Day
(1987). With the exception of
Rochester (where no deaths were recorded), for each centre a Kaplan-Meier
(Kaplan & Meier, 1958)
survival distribution was computed for all deaths.
Clinical outcomes and social disability in subjects traced alive
Outcome data were aggregated (unweighted) within each analytical group.
Although data are not presented by individual FRCs, the range of values is
reported for the principal outcome variables. Associations between diagnostic
group and pattern of course variables were assessed using the
2 statistic.
Predictor variables
Predictive relationships between baseline and early course variables and
longer-term outcome were examined for the DOSMeD cohorts only (461 subjects),
because these were the only subjects for whom a sufficiently consistent
data-set existed. Of those with a baseline diagnosis of psychosis, 60.2% were
found alive and assessed; 30.4% were lost to follow-up; and 9.4% had died. A
separate examination (Drake et
al, 2001) uses a propensity score method
(Rosenbaum & Rubin, 1983)
to assess the potential bias introduced by basing our analysis on the alive
cohort only, and finds it negligible.
Predictive analyses used two measures of outcome at follow-up derived from the GAF scale (symptoms and disability). Course of illness over the entire follow-up period was described in terms of patterns constructed from the data on symptom presence and strength over time obtained via the LCS. These were divided into complete remission (no residual symptoms between episodes, return to premorbid functioning) and incomplete remission (or continuous psychosis). In this, we followed the precedent of Jablensky et al (1992) and Craig et al (1997) to enable comparisons with earlier analyses of short-term outcome.
The set of variables chosen was based on a conceptual framework that links environmental, predisposing and clinical factors to outcomes, and takes account of factors that may mediate their impact. Selected items included variables reported to be related to outcome in the prior reanalysis of short-term outcome (Craig et al, 1997): age at first contact, gender, marital status, contacts with close friends, history of drug or alcohol use, type of onset and diagnosis. We also included others suggested in recent literature, for example symptoms available from the PSE which form part of the deficit syndrome (Kirkpatrick et al, 1989). Duration of untreated psychosis, cited by several researchers (Larsen et al, 1996), could not be used because of insufficient reliable data.
The diagnosis was the baseline ICD-9 clinical consensus diagnosis, converted to ICD-10 and grouped into five categories (schizophrenia, schizoaffective disorder, acute schizophrenia disorder, bipolar disorder/depression and other psychoses). The short-term (2-year) outcome variables were percentage of time experiencing psychosis and pattern of course. Only one subject-level mediating variable could be included in the model family involvement with treatment over the follow-up period. Medication was not used because univariate analysis showed that in the first 2 years nearly all subjects received anti-psychotic medication, while later in the follow-up period the odds of being on medication for those with poor outcome were much higher than for those with good outcome. To find that medication use predicted outcome would thus have been uninformative.
Coarse-grained area-level mediating variables were constructed for social stability, prevailing conventions of illness attribution, and configuration and strength of kinship ties, as well as for certain aspects of the treatment system (e.g., existence of national health insurance). Such constructions made use of qualitative data supplied in answer to open-ended questions by key informants as well as the descriptions of locales by investigators (Hopper et al, 2001). A Delphi-like procedure, employing five independent raters, was used to arrive at composite scores (Siegel et al, 2001).
A two-part statistical procedure was used for the two GAF outcome variables. First, stepwise linear regression was applied to distinguish the variables most highly related to outcome. In these models, sample sizes were considerably reduced from the full cohort size because subjects were excluded from the analysis if data were missing for any regression variable. A second model was fitted using only the variables distinguished in part one. The analyses presented from the clinical outcomes step used a data-set that is about 90% of the total (419/461). Two sets of analysis were carried out: first, centre was included as a categorical variable then, second, centre was replaced by the set of descriptive locale variables.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Attrition in follow-up
Loss to follow-up across all case groups of ISoS ranged from an average 30%
in the DOSMeD cohort to 10% in the RAPyD cohort, amounting to 399 subjects or
about one-quarter of the total (Table
1). Of the 1005 living participants, the treated incidence
(n=776) and prevalence (n=229) cohorts were sub-categorised
by baseline ICD-10 diagnosis into the three analytical groups: schizophrenia
(n=644); psychoses other than schizophrenia (n=361); and all
psychoses (n=1005). Mean ages at follow-up were: schizophrenia
incidence group, 41.4 years; schizophrenia prevalence group, 51.2 years; other
psychosis incidence group, 42.8 years; and other psychose prevalence group,
54.5 years.
