Augmentation with sulpiride for a schizophrenic patient partially responsive to clozapine.

OBJECTIVE: Schizophrenic patients who are only partially responsive to clozapine pose a therapeutic challenge. In these circumstances some clinicians would consider adding in a second antipsychotic. We present a case report and review evidence for the efficacy of such augmentation strategies. METHOD: Single case report and literature review. RESULTS: The total number of patients in studies and case reports of combining clozapine with other antipsychotics is small. There has been only one randomized controlled trial. This found the addition of sulpiride to clozapine resulted in clinical improvement in some patients. CONCLUSION: Further randomized controlled studies of augmentation of clozapine therapy are needed to provide scientific justification for this clinical practice.

Relationship of akathisia to aggressive and self-injurious behaviour: A prevalence study in a UK tertiary referral centre.

INTRODUCTION: Akathisia is a common and distressing side-effect associated with antipsychotic drug administration. The relationship between akathisia and five forms of expressed aggression is investigated. METHOD: Sixty-four mentally disordered patients were assessed for the point prevalence of akathisia, using Barnes' rating scale for drug-induced akathisia. 1 The five types of aggression studied were: verbal abuse/ aggression, threatening behaviour/violence, physical aggression, destruction of property and deliberate self-harm, all of which are routinely recorded for patients. RESULTS: Fourteen subjects (21.9%) experienced akathisia, which was approximately four times more likely to occur in women than in men: four (6.3%) had pseudoakathisia. Akathisia was statistically significantly associated with threatening behaviour (P<0.05) and physical aggression (P<0.05). CONCLUSION: The data provide evidence for a relationship between the experience of akathisia and the expression of two forms of aberrant behaviour.

Lipopigment Changes in Purkinje Cells in Alzheimer's Disease.

Cerebellar tissue was examined from 22 patients with Alzheimer's disease (AD) and from an age-matched group of 20 non-diseased subjects. Intraneuronal lipopigment in the bodies of 1344 Purkinje cells (PCs) (32 per brain) was identified by fluorescence microscopy. The mean total area (per PC) of the outlines of discrete regions of lipopigment in a PC perikaryon for the AD-related group of PCs was significantly greater than the mean for the comparison group (p<0.001). Also, the two groups of PCs showed significant (

The prescribing practices of olanzapine in a psychiatric hospital in Britain.

The aim of this study was to review the prescribing practices at St Andrew's Hospital of the atypical antipsychotic drug olanzapine. Forty-one patients were treated with olanzapine by nine preservers during a 9-month study period. Two distinct categories of patients received the drug. Category A (n=30) patients were long-stay tertiary referrals, predominantly male and with a diagnosis of schizophrenia. For this group olanzapine was prescribed in high doses and half had additional anfipsjchotic medication; 17 patients (57%) improved but 30% were withdrawn from treatment. Category B (n=11) patients were acute admissions, younger, had a variety of diagnoses and were prescribed olanzapine at lower doses. All Category B patients improved after starting olanzapine and there were no dropouts. The presenters consistently reported positive experiences about the use of olanzapine.

Moclobemide in elderly patients with cognitive decline and depression: an international double-blind, placebo-controlled trial.

