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Cognitive and functional changes with aging in schizophrenia
Cognitive and Functional Changes with Aging in Schizophrenia Joseph I. Friedman, Philip D. Harvey, Eileen Kemether, William Byne, and Kenneth L. Davis The variation in functional outcome in schizophrenia appears to be exaggerated in late life. The cognitive and functional deficits commonly seen in younger schizophrenic patients appear to worsen in some cases in late life, while others patients appear to have a stable course of illness without functional decline, and still other patients have been reported to have essentially no residual symptoms in their later years. Cognitive and functional deficits appear to worsen more significantly in patients with a lifetime course of severe functional deficit. Despite the profound functional and cognitive deficits in these patients, neuropathologic studies have found no evidence of typical causes of severe cognitive impairments. This paper reviews the current findings on cognitive and functional changes in aging in schizophrenia, with a specific focus on patients with a poor lifetime functional outcome. Biol Psychiatry 1999;46:921–928 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, cognitive, functional, outcome
Introduction
A
t the turn of the 20th century, Kraepelin (1919) described “dementia praecox” as a single disease entity with a heterogeneous symptom profile, a deteriorating course and generally poor outcome (See Bleuler 1979 for a review). Under this classification scheme, what is now called schizophrenia was diagnosed on the basis of both symptoms and course, such that a poor longitudinal outcome contributed to the differentiation of dementia praecox from manic depressive insanity, which was assumed to have a good longitudinal course and the prospect of recovery. Although an invariably poor prognosis for all patients has been rejected on empirical grounds, the course of the illness is well-known to include a large number of patients with severe disability over their lifetime.
From the Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY. Address reprint requests to Joseph I. Friedman, MD, Mount Sinai School of Medicine, Department of Psychiatry—Box 1230, One Gustave L. Levy Place, New York, NY 10029. Received November 11, 1998; revised March 18, 1999; accepted March 19, 1999.
© 1999 Society of Biological Psychiatry
Evidence points to the fact that Kraepelin’s sample derived selectively from patients who remained continuously hospitalized (Harding et al 1992). Therefore, this sample is not representative of all the possible variations of course and outcome for patients with schizophrenia. Subsequently, Bleuler described the course of schizophrenia more optimistically as variable with a reversibility of symptoms (See Bleuler 1979 for a review). He reported 60% of patients as having achieved a state of only “mild deterioration” (capable of self-support), while 18% had moderate and 22%, severe deterioration (Freyhan 1958). These findings are more consistent with modern notions that recognize substantial heterogeneity associated with symptom presentation and course. Indeed, heterogeneity has plagued long-term follow up studies, which have generated both contradictory and confusing results. The reasons for these contradictions are related to differences in sample selection, different length of follow up, simplistic definitions of outcome as recovered or not recovered and, selective attrition of patients with certain types of functional outcome. It is well established that schizophrenic patients show impairments on many different tests of cognitive functioning, and that considerable cognitive dysfunction is present in many patients as early as the first episode (Hoff et al 1992; Saykin et al 1994). However, research focusing on the stability of cognitive deficits in patients with schizophrenia has resulted in contradictory findings. Some follow up studies of neuropsychological function in schizophrenia have found either no change, or improvement, on cognitive measures (Cohen 1990; Goldberg et al 1993), particularly in patients with good clinical outcome. An important issue in the study of changes in symptom severity over time is that many of these studies have used relatively young patients who vary substantially in their level of chronicity. Despite the fact that schizophrenic symptoms persist into old age, the manifestations of these symptoms in senescence has been infrequently investigated. The variability in outcome in patients who develop schizophrenia in early life is apparently exaggerated in late life. Some are apparently symptom free, others demonstrate a cyclical course with exacerbation in late life, and some appear to have a continuous course of illness, such as the “Kraepelinian” subgroup. Many late-life schizophrenic 0006-3223/99/$20.00 PII S0006-3223(99)00080-3
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patients have extremely severe cognitive impairments and meet criteria for an additional diagnosis of dementia (Davidson et al 1995). Cognitive change with aging in schizophrenia is more common and severe in patients with life-long poor functional outcome. Hence, poor outcome schizophrenic patients may be a particularly good population among the subclasses to study cognitive decline with aging in schizophrenia.
Cross-Sectional Studies A practical, albeit methodologically limited, approach to examine symptom changes with aging is to compare symptom manifestation in cross-sectional studies across age groups. These types of studies have a practical advantage over longitudinal studies in their ability to cover large age ranges and include large sample sizes, so that potential differences in symptoms between age groups are not underestimated. However, cohort effects are a major deficiency of such studies. Studies of chronically institutionalized geriatric schizophrenic inpatients with poor outcome provide some evidence suggesting progression of cognitive and functional deficits, as well as certain symptoms with aging, in a subset of patients. For example, chronically institutionalized geriatric and nongeriatric patients were compared in a large cross-sectional study conducted at a state hospital (Davidson et al 1995). A total of 308 geriatric schizophrenic patients were compared to a group of 85 nongeriatric (under age 65) schizophrenic patients. There were age-associated differences in both positive and negative symptoms. The older patients had significantly more severe negative symptoms. Furthermore, positive symptoms, although reduced in severity in older patients, did not appear to completely, “burn out.” In addition, an assessment of global cognitive performance, the MiniMental Status Exam (MMSE; Folstein et al 1975), indicated that older patients demonstrated significantly poorer cognitive performance than younger patients. The cognitive changes in these patients, estimated by the differences between age groups, averaged 3.0 points on the MMSE per decade. Patients with Alzheimer’s disease tend to decline this much on average in a 1-year period (Morris et al 1993). Even though these differences in MMSE scores between successive age groups are relatively small, they are much larger than the differences associated with normal aging, even when education is considered (Crum et al 1993). Since the level of education differed across the age groups studied, years of formal education was examined as a covariate and the main effect of age group on MMSE was still significant. In addition, there were strong correlations demonstrated between cognitive impairment and negative symptoms, similar to those seen in other
