Course and Outcome of Schizophrenia and Their Prediction

Assen Jablensky

Introduction

The course of schizophrenia is as variable as its symptoms. Systematic investigations of course of the psychoses were initiated by Kraepelin who believed that, in the absence of demonstrable brain pathology and aetiology, a common outcome into ‘psychic weakness’ of the clinical syndromes he grouped together as dementia praecox would provide a validity test for the disease entity. Later, Kraepelin revised his claim that the prognosis of dementia praecox was invariably poor and noted that ‘permanent cures’ had occurred in about 15 per cent of his cases.⁽¹⁾ Subsequent longitudinal studies have confirmed the striking variability of course as one of the salient characteristic of the ‘natural history’ of schizophrenia.

Methodological issues

The large number of studies on the course and outcome of schizophrenia published since the beginning of the twentieth century might suggest that the longitudinal aspects of the disorder are well established and exhaustively documented. Unfortunately, this is not the case since the methodological difficulties that accompany this type of research are complex and few studies have adequately dealt with all the major sources of error and confounding, including sample selection, definition of outcome, and diagnostic criteria used.⁽²^,³⁾

The studies of the course and outcome of schizophrenia comprise statistical reports on admissions and discharges, long-term follow-back studies (in which the initial features of the cases and the course of the disorder are reconstructed retrospectively from admission records), and prospective investigations (in which patients are enlisted at an early stage of the disorder and followed up for a varying length of time). Each design is vulnerable to bias: admission and discharge statistics usually comprise patients at different stages of disease progression; follow-back studies rely on prevalence samples in which chronic cases tend to be overrepresented; and prospective studies, though superior to other designs, tend to exclude patients who initially have diagnoses other than schizophrenia but are subsequently re-diagnosed as schizophrenic. The methodological issues that need to be considered in interpreting the results from longitudinal research into schizophrenia include the following.

Diagnosis

The use of either ‘broad’ or ‘restrictive’ definitions of schizophrenia may result in vastly different samples on which follow-up data are reported. Systems with an inbuilt illness duration criterion, such as DSM-III, DSM-IIIR, and DSM-IV which require at least 6 months of unremitting symptoms and a decline in functioning, are likely to overselect patients already developing a chronic course. The result would be a greater homogeneity of outcome at the cost of a compromised representativeness of the sample as regards the range of
possible outcomes of schizophrenia. Diagnostic systems which emphasize the cross-sectional features of the disorder, such as ICD-10 (which requires 1 month’s duration of clinically characteristic symptoms) avoid this limitation, possibly at the expense of including some cases of good prognosis that may be aetiologically or pathogenetically different from poor prognosis schizophrenia. However, until aetiology is elucidated, or validating biomarkers are established, the decision as to what constitutes ‘true’ schizophrenia will remain arbitrary. With regard to prognostic studies, less restrictive diagnostic systems have the advantage that a broad spectrum of outcomes would be available at the end point of prospective observation, allowing for subgroups to be identified and their characteristics related to the initial manifestations of the disorder and various risk factors.

Definitions and assessment of course and outcome variables

There is no single measure of course and outcome of a complex disorder such as schizophrenia. Blanket terms such as ‘recovery’, ‘improvement’, or ‘deterioration’ tend to conflate substantially different aspects of the evolution of the disorder over time. Most investigators today agree that course (comprising the pathways or trajectories of the disorder) and outcome (the net balance of the clinical and functional descriptors at the end point of observation) are multivariate composites. As a minimum, three domains that need not co-vary over time should be independently assessed: symptom severity; functional impairments including cognitive deficits, and disablement in social and occupational role performance. Each one of these can be further articulated into a number of areas or dimensions. In addition, one must consider extrinsic variables such as measures of environmental and treatment-related influences on course and outcome, as well as subjective experiences commonly described as ‘quality of life’. Standardized, reliable instruments (interviews, inventories, rating scales) are required for the assessment of most variables. Operational definitions and criteria of relapse and remission have been proposed.⁽⁴^,⁵⁾ It should not be forgotten, however, that some of the richest sources of information are the perceptive, in-depth clinical case studies based on personal patient contact over many years. Collectively, such single case observations can generate hypotheses for testing in epidemiologically designed studies.

