Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia.

BACKGROUND: The identification of novel subtypes of the dopamine receptors has renewed interest in the involvement of dopaminergic mechanisms in schizophrenia. We determined the expression of transcripts encoding the dopamine receptors in the brains of schizophrenic patients. METHODS: The levels of the messenger RNA molecules encoding the 5 dopamine receptors were quantified in postmortem brain samples from 16 schizophrenic patients and 9 control subjects. Samples from multiple regions of the prefrontal cortex, primary visual cortex, and striatum were subjected to in situ hybridization followed by quantitative image analysis. RESULTS: Expression of dopamine receptor transcripts did not differ between schizophrenic patients and controls in striatum or visual cortex. Dramatic decreases of dopamine receptor transcripts were found in the prefrontal cortex, but these changes were restricted to the D3 and D4 receptors, and localized to Brodmann area 11 (orbitofrontal cortex). CONCLUSIONS: Cortical dopaminergic neurotransmission may be disrupted in schizophrenia at the level of receptor expression. There appears to be a focal abnormality of D3 and D4 messenger RNA expression in the prefrontal cortex, with down-regulation of both, consistent with prefrontal cortical hypodopaminergia in schizophrenia.

Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia.

BACKGROUND: Cytoarchitectural and neurochemical studies demonstrate disorganization in the cerebral cortex in schizophrenia, which perhaps underlies the severe behavioral disturbances of the disease. This neuronal disarray should be accompanied by synaptic abnormalities. As such, presynaptic proteins have proved valuable indexes of synaptic density and their concentrations have correlated markedly with synaptic loss. Our study sought to determine whether abnormalities exist in the concentrations of presynaptic proteins in the postmortem cerebral cortex of subjects with schizophrenia. METHODS: Presynaptic protein immunoreactivities were assessed in 4 different cerebrocortical regions derived from 16 elderly controls, 19 elderly subjects with schizophrenia, and 24 subjects with Alzheimer's disease. Tissues were assayed with the monoclonal antibodies EP10 and SP4, which recognize synaptophysin, and the monoclonal antibodies SP6 and SP14, which detect syntaxin and synaptosomal-associated protein-25-kd immunoreactivities, respectively. RESULTS: In subjects with schizophrenia relative to controls, presynaptic proteins were increased in the cingulate cortex, but were unchanged in the temporal, frontal, and parietal cortices. In contrast, when cases with Alzheimer's disease were compared with controls, presynaptic proteins were decreased in the frontal, temporal, and parietal samples. CONCLUSIONS: These findings reveal changes in the synaptic organization of the cingulate cortex in schizophrenia relative to other areas examined. These changes are distinct from the deficits in presynaptic proteins observed in Alzheimer's disease.

Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases.

BACKGROUND: Clinical studies suggest that severe cognitive impairment is common among elderly patients with schizophrenia who reside in long-stay psychiatric institutions; however, previous autopsy-based neuropathologic investigations have provided conflicting results about the occurrence of Alzheimer disease (AD) in elderly patients with schizophrenia. We report the results of a comprehensive neuropathologic study performed to identify AD and other dementing neurodegenerative diseases in elderly patients with schizophrenia. METHODS: A neuropathologic examination was performed on 100 consecutive autopsy brain specimens of patients aged 52 to 101 years (mean, 76.5 years). A cognitive assessment of these cases was also done by employing the Clinical Dementia Rating Scale. For comparison, we included 47 patients with nonschizophrenic psychiatric disorders from the same psychiatric hospital and 50 age-matched control subjects. RESULTS: Although 72% of the patients with schizophrenia showed cognitive impairment, AD was diagnosed in only 9% of the patients and other dementing diseases were diagnosed in only 4% of the patients. The degree of senile plaques or neurofibrillary tangles was not different in the group with schizophrenia compared with the age-matched controls or the group with nonschizophrenic psychiatric disorders. The higher Clinical Dementia Rating Scale scores lacked correlation with neuropathologic evidence of dementing disorders. In the 87 cases lacking a neuropathologic diagnosis of AD or other dementing disorders, the mean (+/-SD) Clinical Dementia Rating Scale score was 2.21 (+/-1.14), with 43 of the cases scoring 3 or higher (indicating severe, profound, or terminal cognitive impairment). CONCLUSIONS: This study provides evidence that elderly patients with schizophrenia are not inordinately prone to the development of AD or to increased senile plaques or neurofibrillary tangle formation in the brain. Other dementing neurodegenerative disorders are also uncommon. The cognitive impairment in elderly patients with schizophrenia must, therefore, be related to some alternative mechanisms.