The literature frequently cites gender, mode of onset and short-term course of illness as predictors of outcome (Jablensky et al, 1992; Harrison et al, 1996). To assess bias in the follow-up cohort, we compared their distribution in the living groups versus those subjects lost to follow-up. In the incidence cohorts, there was a higher percentage of females in the living groups compared with those subjects lost to follow-up in the total group with psychotic illnesses (P<0.10) and the group with schizophrenia (P<0.05) (51.9% v. 45.4% and 49.4% v. 38.4%, respectively). The opposite occurred in the prevalence cohorts, where a (non-significant) higher proportion of living males appeared in both analytical groups. Percentages were almost equal for the other psychoses group in both incidence and prevalence cohorts. Mode of onset was divided into sudden/acute and slow/insidious. In all six analytical groups, there was a higher (but non-significant) proportion of acute/sudden cases in the living group, although the power of our analysis may have been low. Favourable early course of illness was defined as complete remission between psychotic episodes. Five of the six analytical groups showed a higher (but non-significant) percentage of complete remissions in the living group compared with those lost at follow-up; in the other psychoses incidence group, the percentages were essentially equal. Overall, therefore, attrition in follow-up appears biased toward males and subjects with slower onsets and less favourable early pattern of course.
Completed assessments
For the main instruments, 88.6% of participants still living at follow-up
were interviewed with the PSE. Seventy-nine per cent had completed DAS scales
(with a further 14% rated on the basis of informants) and 85% had completed
LCS (with a further 15% completed on the basis of information from informants
and extracted from case records).
Reliability
The range of agreement according to the statistic for each of the
three principal instruments (PSE, DAS and LCS) is shown in
Table 2. We adopted the
convention that moderate to very good agreement is reflected by
values
above 0.4 (Fleiss, 1981).
|
In the intracentre reliability exercise before the start of the study, only
two variables for the three instruments had values less than 0.4; for
108 items,
values were higher, indicating acceptable agreement between
raters before additional training. For the intercentre exercise, the best
split of
values showing sufficient variation was set at 25-75% (i.e.,
between 25 and 75% of ratings were scored absent). Moderate to very good
agreement was achieved for 86% of PSE items, 80% of DAS items and 77% of LCS
items.
Mortality
Table 3 lists the sample
size, deaths and SMRs for each centre. Differences in selection criteria and
length of follow-up preclude drawing specific conclusions, but a few patterns
are discernible. In non-industrialised countries, the majority of known deaths
were listed as natural, whereas the reverse was true in industrialised
countries. Suicide accounts for the majority of deaths from unnatural causes.
In contrast to reports from other studies, we did not find that infectious
diseases contributed disproportionately to the natural death toll.
|
All but five centres had SMRs significantly greater than one: two of these were located in non-industrialised countries (Cali and Madras), two were in Eastern European countries (Sofia and Moscow), and Rochester recorded no deaths. The eight highest SMRs were in industrialised centres (including Hong Kong). When examined by gender and age at study entry, a much more variable pattern emerged (see Craig et al, 2001): young-entry male patients tended to have significantly elevated SMRs among the industrialised centres, whereas females showed no significant pattern of mortality risk by centre type. Survival probability estimates at 5, 10 and 15 years showed few significant differences between centres.
Cross-sectional measures of outcome
Table 4 shows global outcome
data for all psychoses, schizophrenia and other psychoses subjects in the
incidence and the prevalence cohorts as defined above. Over half of the living
ISoS participants 56% of the incidence cohort and 60% of the
prevalence were rated recovered on the Bleuler scale and
nearly half had not experienced psychotic episodes in the past 2 years.
Ratings of current symptomatology and functioning closely tracked the more
global assessments. Outcomes for schizophrenia were less favourable than for
other psychoses across all domains, although the percentage rated as globally
recovered was still close to 50%. Wide variation is apparent
across centres, although numbers for some cells were small.
|
Measures of most recent 2-year course of disorders
LCS living arrangements
The majority of living participants, in both incidence and prevalence
cohorts and across all diagnostic groups, had spent most of the past 2 years
living with family or friends. Small percentages, ranging from 3.4% among
people in the other psychoses prevalence cohort to 11.6% among people in the
schizophrenia incidence cohort, had spent the majority of the past 2 years in
institutional settings. Twelve people (1.5%) in the incidence cohort and four
(1.7%) in the prevalence cohort had been homeless (defined as living on the
street or in a designated shelter) at some point in the past 2 years; 4.6% of
the incidence group had been homeless at some point during the follow-up
period.
