Biomedical subjects
Publications and source records attributed to L E Tune.
Physicians have long been wary of chronically administering neuroleptic drugs to the demented elderly for fear of significant side effects. In this article, the authors present evidence to support these fears. A discussion of the early and late emerging side effects of neuroleptic drugs is presented.
Recent neuropathologic investigations in schizophrenia report smaller volume of medial temporal lobe structures. These findings are confirmed by preliminary magnetic resonance imaging (MRI) studies. Direct stimulation of lateral temporal lobe structures in the region of the superior temporal gyrus provokes hallucinations. The authors' MRI study of young schizophrenic patients demonstrates smaller volume of the superior temporal gyrus (an auditory association area) and of the left amygdala. Smaller size of the left superior temporal gyrus and left amygdala is not accounted for by smaller size of the overall brain or temporal lobe. Shrinkage of the left superior temporal gyrus is strongly and selectively correlated with severity of auditory hallucinations.
The relationship of dopamine receptor binding in the caudate nucleus and the putamen to neurological and neuropsychological functioning was examined in 21 patients with Huntington's disease (HD) and eight individuals at risk of developing Huntington's disease. A significant reduction in relative binding of [11C]3-N-methylspiperone to the dopamine receptor was found in both the caudate and putamen of HD patients. Binding in the caudate was correlated only with tests of rapid coding and set alternation, while binding in the putamen was correlated only with duration of illness. The findings indicate that the well-described atrophic changes in the striatum of Huntington's disease patients are accompanied by receptor alterations. They also support previous animal and human studies indicating that the caudate nucleus plays a larger role in cognition than in motor functions.
A sample of 50 DSM-III-diagnosed schizophrenics (mean age, 34 years) intentionally biased to contain a relatively high proportion of persistently unemployed persons was compared with a sample of 87 normal volunteers on three computed tomographic measures. These were lateral ventricle-brain ratio, regional brain computed tomographic density values, and brain slice area. Images were made with the same computed tomographic scanner and identical scan parameters. Computed tomographic data were assessed blindly using a computer-linked image array processor and electronic planimeter. Ventricle-brain ratios were significantly higher in schizophrenics, with 28% of the patient sample exceeding 2 SDs of the control mean. Brain area measures were not associated with an enlarged ventricle-brain ratio. Contrary to our prediction, ventricular enlargement was unassociated with most negative symptom ratings, but was correlated with the absence of positive symptoms. A history of abnormal delivery and the presence of left-handedness were significant predictors of an enlarged ventricle-brain ratio on multiple regression analysis. Schizophrenics had a significantly smaller brain slice area compared with normal controls, a finding not attributable to height differences between groups. Brain slice area was inversely correlated with computed tomographic brain density across all subjects. After correction of computed tomographic density values for area using a linear regression model, no significant regional density differences were detectable between normal controls and schizophrenics. Within normal controls there was a significant relationship between social class and brain slice area, but not ventricle-brain ratio.
Fifty-four patients with Alzheimer's disease performed on the Dementia Assessment Battery that comprised of finger tapping, forward digit span, naming, verbal memory, visual memory, Token Test, digit cancellation, word-list generation, symbol-digit substitution, and copying geometric designs. Four forms of the battery were administered at weekly intervals. The equivalence of the forms, the relative difficulty of the tests, retest reliability, and factorial composition of the battery are presented. Performance improved with repetition. Impairments in visuo-spatial and verbal abilities were independent of each other. The fragility of the patients' working memory was identified as a main cause for their poor recall. The importance of "component analysis" in individual assessment is illustrated.
This chart review study compared 54 schizophrenic patients with onset of illness after age 45 years to 54 young and 22 elderly patients with early-onset schizophrenia (before age 45). The index group was more likely to have visual, tactile, and olfactory hallucinations; a greater number of different types of hallucinations; persecutory delusions; and premorbid schizoid personality traits, and was less likely to have thought disorder and affective flattening, than was either comparison group. Among the two elderly groups, index patients had more auditory and visual sensory impairment. Nearly half (48.1%) of the index patients responded to neuroleptic treatment with complete remission.
A prospective study of antipsychotic drug treatment showed no difference in response between schizophrenic in-patients with or without a familial predisposition to the illness (N = 53). All patients received at least 600 mg chlorpromazine equivalents antipsychotic medication for 6 weeks. Ventricle brain ratios, ratings of cortical sulcal widening and a history of obstetric complications also failed to account for the variability, but early age of onset was associated with unsatisfactory response.