Changes in plasma homovanillic acid concentrations in schizophrenic patients following neuroleptic discontinuation.

Changes in plasma levels of the dopamine metabolite homovanillic acid have been reported to correlate with changes in the severity of schizophrenic symptoms during neuroleptic administration and after neuroleptic discontinuation. This study examined the effects of discontinuation of neuroleptic treatment on plasma homovanillic acid levels in 23 patients with chronic schizophrenia. It was hypothesized that clinical decompensation would be associated with increased plasma homovanillic acid levels. Plasma homovanillic acid was measured during administration of neuroleptic medication and during a subsequent 6-week drug-free period. Nine patients decompensated during the drug-free period and 14 patients did not. Following drug discontinuation, plasma homovanillic acid concentrations were higher in schizophrenic patients who decompensated than in those who did not. Furthermore, peak plasma homovanillic acid elevation after discontinuation of neuroleptic medication was significantly correlated with peak Brief Psychiatric Rating Scale increase. The data suggest that, in some schizophrenic patients, symptomatic decompensation after discontinuation of neuroleptic treatment is associated with increases in dopamine turnover.

Symptom stability in geriatric chronic schizophrenic inpatients: a one-year follow-up study.

The results of previous studies of symptom stability in schizophrenia suggest that negative symptoms manifest traitlike characteristics while positive symptoms fluctuate over time. Various prospective studies of chronic schizophrenic patients have found consistent results, regardless of the follow-up period, yet there is little research addressing symptomatology in geriatric schizophrenic patients. Since these patients have a very poor outcome and more severe negative symptoms, their symptoms might differ from younger patients. This study examined the course of symptomatology in 178 geriatric schizophrenic inpatients who were assessed twice at a 1-year interval with the Positive and Negative Syndrome Scale (PANSS). Intraclass correlations revealed that the distribution of negative symptoms was considerably more stable than that of positive symptoms over the interval, and subtypes based on negative symptoms were the only ones that manifested consistent stability over time. There was also a significant increase in negative symptom severity for the sample, with a slight decrease in positive symptom severity. Thus, even in chronic inpatients, with a very extended illness, positive symptom severity is not particularly stable within patients. These data indicate that the characteristics of negative and positive schizophrenic symptoms are similar in younger and geriatric schizophrenic patients, suggesting a continuity of the illness process. Tentative evidence for increasing severity of negative symptoms over a brief follow-up period suggests the possibility of a steady worsening of clinical state in very elderly patients who remained hospitalized.

4-Aminopyridine in the treatment of Alzheimer's disease.

The cognitive and behavioral effect of 4-aminopyridine (4-AP) was examined in Alzheimer's disease (AD) using a dose finding/replication study design. Fourteen inpatients, aged 54-89 years (mean 66.1 +/- 10.6 SD), meeting NINCDS criteria for probable AD, were studied. Three doses of 4-AP--2.5 mg b.i.d., 5 mg b.i.d., and 10 mg b.i.d.--or placebo were administered for 4 consecutive days in random order. Symptomatic assessment was performed on the fourth day of each condition using the Alzheimer Disease Assessment Scale (ADAS). Thereafter, the dose on which the best performance occurred was readministered, as was placebo. Of the 13 patients who completed the dose-finding phase, 7 patients had at least one dose of 4-AP that was associated with less severe symptoms than was placebo, and those patients were included in the replication phase. Results indicated no significant difference in total ADAS scores (p greater than 0.05). Examination of the ADAS subscales revealed no significant 4-AP effect on any particular symptom. Possible explanations of the lack of a drug effect in this study include the unselective release of neurotransmitters by 4-AP, poor penetration into the central nervous system (CNS), and the presenile onset of the disease in these patients.

Ventricular enlargement in poor-outcome schizophrenia.