BACKGROUND: The new reversible MAOl moclobemide was compared with placebo in the treatment of elderly patients with DSM-III diagnosis of dementia and/or of major depression. METHOD: Six hundred and ninety-four elderly patients with symptoms of depression and cognitive decline entered an international, multi-centre, double blind trial in which they were randomly allocated to treatment with either moclobemide 400 mg daily or placebo for 42 days. Five hundred and eleven patients met DSM-III criteria for dementia and were also depressed (DEM+D); 183 did not meet DSM-III criteria for dementia but met the criteria for DSM-III major depressive episode and also suffered from cognitive decline (MDE+CD). RESULTS: Analysis of the 17 and 24-item Hamilton Depression Scale scores showed that moclobemide, compared with placebo, produced significantly greater improvement in both the demented and depressed groups (P = 0.001 both diagnostic groups). There was an improvement in cognitive function as measured by the SCAG Factor 1 in moclobemide treated patients (P = 0.005 DEM+D; P = 0.02 MDE+CD). There was no evidence of decline in cognitive function as the result of treatment. Clinical global assessment of tolerance was 'excellent' and 'good' in 88% of the moclobemide and in 92% of the placebo treated patients. The proportion of patients discontinuing treatment prematurely was similar in both treatment groups. There were no significant differences in side-effects between treatment groups. There were no significant changes in vital signs, ECG or laboratory findings in either treatment group. There were no dietary restrictions and no report of any tyramine reaction. CONCLUSIONS: Moclobemide was shown to be a safe, well tolerated and effective antidepressant, which did not cause impairment of cognitive function in elderly patients with a DSM-III diagnosis of dementia and/or DSM-III major depression.

Alzheimer's disease: distribution of changes in intraneuronal lipopigment in the frontal cortex.

Brains from 22 patients with Alzheimer's disease (AD) and 20 non-diseased subjects were examined. Intraneuronal lipopigment in 2,440 nucleolated neurons throughout the depth of cortex was identified by fluorescence microscopy. In the AD brains, the mean total area per neuron of the outlines of lipopigment was significantly increased in the region adjacent to the brain surface (sixths 1-3), and analysis of variance showed a significant interaction between depth of cortex (in sixths) and AD for this lipopigment variable (p = 0.012). After relating this lipopigment variable to the size of neuronal bodies, the results indicate that this change occurs in pyramidal neurons, although other neuronal types may also be affected. At least one of three AD-related changes in lipopigment was found in each sixth of the depth of cortex.

Validation of the full and short forms of the CAMDEX interview for diagnosing dementia. Cambridge Examination for Mental Disorders of the Elderly.

The present study compares the sensitivity and specificity of the short and full forms of the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) interview in diagnosing dementia. We tested 73 subjects meeting DSM-IIIR criteria for dementia and 61 matched controls. The short version was applied 3 months after the full one to guarantee a relative stability of the tested functions. Referred to an independent clinical rating made at the beginning of the study, the levels of sensitivity and specificity were not significantly different in the two forms and fully comparable with those of the original full English version. Moreover, the scores on analogous sections of the two versions were highly correlated in the demented and control groups. These findings support the hypothesis that the short form of the CAMDEX maintains the psychometric properties of the full one, and consequently can be used in diagnostic routines for a variety of clinical and research purposes.

Evidence of subtypes of Alzheimer's disease and implications for etiology.

OBJECTIVE: Because age of onset does not reliably define two subtypes of Alzheimer's disease, classification based on the severity of neuronal degeneration was tested. DESIGN: Numbers of extracellular tangles and pyramidal neurons in the hippocampus were used to group patients. PATIENTS: The study population consisted of 46 elderly patients satisfying DSM-III criteria for dementia and NINCDS-ADRDA criteria for definite Alzheimer's disease after death. RESULTS: Univariate logistic regression analysis showed the numbers of neurofibrillary tangles and pyramidal neurons and the duration of dementia were significantly associated with grouping based on the presence of abundant extracellular tangles. Ninety-one percent of patients were correctly classified as compared with 85% correctly classified by age of onset data. Odds ratios showed that increasing numbers of neurofibrillary tangles predicted greater severity of neuronal loss. CONCLUSION: The results of the study indicate the importance of neurofibrillary degeneration, not the deposition of amyloid, in the pathogenesis of Alzheimer's disease. They support a classification of Alzheimer's disease related more closely to the severity of neurofibrillary degeneration than to age at onset.

Changes in intraneuronal lipopigment in Alzheimer's disease.