LCS course type and negative symptoms
Table 5 shows course of
illness over the past 2 years and presence of prominent negative symptoms by
course type. Just over one-quarter (26.8%) of all people in the incidence
cohort had been continuously ill over the past 2 years: 33.6% of those in the
schizophrenia group and 14.6% of people with other psychoses. This pattern was
more common in the prevalence group (37.5%), especially among people with
schizophrenia (46.4%). Negative symptoms were prominent in almost half the
people with continuous illness, across all analytical groups, except those
people in the other psychoses incidence group; they were relatively infrequent
in those with episodic psychoses.
|
LCS employment
As Table 6 shows, employment
figures (including paid work and housework) for people in the incidence and
prevalence cohorts across the two analytical groups range from 56.8% among
people in the schizophrenia incidence cohort, to 73.9% or better in both the
schizophrenia and other psychoses groups in the prevalence cohort. Quality of
work for full-time workers and those doing housework was rated as satisfactory
in 80% or higher, excepting the schizophrenia incidence cohort for housework.
Although men were much more likely to be employed at paid work, performance
ratings for women who did such work were comparable to those of men.
|
LCS help seeking and sources of support
One-fifth (20.9%) of people in the incidence cohort had been hospitalised
for psychiatric reasons at some point in the past 2 years, a considerably
larger number (69.3%) had received some form of substantial psychiatric
treatment (chiefly medication), and a minority (23.8%) had received other
professional help. Over half (52.9%) had been on neuroleptic medication for
most of the past 2 years. Percentages of all forms of treatment were smaller
in the prevalence cohort.
Longitudinal course
Course of illness patterns were constructed
(Table 7) using a modified
version of Bleuler's typology, which combines mode of onset (acute versus
insidious), overall trajectory (simple versus episodic), and end state
(Bleuler recovered or minimal symptomatology (good), versus moderate or severe
impairment (poor)). With the sole exception of the group with schizophrenia in
the prevalence cohort, episodic illness (whether acute or insidious in onset)
accounted for favourable outcomes in well over half of all participants. Of
the episodic group, over two-thirds of people (68%) in the schizophrenia
incidence cohort had at least two illness episodes.
|
Sixteen per cent (15.7%) of schizophrenia cases in the incident cohort showed evidence of late improvement at the 15-year follow-up. That is, they were described as having continuous symptoms (simple course type) in the second epoch, but were rated as recovered in the third. A similar finding emerged (18.4%) in the prevalence cohort.
Stricter operationalisation of recovery
To be meaningful, the concept of recovery requires careful
operationalisation. When defined as receiving both a Bleuler rating of
recovered and a GAF-disability rating greater than 60, 37.8% of people with
schizophrenia and 54.8% of people with other psychoses in the incidence cohort
qualified. Because such rates include subjects who had received treatment or
been hospitalised in the past 2 years, they may be viewed as treated
recovered rates. If we adopt a more stringent concept, excluding those
with a recent (in the past 2 years) episode of treatment (as in
Mason et al, 1995),
the proportion of recovered subjects falls sharply, to only 16.3% of those
people with schizophrenia in the incidence cohort and 35.8% of people without
schizophrenia. Even so, subjects with a GAF score greater than 60 may still
include those with some difficulties in areas of social or
occupational functioning. How such persisting difficulties may affect overall
quality of life we were unable to assess.
Predictors of outcome
For GAFS and GAFD, in all regression models, the percentage
of time experiencing psychotic symptoms in the first 2 years was the strongest
predictor (first to enter stepwise regression models) of both symptom and
disability scores. For symptom scores, the only additional variable that
entered the model in which centre was included
(Table 8) was the variable
centre. In the analysis excluding the centre, but including area
variables, two additional variables entered the model. By order of entry, they
were baseline diagnosis and age at study entry. Those with a baseline
diagnosis of schizophrenia had significantly poorer symptom scores than those
in the acute schizophrenia and the bipolar groups, as did persons who were
younger at study entry.
|
For disability, the variables in addition to the percentage of time experiencing psychotic symptoms that entered the model in which the centre is included were, in order of entry: centre and diagnosis. In a comparison of all centres with Chandigarh Urban, only those in Dublin, Prague and Rochester had significantly poorer disability scores. The finding on diagnosis is similar to that for the symptom score when centre is excluded, except that those with schizoaffective disorder were also significantly better than those with schizophrenia. In the second analysis that excluded the variable centre but included area variables, variables entering the model were, by order of entry: diagnosis, blunted affect, national health insurance, history of drug use and family involvement in treatment. The finding for diagnosis indicated that those with acute schizophrenia and schizoaffective disorders had better outcomes than those with schizophrenia. Those without national health insurance had better disability scores. Family involvement with treatment decisions, presence of blunted affect from the baseline PSE, and premorbid drug use were associated with poorer disability scores.