BACKGROUND: A subset of patients with schizophrenia, defined on the basis of longitudinal deficits in self-care, may show a classic ("Kraepelinian") degenerative course. An independent validator of the phenomenologically defined Kraepelinian subtype might be provided by a structural indicator of possible brain degeneration: ventricular size as measured by computed tomography (CT). METHODS: To examine whether Kraepelinian patients would show a differential increase in ventricular size over time, two CT scans were conducted at intervals separated by > 4 years, an average of 5 years. Fifty-three male patients with DSM-III-R diagnoses of chronic schizophrenia were subdivided into Kraepelinian (n = 22; mean age = 42 +/- 6 years) and non-Kraepelinian (n = 31; mean age = 38 +/- 12.2 years) subgroups. Kraepelinian patients were defined on the basis of longitudinal criteria: > 5 years of complete dependence on others for life necessities and care, lack of employment, and sustained symptomatology. Thirteen normal elderly volunteers (mean age = 60 +/- 17.8) were also scanned at 4-year intervals. CT measurements were made by raters without knowledge of subgroup membership. A semiautomated computer program was used to trace the anterior horn, lateral ventricles, and temporal horns for each slice level on which they were clearly seen. RESULTS: The ventricles showed a bilateral increase in size over the 4-year interval in the Kraepelinian subgroup, more marked in the left hemisphere than the right. By contrast, neither the non-Kraepelinian subgroup nor the normal volunteers showed significant CT changes from scan 1 to scan 2. CONCLUSIONS: Thus, the longitudinal dysfunctions in self-care that characterize the Kraepelinian patients were associated with an independent indicator of brain abnormality.

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex.

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimer's disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study.

The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimer's disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.

Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients.

BACKGROUND: Geriatric schizophrenic patients with a chronic course of institutionalization manifest cognitive and functional impairments that implicate decline at some time point after the onset of illness. The rate of change in cognitive and functional status in these patients has not yet been identified with a longitudinal study. METHODS: Three hundred and twenty-six schizophrenic patients entered a 30-month follow-up study with two separate assessments of the patients. Overall functional and cognitive status was indexed with the Clinical Dementia Rating (CDR). Survival analysis was used to examine changes in cognitive and functional status, including worsening for the less impaired patients and improvements on the part of more impaired patients. RESULTS: Approximately 30% of the patients who had baseline scores in the less impaired range manifested a worsening of their CDR ratings to a score of 2.0 (moderate) or more severe, whereas only 7% of the sample with lower scores at baseline appeared to improve in their functioning. Several characteristics of the patients at baseline assessment predicted increased risk for cognitive and functional decline, including lower levels of education, older age, and more severe positive symptoms. CONCLUSIONS: Cognitive and functional decline can be detected in a short-term follow-up in a subset of geriatric long-stay patients with schizophrenia. This decline appears distributed across patients and not due to the presence of progressive degenerative dementing conditions. Later research will have to identify the causes of this decline, possibly on the basis of the risk factors identified in this study.

Cognitive functioning in late-life schizophrenia: a comparison of elderly schizophrenic patients and patients with Alzheimer's disease.

OBJECTIVE: Previous studies have suggested that geriatric inpatients with chronic schizophrenia manifest profound cognitive impairments. This study investigated how these cognitive impairments resemble those seen in degenerative dementing conditions. METHOD: The neuropsychological battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), widely used to characterize the cognitive deficits of patients with Alzheimer's disease, was used to compare patterns of cognitive impairment in 66 triads of subjects consisting of one elderly patient with Alzheimer's disease, one elderly, institutionalized patient with chronic schizophrenia, and one elderly, cognitively normal comparison subject who were matched on age, gender, and education. For some analyses, the two groups of patients were divided into subgroups according to the degree of their cognitive impairment (mild, moderate, or severe) as determined by their scores on the Mini-Mental State examination. RESULTS: Relative to the comparison subjects, both groups of patients showed cognitive deficits on each of the neuropsychological measures. The schizophrenic patients performed worse than the patients with Alzheimer's disease on tests of naming and constructional praxis but were less impaired on the test of delayed word recall. These differences were consistent across all levels of severity of globally measured cognitive impairment. CONCLUSIONS: Consistent with earlier findings from postmortem studies, these findings suggest that major differences exist in the neurobiologic mechanisms responsible for cognitive impairment in schizophrenia and Alzheimer's disease. Effects directly attributable to social and environmental differences between these two groups of patients may also play a role.

Age-related differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross-sectional study across nine decades.

OBJECTIVE: This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan. METHOD: Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed. RESULTS: Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced. CONCLUSIONS: Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.

Severity of symptoms in chronically institutionalized geriatric schizophrenic patients.

OBJECTIVE: The goal of this study was to characterize the symptoms of geriatric, chronically ill, institutionalized schizophrenic patients and investigate age-related differences in schizophrenic symptoms and cognitive performance from early adulthood to late senescence. METHOD: The Positive and Negative Syndrome Scale and the Mini-Mental State examination were used to assess the schizophrenic symptoms and cognitive performance, respectively, of 393 institutionalized schizophrenic patients stratified into seven groups designated by 10-year age intervals from 25 years to over 85 years. RESULTS: In the comparisons of the seven age groups, significant differences between groups in positive and negative subscale scores on the Positive and Negative Syndrome Scale and in Mini-Mental State scores were revealed. Significant correlations between Mini-Mental State scores and Positive and Negative Syndrome Scale negative symptom scores, but not positive symptom scores, were found for all age groups, except for the youngest patients studied. Current treatment with neuroleptics and prior treatment with ECT, insulin coma, or leukotomy could not account for the poor cognitive performance of the older schizophrenic patients. CONCLUSIONS: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence. Their positive symptoms were moderately less severe and their negative symptoms and cognitive impairment were significantly more severe than those of the younger patients. Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients. These data are relevant to chronically hospitalized geriatric schizophrenic patients but not necessarily to all geriatric schizophrenic patients.

Alzheimer's-disease-related protein in geriatric schizophrenic patients with cognitive impairment.

The authors compared Alz-50 immunoreactivity in the brain tissue of nine cognitively impaired elderly schizophrenic patients and 13 elderly comparison subjects, both without neuritic plaques or neurofibrillary tangles, and 13 patients with Alzheimer's disease. Alz-50 reactivity was absent in the schizophrenic patients, indicating that geriatric, cognitively impaired patients are unlikely to display the pathology of Alzheimer's disease.

AMPA receptor binding and subunit mRNA expression in prefrontal cortex and striatum of elderly schizophrenics.

The dopamine hypothesis of schizophrenia has recently evolved into a model of dysfunctional integration between cortical and subcortical dopaminergic activity. Anatomical data suggest that regional alterations in dopaminergic activity may be linked by means of the rich glutamatergic innervation of the striatum by corticostriatal projections, suggesting a potential role for glutamatergic dysfunction in schizophrenia. Although pharmacological data have implicated the NMDA subtype of glutamate receptor in this illness, disturbance in AMPA receptor expression could potentially lead to the NMDA receptor hypoactivity hypothesized in schizophrenia. To address this possibility, we examined AMPA receptor binding and subunit mRNA levels in prefrontal cortex and striatum of schizophrenics and matched controls. There were no significant differences in AMPA receptor binding or subunit mRNA levels in either prefrontal cortical or striatal regions of schizophrenics. Furthermore, AMPA receptor expression did not seem to be regulated by chronic antipsychotic drug exposure, when neuroleptic treated and drug-free schizophrenics were analyzed separately. These data do not support a role for altered AMPA receptor expression in cortex and striatum in schizophrenia.

Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients.

Plasma levels of the dopamine metabolite homovanillic acid (pHVA) may potentially reflect upon central dopamine activity. This study examines the effects of debrisoquin, haloperidol, and the two drugs combined on pHVA concentrations of schizophrenic patients. Debrisoquin is a drug that suppresses the peripheral formation of homovanillic acid without affecting the central formation. Acute haloperidol administration consistently increased pHVA concentrations in patients pretreated or not pretreated with debrisoquin, suggesting that this increment reflects haloperidol's central and not peripheral effects.

Cognitive impairment and negative symptoms in geriatric chronic schizophrenic patients: a follow-up study.

Cognitive impairment is increasingly recognized as an important aspect of schizophrenia. Since cognitive impairment has many features in common with the negative symptoms of the illness, it is possible that some of the characteristics attributed to negative symptoms are due to an association with cognitive impairments. In order to test this hypothesis, 174 chronically hospitalized geriatric schizophrenic patients were examined twice at a 1-year follow-up with ratings of the severity of their symptoms (using the Positive and Negative Syndrome Scale: PANSS) and assessments of cognitive functions with the Mini-Mental State Examination and a brief neuropsychological battery aimed at the typical impairments seen in dementia. Positive symptoms were unassociated with any of the cognitive variables, while negative symptom severity was correlated with each of the cognitive measures. In the cross-temporal analyses, cognitive impairments were more stable over time than negative symptom scores, but cognitive impairment did not predict the severity of any negative symptom over time. At each assessment, however, cognitive impairment was strongly correlated with each of the seven negative symptoms studied. These data indicate that cognitive impairments and negative symptoms are related, but discriminable, features in schizophrenia and that the considerable overlap between some negative symptoms and estimates of cognitive function may suggest a rethinking of the definition of some of these symptoms.

Cognitive functioning in chronically hospitalized schizophrenic patients: age-related changes and age disorientation as a predictor of impairment.

Although schizophrenic patients manifest cognitive impairments, there is considerable variability across patients in the severity of this impairment. Very chronic patients with a poor outcome, particularly geriatric patients, manifest the most severe impairments, which have often been characterized as resembling dementia. This study examined age-related changes in cognitive functioning in a sample of schizophrenic patients (n = 393) ranging from 25 to 95 years of age, with a specific focus on identifying aspects of performance that were impaired in the youngest patients and preserved in the oldest patients. Age disorientation was examined in detail because it was previously found to predict global intellectual impairment in chronic patients. All 22 test items changed linearly over time (with age), with aspects of orientation, concentration, and delayed recall most impaired in young patients and naming and sentence repetition most preserved in the oldest patients. Age disoriented patients had more severe cognitive impairments at each age and the age-related changes in global impairment were more severe for these patients. The prevalence of age disorientation was consistent with previous reports and a one-year retest of the sample found that age disorientation was extremely stable over time within patients. The types of functions that are preserved in the oldest patients underscore previous findings of differences between geriatric schizophrenic patients and patients with degenerative diseases and the stability of age disorientation suggests that it is a trait of a subset of schizophrenic patients, those who appear to have the most severely declining course of illness.

Time course and clinical predictors of treatment response in schizophrenia.

The severity of schizophrenic symptoms was examined in 50 male chronic patients while neuroleptic free for at least 3 weeks and during 6 weeks of treatment with haloperidol. The results suggested that 50% of the improvement associated with haloperidol administration occurred by the end of the first treatment week and that early improvement, at both 1 and 4 weeks of treatment, was predictable from drug-free symptom severity. There was a negative correlation between week 1 improvement and improvement during the next 3 weeks of treatment, suggesting that medication response is not linear. Finally, dose increases after 4 weeks of treatment with 20 mg of haloperidol did not lead to any clinical improvement. These results are discussed in terms of their implications for selecting chronic schizophrenic patients who will and will not benefit from medication treatment.

Assessment of dementia in elderly schizophrenics with structured rating scales.

Although a number of elderly institutionalized schizophrenic patients appear to suffer from dementia, little is known about the characteristics of the cognitive impairment or its prevalence in this population. In order to answer these questions it is necessary to first reliably and validly assess dementia in elderly schizophrenic patients. This paper reports the results of a study examining the reliability of assessments of the severity of dementia in schizophrenia using scales designed for other dementing conditions and examining the convergence of ratings of the severity of dementia generated from all available sources of information (patient, caregiver, and chart) versus the chart alone. It was found that the interrater reliability of these ratings was very high. On the other hand ratings generated from the hospital chart alone, without contact with either the patient or caregiver, manifested a systematic bias toward overestimation of the severity of dementia. These results suggest that dementia assessment in schizophrenia does not require different instrumentation from that used in other conditions but that relying on the medical chart alone would induce a systematic bias in the results.