Length of follow-up

The evidence from previous research suggests that very different impressions of the course and outcome of schizophrenia would be gained depending on the duration of prospective observation and the degree of control over the inclusion of patients that are comparable in terms age and length of previous illness.

Cohort attrition

In any follow-up study, a proportion of cases will be lost to observation because of death, migration, refusal of contact, or other reasons for untraceability. Since such loss of subjects is likely to correlate with particular patterns of course and outcome, it is essential to estimate its possible effect (e.g. by statistical modelling) on the interpretation of the final results, especially if cohort attrition is greater than 15-20 per cent of the original sample.

Other aspects of study design

Variation in the sources of recruitment of cases (e.g. any admission to a treatment facility or catchment area sampling), and of information regarding course and outcome variables (e.g. face-to-face interviews or collateral data from case notes or informants), can obviously influence the results of any follow-up study. In addition, subtle variations in study design, such as whether investigators assessing patients’ symptoms and functioning at any point in time are ‘blind’ to data from previous assessments, can bias the final results. Inclusion of a comparison group (e.g. patients with other psychotic disorders) would help evaluate the extent to which any observed patterns of course and outcome are specific to schizophrenia, whereas appropriate controls drawn from the general population can provide reference points for assessing social variables, such as occupational functioning, stressful life events, or habit-related behaviour such as substance use.

Statistical analysis

Longitudinal research poses a number of specific requirements with regard to data analysis. Thus, the problem of multiple comparisons is likely to arise when examining the data for significant associations; time series, survival, or path analysis may be required when observations are made and recorded at successive time points in the evolution of the disorder; and methods of unconfounding are called for at each step of the analysis of longitudinal data. While no single study up to date has met all the rigorous methodological requirements, a number of studies have succeeded in controlling at least some of the sources of bias and confounding. The results from previous research are, therefore, not strictly comparable in specific detail, but are informative as regards general trends and patterns.

The ‘natural history’ of schizophrenia before the neuroleptic era

Since the great majority of schizophrenic patients are today receiving pharmacological treatment, current and recent studies may not reflect the ‘natural’ course and outcome of the disorder. Studies in urban communities in Scotland⁽⁶⁾ and India,⁽⁷⁾ and a study in a rural community in China⁽⁸⁾ estimated the proportions of never hospitalized schizophrenic patients at 6.7 per cent, 28.7 per cent, and 30.6 per cent, respectively. About half of the Scottish patients had been prescribed neuroleptics by their general practitioners while the Indian and Chinese patients had been virtually untreated. In all three settings the outcomes of these interesting samples (which presumably approximate the ‘natural’ history of the disorder) were heterogeneous but, except for a larger proportion of Chinese patients having marked psychotic symptoms, they did not differ much from the outcomes in the treated groups. In a historical study of 70 Swedish patients with first admissions in 1925, lifetime records were retrieved and re-diagnosed in accordance with DSM-III.⁽⁹⁾ None of these patients had received neuroleptics. The final outcome was rated as good in 33 per cent (but no patient was considered as completely recovered), as ‘profoundly deteriorated’ in 43 per cent, and as intermediate in 24 per cent.

A long-term perspective on the course of schizophrenia ove successive generations is provided by a meta-analysis of 320 outcome studies on schizophrenia or dementia praecox published between 1895 and 1992 and including a total of 51 800 subjects.⁽¹⁰⁾
Overall, about 40 per cent of the patients were reported as improved after an average length of follow-up 5.6 years. There was a significant increase in the rate of improvement during the period 1956-1985 compared to 1895-1955, clearly related to the introduction of neuroleptic treatment, but a secular trend towards better outcomes with every successive decade had been present for much longer. Coupled with the virtual disappearance of the most malignant or ‘catastrophic’ forms of schizophrenia resulting in a profound defect state after a first psychotic episode, or death (‘lethal catatonia’), these observations suggest that a transition to a less deteriorating course of the disorder had occurred prior to modern pharmacological treatment. Among the factors explaining this shift one should consider improvements in general care, progressive changes in attitudes and hospital regime which occurred in a number of institutions on both sides of the Atlantic in the 1930s and 1940s, as well as heightened expectations that psychosocial measures such as psychotherapy or rehabilitation could result in a cure in some cases.