Brains were examined from 22 patients with Alzheimer's disease (AD) (mean age 80.5, S.D. 11.5) and were compared with brains from 20 nondiseased subjects (mean age 81.1, S.D. 10.2). Intraneuronal lipopigment in all layers of a region of the superior frontal cortex was identified by fluorescence microscopy. The areas enclosed by the outlines of discrete regions of lipopigment autofluorescence were measured and assigned to a range of size categories. AD was associated with significant (p less than 0.05) decreases in the mean number (per neuron) of discrete regions of yellow lipopigment autofluorescence in the three smallest size categories and a significant increase in one of the larger size categories. Also, AD was associated with a significant decrease in the mean number (per neuron) of discrete regions of lipopigment autofluorescence (p less than 0.001). Significant (p less than 0.05) correlations were obtained between the Blessed dementia score (obtained within 2 years of death) and these lipopigment variables. The changes in neuronal lipopigment in AD may reflect an increased rate of lipopigment formation related to membrane and lysosomal abnormalities.

Cerebral cortical calbindin D28K and parvalbumin neurones in Down's syndrome.

Anti-calbindin D28K (CaBP) and anti-parvalbumin (PVA) antibodies were used to study the number and size of neurones containing these two calcium binding proteins in post-mortem brains from 7 neurologically normal controls and from 4 elderly patients with clinically diagnosed Down's syndrome (DS) and whose brains contained numerous senile plaques and neurofibrillary tangles. The possible co-existence of these two calcium binding proteins in human cerebral cortex was also examined. In the controls, CaBP immunoreactive neurones were mainly non-pyramidal neurones although some pyramidal neurones were also CaBP immunoreactive. All the PVA immunoreactive neurones were non-pyramidal cells. CaBP and PVA did not apparently co-exist with each other in cortical neurones. When compared with the neurologically normal controls, the number and size of CaBP and PVA immunoreactive neurones were significantly reduced in the cortex of patients with DS. These findings show that CaBP and PVA containing cortical neurones are affected in elderly persons with DS.

Neurofibrillary degeneration and neuronal loss in Alzheimer's disease.

Neuronal loss in Alzheimer's disease, especially in cerebral cortex and hippocampus, appears closely associated with the process of neurofibrillary degeneration. In certain noncortical nuclei neuronal loss appears not to depend upon the formation of neurofibrillary tangles. Neurofibrillary tangles and neurons were counted in the same populations of neurons in five brain regions. In the locus ceruleus and nucleus basalis, where tangles have a loose or globose structure, correlations with neuronal counts were not significant. In cerebral cortex and hippocampus, tangles have a more dense and often a flame-like appearance and their correlations with neuronal counts were significant. The relationships between tangles and noncortical neurons reported here suggest that the appearance of tangles does not necessarily herald the demise of a neuron in Alzheimer's disease. It can be reasonably anticipated that these relationships depend upon the clinical heterogeneity of Alzheimer's disease, regional differences in the brain and/or the macromolecular composition of neurofibrillary tangles.

Calbindin-immunoreactive cholinergic neurones in the nucleus basalis of Meynert in Alzheimer-type dementia.

An antibody to the calcium binding protein, calbindin D28K (CaBP), was used to study the number and size of CaBP-immunoreactive neurones in the nucleus basalis of Meynert (nbM) of postmortem human brains from neurologically normal controls and from patients with neuropathologically diagnosed Alzheimer-type dementia (ATD). In controls, almost all the large neurones and their processes in the nbM were CaBP immunoreactive. Compared to neurologically normal controls the number of CaBP-immunoreactive neurones in the nbM in patients dying with ATD was significantly reduced and there was a clear loss of the majority of CaBP immunoreactive neurones. The few remaining nbM CaBP immunoreactive neurones in the ATD cases were smaller than those in the neurologically normal controls. Double-staining experiments revealed that many of the nbM CaBP-immunoreactive neurones contained choline acetyltransferase immunoreactivity, so that CaBP is an alternative marker for the nbM cholinergic neurones in the human fore-brain. These findings suggest that a disturbance in calcium homeostasis may be a possible factor contributing to the loss of these cholinergic/CaBP-containing neurones.

Vicia villosa lectin-positive neurones in human cerebral cortex. Loss in Alzheimer-type dementia.