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studies of younger patients (Addington and Addington 1991; McKenna et al 1989), with these correlations remaining stable across the age range of the patients studied. It is clear from the results of this study that severe positive and negative symptoms persist into senescence in chronically institutionalized schizophrenic patients. Contrary to other studies of geriatric schizophrenic patients living in the community (Harding et al 1992), positive symptoms in this poor outcome group did not completely “burn out” and functional deficits were clearly still present. Although this patient population is not representative of all elderly patients with schizophrenia (e.g., resisting several waves of deinstitutionalization to remain hospitalized for many years), these findings have been replicated by other groups who have demonstrated profound cognitive impairment in similar elderly schizophrenic patients with a chronic course of illness (Arnold et al 1995; Bartels et al 1997; Bilder et al 1992). In fact, in a cross-national study conducted in collaboration with British researchers studying institutional care in the UK, it was found that the average MMSE score of institutionalized patients in the UK, who were similar in age, education, and institutional stay, was essentially identical to those in the United States (Harvey et al 1997). Despite the extensive history of somatic treatment applied to chronic, elderly patients with poor outcome schizophrenia, exposure to ECT, leukotomy, insulin coma, and lifetime neuroleptic dosing have all been found to be unrelated to the severity of cognitive and functional impairment (Davidson et al 1995; Harvey et al 1993). It has been suggested that the lack of stimulating social environment associated with long-term institutions worsens certain schizophrenic symptoms, such as negative and cognitive symptoms, and this factor could have affected the rating of institutionalized patients. Some studies, attempting to distinguish between symptom manifestations associated with the illness itself and the confounding aspects of institutionalization, have compared institutionalized patients with those discharged into the community (Johnstone et al 1981). In the TAPS study in the UK (Leff 1994), discharged patients were found to have stable cognitive impairments and positive symptoms after discharge from chronic psychiatric care, but to demonstrate notable improvements in their negative symptoms. Thus, negative symptoms appeared more related to institutionalization than did cognitive impairments. In a subsequent study, comparably aged geriatric schizophrenic patients were studied across three treatment sites including chronic hospitalization, nursing home, and acute admission (Harvey et al 1998). Although the patients in nursing home care had been discharged from psychiatric care several years previously, the nursing home and chronically hospital-
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ized patients did not differ on the severity of their negative or cognitive symptoms. This finding demonstrates that the severe cognitive and adaptive deficits in geriatric chronically institutionalized schizophrenic patients are also found in other geriatric schizophrenic patients, such as those residing in nursing homes. This represents a significant number of patients, since it is estimated that more than 200,000 patients with schizophrenia have been referred to nursing homes as a part of the deinstitutionalization movement (Goldman et al 1986). In contrast, other investigators using this cross-sectional design to study schizophrenia concluded that no progressive decline is seen in adulthood (Hyde et al 1994). The problem with generalizing from this study is that the previous course of illness of the patients was not clearly defined. A second potential limitation of this particular study is that older and younger patients were matched on reading skill. Since older individuals in an age range from 20 years to 70 years are likely to have less formal education than younger ones, the older patients are possibly selected for higher levels of premorbid functioning. If premorbid functioning was related to risk for decline, the older groups would include patients partially protected from decline. A final problem is the relationship of cognitive functioning and reading skill. Although reading skill is not found to decline to a great extent in good outcome patients with schizophrenia, reading skills and global cognitive status were found to be correlated to a moderate extent in poor outcome geriatric patients with schizophrenia (Harvey et al 1997). Studies examining the characteristics of late-life patients with a lifetime course of more adequate adaptive status do not find progression of cognitive and functional deficits observed in poorer outcome patients. For example, Heaton and coworkers (1994) reported no age-related differences in cognitive functioning in a better outcome sample; and in another report from this group, Paulsen and colleagues (1995) found that almost a quarter of these patients had a normal profile of memory functioning. These findings are also consistent with the results of studies examining the cognitive functioning of patients with late onset schizophrenia (Jeste et al 1995). These patients, many of whom have had a lifetime of adequate adaptive functioning, have cognitive performance that is better than patients with a lifetime course of schizophrenia with reasonable functional status. Thus, the differences between cross-sectional studies of cognitive deficits appear to be associated with lifetime differences in adaptive status.
Longitudinal Studies There is evidence of considerable variation in the results of both short-term and long-term longitudinal studies of elderly patients with schizophrenia. The catamnestic stud-
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ies of Ciompi (1980) and Bleuler reported that most patients did not have a return to premorbid functioning (see Bleuler 1979 for review), although the outcome for many patients was not a grossly deteriorated state. Some studies have found even better outcomes. For example, the Vermont Longitudinal Study (Harding et al 1987a, 1987b) followed chronic patients from 1987b a state hospital over a period that ranged from 22 to 59 years. Analysis of symptoms rated during the follow up assessments revealed that 68% of the schizophrenic subjects did not display any further positive or negative symptoms at follow-up, and that 45% of the sample displayed no psychiatric symptoms at all. Two-thirds were not even receiving psychotropic medication in their clinically remitted state. In addition, measures of combined psychological and social functioning demonstrated that over 60% of the schizophrenic patients had achieved good overall functioning. In contrast, the National Institute of Health’s longitudinal study of chronic schizophrenia examined much younger patients (Breier et al 1991) and produced data that demonstrated substantial levels of impairment and symptoms a mean of 6 years after index assessments. In fact, only 20% of this sample demonstrated a good outcome as determined by global assessments, social and occupational function, and positive and negative symptoms. Some studies of elderly patients with poor overall lifetime functional outcome have demonstrated an even poorer picture. In a recent study conducted by our group examining the course of cognitive and functional impairment in chronically institutionalized schizophrenic inpatients over a 30-month period (Harvey et al 1999), the longitudinal course of overall functional status for a sample of over 300 patients was examined. The focus was on those patients, who at baseline, had no or minimally severe scores on a global measure of cognitive and functional impairment (the Clinical Dementia Rating; CDR: Berg 1988) (148 patients in total). Newly incident cases of more severe cognitive and functional impairment were identified at follow-up. The techniques of survival analysis were used to examine the risk for new onset severe cognitive and functional impairment for those previously less impaired patients over the follow-up period. At the first follow-up (12 months), the risk of cognitive decline [conversion of CDR score from 1 (mild) or less to 2 (moderate) or greater] was 12.6%. At the second follow-up (30 months), an additional 15% met criteria for worsening over the follow-up period, for a total rate of cognitive decline of 27.6%. Additional analyses of this study population were performed to identify possible risk factors for cognitive and functional decline and changes in overall functional status. Gender was not associated with risk for cognitive and functional decline or neuroleptic treatment status, negative