In an earlier analysis, Craig et al (1997) re-analysed 2-year outcome data from the DOSMeD study in order to examine the role that the centre plays in predicting course. A statistical approach (recursive partitioning or Classification and Regression Trees (CARTs); Breiman et al, 1984) was used in which predictor variables are not pre-grouped. Their analysis confirmed earlier findings (Jablensky et al, 1992) that a strong predictor of pattern of course was a certain grouping of centres. However, in the CART analysis that grouping, while resembling the developing/developed dichotomy reported in earlier WHO studies, was not identical to it. Subjects in Nottingham and Prague joined the developing countries to form a sub-group with more favourable outcomes. A CART analysis of the present follow-up data of the DOSMeD cohort (Siegel et al, 2001) found that Chandigarh Rural and Nottingham had better outcome than other centres; however, this was true only for those subjects whose percentage of time experiencing psychotic symptoms in the early part of their illness (first 2 years) was 13.5% or less.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Limitations of the data
In far-flung collaborative studies of this sort, data quality control is
always of concern. Experience, repeated training, reliability checks, and
centralised data management and monitoring served, we believe, to minimise
this hazard. Success in follow-up was encouraging. Still, findings require
qualification in view of certain methodological constraints. The marked
heterogeneity in outcome across ISoS centres, for example, might be partially
due to biases in case ascertainment at follow-up and assessment methods.
The ISoS living cohort differs from those lost to follow-up in ways that potentially bias outcome data in a more favourable direction. Making the most conservative assumption that all cases lost to follow-up fell into the poor outcome categories we recalculated results. Thus corrected, the percentage of Bleuler recovered cases falls from 56% to 41% for all psychoses, and from 48% to 35.7% for schizophrenia. A similar range of adjusted outcome values was obtained for the GAFS and GAFD global outcome variables. However, for the predictive analyses of the DOSMeD cohort, the Drake et al (2001) examination found that biasing effects introduced by basing analysis on the living cohort alone were negligible. We conclude that our findings, while attenuated somewhat, cannot be explained by systematic biases in follow-up.
Because they appear so consistently across the ISoS centres, the case attrition data are also informative concerning likely biases in similar follow-up studies. Intuitively, we might predict that those with better outcomes would be more likely lost to follow-up because of greater social and occupational mobility and reluctance to consent to interview about past events with strongly negative associations. We found a trend in the opposite direction, with males, those with slow illness onset and individuals with poor short-term course more likely lost to follow-up. The implication that those most at risk of deteriorating are being lost from psychiatric aftercare should concern mental health service providers.
Reliability of case definition at entry is another potential source of error. Although ICD10 diagnoses were generated using crosswalk algorithms, the original diagnoses in ICD8 or ICD9 were not operationalised, and criteria may have been applied inconsistently. However, for all but one of the study cohorts (Hong Kong) baseline diagnoses were established using the same semi-structured mental state assessment tool (the PSE), followed by consensus research diagnosis meetings in most centres. This is likely to have substantially reduced information variance and the chances of systematic diagnostic bias operating between centres.
Although reliability in the application of follow-up instruments was tested
by formal reliability exercises (assessment of videotaped interviews), its
implementation was incomplete. The majority did, however, complete three or
more. Nor was there sufficient variability across all the items in the three
principal instruments to ensure the sensitivity of as a measure of
reliability, and therefore the number of test items was restricted.
Nevertheless, we found a fair to very good measure of agreement both within
and across the FRCs, even with videotaped interviews having been conducted in
English, which was not the first language for many study participants.
Further, the DAS requires knowledge of local norms and conventions in order to
rate dimensions of social disability, which may have reduced intercentre
reliability for this instrument.