Long-term prognosis

Results of course and outcome studies published over the last six decades are shown in Table 4.3.7.1. The studies have been selected on the basis of the length of follow-up (>5 years), effective sample size (>50), and intensity of follow-up and assessment to provide a global overview of the long-term course of schizophrenia.

Table 4.3.7.1 Results of selected course and outcome studies in schizophrenia, 1972-2005

Author	Country	Sample size	Length of follow-up (years)	Proportion good outcome^*
Bleuler (1972)⁽¹¹⁾	Switzerland	208	23	20% Complete remission; 33% mild defect
Tsuang et al. (1979)⁽¹³⁾	USA	186	35	46% Recovered or improved significantly
Ciompi (1980)⁽¹⁴⁾	Switzerland	289	37	20% Recovered; 43% definitely improved
Huber et al. (1980)⁽¹⁵⁾	Germany	502	22	26% Recovered; 31% remission with mild defect
Harding et al. (1987)⁽¹⁶⁾	USA	118	32	62% Recovered or improved significantly
Ogawa et al. (1987)⁽¹⁷⁾	Japan	140	21-27	31% Recovered; 46% improved
Shepherd et al. (1989)⁽¹⁸⁾	UK	107	5	22% Recovered, no relapse
Johnstone et al. (1990)⁽¹⁹⁾	UK	530	3-13	14% Excellent; 18.5% very good social adjustment
Carone et al. (1991)⁽²⁰⁾	USA	79	5	17% Complete remission
Marneros et al. (1992)⁽²¹⁾	Germany	249	25	Full remission in 24% (‘broad’) or 7% (‘pure’) schizophrenia
Thara et al. (1994)⁽²²⁾	India	90 (first-onset cases)	10	12% Complete recovery; 62% remission
Mason et al. (1995)⁽²³⁾	UK	67	13	17% Complete recovery; 52% remission
Wieselgren and Lindström (1996)⁽²⁴⁾	Sweden	120	5	30% Good outcome
Wiersma et al. (1998)⁽²⁵⁾	Holland	82	15	27% Complete; 50% partial remission
Ganev et al. (1998)⁽²⁶⁾	Bulgaria	60	16	32% Complete; 5% partial remission
Gureje and Bamidele (1999)⁽²⁷⁾	Nigeria	120	13	22% Unimpaired (social outcome); 19% some impairment
Finnerty et al. (2002)⁽²⁸⁾	Ireland	67 (first-onset cases)	15	35%Complete remission; 46% partial remission
Thara (2004)⁽²⁹⁾	India	90 (first-onset cases)	20	6% Complete recovery; 15% clinically stable
Lauronen et al. (2005)⁽³⁰⁾	Finland	91 (birth cohort members)	To age 31 years	4% Complete recovery; 3% partial remission
^*Descriptive categories used by the authors.

Although the studies differ in their design (prospective, follow-back, or retrospective), their results have much in common.

Manfred Bleuler’s monograph⁽¹¹⁾ is the account of an intensive study of 208 patients first admitted in 1942-1943 and personally followed up by the author for 22 years or until death. A recent re-interpretation of Bleuler’s diagnoses in terms of DSM-IIIR, DSM-IV, and ICD-10 diagnostic criteria concluded that although some 30 per cent of the original cases would today meet criteria for schizoaffective disorder, the distribution of the types of long-term course did not change significantly.⁽¹²⁾ Another 23-year follow-up of 504 patients admitted in 1945-1959 has been completed by Ciompi,⁽¹⁴⁾ and Huber et al.⁽¹⁵⁾ interviewed 289 surviving patients in Switzerland first admitted between 1900 and 1962 (median follow-up length 36.9 years).

Notwithstanding methodological constraints which apply to these studies, their findings are a unique record of what probably represents the closest approximation to the ‘natural history’ of schizophrenia. In summary, they indicate the following.

Lasting recovery (‘complete cure’) occurred in 15 per cent to 26 per cent of the cases; 43 per cent had either remitted or exhibited mild residual abnormalities which did not interfere with their living in the community.
Forty-four per cent were still in hospital and severe chronic states had developed in 14 to 24 per cent.
In 50 per cent to 75 per cent of the patients, a clinically stable state set in after the fifth year since onset, with no significant further deterioration.
Remitting course with multiple episodes and full remissions characterized 22 per cent of the patients; catastrophic course (rapid onset of chronic deterioration) was observed in 1 per cent to 4 per cent.
The 20-year suicide rate was 14 per cent to 22 per cent.

Two American studies largely concur with these findings. In the Vermont study,⁽¹⁶⁾ no less than 62 per cent of the cohort had achieved significant improvement or recovery after an average length of follow-up 32 years; the corresponding proportion in the Iowa 500 study⁽¹³⁾ was 46 per cent.

The most striking finding from the long-term follow-up studies is the high proportion of patients who recover, either completely or with mild residual abnormalities, after decades of severe illness⁽³¹⁾ This contrasts with the ingrained image of schizophrenia as an intractable, deteriorating illness that many clinicians tend to adopt on the basis of a limited follow-up horizon and patient samples selected for unfavourable course and treatment response. It is unlikely that the high percentage of recoveries in the long-term studies could be explained by cases of affective illness or brief transient psychoses misdiagnosed as schizophrenia (the retrospective re-diagnosis of cases according to DSM-III criteria in the American studies did not alter significantly the results). Similarly unlikely would be the attribution of all the good outcomes to the antipsychotic treatment many of these patients received in the later stages of their illnesses, since comparable proportions of improvement of recovery had been reported for patients who never received neuroleptics.⁽³²⁾ A tentative conclusion from such follow-up research would be that schizophrenia is not an invariably chronic deteriorating disorder, and that the progression of the disease can be arrested or even reversed at any stage. The causes of such reversibility remain poorly understood, but research focusing specifically on the recovering cases will undoubtedly provide essential clues for understanding the nature of schizophrenia.

The results of longitudinal studies published in the last decade generally tend to corroborate the pattern of outcomes outlined by the earlier studies. However, several recent studies suggest a trend of worsening clinical and social outcomes in patients with schizophrenia in both developed countries⁽²⁸^,³⁰⁾ and developing countries.⁽²⁷^,²⁹⁾ A 13-year follow-up of 120 Nigerian patients⁽²⁷⁾ reported much higher rates of severe impairment in social and occupational functioning than those found in the same region of the country by follow-up studies in the 1970-1980s.

Patterns and stages of the course of schizophrenia

The marked heterogeneity of the course of schizophrenia can be reduced to a limited number of patterns into which cases tend to cluster over time. In earlier long-term follow-up studies, eight different categories of course have been described by Bleuler⁽¹¹⁾ and by Ciompi,⁽¹⁴⁾ and 12 by Huber et al.⁽¹⁵⁾ These classifications were derived from empirical observation, rather than statistical modelling, and conflated into single categories the mode of onset, longitudinal aspects such as frequency and duration of psychotic episodes, remissions, and end states. Treating these various aspects of the longitudinal profile of the illness as independent dimensions has been recommended.⁽¹⁹⁾ However, the complexity of statistical modelling of the course of schizophrenia is such that the development of a classification of course that would be both useful in clinical practice and rigorous in a statistical sense may not be easy to achieve. Therefore, a heuristic compromise between these two requirements should, as a minimum, define operationally and assess separately: (i) the number and duration of discrete episodes of illness; (ii) the predominant clinical features of each episode (e.g. psychotic or affective); (iii) the number and length of remissions and their quality (presence/absence of residual negative or deficit symptoms and signs). By combining these variables, several patterns of course have been derived that have found good empirical support in international follow-up studies:

1 single psychotic episode followed by complete remission;

2 single psychotic episode followed by incomplete remission;

3 two or more psychotic episodes, with complete remissions between episodes;

4 two or more psychotic episodes, with incomplete remissions between episodes;

5 continuous (unremitting) psychotic illness.