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symptom severity at the time of the baseline assessment, or age at the first psychiatric admission. The risk factors that were associated with increases in risk for cognitive and functional decline included: older age, lower levels of formal education, and more severe positive symptoms at baseline. Although age and educational attainment are well-understood risk factors for cognitive decline in dementia, the finding of more severe positive symptoms predicting greater risk for global functional decline was unexpected. Since positive symptoms were not found to be associated with functional status at baseline, these data suggest a longitudinal relationship between more severe positive symptoms and subsequent risk for decline during a 30-month period. This same relationship is not found for baseline severity of negative symptoms. In addition to cognitive functioning, adaptive functioning was noted to significantly decline in this population over a relatively brief follow-up period. Examination of 57 patients in a chronic psychiatric hospital, reinstitutionalized to nursing home care, and then reevaluated an average of 30 months later, demonstrated several differences in cognitive and functional status. Both cognitive functioning (estimated by the MMSE) and scores on a rating scale of behavioral aspects of functional status were found to decline to a significant extent, while positive and negative symptoms were temporally stable. Changes in cognitive functioning accounted for 25% of the variance in adaptive decline, while baseline severity of cognitive impairment and schizophrenic symptoms were uncorrelated with adaptive decline (Harvey et al 1999). These data indicate that cognitive decline may predict deterioration in overall functional status. The correlation of cognitive and adaptive decline seen in these geriatric poor outcome patients is consistent with previous reviews on the functional consequences of cognitive deficits in schizophrenia (Green 1996) and with findings from the dementia literature suggesting that cognitive decline is a better predictor of subsequent functional deficit than other aspects of the illness (Green 1993). Previous studies of better outcome patients with much higher MMSE scores also demonstrate significant cross-sectional correlations between MMSE scores and adaptive functioning deficits (Klapow et al 1997). In summary, short-term prospective studies of poor outcome patients with schizophrenia indicate that some of these patients manifest declines in their cognitive and functional status. These declines are stepwise, rather than continuously progressive, and distributed across patients, not being present in all cases. The characteristics of this progression, much like the profiles of impairment previously discussed, are not consistent with the rate or profile of progression seen in degenerative diseases, and the lack of concurrent vascular events argues against vascular dementia as a cause of this stepwise change.
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Possible Biological Substrates of Cognitive Changes With Aging While the timing and overall prevalence of functional decline in schizophrenia is not clear, there are recent studies that suggest that progressive changes in brain structure may be detectable even relatively soon after the onset of the illness. One recent study (DeLisi et al 1997) found evidence of active changes in brain structure in a follow-up study of first-episode patients with schizophrenia. Rapoport and colleagues (1997) found notable changes in ventricular size and in specific brain structures in adolescent patients with childhood onset schizophrenia an average of 4.6 and 6.6 years after the onset of illness. A similar study of middle-aged patients also noted qualitatively similar progressive brain changes that were restricted to patients with poorer functional outcome and not found in patients with better prognoses (Davis et al 1998). Thus, a possible correlate of the deterioration in functional status seen in some subsets of poor outcome patients with schizophrenia is a structural change in the brain.
Absence of Alzheimer’s Disease (AD) And Other Common Forms of Neurodegenerative Pathology in Demented Schizophrenic Patients To account for its symptomatology and clinical course, early theories of schizophrenia involved progressive neural degeneration; however, despite some early reports to the contrary (for review see Shapiro 1993), the consensus that has emerged from recent and better controlled studies is that, at the time of autopsy and in the absence of comorbidity, the brains of patients with schizophrenia do not exhibit high levels of the classical manifestations of neurodegenerative change (e.g., reactive gliosis, plaques, tangles, vascular changes, dystrophic neurites; Arnold et al 1998; Powchik et al 1998; Purohit et al 1998; Trojanowski et al 1998). Of the 100 cases studied in the Purohit and co-workers investigation, only 10% met Khachaturian (1985) criteria for AD. Even among severely cognitively impaired schizophrenics, plaque counts were less than half that seen in AD cases of identical age. Schizophrenics without plaques were on average more than 10 years younger than those with plaques. The prevalence of vascular dementia and other identifiable neuropathology in this sample was found to be less than 10%, which cannot account for the high prevalence of profound impairment, as high as 66%, seen in this patient sample (Purohit et al 1998). From these data, it appears clear that most cases of cognitive impairment in schizophrenia are not the result of AD; a finding reported by other research groups in independent samples of similar patients (Arnold et al 1995). The absence of classical histopathologic evidence of
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degeneration, together with evidence of possible neurodevelopmental anomalies, led many researchers to abandon a simple hypothesis of neural degeneration. Instead, it has been proposed that schizophrenia results from an early lesion; that this lesion is static (i.e., nonprogressive), and that the behavioral expression of the lesion varies over time as a function of the developmental state of the brain (see Wolf et al 1993 for an example of this theory). However, a more complex picture is necessary to explain progressive cognitive decline in poor outcome schizophrenia. It is likely that an early neurodevelopmental abnormality sets the stage for, or interacts with, subsequent neuronal changes. These changes may vary across patients and be expressed in terms of cognitive and functional deterioration in some patients. Moreover, the progressive changes may be atrophic (involving neuronal shrinkage or retraction of processes and synapses; see Selemon and Goldman-Rakic 1999 for such a description) rather than necrotic (involving the death of one or more neurons or the destruction of neuronal processes), explaining the absence of markers of degeneration. Hence, the schizophrenia “lesion,” like many other neurodevelopmental lesions (i.e., Huntington’s disease), is dynamic, not static.
