Philip D. Harvey, PhD

Cognitive deficits are increasingly being recognized as a central feature of schizophrenia. Some impairments are present before the hallmark positive symptoms of the illness emerge (Cornblatt et al., 1999; Davidson et al., 1999), and moderate-to-severe impairments across many cognitive domains are detectable at the time of the first episode (Bilder et al., 2000; Saykin et al., 1994). Cognitive deficits appear to be largely consistent in severity across changes in clinical state (Harvey et al., 1990) and appear stable from emergence of the first episode until after middle age (Rund, 1998). These findings suggest that cognitive deficits are not simply a consequence of the symptoms of the illness or its treatment. Throughout the course of the illness, positive symptoms fluctuate depending on the overall pattern of treatment response of the patient, while cognitive deficits are typically reported to manifest minimal improvement and to be the best predictors of impairments in functional skills (Green, 1996). Studies of cognitive deficits in schizophrenia have moved from descriptive to predictive since their link to functional outcome has been well-replicated (Green et al., 2000). Thus, cognitive deficits are now recognized as an important treatment goal.

With the aging of the baby boomer generation, a large number of patients with schizophrenia are now reaching late life. Yet, many studies of the course of schizophrenia have failed to include truly elderly patients. This may lead to misperceptions regarding the characteristics of cognitive impairments in later life, if the course of the illness is inferred from studies with truncated age ranges. In addition, many studies of possible age effects on cognition are cross-sectional, such that they compare the functioning of elderly patients to a younger cohort. This methodology is certainly more feasible and is often useful in generating hypotheses for longitudinal designs. However, conclusions from any cross-sectional studies about the course of any illness must be viewed with caution. An additional consideration involves overall lifetime outcome of the illness, often indexed by the residential status of older patients with schizophrenia. Those patients with substantial functional deficits would be expected to be more impaired than ambulatory patients, who have often had a much more variable course. In this review, we will discuss age-related changes in cognitive functioning in schizophrenia. 

A number of cross-sectional studies have been employed to compare cognitive functioning in older to younger patients with schizophrenia. Heaton et al. (1994) found that the cognitive profiles and levels of impairment in older ambulatory patients with schizophrenia were consistent with the impairments seen in younger patients. Both younger and older patients had prominent deficits in learning and memory, executive functioning, and attention, compared to control subjects. They even performed more poorly than patients with Alzheimer's disease (AD) on most domains. Although there were no age-associated differences in performance, the level of impairment was quite severe. Similar results were reported for scores on the Mattis Dementia Rating Scale (MDRS) (a global index of cognitive functioning) across the age range (Eyler Zorrilla et al., 2000). In this study, older ambulatory patients with schizophrenia were found to have no age-corrected greater impairments than younger patients. These cross-sectional studies suggest that cognitive impairments are stable from mid-life to later years, although the age range of these samples did not include a large number of truly elderly patients.

Although Heaton et al. (1994) and Eyler Zorrilla et al. (2000) found no age-related differences in cognition, it is important to examine additional cohorts, such as those patients with more chronic schizophrenia. While efforts at deinstitutionalization and community integration persist, a substantial number of patients with schizophrenia remain in psychiatric hospitals or other full-care residences, such as nursing homes, into late life. Since these patients have had a very different course of illness during most of their lives, compared to ambulatory patients, other characteristics may differ as well. Evans et al. (1999) found that institutionalized patients performed more poorly on the MDRS than ambulatory patients. Similarly, Harvey et al. (1998) found substantial differences between acutely and chronically ill patients using a neuropsychological battery designed for the assessment of older individuals. Other groups have also found more severe cognitive impairments in patients residing innursing homes compared to ambulatory patients (Auslander et al., 2001; Bartels et al., 1997).

Davidson et al. (1995) found age-related differences on the Mini-Mental State Examination (MMSE) in a sample of poor-outcome patients ranging from ages 25 to 95. Patients between ages 85 and 95 received an average score of only 9.6 (even when patients with scores of zero were excluded), a significant difference from the average score of 16 for patients between ages 65 and 75. These levels of impairment are consistent with the results of other studies of demographically similar patients in the United States (Arnold et al., 1995), the United Kingdom (Harvey et al., 1997a) and Japan (Seno et al., 1998). Bowie et al. (2002) found that age was associated with differences in cognition even for patients who had MMSE scores 18. This may have limited the ability to detect potential impairments in lower-functioning patients. 

