School of Psychiatry, University of New South Wales, Sydney, Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Sydney, Australia
School of Psychiatry, University of New South Wales, Sydney, Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia
Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Sydney, Australia
Correspondence: Professor Henry Brodaty, Academic Department for Old Age Psychiatry, Euroa Centre, Prince of Wales Hospital, Avoca St, Randwick, NSW 2031, Australia. Tel: 2 9382 3759; fax: 2 9382 3762; e-mail: hbrodaty{at}unsw.edu.au
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ABSTRACT |
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Aims To examine the long-term outcome of a group of patients with late-onset schizophrenia.
Method Patients with onset of DSMIIIR schizophrenia at age 50 years or over, but without dementia, and a healthy control group were assessed at baseline (n=27 andn=34, respectively), after 1 year and after 5 years (n=19 and n=24, respectively) on measures of psychopathology, cognition and general functioning, and compared on rates of decline and incidence of dementia.
Results Nine patients with late-onset schizophrenia and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, 3 dementia of unknown type) at 5-year follow-up. There appeared to be a subgroup of late-onset schizophrenia patients without signs of dementia at baseline or at 1 year follow-up who subsequently declined.
Conclusions Late-onset schizophrenia may be a prodrome of Alzheimer-type dementia. More longitudinal studies are required to determine its nosological status.
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INTRODUCTION |
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METHOD |
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A low MMSE threshold was set because of the effects of psychosis on test results. Results were reanalysed for subsamples of participants with higher baseline MMSE thresholds.
Of 112 participants assessed, 21 were excluded, leaving 27 late-onset schizophrenia patients (mean age of onset 66.4 years, range 5087), 30 patients with early-onset disease (whose results are not included in this paper) and 34 normal controls (details described by Brodaty et al, 1999). One late-onset schizophrenia patient attained a score of 19 on the MMSE, but this was considered to be an underestimate. This patient was included in the study, and scored 23 at reassessment a year later, supporting the contention that the poor initial performance was due to psychosis rather than underlying cognitive disorder. The psychiatric, neurological, neuropsychological and magnetic resonance imaging (MRI) characteristics of the study sample have been reported by Sachdev et al (1999, 2000).
The late-onset schizophrenia and normal control groups were comparable on
age, gender and socio-economic status at baseline. However, the patients had
significantly fewer years of education (Uz=-3.48,
P=0.001) and were significantly more likely to have never been
married (Yatess continuity correction CC2=6.53, d.f.=1,
P=0.008) than the controls.
Assessments
The following standardised instruments were employed at 5-year follow-up:
Global Assessment of Functioning (GAF;
American Psychiatric Association,
1987), Instrumental Activities of Daily Living (IADL;
Lawton & Brody, 1969),
Activities of Daily Living (ADL; Katz
& Apkon, 1976), Clinical Dementia Rating (CDR;
Hughes et al, 1982),
MMSE (Folstein et al,
1975), Cognitive Decline Scale
(Jorm et al, 1995; a
10-item informant-rated scale, assessing aspects of cognitive decline),
Cambridge Mental Disorders of the Elderly Examination (CAMDEX;
Roth et al, 1986) and
the Hachinski Ischaemia Scale (Hachinski
et al, 1975). A neurological examination and MRI scan
were performed at baseline assessment (details described by
Sachdev et al,
1999).
Diagnosis of schizophrenia at 5-year follow-up was based on DSMIV criteria (American Psychiatric Association, 1994). Current psychopathological symptoms were assessed using the Brief Psychiatric Rating Scale (Overall & Gorham, 1962), an 18-item scale with each item rated from 0 (not present) to 6 (extremely severe). Diagnosis of dementia at 5-year follow-up was based on DSMIV criteria, using information from the CDR, MMSE, Cognitive Decline Scale and items from the CAMDEX. This was reached by consensus in case conferences involving two psychiatrists experienced in diagnosing dementia (H.B. and P.S.) and a research psychologist. Participants identifying information was excluded from these conferences. Patients were considered to be diagnosable as having mild cognitive impairment at baseline if their score on the Logical Memory I or II subtest of the Wechsler Memory Scale (Wechsler, 1981) was 1.5 standard deviations below the Age Scale score.