Neurochemical Findings in Cognitively Impaired Schizophrenic Patients Despite the lack of identifiable pathologic lesions in patients with schizophrenia, it is still be possible that demented schizophrenic patients suffer from a neurochemical deficit as a basis for their cognitive impairment. For example, a study was undertaken to determine if a cholinergic abnormality was present in cognitively impaired elderly schizophrenic patients (Haroutunian et al 1994). A comparison of cognitively impaired schizophrenic subjects, AD subjects, and control subjects, revealed that cholinergic marker activity as measured by ChAT (choline acetyltransferase) and acetylcholinesterase was significantly reduced in AD subjects compared to both schizophrenic and control subjects. Although, the activity of ChAT was not significantly reduced in the parietal cortex of the schizophrenic cases, nevertheless, ChAT activity did significantly correlate negatively with the degree of cognitive impairment within the schizophrenic group. Additional ongoing surveys of neurochemical characteristics of postmortem brain tissue from schizophrenic subjects included assays of cortical norepinephrine (NE), MHPG, 5-HT (hydroxytryptamine), and 5-HIAA (hydroxy indole acetic acid) (methods described in Powchik et al 1998). To date, samples from six cortical regions have been derived from 19 elderly chronic schizophrenics (12 of whom were cognitively impaired, (i.e., CDR ⱖ 1). All schizophrenic subjects in this study had antemortem
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evaluations of cognitive functioning within 1 year of death. Those schizophrenic subjects with cognitive impairment (i.e., those with CDR scores ⬎ ⫽ 1) showed marked deficits in cortical 5-HT (Brodmann area 32 and 22) and 5-HIAA compared to those with CDR scores of 0 or 0.5. Since serotonergic deficits can be age-related, it is important to note that age was not significantly different in the two groups. Similar to the serotonin findings, norepinephrine was significantly reduced in frontal cortex in 12 cognitively impaired (i.e., CDR ⱖ 1) schizophrenic subjects compared to 7 schizophrenic subjects with CDRs of 0 or 0.5. There were trend level reductions in temporal cortical NE. Similar, but less pronounced, deficits of MHPG were also found. The data for NE are consistent with the report of Bridge and co-workers (Bridge et al 1985), which described NE deficits in hippocampus and nucleus accumbens correlated with the severity of cognitive impairment. Since noradrenergic deficits can be age-related, it is also important to note that age was not significantly different in the two groups. Taken together, the postmortem data support the following conclusions. Alzheimer’s disease and other common pathology does occur in schizophrenia, though no more frequently than in a community-based sample of subjects matched to the elderly cohort of schizophrenic patients. Therefore, these processes are insufficient to explain cognitive impairment in elderly persons with schizophrenia. Both noradrenergic and serotonergic deficits are present in elderly cognitively impaired schizophrenic subjects, with serotonergic deficit occurring in frontal and temporal cortex and noradrenergic deficits apparently restricted to frontal cortex. These deficits cannot be explained by differences in ages between demented and nondemented subjects.
Conclusions and Implications The work presented in this review demonstrates that there is substantial heterogeneity associated with symptom manifestation and course of illness associated with aging in schizophrenia. The results of studies to date addressing the question of symptom progression in schizophrenia have been conflicting. For patients manifesting progressive cognitive and functional impairment, life-long poor outcome has been demonstrated to be a consistent risk factor (Arnold et al 1995; Bartels et al 1997; Davidson et al 1995). Some of the distinguishing features of this chronically deteriorated, poor outcome schizophrenic population may provide direction for identifying risk factors for progression of cognitive and functional deficits. For example, more chronically deteriorated schizophrenic patients compared to less chronic patients have worse social
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and occupational functioning, spend more time in psychiatric hospitals, do not respond to neuroleptic treatment, and show a greater progressive increase in ventricular volume (Keefe et al 1987). Recent work continues to support neurodevelopmental factors contributing to the symptoms of schizophrenia. It is likely that very early events during the first or early second trimester, as well as subsequent obstetric complications underlie some of the premorbid psychosocial abnormalities of childhood, in addition to the subsequent manifestations of schizophrenic symptomatology seen in these patients. However, substantial evidence supports the existence other risk factors, which may interact with these neurodevelopmental influences to alter the manifestation and course of the illness. These may provide critical points of intervention to influence the course of schizophrenia. Lower levels of education and poorer premorbid adjustment are associated with a poorer outcome at follow up (Lindstrom 1996; Wieselgren and Lindstrom 1996). Although the level of educational attainment may be viewed as inevitable, an early manifestation of a neurodevelopmentally determined predisposition for poor premorbid intellectual function and progressive cognitive decline later in life, it has not been disproved that the level of educational attainment itself is an important environmental influence. Perhaps, early interventions targeting educational achievement or intellectual enrichment may influence future vulnerability for cognitive and functional decline. Additional clinical observations have shown that multiple periods of severe symptomatic exacerbation are associated with an overall poorer outcome. Moreover, findings suggest that significant delays in initiating antipsychotic treatment early in the course of illness may be associated with poorer treatment response and more severe symptoms subsequently (Haas et al 1998). Indeed, the data demonstrate that early intervention with antipsychotic medication decreases some of the long-term morbidity associated with schizophrenia (Wyatt and Henter 1998). Since the effects of severe positive symptoms on outcome are present in both first admission and chronic schizophrenic patients with multiple previous hospitalizations (Haas et al 1998), it appears that the deleterious effects of severe positive symptoms continue to exert an effect on outcome later in the illness. The longitudinal data of Harvey and colleagues (1999) demonstrates that geriatric patients at greater risk for cognitive and functional decline during a 30-month period had more severe positive symptoms at baseline. Therefore, contemporary evaluations of the impact of antipsychotics should also focus on the prolonged effect of these drugs on those at risk for cognitive and functional decline. Future research should focus on additional causes of
cognitive and adaptive decline in poor outcome schizophrenic patients. The knowledge gained from such studies should guide the development of treatments to address this dimension of the illness.
This work was presented at the conference, Schizophrenia: From Molecule to Public Policy, held in Santa Fe, New Mexico in October 1998. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.