In a longitudinal study of older ambulatory patients, Heaton et al. (2001) found no evidence of change over an average of 60 months on a comprehensive neuropsychological battery. However, only 22 of the 142 patients were over age 65 at entry into the study. Another longitudinal study reported that older patients had selectively greater impairments in abstraction abilities than younger patients, with no increased age-related differences in other aspects of cognitive functioning (Fucetola et al., 2000). Further, Granholm et al. (2000) reported that older patients had a reduced ability to process complex information, as shown by increased utilization of information-processing resources while performing an attentional task. There is some evidence of age-related changes in the ability to perform complex and resource-demanding tasks even in ambulatory patients.

In a study of hospitalized patients with chronic schizophrenia (age>65) with MMSE scores >17, 30% declined over a 30-month period (Harvey et al., 1999b). The best two predictors of cognitive decline were lower education and greater severity of positive symptoms at baseline. A follow-up study of geriatric patients with schizophrenia who entered the study while hospitalized and who were reassessed after they were discharged to nursing homes also demonstrated cognitive decline over an average of 2.5 years (Harvey et al., 1999a). 

Additional support for age-related cognitive decline comes from a study of chronically institutionalized patients ranging in age from 25 to 85 who were followed for six years and compared to healthy individuals and patients with AD (Friedman et al., 2001). This study found that the patients with schizophrenia had an age-associated risk of cognitive decline not found in the patients with AD or the healthy controls. The oldest patients with schizophrenia (ages 75 to 80 at baseline) dropped by six MMSE points in six years, while those under the age of 65 did not change in their functioning over the follow-up period. Furthermore, patients with AD declined by 12 or more MMSE points, regardless of age at entry into the study. This suggests that chronicity alone is not a sufficient determinant of cognitive decline until patients cross a certain age threshold. Later studies have indicated that newly incident medical conditions predict risk for cognitive decline (Friedman et al., 2002) and have sug-gested more recently that declines in cognitive functioning over time in poor-outcome patients predict the course of functional decline as well (Harvey and Davidson, 2002).

While a number of studies on cognition in older patients with schizophrenia have been published in the past decade, the specific effect of aging remains unclear. It appears that cognitive decline with aging in schizophrenia is multi-determined. While the decline does not appear to occur at all in younger patients, even those with a chronic course of illness, it is also not likely to be a pattern found in all older individuals with schizophrenia. 

It appears that certain risk factors-possibly a chronic course of illness, less education, higher levels of positive symptoms and poor baseline cognitive functioning-are associated with the age-related cognitive decline observed in some patients. Ambulatory patients may also decline in late life on particularly complex tasks. However, the timing and severity of the decline may differ from poor-outcome patients. 

Complicating the identification of those at risk for cognitive decline are the different research designs employed by various groups of researchers. This leads to the difficulty of parsing out the effects on cognition of life-long institutionalization, chronic psychosis, long-term antipsychotic medication administration and other factors. The Figure illustrates that longitudinal studies of chronically ill patients universally find global cognitive decline, while the only cross-sectional studies that failed to find age-related differences in cognition assessed only one specific domain and excluded low-functioning patients. In addition, a longitudinal study that failed to observe cognitive decline was of somewhat younger ambulatory patients. Since expected declines in cognition for healthy individuals only become substantial after age 65, it stands to reason that examination of patients with schizophrenia who are younger than 65 may be insufficient to detect decline.

Future longitudinal studies will assist in determining why cognitive decline occurs in late life for some patients with schizophrenia, but not for others. Consequently, treatment strategies for those at highest risk for decline may be developed in the near future. In turn, functional outcome, by way of improving or at least preserving cognitive functions, may be improved for the large number of elderly patients with schizophrenia.

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Recent studies have shown that patients with schizophrenia experience a greater decline in cognitive abilities with age. Given the large baby boomer population, how will this influence treatment for aging patients with schizophrenia?

Philip D. Harvey, PhD

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