We also regret that we were unable to carry out a systematic needs assessment (e.g. for social support, residential care, treatment) using standardised measures. The LCS rating of living independently in the community proved an unreliable proxy for met need in terms of either the appropriateness of residential placement or the level of social support. We learned, for example, that although three-quarters of the 259 subjects from Beijing, Madras, Hong Kong and Sofia (the group for whom sufficient data were available) were coded as living with family, for a substantial percentage (39.5%) this amounted to a surrogate institutional arrangement in terms of the intensive support required. Similarly, in the judgement of the Nottingham field-worker, about 10% of cases rated as living with family or friends could not sustain independent function in the community were this level of support to be withdrawn (Harrison et al, 1994). Residential ratings of living independently must be interpreted with great caution, as the burden of care on many families may have been considerable. Rates of institutionalisation (hospitalisation and supervised residence) are also problematic, reflecting administrative policy and resource availability at least as much as need for care. Proportions in supported residential accommodation were higher for industrialised FRCs with the exception of Hong Kong and Moscow.
Working concepts of recovery require qualification as well. Our study relied heavily upon absence of symptoms, social disability and resource utilisation. This should not be equated with recovery of the level of function achieved before the onset of illness, and even less with the recovery of lost potential. Commentators advocating the user-perspective (e.g. Prior, 2000) focus on the individual's recovering a meaningful and fulfilling life within the limitations of the disorder, an important judgement our data do not allow us to make. Nor did our methods permit investigation of the subtle, but potentially powerful effects of operant cultural or environmental factors on course of illness and restoration of function. Finally, as noted earlier, data on the timing of onset more precisely, on the emergence of early symptoms that would have enabled us to estimate duration of untreated psychosis were not reported consistently enough to permit analysis of its potential effect.
Mortality
For those few centres in which a substantial proportion were lost to
follow-up, it is possible that the mortality risk was some-what overstated, as
the status of deceased individuals is probably ascertained more readily than
that of living ones. This limitation is mitigated by the use of statistical
methods that take into account censored follow-up data. It is also possible
that cross-centre variation in the reliability and validity of routine death
certificate data may have resulted in unnatural causes of death going
undetected, particularly in non-industrialised centres.
Such limitations notwithstanding, the ISoS findings nevertheless extend and refine the findings of earlier studies in populations from largely industrialised settings. First, despite marked variations in SMR across cultural settings, the absolute mortality risk for patients with schizophrenia and related psychoses is high and remarkably similar in all the countries examined. Second, differences between developed and non-industrialised countries may be pronounced. For centres in industrialised countries, our results tend to replicate earlier reports of increased mortality risk for unnatural death and for younger patients. For non-industrialised countries, however, they suggest different, setting-specific risk factors, reinforcing the need for future studies to examine mortality in a broader range of cultures (see Simpson & Tsuang, 1996).
Predictors of long-term course and outcome for the DOSMeD cohort
The robust finding of this analysis is that, of all the variables thought
to relate to long-term outcome, the strongest predictors were measures of
early illness course. Percentage of time spent experiencing psychotic symptoms
in the 2 years following onset was the best predictor for all outcome
measures: the shorter the percentage of time with psychotic symptoms, the
better the longer-term symptom and disability scores, as well as overall
course of illness. A CART analysis of the data revealed that pattern of course
in the first 2 years was also related to long-term pattern of course. Also, a
presenting diagnosis of schizophrenia (in contrast to, depending on the
analysis, either schizoaffective disorder, acute schizophrenia or bipolar
disorder/depressive psychosis) enhanced the likelihood of poor symptom or poor
disability scores. Although type of onset did not play an independent
explanatory role for any study measures, it may be viewed as having an effect
at one remove, since it was significantly related to percentage of time with
psychotic symptoms in the 2-year follow-up study of this cohort
(Jablensky et al,
1992). In addition, baseline variables of age (younger), family
involvement in treatment, history of drug use, symptoms of blunted affect and,
from the CART analysis, lack of close contact with friends, as well as loss of
interest, were somewhat related to an increased likelihood of poor course or
outcome.
The regression models also highlight the role that cultural variables may play in explaining outcome. The centre variable entered the stepwise regression models for both symptoms and disability at the second step, indicating that rates of recovery do vary by location. The effect that those with national health insurance have poorer outcomes may only be approximating a developing country effect since those without such insurance are in large part those in the two Indian centres (n=113). The other centres without national health insurance, Honolulu and Rochester, only contribute an additional 57 persons. Overall, the data show that early poor outcome predicts a continuation of incomplete remission and unfavourable long-term status in both symptom and disability assessments. Premorbid signs and symptoms suggesting poor social adjustment also enhance the likelihood of adverse long-term outcomes, as do symptoms of a deficit syndrome. That said, living in certain areas appears to improve chances of recovery, even for subjects with unfavourable early-illness course. The precise nature of these setting- or culture-specific effects remains to be unravelled.