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Shapiro RM (1993): Regional neuropathology in schizophrenia: Where are we? Where are we going? Schizophr Res 10:187– 239. Trojanowski JQ, Growdon JH (1998): A new consensus report on biomarkers for the early antemortem diagnosis of Alzheimer disease: Current status, relevance to drug discovery, and recommendations for future research. J Neuropathol Exper Neurol 57:643– 644. Wieselgren IM, Lindstrom LH (1996): A prospective 1–5 year
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outcome study in first-admitted and readmitted schizophrenic patients: Relationship to heredity, premorbid adjustment, duration of illness and education level at index admission and neuroleptic treatment. Acta Psychiatr Scand 93(1):9 –19. Wolf SS, Hyde TM, Weinberger DR (1993): Neurobiology of schizophrenia. Curr Opin Neurol Neurosurg 6:86 –92. Wyatt RJ, Henter ID (1998): The effects of early and sustained intervention on the long-term morbidity of schizophrenia. J Psychiatric Res 32(3– 4):169 –177.
Introduction
A
t the turn of the 20th century, Kraepelin (1919) described “dementia praecox” as a single disease entity with a heterogeneous symptom profile, a deteriorating course and generally poor outcome (See Bleuler 1979 for a review). Under this classification scheme, what is now called schizophrenia was diagnosed on the basis of both symptoms and course, such that a poor longitudinal outcome contributed to the differentiation of dementia praecox from manic depressive insanity, which was assumed to have a good longitudinal course and the prospect of recovery. Although an invariably poor prognosis for all patients has been rejected on empirical grounds, the course of the illness is well-known to include a large number of patients with severe disability over their lifetime.
From the Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY. Address reprint requests to Joseph I. Friedman, MD, Mount Sinai School of Medicine, Department of Psychiatry—Box 1230, One Gustave L. Levy Place, New York, NY 10029. Received November 11, 1998; revised March 18, 1999; accepted March 19, 1999.
© 1999 Society of Biological Psychiatry
Evidence points to the fact that Kraepelin’s sample derived selectively from patients who remained continuously hospitalized (Harding et al 1992). Therefore, this sample is not representative of all the possible variations of course and outcome for patients with schizophrenia. Subsequently, Bleuler described the course of schizophrenia more optimistically as variable with a reversibility of symptoms (See Bleuler 1979 for a review). He reported 60% of patients as having achieved a state of only “mild deterioration” (capable of self-support), while 18% had moderate and 22%, severe deterioration (Freyhan 1958). These findings are more consistent with modern notions that recognize substantial heterogeneity associated with symptom presentation and course. Indeed, heterogeneity has plagued long-term follow up studies, which have generated both contradictory and confusing results. The reasons for these contradictions are related to differences in sample selection, different length of follow up, simplistic definitions of outcome as recovered or not recovered and, selective attrition of patients with certain types of functional outcome. It is well established that schizophrenic patients show impairments on many different tests of cognitive functioning, and that considerable cognitive dysfunction is present in many patients as early as the first episode (Hoff et al 1992; Saykin et al 1994). However, research focusing on the stability of cognitive deficits in patients with schizophrenia has resulted in contradictory findings. Some follow up studies of neuropsychological function in schizophrenia have found either no change, or improvement, on cognitive measures (Cohen 1990; Goldberg et al 1993), particularly in patients with good clinical outcome. An important issue in the study of changes in symptom severity over time is that many of these studies have used relatively young patients who vary substantially in their level of chronicity. Despite the fact that schizophrenic symptoms persist into old age, the manifestations of these symptoms in senescence has been infrequently investigated. The variability in outcome in patients who develop schizophrenia in early life is apparently exaggerated in late life. Some are apparently symptom free, others demonstrate a cyclical course with exacerbation in late life, and some appear to have a continuous course of illness, such as the “Kraepelinian” subgroup. Many late-life schizophrenic 0006-3223/99/$20.00 PII S0006-3223(99)00080-3
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patients have extremely severe cognitive impairments and meet criteria for an additional diagnosis of dementia (Davidson et al 1995). Cognitive change with aging in schizophrenia is more common and severe in patients with life-long poor functional outcome. Hence, poor outcome schizophrenic patients may be a particularly good population among the subclasses to study cognitive decline with aging in schizophrenia.
Cross-Sectional Studies A practical, albeit methodologically limited, approach to examine symptom changes with aging is to compare symptom manifestation in cross-sectional studies across age groups. These types of studies have a practical advantage over longitudinal studies in their ability to cover large age ranges and include large sample sizes, so that potential differences in symptoms between age groups are not underestimated. However, cohort effects are a major deficiency of such studies. Studies of chronically institutionalized geriatric schizophrenic inpatients with poor outcome provide some evidence suggesting progression of cognitive and functional deficits, as well as certain symptoms with aging, in a subset of patients. For example, chronically institutionalized geriatric and nongeriatric patients were compared in a large cross-sectional study conducted at a state hospital (Davidson et al 1995). A total of 308 geriatric schizophrenic patients were compared to a group of 85 nongeriatric (under age 65) schizophrenic patients. There were age-associated differences in both positive and negative symptoms. The older patients had significantly more severe negative symptoms. Furthermore, positive symptoms, although reduced in severity in older patients, did not appear to completely, “burn out.” In addition, an assessment of global cognitive performance, the MiniMental Status Exam (MMSE; Folstein et al 1975), indicated that older patients demonstrated significantly poorer cognitive performance than younger patients. The cognitive changes in these patients, estimated by the differences between age groups, averaged 3.0 points on the MMSE per decade. Patients with Alzheimer’s disease tend to decline this much on average in a 1-year period (Morris et al 1993). Even though these differences in MMSE scores between successive age groups are relatively small, they are much larger than the differences associated with normal aging, even when education is considered (Crum et al 1993). Since the level of education differed across the age groups studied, years of formal education was examined as a covariate and the main effect of age group on MMSE was still significant. In addition, there were strong correlations demonstrated between cognitive impairment and negative symptoms, similar to those seen in other
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studies of younger patients (Addington and Addington 1991; McKenna et al 1989), with these correlations remaining stable across the age range of the patients studied. It is clear from the results of this study that severe positive and negative symptoms persist into senescence in chronically institutionalized schizophrenic patients. Contrary to other studies of geriatric schizophrenic patients living in the community (Harding et al 1992), positive symptoms in this poor outcome group did not completely “burn out” and functional deficits were clearly still present. Although this patient population is not representative of all elderly patients with schizophrenia (e.g., resisting several waves of deinstitutionalization to remain hospitalized for many years), these findings have been replicated by other groups who have demonstrated profound cognitive impairment in similar elderly schizophrenic patients with a chronic course of illness (Arnold et al 1995; Bartels et al 1997; Bilder et al 1992). In fact, in a cross-national study conducted in collaboration with British researchers studying institutional care in the UK, it was found that the average MMSE score of institutionalized patients in the UK, who were similar in age, education, and institutional stay, was essentially identical to those in the United States (Harvey et al 1997). Despite the extensive history of somatic treatment applied to chronic, elderly patients with poor outcome schizophrenia, exposure to ECT, leukotomy, insulin coma, and lifetime neuroleptic dosing have all been found to be unrelated to the severity of cognitive and functional impairment (Davidson et al 1995; Harvey et al 1993). It has been suggested that the lack of stimulating social environment associated with long-term institutions worsens certain schizophrenic symptoms, such as negative and cognitive symptoms, and this factor could have affected the rating of institutionalized patients. Some studies, attempting to distinguish between symptom manifestations associated with the illness itself and the confounding aspects of institutionalization, have compared institutionalized patients with those discharged into the community (Johnstone et al 1981). In the TAPS study in the UK (Leff 1994), discharged patients were found to have stable cognitive impairments and positive symptoms after discharge from chronic psychiatric care, but to demonstrate notable improvements in their negative symptoms. Thus, negative symptoms appeared more related to institutionalization than did cognitive impairments. In a subsequent study, comparably aged geriatric schizophrenic patients were studied across three treatment sites including chronic hospitalization, nursing home, and acute admission (Harvey et al 1998). Although the patients in nursing home care had been discharged from psychiatric care several years previously, the nursing home and chronically hospital-
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ized patients did not differ on the severity of their negative or cognitive symptoms. This finding demonstrates that the severe cognitive and adaptive deficits in geriatric chronically institutionalized schizophrenic patients are also found in other geriatric schizophrenic patients, such as those residing in nursing homes. This represents a significant number of patients, since it is estimated that more than 200,000 patients with schizophrenia have been referred to nursing homes as a part of the deinstitutionalization movement (Goldman et al 1986). In contrast, other investigators using this cross-sectional design to study schizophrenia concluded that no progressive decline is seen in adulthood (Hyde et al 1994). The problem with generalizing from this study is that the previous course of illness of the patients was not clearly defined. A second potential limitation of this particular study is that older and younger patients were matched on reading skill. Since older individuals in an age range from 20 years to 70 years are likely to have less formal education than younger ones, the older patients are possibly selected for higher levels of premorbid functioning. If premorbid functioning was related to risk for decline, the older groups would include patients partially protected from decline. A final problem is the relationship of cognitive functioning and reading skill. Although reading skill is not found to decline to a great extent in good outcome patients with schizophrenia, reading skills and global cognitive status were found to be correlated to a moderate extent in poor outcome geriatric patients with schizophrenia (Harvey et al 1997). Studies examining the characteristics of late-life patients with a lifetime course of more adequate adaptive status do not find progression of cognitive and functional deficits observed in poorer outcome patients. For example, Heaton and coworkers (1994) reported no age-related differences in cognitive functioning in a better outcome sample; and in another report from this group, Paulsen and colleagues (1995) found that almost a quarter of these patients had a normal profile of memory functioning. These findings are also consistent with the results of studies examining the cognitive functioning of patients with late onset schizophrenia (Jeste et al 1995). These patients, many of whom have had a lifetime of adequate adaptive functioning, have cognitive performance that is better than patients with a lifetime course of schizophrenia with reasonable functional status. Thus, the differences between cross-sectional studies of cognitive deficits appear to be associated with lifetime differences in adaptive status.
Longitudinal Studies There is evidence of considerable variation in the results of both short-term and long-term longitudinal studies of elderly patients with schizophrenia. The catamnestic stud-
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ies of Ciompi (1980) and Bleuler reported that most patients did not have a return to premorbid functioning (see Bleuler 1979 for review), although the outcome for many patients was not a grossly deteriorated state. Some studies have found even better outcomes. For example, the Vermont Longitudinal Study (Harding et al 1987a, 1987b) followed chronic patients from 1987b a state hospital over a period that ranged from 22 to 59 years. Analysis of symptoms rated during the follow up assessments revealed that 68% of the schizophrenic subjects did not display any further positive or negative symptoms at follow-up, and that 45% of the sample displayed no psychiatric symptoms at all. Two-thirds were not even receiving psychotropic medication in their clinically remitted state. In addition, measures of combined psychological and social functioning demonstrated that over 60% of the schizophrenic patients had achieved good overall functioning. In contrast, the National Institute of Health’s longitudinal study of chronic schizophrenia examined much younger patients (Breier et al 1991) and produced data that demonstrated substantial levels of impairment and symptoms a mean of 6 years after index assessments. In fact, only 20% of this sample demonstrated a good outcome as determined by global assessments, social and occupational function, and positive and negative symptoms. Some studies of elderly patients with poor overall lifetime functional outcome have demonstrated an even poorer picture. In a recent study conducted by our group examining the course of cognitive and functional impairment in chronically institutionalized schizophrenic inpatients over a 30-month period (Harvey et al 1999), the longitudinal course of overall functional status for a sample of over 300 patients was examined. The focus was on those patients, who at baseline, had no or minimally severe scores on a global measure of cognitive and functional impairment (the Clinical Dementia Rating; CDR: Berg 1988) (148 patients in total). Newly incident cases of more severe cognitive and functional impairment were identified at follow-up. The techniques of survival analysis were used to examine the risk for new onset severe cognitive and functional impairment for those previously less impaired patients over the follow-up period. At the first follow-up (12 months), the risk of cognitive decline [conversion of CDR score from 1 (mild) or less to 2 (moderate) or greater] was 12.6%. At the second follow-up (30 months), an additional 15% met criteria for worsening over the follow-up period, for a total rate of cognitive decline of 27.6%. Additional analyses of this study population were performed to identify possible risk factors for cognitive and functional decline and changes in overall functional status. Gender was not associated with risk for cognitive and functional decline or neuroleptic treatment status, negative
