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BRIEF
AmREPORTS
J Psychiatry 154:6, June 1997
Objective: To evaluate the hypothesis that patients with schizophrenia who have been treated
with neuroleptics have a high rate of Alzheimers disease-like neuropathology. Method: Neuro-
pathological studies indicating the presence or absence of Alzheimers disease-like neuropathol-
ogy in the postmortem brains of patients with schizophrenia, normal comparison subjects, and
comparison subjects who had affective disorder were evaluated with Mantel-Haenszel chi-square
and odds ratio analyses. Results: Ten studies with relevant data were reviewed; none of eight
with comparisons indicated that Alzheimers disease-like neuropathology was more likely to be
found in the brains of patients with schizophrenia than in the brains of comparison subjects.
Conclusions: Suggestions that cerebral plaques and neurofibrillary tangles are more common in
schizophrenia in association with neuroleptic treatment were not supported.
(Am J Psychiatry 1997; 154:861863)
TABLE 1. Description of Studies of Alzheimer-Like Neuropathology in Postmortem Brains of Patients With Schizophrenia and Comparison
Subjects
Diagnostic Criteria Age of Subjects (years) % Men
For Alzheimers
Comparison For Disease-Like Patients With Comparison Patients With Comparison
Study Year Group Schizophrenia Neuropathology Schizophrenia Subjects Schizophrenia Subjects
Corsellis (6) 1962 Patients with Unspecified Unspecified 65 53 50 52
affective clinical criteria clinical criteria
disorder
Jellinger (7) 1985 Normal St. Louis Unspecified 64
subjects criteria (14) clinical criteria
Buhl and Bojsen- 1988 Patients with ICD-8 Unspecified 80 70 39 43
Mller (8) affective clinical criteria
disorder
Soustek (9) 1989 None Unspecified Unspecified 58 58
clinical criteria clinical criteria
Bruton et al. (10) 1990 Normal St. Louis Unspecified 72 71 59 57
subjects criteria (14) clinical criteria
Prohovnik et al. (11) 1993 Patients with Unspecified National Insti- 78 75 46 30
affective clinical criteria tute on Aging
disorder criteria (14)
Purohit et al. (12) 1993 Normal DSM-III-R National Insti- 77 75 54
subjects tute on Aging
criteria (14)
Arnold et al. (13) 1994 Normal DSM-III-R National Insti- 77 71 60 40
subjects tute on Aging
criteria (14)
Wisniewski et al. (4) 1994 None Unspecified Unspecified 79
clinical criteria clinical criteria
Bird and Benes (un- 1996 Normal St. Louis National Insti- 50 66 78 54
published)a subjects criteria (14) tute on Aging
criteria (14)
b
Mean 70 69 54 50
aNew data (diagnostic methods reported in reference 14).
bMean ages of the schizophrenic and comparison groups were not significantly different (t=0.28, df=15, p=0.78).
TABLE 2. Findings of Alzheimer-Like Neuropathology in Studies of Postmortem Brains of Patients With Schizophrenia and Comparison
Subjects
Subjects With Alzheimers
Disease-Like Neuropathology Analysis
Number of Subjects Schizophrenia Comparison 95%
Odds Confidence
Study Schizophrenia Comparison N % N % Ratio Interval
Corsellis (6) 16 27 4 25.0 8 29.6 0.79 0.183.12
Jellinger (7) 172 117 16 9.3 8 6.8 1.40 0.593.55
Buhl and Bojsen-Mller (8) 23 14 8 34.8 4 28.6 1.33 0.326.12
Soustek (9) 225 44 19.6
Bruton et al. (10) 48 56 16 33.3 18 32.1 1.06 0.462.40
Prohovnik et al. (11)a 544 47 52 9.6 7 14.9 0.60 0.271.53
Purohit et al. (12) 13 12 0 0.0 0 0.0
Arnold et al. (13) 15 5 1 6.7 0 0.0
Wisniewski et al. (4) 102 35 34.3
Bird and Benes (unpublished)b 135 201 12 8.9 34 16.9 0.48 0.230.94
Total 1,293 479 188 14.5 79 16.5 0.86 0.651.15
aCorrected for 33% verification of Alzheimers disease findings in subsample.
bNew data (diagnostic methods in reference 14).
the eight studies with comparisons indicated a signifi- which the comparison patients with affective disorder
cantly higher rate of Alzheimers disease-like neuropa- were significantly older than the patients with schizo-
thology in the brains of patients with schizophrenia phrenia (mean=66.0 years, SD=16.0, versus mean=49.5
(overall Mantel-Haenszel 2=1.44, df=1, p=0.23), but years, SD=20.0) (t=8.4, df=334, p<0.001), we found a
there was some lack of homogeneity of rates across weakly lower rate of Alzheimers disease-like neuropa-
studies (Mantel-Haenszel 2=5.47, df=1, p=0.02). thology in the brains of patients with schizophrenia
In the new data (E.D. Bird and F.M. Benes, 1996), in (2=4.40, df=1, p=0.04) (table 2). However, among the
subjects with Alzheimers-disease neuropathology, the impairments (15). Cross-sectional assessments have not
mean ages of the patients with schizophrenia (76.5, indicated declining cognition in schizophrenia: in 10
SD=8.70) and the patients with affective disorder (77.3, studies published in 19641980 (15), IQ and year of
SD=9.4) were similar (t=0.03, df=44, p>0.90). study were uncorrelated (r=0.09, df=8, p>0.1). Instead,
Across studies, the risk of Alzheimers disease-like many psychotic patients show improvements in cogni-
changes did not increase significantly with age in tion during antipsychotic treatment, generally with oth-
schizophrenia (rs=0.40, df=8, p=0.23). The mean rates erwise improved clinical status (1618).
of Alzheimers disease-like neuropathology were simi- The information reviewed here provides little support
lar in the brains of patients with schizophrenia and for the proposal that Alzheimers disease-like neurode-
those of normal comparison subjects and patients with generative changes are more common in schizophrenia
affective disorder, and the overall odds ratio (0.86) was than in other idiopathic psychiatric disorders or in nor-
not elevated above 1.0 (table 2). mal subjects. Moreover, the unsettling proposal that
Reanalysis of the data of Wisniewski et al. (4) yielded such neuropathological changes may have increased
only weak support for the hypothesis that postmortem since the introduction of long-term maintenance treat-
incidence of Alzheimers disease-like changes has in- ment with neuroleptic agents remains unproved.
creased in association with antipsychotic drug treat-
ment in schizophrenia. The rates of plaques with or
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