Implications for long-term management of psychotic illness
The ISoS mortality findings suggest that, for industrialised countries,
clinical (and public health) efforts to reduce the causes of unnatural death
(e.g. suicide prevention strategies) could reduce the mortality risk,
especially among young males. In non-industrialised countries, the
predominance of unnatural deaths may be due to differences in access to
medical care between persons with schizophrenia and the general population; if
so, health services should aim at earlier and better diagnosis and at
treatment of comorbid medical conditions. Our findings fail to replicate
earlier studies whose results (increased deaths from infectious disease among
psychiatric patients) suggested compromised immune systems. More recent
studies, especially in settings heavily affected by the AIDS epidemic, may
produce different findings.
The ISoS data underline the heterogeneous nature of recovery in schizophrenia across linked but separate domains of outcome. This is nowhere more apparent than in the 20% or more of individuals who managed to sustain employment despite some persisting symptoms and/or disability. These data highlight the need for a better understanding of the unevenness of restored function, and the different schedules of recovery that may obtain across different domains, at varying paces, to disparate degrees of thoroughness (Strauss & Carpenter, 1972; Davidson & Strauss, 1992). Future research should examine how such discrepancies are handled by people, how they infiltrate identity (Weingarten, 1994) and how variant schedules of recovery might be supported or subverted by community-based interventions and treatment programmes.
Our data also give evidence of a late recovery effect. If one allows for differences in measurement of mode of onset, there are striking parallels in the course of illness patterns found by Bleuler (1978) and the trajectories of incidence ISoS cases. Approximately half of each group was characterised by episodic course type with good global outcome. Episodic courses eventuating in poor outcomes, which accounted for nearly one-third of the Vermont cohort (Harding et al, 1987), amounted to only 9% of people in the Bleuler and ISoS incidence cohort. Conversely, at the 15-year point of follow-up of the incidence cohort, we observed a pattern of good outcome following a simple (that is, continuous impairment) course type in 16% of incidence cases. Although our effect was weaker compared with Harding et al (1987), these data support the case for maintaining therapeutic optimism and for re-instituting employment and rehabilitation programmes despite failures earlier in the course of the illness.
Our data underscore but fail to elucidate the contribution of sociocultural factors to the longer-term course and outcome of psychosis. Unravelling the epigenetic puzzle of how complex gene-to-environment interactions influence different aspects of life course in schizophrenia may eventually require dimensional rather than categorical conceptualisations of psychosis. However, those interactions occurring at the time of early symptom development may prove most toxic in terms of long-term outcome, offering a critical window for therapeutic intervention. This will need to embrace social as well as pharmaceutical measures, but because our data are silent with respect to local cultural responses to early behavioural change, we cannot yet say how early intervention strategies might be designed to enhance their therapeutic impact.
The overarching message of ISoS is that schizophrenia and related psychoses are best seen developmentally as episodic disorders with a rather favourable outcome for a significant proportion of patients. Because expectation can be so powerful a factor in recovery, patients, families and clinicians need to hear this. At the same time, the hope these data represent should not be overdrawn. Subjects with poor prognostic indicators were overrepresented in those lost to follow-up, and mortality was elevated throughout. A relatively modest proportion (about one-sixth) was judged as having achieved complete recovery, in the sense of no longer requiring any form of treatment.
Despite these notes of caution, the ISoS findings join others in relieving patients, carers and clinicians of the chronicity paradigm which dominated thinking throughout much of the 20th century. They offer robust reasons for therapeutic optimism and point to a critical window of opportunity in the early period of syndromal differentiation. If the course of these disorders depends upon short-term outcome and sociocultural setting, then early intervention programmes and intensive engagement strategies may have a favourable impact upon the evolution of symptoms over the next 15-25 years, at least for some patients. The dual challenge remaining is first to open up further the black box of culture subsumed under centre effects and then to find ways of translating customary practices into interventions by design. Future studies will require both qualitative and quantitative methods to explore the characteristics of environment that promote recovery.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The chief collaborating investigators in the field research centres are: Aarhus, A. Bertelsen; Agra, K. C. Dube; Beijing, Y. Shen; Cali, C. Leon; Chandigarh, V. Varma and (since 1994) S. Malhotra; Dublin, D. Walsh; Groningen, R. Giel and (since 1994) D. Wiersma; Hong Kong, P. W. H. Lee; Honolulu, A. J. Marsella; Madras, R. Thara; Mannheim, H. Hafner and (since 1989) W. an der Heiden; Moscow, S. J. Tsirkin; Nagasaki, Y. Nakane; Nottingham, G. Harrison; Prague, C. Skoda; Rochester, L. Wynne; and Sofia, K. Ganev. Coordination of the data collection, experimental design and data analysis were carried out by the WHO Collaborating Centre at the Nathan S. Kline Institute for Psychiatric Research under the direction of E. Laska. At WHO headquarters, Geneva, the study has been coordinated by N. Sartorius (until August 1993), by W. Gulbinat (September 1993April 1996) and by A. Janca (since May 1996).