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symptom severity at the time of the baseline assessment, or age at the first psychiatric admission. The risk factors that were associated with increases in risk for cognitive and functional decline included: older age, lower levels of formal education, and more severe positive symptoms at baseline. Although age and educational attainment are well-understood risk factors for cognitive decline in dementia, the finding of more severe positive symptoms predicting greater risk for global functional decline was unexpected. Since positive symptoms were not found to be associated with functional status at baseline, these data suggest a longitudinal relationship between more severe positive symptoms and subsequent risk for decline during a 30-month period. This same relationship is not found for baseline severity of negative symptoms. In addition to cognitive functioning, adaptive functioning was noted to significantly decline in this population over a relatively brief follow-up period. Examination of 57 patients in a chronic psychiatric hospital, reinstitutionalized to nursing home care, and then reevaluated an average of 30 months later, demonstrated several differences in cognitive and functional status. Both cognitive functioning (estimated by the MMSE) and scores on a rating scale of behavioral aspects of functional status were found to decline to a significant extent, while positive and negative symptoms were temporally stable. Changes in cognitive functioning accounted for 25% of the variance in adaptive decline, while baseline severity of cognitive impairment and schizophrenic symptoms were uncorrelated with adaptive decline (Harvey et al 1999). These data indicate that cognitive decline may predict deterioration in overall functional status. The correlation of cognitive and adaptive decline seen in these geriatric poor outcome patients is consistent with previous reviews on the functional consequences of cognitive deficits in schizophrenia (Green 1996) and with findings from the dementia literature suggesting that cognitive decline is a better predictor of subsequent functional deficit than other aspects of the illness (Green 1993). Previous studies of better outcome patients with much higher MMSE scores also demonstrate significant cross-sectional correlations between MMSE scores and adaptive functioning deficits (Klapow et al 1997). In summary, short-term prospective studies of poor outcome patients with schizophrenia indicate that some of these patients manifest declines in their cognitive and functional status. These declines are stepwise, rather than continuously progressive, and distributed across patients, not being present in all cases. The characteristics of this progression, much like the profiles of impairment previously discussed, are not consistent with the rate or profile of progression seen in degenerative diseases, and the lack of concurrent vascular events argues against vascular dementia as a cause of this stepwise change.
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Possible Biological Substrates of Cognitive Changes With Aging While the timing and overall prevalence of functional decline in schizophrenia is not clear, there are recent studies that suggest that progressive changes in brain structure may be detectable even relatively soon after the onset of the illness. One recent study (DeLisi et al 1997) found evidence of active changes in brain structure in a follow-up study of first-episode patients with schizophrenia. Rapoport and colleagues (1997) found notable changes in ventricular size and in specific brain structures in adolescent patients with childhood onset schizophrenia an average of 4.6 and 6.6 years after the onset of illness. A similar study of middle-aged patients also noted qualitatively similar progressive brain changes that were restricted to patients with poorer functional outcome and not found in patients with better prognoses (Davis et al 1998). Thus, a possible correlate of the deterioration in functional status seen in some subsets of poor outcome patients with schizophrenia is a structural change in the brain.
Absence of Alzheimer’s Disease (AD) And Other Common Forms of Neurodegenerative Pathology in Demented Schizophrenic Patients To account for its symptomatology and clinical course, early theories of schizophrenia involved progressive neural degeneration; however, despite some early reports to the contrary (for review see Shapiro 1993), the consensus that has emerged from recent and better controlled studies is that, at the time of autopsy and in the absence of comorbidity, the brains of patients with schizophrenia do not exhibit high levels of the classical manifestations of neurodegenerative change (e.g., reactive gliosis, plaques, tangles, vascular changes, dystrophic neurites; Arnold et al 1998; Powchik et al 1998; Purohit et al 1998; Trojanowski et al 1998). Of the 100 cases studied in the Purohit and co-workers investigation, only 10% met Khachaturian (1985) criteria for AD. Even among severely cognitively impaired schizophrenics, plaque counts were less than half that seen in AD cases of identical age. Schizophrenics without plaques were on average more than 10 years younger than those with plaques. The prevalence of vascular dementia and other identifiable neuropathology in this sample was found to be less than 10%, which cannot account for the high prevalence of profound impairment, as high as 66%, seen in this patient sample (Purohit et al 1998). From these data, it appears clear that most cases of cognitive impairment in schizophrenia are not the result of AD; a finding reported by other research groups in independent samples of similar patients (Arnold et al 1995). The absence of classical histopathologic evidence of
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degeneration, together with evidence of possible neurodevelopmental anomalies, led many researchers to abandon a simple hypothesis of neural degeneration. Instead, it has been proposed that schizophrenia results from an early lesion; that this lesion is static (i.e., nonprogressive), and that the behavioral expression of the lesion varies over time as a function of the developmental state of the brain (see Wolf et al 1993 for an example of this theory). However, a more complex picture is necessary to explain progressive cognitive decline in poor outcome schizophrenia. It is likely that an early neurodevelopmental abnormality sets the stage for, or interacts with, subsequent neuronal changes. These changes may vary across patients and be expressed in terms of cognitive and functional deterioration in some patients. Moreover, the progressive changes may be atrophic (involving neuronal shrinkage or retraction of processes and synapses; see Selemon and Goldman-Rakic 1999 for such a description) rather than necrotic (involving the death of one or more neurons or the destruction of neuronal processes), explaining the absence of markers of degeneration. Hence, the schizophrenia “lesion,” like many other neurodevelopmental lesions (i.e., Huntington’s disease), is dynamic, not static.