Reduced perceptual span has been suggested to be a cognitive marker of vulnerability to schizophrenia. However, the specificity of this impairment in visual information processing to schizophrenia is not well established. This preliminary study examined perceptual span in schizophrenic and manic patients divided into subgroups with and without active symptomatology. Symptomatic patients had reduced span in comparison with less symptomatic groups, but there were no differences between schizophrenic and manic patients.
In a surgical intensive care unit, plasma anticholinergic activity was significantly higher in nine delirious patients than in 16 patients without delirium. The delirium may have been related to medications that are known to be associated with delirium and/or anticholinergic activity.
In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.
Computed tomography (CT) was performed in 16 patients with a diagnosis of senile dementia of the Alzheimer type (SDAT). CT scans were rated without knowledge of clinical and laboratory data, and lateral ventricle-brain ratios (VBRs) calculated. Cerebrospinal fluid (CSF) acetylcholinesterase (AChE) activity was measured by radioenzymatic assay in all patients, and degree of dementia quantified using the Mini-Mental State Examination (MMSE). There were significant correlations between cerebral atrophy as assessed by VBR and CSF AChE activity. Cognitive impairment on MMSE also correlated significantly with VBR. These correlations were not accounted for by age, dilutional effects, or duration of illness. The relationship between VBR and AChE activity demonstrates an association between two independently determined pre-mortem measures of illness.
Evidence of task reliability is critical for use of measures of attention in studies of individual differences among members of clinical populations. Test-retest reliability of several measures of attention and information processing was studied in 14 chronic schizophrenics. Performance was stable over a 6-month period, except for decreases in reaction time.
Distractibility and reaction time were measured in 25 clinically stable chronic schizophrenic subjects receiving psychotropic medications. Higher serum neuroleptic levels were associated with lessened distractibility. Extrapyramidal side effects and level of symptoms were each related to slow and variable reaction times.
Serum neuroleptic levels were measured by radioreceptor assay in patients treated with the antidepressant amoxapine. When compared to standard neuroleptics, amoxapine produced relatively weak neuroleptic activity. Amoxapine dose correlated significantly with serum neuroleptic level. Three of eight patients developed significant extrapyramidal side effects. Neither dose of amoxapine nor neuroleptic level correlated with the presence or severity of EPS.
A prospective clinical and biochemical study on the effects of treatment with haloperidol has been performed in seven patients with Tourette syndrome. Pretreatment cerebrospinal fluid levels of homovanillic acid (CSF HVA) were significantly reduce in all patients, whereas 5-hydroxyindoleacetic acid was reduced in only two. With haloperidol treatment, symptoms decreased in all cases (21 to 88%) and clinical improvement was associated with an increased level of CSF HVA, often returning to the normal range. Optimal therapeutic response was found with serum levels of haloperidol between 1 and 4 ng/ml; however, disturbing side effects also occurred within this range. These results support the hypothesis that Tourette syndrome may result from a supersensitivity of dopaminergic receptors.
Preliminary studies with the radioreceptor assay for neuroleptics suggest several advantages of this technique. Consistent with results obtained with other techniques, it is obvious that there is variation among individuals in terms of the serum levels obtained on given oral doses of neuroleptics; in addition, total daily dose correlates poorly with serum levels. The radioreceptor assay technique, however, is relatively uncomplicated and inexpensive and relies on methods that are commonly used in general hospital laboratories. Unlike gas chromatography/mass spectrometry, gas-liquid chromatography, and even radioimmunoassay--which are highly discriminative--the radioreceptor assay detects both parent drugs and active metabolites of virtually all classes of neuroleptics on the basis of their presumed physiologic mechanism of action.
The authors tested working or recent memory in 24 stabilized schizophrenic outpatients who were taking psychotropic medication. Memory performance did not correlate with severity of schizophrenic symptoms, verbal IQ, or serum neuroleptic levels, but there was a significant inverse correlation between serum anticholinergic levels and performance on the memory task. The results suggest that therapeutic doses of anticholinergics may cause subtle impairments of cognitive functions.
Our studies have demonstrated that TS patients show a high degree of sensitivity to butyrophenone blockade of dopaminergic receptors. The clinical response to extremely low serum levels of haloperidol includes sedating side effects, as well as therapeutic effects. These clinical changes are associated with significant increases in CSF HVA levels, which were abnormally decreased before treatment. CSF HIAA levels tended to be normal and did not change with haloperidol treatment. These results lend additional support to the hypothesis that TS is related to supersensitivity of dopaminergic receptors.