The authors also gratefully acknowledge the contribution of Ezra Susser, Sarah Conover and John Cooper to the early design and development of instruments for the ISoS.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Andreasen, N. C. (1989) The scale for the assessment of negative symptoms (SANS): conceptual and theoretical foundations. British Journal of Psychiatry, 155 (suppl 7), 49-52.
Bleuler, M. (1978) The Schizophrenia Disorders. Long-Term Patient and Family Studies (trans. by S. M. Clemens). New Haven and London: Yale University Press.
Breiman, L., Friedman, J., Olshen, R., et al (1984) Classification and Regression Trees. New York: Chapman and Hall.
Breslow, N. E. & Day, N. E. (1987) Statistical Methods in Cancer Research, Volume II: The Design and Analysis of Cohort Studies (ed. E. Heseltine). Lyon: World Health Organization and International Agency for Research on Cancer.
Ciompi, L. (1980) Catamnestic long-term study on the course of life and ageing of schizophrenics. Schizophrenic Bulletin, 5, 606-618.
Craig, T. J., Siegel, C., Hopper, K., et al (1997) Outcome in schizophrenia and related disorders compared between developing and developed countries. A recursive partitioning re-analysis of the WHO DOSMD data. British Journal of Psychiatry, 170, 229-233.[Abstract]
Craig, T. J., Wanderling, J. & Janca, A. (2001) Long-term diagnostic stability in international cohorts of persons with schizophrenia and related psychoses. In Prospects of Recovery from Schizophrenia An International Investigation (eds K. Hopper, G. Harrison, A. Janca, et al). Madison, CT: Psychosocial Press, in press.
Davidson, I. & Strauss, J. S. (1992) Sense of self in recovery from severe mental illness. British Journal of Medical Psychology, 65, 131-145.[Medline]
Drake, C., Levine, R. & Laska, E. (2001) Identifying prognostic factors that predict recovery in the presence of loss to follow-up. In Prospects of Recovery from Schizophrenia An International Investigation (eds K. Hopper, G. Harrison, A. Janka, et al). Madison, CT: Psychosocial Press, in press.
Endicott, J., Spitzer, R. L., Fleiss, J. L., et al (1976) The Global Assessment Scale. A procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry, 33, 766-771.[Abstract]
Fleiss, J. L. (1981) Statistical Methods for Rates and Proportions (2nd edn). New York: John Wiley & Sons.
Ganev, K., Onchev, G. & Ivanov, P. (1998) A 16-year follow-up study of schizophrenia and related disorders in Sophia, Bulgaria. Acta Psychiatrica Scandinavica, 96, 200-207.
Harding, C. M., Brooks, G. W., Ashikaga, T., et al (1987) The Vermont longitudinal study of persons with severe mental illness. I. Methodology, study samples, and overall status 32 years later. American Journal of Psychiatry, 144, 718-726.[Abstract]
Harrison, G., Mason, P., Glazebrook, C., et al
(1994) Residence of incident cohort of psychotic patients
after 13 years of follow-up. British Medical Journal,
308,
813-816.
Harrison, G., Croudace, T., Mason, P., et al (1996) Predicting the long-term outcome of schizophrenia. Psychological Medicine, 26, 697-705.[Medline]
Hopper, K., Harrison, G., Janca, A., et al (2001) Prospects of Recovery from Schizophrenia An International Investigation. Madison, CT: Psychosocial Press, in press.
Huber, G., Gross, G. & Schuttler, R. (1975) A long-term follow-up study of schizophrenia: psychiatric course of illness and prognosis. Acta Psychiatrica Scandinavica, 52, 49-57.[Medline]
Jablensky, A., Schwartz, R., Tomov, T. (1980) WHO collaborative study on impairments and disabilities associated with schizophrenia. Acta Psychiatrica Scandinavica, 62 (suppl. 285), 152-163.