Method of follow-up
Participants were assessed 1 year and 5 years after the baseline
investigation. They were located by telephone and written contact, directly or
through their next of kin, or were traced through the electoral roll (in
Australia, registration on the electoral roll is compulsory). Death
certificates and medical notes were obtained where possible for those who had
died. Follow-up interviews with participants and/or their informants were
conducted by a physician. The next of kin of those who had died were
interviewed where possible.
Data analysis
The Statistical Package for the Social Sciences (SPSS) version 9 for
Windows was used for all statistical analyses
(SPSS, 1999). Two-sample
t-tests were employed for between-group comparisons on continuous
variables. In the case of IADL, ADL, Cognitive Decline Scale and CDR, age
differences between the patient and control groups approached significance
(P=0.059), and so age was used as a covariate in between-group
analyses involving these variables. MannWhitney U-tests were
used for skewed continuous data. Chi-squared analyses were used for
between-group comparisons on categorical variables. For 2x2 tables,
Yatess continuity correction (denoted by CC2) is
reported. Fishers exact test was used in the analysis of 2x2
tables with expected frequencies lower than 5 in two or more cells. Change
within groups over time on outcome variables was analysed using repeated
measures analysis of variance (ANOVA) or multivariate analysis of variance
(MANOVA). Age at institutionalisation was compared between groups using
KaplanMeier survival analysis. For all analyses, probability levels
reported were two-tailed, and the level of significance was set at 0.05.
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RESULTS |
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Change over 5 years
On most measures, the patients had a worse outcome after 5 years than did
controls (Table 2). They were
institutionalised at a younger age, their IADL and ADL scores declined more,
and their level of cognitive decline, as measured by the CDR and Cognitive
Decline Scale, was significantly worse than that of controls. Their mean MMSE
score declined by 6.5 points over 5 years while that of controls remained
stable. Of ten patients who were alive at 5-year follow-up, three patients
were not interviewed. Of the seven who were interviewed, one met DSMIV
criterion A for schizophrenia at 5-year follow-up, and six out of seven
patients assessed with the BPRS (including the patient meeting criterion A)
had symptoms of psychosis: five with delusions or hallucinations, one with
grandiose ideation and probable psychosis. Despite decline in other areas,
global functioning (GAF score), while lower than that of controls, did not
decline in the late-onset schizophrenia group as a whole over the 5-year
period. However, patients with dementia at 5-year follow-up had a mean GAF
score of 28.1 (s.d.=19.6, n=9), in contrast to a mean GAF of 61.6
(s.d.=18.9, n=10) in patients without dementia at 5 years. The
late-onset schizophrenia patients and controls did not differ significantly in
levels of neurological abnormality at 5-year follow-up.
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Incidence of dementia
At 5-year follow-up we found that nine of the 19 late-onset schizophrenia
patients met DSMIV criteria for dementia. Five of these met
DSMIV criteria for Alzheimers disease and one met criteria for
vascular dementia. The remaining three had dementia of unknown type. None of
the controls was found to have dementia. A 2 analysis
comparing incidence of any dementia between the two groups was highly
significant (CC
2=11.7, d.f.=1, P < 0.001). Since
odds ratios do not allow for zero cells, pseudo-Bayes estimates were
calculated for this table (Bishop et
al, 1975). The resulting odds ratio of 16.52 had a very wide
95% confidence interval, 1.85147.8, which is not surprising considering
the zero cell for the control group. If the most extreme case
scenario is considered and all patients (and controls) lost to
follow-up did not have dementia, the analysis comparing the incidence of
dementia between the two groups would remain highly significant
(
2=12.8, d.f.=1, Fishers exact test P <
0.001). The pseudo-Bayes estimate for the odds ratio is 9.98 (95% CI
1.4469.37).