Neurochemical Findings in Cognitively Impaired Schizophrenic Patients Despite the lack of identifiable pathologic lesions in patients with schizophrenia, it is still be possible that demented schizophrenic patients suffer from a neurochemical deficit as a basis for their cognitive impairment. For example, a study was undertaken to determine if a cholinergic abnormality was present in cognitively impaired elderly schizophrenic patients (Haroutunian et al 1994). A comparison of cognitively impaired schizophrenic subjects, AD subjects, and control subjects, revealed that cholinergic marker activity as measured by ChAT (choline acetyltransferase) and acetylcholinesterase was significantly reduced in AD subjects compared to both schizophrenic and control subjects. Although, the activity of ChAT was not significantly reduced in the parietal cortex of the schizophrenic cases, nevertheless, ChAT activity did significantly correlate negatively with the degree of cognitive impairment within the schizophrenic group. Additional ongoing surveys of neurochemical characteristics of postmortem brain tissue from schizophrenic subjects included assays of cortical norepinephrine (NE), MHPG, 5-HT (hydroxytryptamine), and 5-HIAA (hydroxy indole acetic acid) (methods described in Powchik et al 1998). To date, samples from six cortical regions have been derived from 19 elderly chronic schizophrenics (12 of whom were cognitively impaired, (i.e., CDR ⱖ 1). All schizophrenic subjects in this study had antemortem
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evaluations of cognitive functioning within 1 year of death. Those schizophrenic subjects with cognitive impairment (i.e., those with CDR scores ⬎ ⫽ 1) showed marked deficits in cortical 5-HT (Brodmann area 32 and 22) and 5-HIAA compared to those with CDR scores of 0 or 0.5. Since serotonergic deficits can be age-related, it is important to note that age was not significantly different in the two groups. Similar to the serotonin findings, norepinephrine was significantly reduced in frontal cortex in 12 cognitively impaired (i.e., CDR ⱖ 1) schizophrenic subjects compared to 7 schizophrenic subjects with CDRs of 0 or 0.5. There were trend level reductions in temporal cortical NE. Similar, but less pronounced, deficits of MHPG were also found. The data for NE are consistent with the report of Bridge and co-workers (Bridge et al 1985), which described NE deficits in hippocampus and nucleus accumbens correlated with the severity of cognitive impairment. Since noradrenergic deficits can be age-related, it is also important to note that age was not significantly different in the two groups. Taken together, the postmortem data support the following conclusions. Alzheimer’s disease and other common pathology does occur in schizophrenia, though no more frequently than in a community-based sample of subjects matched to the elderly cohort of schizophrenic patients. Therefore, these processes are insufficient to explain cognitive impairment in elderly persons with schizophrenia. Both noradrenergic and serotonergic deficits are present in elderly cognitively impaired schizophrenic subjects, with serotonergic deficit occurring in frontal and temporal cortex and noradrenergic deficits apparently restricted to frontal cortex. These deficits cannot be explained by differences in ages between demented and nondemented subjects.
Conclusions and Implications The work presented in this review demonstrates that there is substantial heterogeneity associated with symptom manifestation and course of illness associated with aging in schizophrenia. The results of studies to date addressing the question of symptom progression in schizophrenia have been conflicting. For patients manifesting progressive cognitive and functional impairment, life-long poor outcome has been demonstrated to be a consistent risk factor (Arnold et al 1995; Bartels et al 1997; Davidson et al 1995). Some of the distinguishing features of this chronically deteriorated, poor outcome schizophrenic population may provide direction for identifying risk factors for progression of cognitive and functional deficits. For example, more chronically deteriorated schizophrenic patients compared to less chronic patients have worse social
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and occupational functioning, spend more time in psychiatric hospitals, do not respond to neuroleptic treatment, and show a greater progressive increase in ventricular volume (Keefe et al 1987). Recent work continues to support neurodevelopmental factors contributing to the symptoms of schizophrenia. It is likely that very early events during the first or early second trimester, as well as subsequent obstetric complications underlie some of the premorbid psychosocial abnormalities of childhood, in addition to the subsequent manifestations of schizophrenic symptomatology seen in these patients. However, substantial evidence supports the existence other risk factors, which may interact with these neurodevelopmental influences to alter the manifestation and course of the illness. These may provide critical points of intervention to influence the course of schizophrenia. Lower levels of education and poorer premorbid adjustment are associated with a poorer outcome at follow up (Lindstrom 1996; Wieselgren and Lindstrom 1996). Although the level of educational attainment may be viewed as inevitable, an early manifestation of a neurodevelopmentally determined predisposition for poor premorbid intellectual function and progressive cognitive decline later in life, it has not been disproved that the level of educational attainment itself is an important environmental influence. Perhaps, early interventions targeting educational achievement or intellectual enrichment may influence future vulnerability for cognitive and functional decline. Additional clinical observations have shown that multiple periods of severe symptomatic exacerbation are associated with an overall poorer outcome. Moreover, findings suggest that significant delays in initiating antipsychotic treatment early in the course of illness may be associated with poorer treatment response and more severe symptoms subsequently (Haas et al 1998). Indeed, the data demonstrate that early intervention with antipsychotic medication decreases some of the long-term morbidity associated with schizophrenia (Wyatt and Henter 1998). Since the effects of severe positive symptoms on outcome are present in both first admission and chronic schizophrenic patients with multiple previous hospitalizations (Haas et al 1998), it appears that the deleterious effects of severe positive symptoms continue to exert an effect on outcome later in the illness. The longitudinal data of Harvey and colleagues (1999) demonstrates that geriatric patients at greater risk for cognitive and functional decline during a 30-month period had more severe positive symptoms at baseline. Therefore, contemporary evaluations of the impact of antipsychotics should also focus on the prolonged effect of these drugs on those at risk for cognitive and functional decline. Future research should focus on additional causes of
cognitive and adaptive decline in poor outcome schizophrenic patients. The knowledge gained from such studies should guide the development of treatments to address this dimension of the illness.
This work was presented at the conference, Schizophrenia: From Molecule to Public Policy, held in Santa Fe, New Mexico in October 1998. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.
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