Jablensky, A., Sartorius, N., Ernberg, G., et al (1992) Schizophrenia: manifestations, incidence and course in different cultures: a World Health Organisation 10- country Study. Psychological Medicine, Monograph supplement 20, 1-97.
Kaplan, E. L. & Meier, P. (1958) Nonparametric estimation from incomplete observations. Journal of the American Statistical Association, 53, 457-481.
Kirkpatrick, B., Buchanan, R. W., McKenney, P. D., et al (1989) The Schedule for the Deficit Syndrome: an instrument for research in schizophrenia. Psychiatry Research, 30, 119-123.[CrossRef][Medline]
Larsen, T. K., McGlashan, T. H. & Moe, L. C. (1996) First episode schizophrenia: I. Early course parameters. Schizophrenia Bulletin, 22, 241-256.[Medline]
Mason, P., Harrison, G., Glazebrook, C., et al (1995) Characteristics of outcome in schizophrenia at 13 years. British Journal of Psychiatry, 167, 596-603.[Abstract]
Prior, C. (2000) Recovering a meaningful life
is possible (letter). Psychiatric Bulletin,
24, 30.
Rosenbaum, P. R. & Rubin, D. B. (1983) The central role of the propensity score in observational studies for causal effects. Biometrika, 70, 41-55.
Sartorius, N., Gulbinat, W., Harrison, G., et al (1996) Long-term follow-up of schizophrenia in 16 countries. Social Psychiatry and Psychiatric Epidemiology, 31, 249-258.[Medline]
Shen, Y. C., Chen, C. H. & Zhang, W. X. (1986) An epidemiological investigation of mental disorders in 12 regions of China. Methodology and data analysis. Chinese Journal of Neurology and Psychiatry, 19, 65-69.
Shepherd, M., Watt, D., Falloon, I., et al (1989) The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychological Medicine, Monograph supplement 16, 1-45.
Siegel, C., Wanderling, J., Shang, L., et al (2001) Predictors of long term course and outcome for the DOSMeD cohort. In Prospects of Recovery from Schizophrenia An International Investigation (eds K. Hopper, G. Harrison, A. Janca, et al). Madison, CT: Psychological Press, in press.
Simpson, J. C. & Tsuang, M. T. (1996) Mortality among patients with schizophrenia. Schizophrenia Bulletin, 22, 485-499.[Medline]
Strauss, J. S. & Carpenter, W. T. (1972) Prediction of outcome in schizophrenia: I. Characteristics of outcome. Archives of General Psychiatry, 27, 739-746.[CrossRef][Medline]
Thara, R. & Eaton, W. W. (1996) Ten-year outcome of schizophrenia the Madras Longitudinal Study. Australian and New Zealand Journal of Psychiatry, 30, 482-488.
Weingarten, R. (1994) The ongoing processes of recovery. Psychiatry, 57, 369-375.[Medline]
Wiersma, D., Nienhuis, F. J., Giel, R., et al (1996) Assessment of the need for care 15 years after onset of a Dutch cohort of schizophrenic patients and an international comparison. Social Psychiatry and Psychiatric Epidemiology, 31, 114-121.[Medline]
Wiersma, D., Nienhuis, F. J., Slooff, C. J., et al (1998) Natural course of schizophrenic disorders: a 15-year follow-up of a Dutch incidence cohort. Schizophrenia Bulletin, 1, 75-85.
Wiersma, D., Wanderling, J, Dragomirecka, E., et al (2000) Social disability in schizophrenia: its development and prediction over 15 years in incidence cohorts in 6 European centres. Psychological Medicine, 30, 1155-1167.[CrossRef][Medline]
Wing, J. K., Cooper, J. E. & Sartorius, N. (1974) The Measurement and Classification of Psychiatric Symptoms. London: Cambridge University Press.
World Health Organization (1973) Schizophrenia: An International Follow-Up Study. New York: John Wiley and Sons.
World Health Organization (1978) International Classification of Diseases (Glossary). Geneva: WHO.
World Health Organization (1992) Psychological Impairments Rating Scale. Geneva: WHO.
World Health Organization (1993) The ICD10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. Geneva: WHO.
World Health Organization (1994) The ICD10 Classification of Mental and Behavioural Disorders: Conversion Tables between ICD8, ICD9 and ICD10, Revision 1 (WHO/MNH/92.16Rev.1). Geneva: WHO.
World Health Organization (1996) Statistical Information System: The Mortality Database. Geneva: WHO.
Received for publication May 15, 2000. Revision received November 20, 2000. Accepted for publication December 12, 2000.
Related articles in BJP: