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Long-term course and outcome of schizophrenia
Course and outcome
Long-term course and outcome of schizophrenia
c ondition adequately on their own and therefore do not require contact with psychiatric services.
Judith Allardyce
The outcome of schizophrenia is complex – a dynamic process, influenced by a number of poorly understood personal, social, and nosological factors that operate across multiple domains. Symptom domains examine the form and content of the psychopathological experiences, their severity and periodicity. Social functioning domains – psychopathological symptoms alone do not adequately reflect the course of schizophrenia, especially when evaluating long-term outcome. Aspects of social functioning, such as independent living, education, vocational history, the ability to maintain social relationships, and quality of life and well-being measures, are all potentially informative. However, studies examining risk factors for the persistence of schizophrenia, and intervention studies, should measure symptom course and social functioning domains independently (rather than using composite scales), because the different domains, although unlikely to co-vary directly, are likely at least in part to be derived from adequate control of the clinical symptoms.
Outcome measures in schizophrenia
Jim van Os
Abstract This article reviews the finds from recent meta-analyses on the course, outcome and mortality of schizophrenia, and outlines the methodological difficulties encountered when trying to carry out such studies. It discusses the concept of remission in schizophrenia and the recently proposed criteria on remission.
Keywords course; outcome; psychosis; remission criteria; schizophrenia
Evidence from long-term follow-up studies of schizophrenia reveals marked heterogeneity in the course and outcome of the condition, ranging from a single mild episode of psychosis with no lasting impairment, to a disorder characterized by severe chronic symptoms and associated social disability. This is counter to the pervading clinical view that schizophrenia is almost inevitably associated with marked functional deterioration. Why is there such a discrepancy between the evidence base and the view of clinicians?1 The perpetuation of this prognostic pessimism may be a historical legacy – kept alive in medical education and some textbooks – stemming from the Kraepelinian description of schizophrenia (dementia praecox), which asserted that, although the course and progression of the illness varied from person to person, poor outcome was almost universal and a defining characteristic, and, as such, was embedded in the original diagnostic construct. Further, it may be the result of a phenomenon known as the ‘clinician’s illusion’,2 which refers to the tendency of mental health workers (whose clinical caseloads are generally biased towards patients with prolonged illnesses) to assume that the presentation of schizophrenia in the clinical setting is representative of the disorder in non-clinical settings and also across time. However, it is likely that during periods of symptomatic relief and functional improvement people are able to manage their
Findings of systematic reviews and meta-analyses of long-term outcome3–5 Problems with the evidence base The longitudinal course and outcome of schizophrenia have been studied extensively, yet the evidence base remains weak, primarily due to the limitations inherent in carrying out follow-up studies in naturalistic settings. There is significant methodological heterogeneity among the published studies, which makes comparison difficult. These methodological differences may in part explain some of the observed heterogeneity and can be summarized as follows. Variation in populations from which patients are selected – many studies have relied only on inpatients. However, approximately 20% of schizophrenic patients are never admitted to hospital; they may differ from those admitted in important variables associated with outcome. In addition, different diagnostic classification systems have been used to identify cases. Variation in length of illness before entry into follow-up studies – if this varies then subjects with an admixture of followup epochs and levels of chronicity are being studied. Variation in length of follow-up and variability of attrition rate – in any follow-up study a proportion of patients are lost as a result of death, migration, refusal, or other reasons. Many published studies have high rates of attrition (greater than 20%). However, drop out is likely to be related to such characteristics as the age of onset and particular patterns of course and outcome, which will bias the findings of outcome studies. Variation in methods used to assess course and outcome – there is no single measure of course and outcome for complex disorders, and qualitative summary terms such as ‘recovery’, ‘improvement’, and ‘deterioration’ are used inconsistently in the literature. Variation in characteristics of the general population – for example, social outcomes such as unemployment are also influenced by general unemployment rates in the area.