With some modifications, these longitudinal patterns have been incorporated into ICD-10 and DSM-IV as additional descriptors.

Although the components of the course patterns, such as episode, remission, residual symptomatology, etc. may not represent ‘pure’ dimensions, it is desirable to restrict the definition of pattern of course to clinical variables only, in order to be able to examine its correlations with risk factors and predictors, such as premorbid impairments, mode of onset, or social outcomes. Assessing social functioning independently of the clinical pattern of course is critical to the study of illness-environment interactions and the causes of disablement in schizophrenia.

At present it does not seem possible to define with any precision discrete stages in the progression of schizophrenic illnesses by using combined clinical and pathological criteria, as in cancer or cardiovascular disease. Nevertheless, a ‘softer’ form of staging is feasible since there is on the whole a good agreement between the results of different studies on the general pattern of course in schizophrenia. On the basis of long-term follow-up studies, the lifetime course of schizophrenia can be articulated into a premorbid phase (from birth to the onset of psychosis), a phase of acute or positive schizophrenic symptomatology, and a residual phase.⁽²¹⁾ Various sub-stages have been proposed to describe in finer detail the pre-onset and early psychosis period.⁽³³^,³⁴⁾ For most practical and research purposes, a three-stage classification of post-onset course has been proposed:⁽²⁴⁾

1 an early deteriorating phase (the first 5-10 years);

2 a middle (stabilization) phase;

3 a gradual improvement phase.

This model agrees well with the empirical evidence and could be useful in the collection and summarizing of data on individual risks and prognosis.

Geographical and cultural variation

Three prospective investigations initiated by the World Health Organization (WHO): the International Pilot Study on
Schizophrenia (IPSS);⁽³⁵^,³⁶⁾ the 10-country study on Determinants of Outcome of Severe Mental Disorders;⁽³⁷⁾ and the study on Assessment and Reduction of Psychiatric Disability⁽³⁸^,³⁹⁾ laid the ground for a broad-based, cross-cultural evaluation of the course and outcome of schizophrenia. These studies comprise extensive initial and follow-up information on a total of 2736 patients in 16 countries, diagnosed with schizophrenia according to strict and comparable criteria. Identical or closely similar, standardized assessment procedures and instruments were employed, ensuring a high level of comparability across the multiple sites. Results of the WHO 10-country study (pooled data on 1070 patients in all the research sites) are presented in Table 4.3.7.2.

Table 4.3.7.2 Two-year course and outcome features of 1070 patients with schizophrenia in the WHO 10-country study⁽³⁷⁾

Course and outcome descriptor	% Patients in developing countries¹ (n = 467)	% Patients in developed countries² (n = 603)
Remitting, complete remissions	62.7	36.8
Continuous or episodic, no complete remission	35.7	60.9
Psychotic <5% of the follow-up	18.4	18.7
Psychotic >75% of the follow-up	15.1	20.2
No complete remission during follow-up	24.1	57.2
Complete remission for >75% of the follow-up	38.3	22.3
On antipsychotic medication >75% of the follow-up	15.9	60.8
No antipsychotic medication during follow-up	5.9	2.5
Hospitalized for >75% of follow-up	0.3	2.3
Never hospitalized during follow-up	55.5	8.1
Impaired social functioning throughout follow-up	15.7	41.6
Unimpaired social functioning >75% of follow-up	42.9	31.6
¹Colombia, India, Nigeria. ²Czech Republic, Denmark, Ireland, Japan, Russia, United Kingdom, United States.

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Sep 9, 2016 | Posted by drzezo in PSYCHIATRY | Comments Off

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