Frontal and temporal sections of 4 normal human brains and 3 brains from patients with a diagnosis of Alzheimer-type dementia (ATD) were stained with Vicia villosa lectin conjugated to biotin to localize glycoproteins containing terminal N-acetylgalactosamine. These lectin binding sites were localized at the surface of a population of non-pyramidal interneurones. Examination of the co-existence of calbindin D28K or parvalbumin (PVA) with the lectin-binding material revealed that in the human cerebral cortex the lectin labelled only the PVA-immunoreactive neurones. Cell counts of the number of lectin-staining cells revealed that these cells are lost in ATD. The few remaining lectin-staining cells in ATD are shrunken and showed reduced expression of the lectin-staining material.

A pathological study of the association between Lewy body disease and Alzheimer's disease.

The possibility of an association between Parkinson's disease and Alzheimer's disease has been examined by studying the age-specific prevalence of Lewy bodies in the substantia nigra in a group of 273 control cases without Parkinson's disease and 121 cases of Alzheimer's disease. The substantia nigra was also studied in 14 cases of Down's syndrome, 13 of which had cortical Alzheimer pathology. Twelve (7.8%) of the controls aged over 60 years showed nigral Lewy bodies. There was mild nerve cell degeneration and/or an extranigral distribution of Lewy bodies, suggestive of presymptomatic Parkinson's disease. Twenty five (22.5%) of the Alzheimer's disease cases over 60 years showed Lewy bodies, but only 14 (14.0%) of these had mild nigral cell loss consistent with presymptomatic Parkinson's disease. No case of Down's syndrome had Lewy bodies. Counts of tangles and plaques in hippocampus, frontal and temporal cortex were lower in cases of Alzheimer's disease with Lewy bodies compared with those without, but cortical choline acetyltransferase (ChAT) activities were similar. This suggests that Lewy body degeneration in the nucleus basalis of Meynert contributes to the deficit of cortical ChAT, but not to the cortical Alzheimer pathology. The relatively small difference in the prevalence of Lewy bodies between controls and Alzheimer's disease could be explained by the additive effects of Lewy body and tangle pathology causing dementia, rather than a greater than chance association between Parkinson's disease and Alzheimer's disease.

The substantia nigra and ventral tegmental area in Alzheimer's disease and Down's syndrome.

Degenerative changes in the substantia nigra and ventral tegmental area were investigated in 104 cases of Alzheimer's disease and 13 cases of Down's syndrome. Frequencies of tangles in three groups of patients with Alzheimer's disease were 86%, 44% and 46% (54% overall) respectively. About half of those with tangles, but no Lewy bodies, had excess nigral cell loss, and 16% had moderate or severe neuronal fallout, but none had a Parkinsonian syndrome. Cases with nigral tangles were younger, tended to have more hippocampal and cortical tangles and plaques, and lower activities of cortical choline acetyltransferase. In most cases of Alzheimer's disease degeneration in nigral and tegmental areas was greater than controls, and tangles were evenly distributed. All the cases of Down's syndrome had tangles in the nigra and eight showed mild cell loss. Mild degenerative changes accompanied by tangles in the substantia nigra and ventral tegmental area are common in Alzheimer's disease, but severe cell loss is rare. When a Parkinsonian syndrome occurs in Alzheimer's disease it is likely to be due to Lewy body pathology.

Loss of calbindin-28K immunoreactive neurones from the cortex in Alzheimer-type dementia.

An antibody raised against chick intestinal calbindin D28K was used to study the number and size of calbindin immunoreactive neurones in postmortem human brains from neurologically normal controls and from patients with neuropathologically diagnosed Alzheimer-type dementia (ATD). In the controls, calbindin immunoreactive neurones were observed in all cerebral cortex areas examined including the frontal, temporal and parietal cortices. When compared with the controls, the number and size of calbindin immunoreactive neurones were significantly reduced in the cortices of patients with ATD. These findings suggest that calbindin containing neurones are affected in ATD.