Judith Allardyce MPH MD MRCPsych is a researcher at the Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands. Conflicts of interest: none declared. Jim van Os MSc PhD is Professor of Psychiatry at the Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands. He is also visiting Professor at the Institute of Psychiatry, London, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:10
440
© 2008 Elsevier Ltd. All rights reserved.
Course and outcome
Variation in statistical techniques and adjustment of confounding – methods dealing with multiple comparisons at different time-points were not available or were not utilized at the time of publication of many of the studies. Variation in long-term management of psychosis – different studies carried out at different times and in different places result in different treatments.
methodological differences rather than clinical variation indicative of different underlying pathophysiology. Variation in outcome of schizophrenia in time and place Examination of trends in the outcome of schizophrenia over the past century revealed substantial gains in favourable outcome from the 1920s to the 1970s, with the proportion of patients rated as clinically improved doubling over this period, although rates of good outcome started to decline again (slightly) from the early 1980s. This biphasic trend may reflect the effect of new treatments, changes in diagnostic criteria, and possible effects of sampling bias. In terms of variation in prognosis with place, the World Health Organization’s cross-national study of the course of schizophrenia suggested that outcome is generally better in developing than in developed countries. However, a recent systematic review has called this finding into question.7 It included studies from a broad range of sociocultural environments and found significant variation in clinical outcome and symptom patterns in developing countries; some studies in India supported the assertion of better prognosis, but this was not uniform as studies from Brazil and China showed significantly poorer than expected outcomes.
Overview of findings Despite the methodological heterogeneity, some patterns have emerged regarding the long-term course of schizophrenia. First, the course of schizophrenia is variable both within and between patient cohorts, ranging from complete recovery (no or only minimal residual symptoms) to continuous unremitting psychopathology, cognitive performance and social functioning. Between these extremes, a substantial number of patients present with multiple episodes of psychosis interspersed with at least partial remission. A systematic review of prospectively designed studies published from 1966 to 2003 that examined the outcome of first-episode schizophrenia (and other psychoses) found a good outcome in 42%, an intermediate outcome in 35%, and a poor outcome in 27% of patients with a diagnosis of schizophrenia. This frequency distribution across outcome categories is comparable with distributions found in an earlier meta-analysis of long-term follow-up studies published between the turn of the twentieth century and 1998. Second, in comparison with other baseline psychotic diagnoses, patients with schizophrenia, on average, do more poorly in multiple domains, whereas schizo-affective disorder occupies an intermediate position between schizophrenia and affective psychosis. Third, the greatest variability in symptom course occurs during the first five years, after which time the course tends to plateau out with no evidence of a deteriorating pattern. Fourth, estimates of course and outcome vary depending on the diagnostic category used to select patients. Studies that employ a broad definition of schizophrenia generally show better outcomes than those with a more narrow definition (such as the categorizations of Kraepelin, Feigner, and the Diagnostic and Statistical Manual of Mental Disorders, third edition onwards). Fifth, symptom and social function domains are intercorrelated. Sixth, for individual patients (and their families), vocational and social functioning and quality of life may be a more pertinent indicator of the impact of schizophrenia. A systematic review6 of prospectively designed studies of functional outcome associated with first-episode psychosis published between 1985 and 2005 found only four studies that examined outcome on vocational adjustment for long-term follow-up (five years or more), none of which looked specifically at the category of schizophrenia. All found low rates of recovery (mean duration of engagement in activity ranged from 3.4 to 16.6 hours). External factors that influence employment, such as employment rates within the community and social stigma, are generally unexplored in the literature. Finally, no consistent or replicated set of factors has been identified that helps to explain the variation in the long-term course and outcome of schizophrenia, and it is difficult to determine how much of the observed heterogeneity is a reflection of
PSYCHIATRY 7:10
Long-term course of neurocognitive impairment in schizophrenia8,9 Cognitive dysfunction is a cardinal feature of schizophrenia, present in approximately 70% of patients. What is less well established is the long-term course of these deficits. Systematic reviews of the longitudinal trajectory differ across the age range of patients studied. Results from patients aged under 65 years living independently in the community have shown generalized cognitive impairment compared with healthy controls, but importantly have not demonstrated deterioration over time or across stages of the disorder. In contrast to this, older patients living in institutions seem to have a different pattern of deficit, with some studies suggesting a decline in global cognitive functioning in those over 50 years. Mortality in schizophrenia A recent meta-analysis of mortality in schizophrenia10 found that people with schizophrenia have a significantly higher risk of death (from all causes), around two and a half times that of the general population (although there was marked variability of estimates across studies), which appears to operate equally across the sexes. There was clear evidence of a linear trend in standardized mortality ratios (SMRs) between 1980 and 2006, suggesting that the heath gap between people with schizophrenia and the general population has widened over the past three decades. The suicide rate was 12 times greater than that expected in the standard general population, although the SMR associated with many different causes of death was increased in people with schizophrenia, suggesting that systematic monitoring of these patients may be beneficial. Remission as a standard measure of outcome The studies examined in the systematic reviews discussed above found considerable variation in the definition of symptomatic outcome and practical difficulties in the use of symptom rating scales to evaluate outcome, and have prompted development 441
© 2008 Elsevier Ltd. All rights reserved.
Course and outcome
have to be extended to include cognition and measures of social functioning. ◆
Remission criteria using Positive And Negative Syndrome Scale (PANSS) ratings Core dimensions of psychopathology
Individual items
Score of mild or absent for a minimum of 6 months
Reality distortion
Delusions Unusual thought content Hallucinations Conceptual disorganization Mannerisms and posturing Blunted affect Social withdrawal Lack of spontaneity
P1 G9 P3 P2 G5 N1 N4 N6
Disorganization Negative dimension
References 1 Davidson L, Schmutte T, Dinzeo T, Andres-Hyman R. Remission and recovery in schizophrenia: practitioner and patient perspectives. Schizophr Bull 2008; 34: 5–8. 2 Cohen P, Cohen J. The clinician’s illusion. Arch Gen Psychiatry 1984; 41: 1178–82. 3 Bromet EJ, Naz B, Fochtmann LJ, Carlson GA, Tanenberg-Karant M. Long-term diagnostic stability and outcome in recent first-episode cohort studies of schizophrenia. Schizophr Bull 2005; 31: 639–49. 4 Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994; 151: 1409–16. 5 Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of first-episode psychosis. Psychol Med 2006; 36: 1349–62. 6 Malla A, Payne J. First-episode psychosis: psychopathology, quality of life, and functional outcome. Schizophr Bull 2005; 31: 650–71. 7 Cohen A, Patel V, Thara R, Gureje O. Questioning an axiom: better prognosis for schizophrenia in the developing world. Schizophr Bull 2008; 34: 299–344. 8 Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res 2005; 74: 15–26. 9 Rund BR. A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 1998; 24: 425–35. 10 Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia. Arch Gen Psychiatry 2007; 64: 1123–31. 11 Mortimer AM. Symptom rating scales and outcome in schizophrenia. Br J Psychiatry 2007; 50(Suppl): s7–s14. 12 Andreasen NC, Carpenter Jr. WT, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162: 441–49.
Table 1
of the concept of remission in schizophrenia.11 The Remission in Schizophrenia Working Group has developed a standardized consensus definition of remission in schizophrenia.12 A person is considered to be in remission when a number of symptom items, considered to be core features of the condition, and measured by means of commonly used rating scales – Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS), or Brief Psychiatric Rating Scale (BPRS) – are rated as mild (or less) for at least six months (Table 1). Evaluation of the proposed remission criteria show that the concept is feasible and useful in clinical settings, allowing consistent evaluation of symptoms across the course of the disorder. In clinical trials and research, the concept may
PSYCHIATRY 7:10
442
© 2008 Elsevier Ltd. All rights reserved.
Long-term course and outcome of schizophrenia
c ondition adequately on their own and therefore do not require contact with psychiatric services.
Judith Allardyce
The outcome of schizophrenia is complex – a dynamic process, influenced by a number of poorly understood personal, social, and nosological factors that operate across multiple domains. Symptom domains examine the form and content of the psychopathological experiences, their severity and periodicity. Social functioning domains – psychopathological symptoms alone do not adequately reflect the course of schizophrenia, especially when evaluating long-term outcome. Aspects of social functioning, such as independent living, education, vocational history, the ability to maintain social relationships, and quality of life and well-being measures, are all potentially informative. However, studies examining risk factors for the persistence of schizophrenia, and intervention studies, should measure symptom course and social functioning domains independently (rather than using composite scales), because the different domains, although unlikely to co-vary directly, are likely at least in part to be derived from adequate control of the clinical symptoms.
Outcome measures in schizophrenia
Jim van Os
Abstract This article reviews the finds from recent meta-analyses on the course, outcome and mortality of schizophrenia, and outlines the methodological difficulties encountered when trying to carry out such studies. It discusses the concept of remission in schizophrenia and the recently proposed criteria on remission.
Keywords course; outcome; psychosis; remission criteria; schizophrenia
Evidence from long-term follow-up studies of schizophrenia reveals marked heterogeneity in the course and outcome of the condition, ranging from a single mild episode of psychosis with no lasting impairment, to a disorder characterized by severe chronic symptoms and associated social disability. This is counter to the pervading clinical view that schizophrenia is almost inevitably associated with marked functional deterioration. Why is there such a discrepancy between the evidence base and the view of clinicians?1 The perpetuation of this prognostic pessimism may be a historical legacy – kept alive in medical education and some textbooks – stemming from the Kraepelinian description of schizophrenia (dementia praecox), which asserted that, although the course and progression of the illness varied from person to person, poor outcome was almost universal and a defining characteristic, and, as such, was embedded in the original diagnostic construct. Further, it may be the result of a phenomenon known as the ‘clinician’s illusion’,2 which refers to the tendency of mental health workers (whose clinical caseloads are generally biased towards patients with prolonged illnesses) to assume that the presentation of schizophrenia in the clinical setting is representative of the disorder in non-clinical settings and also across time. However, it is likely that during periods of symptomatic relief and functional improvement people are able to manage their
Findings of systematic reviews and meta-analyses of long-term outcome3–5 Problems with the evidence base The longitudinal course and outcome of schizophrenia have been studied extensively, yet the evidence base remains weak, primarily due to the limitations inherent in carrying out follow-up studies in naturalistic settings. There is significant methodological heterogeneity among the published studies, which makes comparison difficult. These methodological differences may in part explain some of the observed heterogeneity and can be summarized as follows. Variation in populations from which patients are selected – many studies have relied only on inpatients. However, approximately 20% of schizophrenic patients are never admitted to hospital; they may differ from those admitted in important variables associated with outcome. In addition, different diagnostic classification systems have been used to identify cases. Variation in length of illness before entry into follow-up studies – if this varies then subjects with an admixture of followup epochs and levels of chronicity are being studied. Variation in length of follow-up and variability of attrition rate – in any follow-up study a proportion of patients are lost as a result of death, migration, refusal, or other reasons. Many published studies have high rates of attrition (greater than 20%). However, drop out is likely to be related to such characteristics as the age of onset and particular patterns of course and outcome, which will bias the findings of outcome studies. Variation in methods used to assess course and outcome – there is no single measure of course and outcome for complex disorders, and qualitative summary terms such as ‘recovery’, ‘improvement’, and ‘deterioration’ are used inconsistently in the literature. Variation in characteristics of the general population – for example, social outcomes such as unemployment are also influenced by general unemployment rates in the area.