Of the 12 patients who had a baseline MMSE score of 25 or over, five
developed dementia, as did four of seven with initial MMSE scores below 25. If
the rates of dementia are calculated only in participants whose MMSE scores
were 25 or over at baseline, the rate of dementia at follow-up was still
significantly higher in the patients than in the controls (5/12 v.
0/24; 2=11.6, d.f.=1, Fishers exact test
P=0.002). Even restricting the comparison to those with MMSE scores
of 28 or more, the rate of dementia was significantly higher among patients
than controls (2/7 v. 0/23;
2=7.0, d.f.=1,
Fishers exact test P=0.05).
We considered whether some of the patients might have been diagnosable as having mild cognitive impairment. All seven patients with baseline MMSE scores below 25 had scores on the Logical Memory I or II subtest of the Wechsler Memory Scale at least 1.5 s.d. below the Age Scale score, as did 7 of the 12 with MMSE scores or 25 or over. No control had diagnosable mild cognitive impairment using this criterion. Seven of the 14 late-onset schizophrenia patients with diagnosable mild cognitive impairment developed dementia, as did two of five patients without mild cognitive impairment.
We conducted post hoc comparisons of baseline characteristics between late-onset schizophrenia patients who went on to develop dementia (n=9) and those who did not (n=10). Patients who subsequently developed dementia were older at baseline, of lower socio-economic status, with longer duration of illness and with worse IADL, ADL and MMSE scores than those who did not develop dementia (Table 3), but none of these comparisons reached statistical significance. Re-analysis correcting for age differences did not change these findings. There were non-significant differences between the groups on baseline MRI variables, with the subsequently demented patients having had greater ventricle-to-brain ratio (see Victoroff et al, 1994) and more periventricular and centrum semiovale hyperintensities (see Fazekas et al, 1987) on T2-weighted imaging (Table 3).
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We examined the influence of possible confounding factors, namely intercurrent illness and medication usage, on dementia incidence. There was no significant difference between late-onset schizophrenia patients with and those without dementia as regards occurrence (between the 1-year and 5-year assessments) of any of the following: myocardial infarction, stroke, transient ischaemic attack, cerebrovascular disease, other neurological changes and surgery. There was no significant difference between the two groups in rates of current usage of psychoactive medications in general, or antipsychotics specifically. We did not have sufficient data on history of alcohol misuse to include it in our analyses, but no participant was alcohol-dependent.
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DISCUSSION |
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Our study suggests that long-term follow-up of people with late-onset schizophrenia often yields a picture of progressive cognitive decline. Cross-sectional assessments in our patients at the time of entry into the study, as reported previously (Sachdev et al, 1999), did not show significant differences in cognitive function between late- and early-onset schizophrenia, with both diagnostic groups performing worse than healthy individuals. Even at 1-year follow-up (Brodaty et al, 1999), we did not see evidence of decline in our late-onset schizophrenia sample. The picture was quite different at 5 years, with high rates of dementia and institutionalisation. Our study supports the findings of Craig & Bregman (1988) and Holden (1987) that late-onset schizophrenia is a prelude to dementia in a high proportion of cases. Holden reported that 13 of 37 patients with a diagnosis of paranoid psychosis, and having a minimum score of 21 out of 43 on a scale of orientation, general knowledge and memory, progressed to dementia within 3 years (i.e. 35%, or 11.7% per annum compared with the present rate of 47.4% over 5 years or 9.5% per annum). Palmer et al (2003) did not find evidence of decline in a group of patients with late-onset schizophrenia-spectrum disorders over 2 years of follow-up, but conceded that longer follow-up periods could reveal that late onset schizophrenia disorder patients experience a very slow cognitive decline that is obscured by normal practice effects when observed over shorter periods. Alternatively, sampling differences might explain the discrepancies in findings.