Judith Allardyce MPH MD MRCPsych is a researcher at the Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands. Conflicts of interest: none declared. Jim van Os MSc PhD is Professor of Psychiatry at the Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands. He is also visiting Professor at the Institute of Psychiatry, London, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:10
440
© 2008 Elsevier Ltd. All rights reserved.
Course and outcome
Variation in statistical techniques and adjustment of confounding – methods dealing with multiple comparisons at different time-points were not available or were not utilized at the time of publication of many of the studies. Variation in long-term management of psychosis – different studies carried out at different times and in different places result in different treatments.
methodological differences rather than clinical variation indicative of different underlying pathophysiology. Variation in outcome of schizophrenia in time and place Examination of trends in the outcome of schizophrenia over the past century revealed substantial gains in favourable outcome from the 1920s to the 1970s, with the proportion of patients rated as clinically improved doubling over this period, although rates of good outcome started to decline again (slightly) from the early 1980s. This biphasic trend may reflect the effect of new treatments, changes in diagnostic criteria, and possible effects of sampling bias. In terms of variation in prognosis with place, the World Health Organization’s cross-national study of the course of schizophrenia suggested that outcome is generally better in developing than in developed countries. However, a recent systematic review has called this finding into question.7 It included studies from a broad range of sociocultural environments and found significant variation in clinical outcome and symptom patterns in developing countries; some studies in India supported the assertion of better prognosis, but this was not uniform as studies from Brazil and China showed significantly poorer than expected outcomes.
Overview of findings Despite the methodological heterogeneity, some patterns have emerged regarding the long-term course of schizophrenia. First, the course of schizophrenia is variable both within and between patient cohorts, ranging from complete recovery (no or only minimal residual symptoms) to continuous unremitting psychopathology, cognitive performance and social functioning. Between these extremes, a substantial number of patients present with multiple episodes of psychosis interspersed with at least partial remission. A systematic review of prospectively designed studies published from 1966 to 2003 that examined the outcome of first-episode schizophrenia (and other psychoses) found a good outcome in 42%, an intermediate outcome in 35%, and a poor outcome in 27% of patients with a diagnosis of schizophrenia. This frequency distribution across outcome categories is comparable with distributions found in an earlier meta-analysis of long-term follow-up studies published between the turn of the twentieth century and 1998. Second, in comparison with other baseline psychotic diagnoses, patients with schizophrenia, on average, do more poorly in multiple domains, whereas schizo-affective disorder occupies an intermediate position between schizophrenia and affective psychosis. Third, the greatest variability in symptom course occurs during the first five years, after which time the course tends to plateau out with no evidence of a deteriorating pattern. Fourth, estimates of course and outcome vary depending on the diagnostic category used to select patients. Studies that employ a broad definition of schizophrenia generally show better outcomes than those with a more narrow definition (such as the categorizations of Kraepelin, Feigner, and the Diagnostic and Statistical Manual of Mental Disorders, third edition onwards). Fifth, symptom and social function domains are intercorrelated. Sixth, for individual patients (and their families), vocational and social functioning and quality of life may be a more pertinent indicator of the impact of schizophrenia. A systematic review6 of prospectively designed studies of functional outcome associated with first-episode psychosis published between 1985 and 2005 found only four studies that examined outcome on vocational adjustment for long-term follow-up (five years or more), none of which looked specifically at the category of schizophrenia. All found low rates of recovery (mean duration of engagement in activity ranged from 3.4 to 16.6 hours). External factors that influence employment, such as employment rates within the community and social stigma, are generally unexplored in the literature. Finally, no consistent or replicated set of factors has been identified that helps to explain the variation in the long-term course and outcome of schizophrenia, and it is difficult to determine how much of the observed heterogeneity is a reflection of