Possible explanations for cognitive decline in late-onset
schizophrenia
Our findings do not appear to be a result of undiagnosed cases of dementia
among participants with late-onset schizophrenia at baseline, as rates of
dementia remained significantly higher when we compared late-onset
schizophrenia subsamples with higher index MMSE scores or those without
diagnosable mild cognitive impairment and controls. We were surprised that
dementia cases were predominantly of Alzheimer type as evidenced by the
patients gradual decline in function, prominent disturbance of episodic
memory and absence of clinical stigmata of cerebrovascular disease. Based on
the finding of increased T2-weighted hyperintensities in
the white matter and subcortical nuclei in our patients at the start of the
study, we had predicted an increased incidence of vascular dementia. This was
not the case, as judged on a clinical basis. A limitation of our diagnostic
process was the absence of neuroimaging at 5-year follow-up, which would have
further increased confidence in the diagnosis. It is recognised that
subcortical vascular dementia may present like Alzheimers disease
(Jeste et al, 1998)
and we cannot rule out this possibility, except that hypertension was not in
excess in the late-onset schizophrenia sample, and these patients
clinical picture was not characterised by the subcortical
features of psychomotor slowing and frontal executive deficits. Our
participants did not consent to post-mortem examination, which was not
surprising since they needed much persuasion at every stage of the study.
Could psychosis have contributed to the development of Alzheimers disease in our study group? Published research such as the EURODEM study (Jorm et al, 1995) on psychiatric risk factors for this disease did not find any such association. Nor was an excess of plaques and tangles found in a post-mortem study of patients with schizophrenia (Purohit et al, 1998). There is also no evidence, after more than 50 years of their usage, that antipsychotic agents contribute to the development of dementia (Spohn & Strauss, 1989). One possible explanation for our finding is that we inadvertently included people with early dementia in our late-onset schizophrenia sample. Even on retrospective review of our early data, the diagnosis of dementia was not warranted in any case, at baseline or at 1-year follow-up. There was, however, a tendency for those who had dementia at 5-year assessment to have had slightly worse MMSE, ADL and IADL scores at baseline. It will be of great clinical interest to see whether the patients who were still cognitively intact at 5 years will also progress to dementia later in the course of their illness.
Pathogenesis of cognitive decline in late-onset schizophrenia
The occurrence of a schizophrenia-like psychosis for many years before
dementia becomes manifest warrants speculation on its pathogenesis. It is
parsimonious to argue that late-onset schizophrenia in these cases is a
manifestation of changes associated with the dementing process. Delusions are
common in Alzheimers disease, but generally occur in the middle stages
of the disease rather than being its presenting feature
(Jeste et al, 1992).
It is possible that in a few patients with Alzheimers disease the brain
regions affected in the early stages cause a propensity for the development of
psychosis. In particular, lesions of the temporal lobes have been implicated
(Lewis, 1995). We must
emphasise that dementia did not develop in all our patients, and about half of
the sample were cognitively stable, suggesting that late-onset schizophrenia
is a heterogeneous syndrome. This is further underscored by the clear gulf in
global functioning scores between the demented and non-demented patients.
While the mean GAF score of those with dementia declined, the mean score of
those without dementia rose from 41.4 to 61.6 over the 5 years, which is
likely to be due to the full or partial resolution of psychosis in many cases.
The eventual fate of the non-demented group is, however, of future
interest.
Implications of the study
Among the strengths of this study were the detailed nature of the follow-up
assessment, which encompassed information from both participants and
informants, and the strict consensus diagnoses of schizophrenia and dementia
using DSM criteria. We were constrained somewhat by the availability of
informant information only, in cases where the participant had died before the
5-year assessment. We were also limited by our small sample size and by the
level of attrition. However, there was no difference at baseline between those
followed up and those not. Although the small sample size limits the power of
this study, it makes our finding of a high incidence of dementia all the more
striking.
This study has implications for our understanding of the presentation and
course of schizophrenia and dementia in the elderly. Further long-term
follow-up of patients with late-onset schizophrenia, encompassing cognitive
measures, functional neuroimaging and genotyping (e.g. for the apolipoprotein
E 4 isoform) would be of benefit in clarifying the possibility that
late-onset schizophrenia is an early presentation of dementia. Why some
patients present in this way should then become the focus of inquiry.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication September 22, 2002. Revision received February 28, 2003. Accepted for publication May 1, 2003.
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