PSYCHIATRY 7:10
Long-term course of neurocognitive impairment in schizophrenia8,9 Cognitive dysfunction is a cardinal feature of schizophrenia, present in approximately 70% of patients. What is less well established is the long-term course of these deficits. Systematic reviews of the longitudinal trajectory differ across the age range of patients studied. Results from patients aged under 65 years living independently in the community have shown generalized cognitive impairment compared with healthy controls, but importantly have not demonstrated deterioration over time or across stages of the disorder. In contrast to this, older patients living in institutions seem to have a different pattern of deficit, with some studies suggesting a decline in global cognitive functioning in those over 50 years. Mortality in schizophrenia A recent meta-analysis of mortality in schizophrenia10 found that people with schizophrenia have a significantly higher risk of death (from all causes), around two and a half times that of the general population (although there was marked variability of estimates across studies), which appears to operate equally across the sexes. There was clear evidence of a linear trend in standardized mortality ratios (SMRs) between 1980 and 2006, suggesting that the heath gap between people with schizophrenia and the general population has widened over the past three decades. The suicide rate was 12 times greater than that expected in the standard general population, although the SMR associated with many different causes of death was increased in people with schizophrenia, suggesting that systematic monitoring of these patients may be beneficial. Remission as a standard measure of outcome The studies examined in the systematic reviews discussed above found considerable variation in the definition of symptomatic outcome and practical difficulties in the use of symptom rating scales to evaluate outcome, and have prompted development 441
© 2008 Elsevier Ltd. All rights reserved.
Course and outcome
have to be extended to include cognition and measures of social functioning. ◆
Remission criteria using Positive And Negative Syndrome Scale (PANSS) ratings Core dimensions of psychopathology
Individual items
Score of mild or absent for a minimum of 6 months
Reality distortion
Delusions Unusual thought content Hallucinations Conceptual disorganization Mannerisms and posturing Blunted affect Social withdrawal Lack of spontaneity
P1 G9 P3 P2 G5 N1 N4 N6
Disorganization Negative dimension
References 1 Davidson L, Schmutte T, Dinzeo T, Andres-Hyman R. Remission and recovery in schizophrenia: practitioner and patient perspectives. Schizophr Bull 2008; 34: 5–8. 2 Cohen P, Cohen J. The clinician’s illusion. Arch Gen Psychiatry 1984; 41: 1178–82. 3 Bromet EJ, Naz B, Fochtmann LJ, Carlson GA, Tanenberg-Karant M. Long-term diagnostic stability and outcome in recent first-episode cohort studies of schizophrenia. Schizophr Bull 2005; 31: 639–49. 4 Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994; 151: 1409–16. 5 Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of first-episode psychosis. Psychol Med 2006; 36: 1349–62. 6 Malla A, Payne J. First-episode psychosis: psychopathology, quality of life, and functional outcome. Schizophr Bull 2005; 31: 650–71. 7 Cohen A, Patel V, Thara R, Gureje O. Questioning an axiom: better prognosis for schizophrenia in the developing world. Schizophr Bull 2008; 34: 299–344. 8 Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res 2005; 74: 15–26. 9 Rund BR. A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 1998; 24: 425–35. 10 Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia. Arch Gen Psychiatry 2007; 64: 1123–31. 11 Mortimer AM. Symptom rating scales and outcome in schizophrenia. Br J Psychiatry 2007; 50(Suppl): s7–s14. 12 Andreasen NC, Carpenter Jr. WT, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162: 441–49.
Table 1
of the concept of remission in schizophrenia.11 The Remission in Schizophrenia Working Group has developed a standardized consensus definition of remission in schizophrenia.12 A person is considered to be in remission when a number of symptom items, considered to be core features of the condition, and measured by means of commonly used rating scales – Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS), or Brief Psychiatric Rating Scale (BPRS) – are rated as mild (or less) for at least six months (Table 1). Evaluation of the proposed remission criteria show that the concept is feasible and useful in clinical settings, allowing consistent evaluation of symptoms across the course of the disorder. In clinical trials and research, the concept may
PSYCHIATRY 7:10
442
© 2008 Elsevier Ltd. All rights reserved.