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Biomedical subjects

S R Hirsch

Publications and source records attributed to S R Hirsch.

At least 19 recordsLinked to original sources
PubMed1998

Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia.

OBJECTIVE: A pilot study of the density of dendritic spines on pyramidal neurons in layer III of human temporal and frontal cerebral neocortex in schizophrenia. METHODS: Postmortem material from a group of eight prospectively diagnosed schizophrenic patients, five archive schizophrenic patients, 11 non-schizophrenic controls, and one patient with schizophrenia-like psychosis, thought to be due to substance misuse, was impregnated with a rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons in temporal and frontal association areas, of which the soma was in layer III (which take part in corticocortical connectivity) and which met strict criteria for impregnation quality. Altogether 25 blocks were studied in the schizophrenic group and 21 in the controls. If more than one block was examined from a single area, the counts for that area were averaged. All measurements were made blind: diagnoses were only disclosed by a third party after measurements were completed. Possible confounding affects of coexisting Alzheimer's disease were taken into account, as were the effects of age at death and postmortem interval. RESULTS: There was a significant (p<0.001) reduction in the numerical density of spines in schizophrenia (276/mm in control temporal cortex and 112/mm in schizophrenic patients, and 299 and 101 respectively in the frontal cortex). An analysis of variance, taking out effects of age at death and postmortem interval, which might have explained the low spine density for some of the schizophrenic patients, did not affect the significance of the results. CONCLUSION: The results support the concept of there being a defect in the fine structure of dendrites of pyramidal neurons, involving loss of spines, in schizophrenia and may help to explain the loss of cortical volume without loss of neurons in this condition, although the effect of neuroleptic drugs cannot be ruled out.

Adult↗
PubMed1998

Nitric oxide, free radicals and polyamines may have a role in the membrane pathology of schizophrenia.

Studies on skin fibroblasts in culture derived from schizophrenic and control subjects showed that polyamines are increased, nitrate levels are reduced and thiobarbituric acid reacting substances did not alter in cultured cells from schizophrenic patients compared to control subjects. Results seem to indicate some alteration in membrane functions in schizophrenia, which is susceptible to neuroleptic treatment. Significantly increased levels of polyamines in drug-treated schizophrenic cells indicates a possible role of polyamines in the activation of proposed hypofunctional NMDA subtype of glutamate receptor systems in schizophrenia.

Adolescent↗
PubMed1998

Prefrontal cortex activity in people with schizophrenia and control subjects. Evidence from positron emission tomography for remission of 'hypofrontality' with recovery from acute schizophrenia.

BACKGROUND: Hypo-activation of the left dorsolateral prefrontal cortex is inconsistently found in neuroimaging studies of schizophrenia. As the left dorsolateral prefrontal cortex is involved in the generation of action, disordered function in this region may be implicated in schizophrenic symptomatology. METHOD: We used H2 15O positron emission tomography to study dorsolateral prefrontal cortical function in men with schizophrenia (n = 13) and male control subjects (n = 6) performing joystick movements on two occasions, 4-6 weeks apart. The patients were initially in relapse. To clarify dorsolateral prefrontal cortical function we also scanned another group of control subjects (n = 5) performing mouth movements. RESULTS: The control subjects performing hand or mouth movements activated the left dorsolateral prefrontal cortex to a maximum when the movements were self-selected. The men with relapsed schizophrenia exhibited left dorsolateral prefrontal cortical hypoactivation, which remitted with symptomatic improvement. CONCLUSIONS: Hypofrontality in these patients is a dynamic phenomenon across time, possibly related to current symptomatology. The most appropriate question about the presence of hypofrontality in schizophrenia may be when, rather than whether, it will occur.

Adult↗
PubMed1997

Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.

BACKGROUND: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). METHODS: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. RESULTS: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. CONCLUSIONS: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

Adult↗
PubMed1997

A pivotal role for glutamate in the pathogenesis of schizophrenia, and its cognitive dysfunction.

There is mounting evidence of a glutamate dysfunction in schizophrenia, as suggested by the fact that schizophrenia and phencyclidine psychosis are similar and phencyclidine is known to block the N-methyl-D-aspartate (NMDA) subtypes of glutamate. Both occur mainly after puberty, suggesting they may share similar underlying developmental processes. Direct evidence is now accumulating from the study of messenger RNA that glutamate receptor deficiencies occur in schizophrenia and are regionally and specifically distributed. These results find support from studies of memory, electrophysiological findings, clinical treatment, and pharmacological studies in mammals and humans. Our recent findings of: a) a marked decrease in pyramidal cell dendritic spines in layer III of the frontal and temporal cortex, and b) a greater than 0.90 correlation between decrease in mRNA for the NMDA glutamate receptor and cognitive deterioration in elderly schizophrenics, present the strongest evidence to date that glutamate dysfunction plays an important role in schizophrenia.

Animals↗
PubMed1997

A PET study of voluntary movement in schizophrenic patients experiencing passivity phenomena (delusions of alien control).

Schizophrenic patients experiencing passivity phenomena believe their thoughts and actions to be those of external, or alien, entities. We wished to test the hypothesis that voluntary motor action in such patients would be associated with aberrant patterns of activation within the cerebral motor system. We used H2(15)O PET to study patients while they performed paced joystick movements on two occasions 4-6 weeks apart. During the first scan passivity symptoms were maximal, while by the second scan these symptoms had significantly improved in five of the seven patients. Two control groups were also scanned on two occasions: deluded schizophrenic patients without passivity phenomena and normal subjects. In normal subjects, performance of freely selected joystick movements with the right hand, compared with rest, revealed relative activation of prefrontal, premotor, motor and parietal cortical regions. Schizophrenic patients with passivity showed hyperactivation of parietal and cingulate cortices. This hyperactivation remitted in those subjects in whom passivity decreased over time. This reversible hyperactivity was not a feature of schizophrenics without passivity. Given that these hyperactive cerebral regions subserve attention to internal and external bodily space, and the attribution of significance to sensory information, they provide a plausible anatomical substrate for the misattribution of internally generated acts to external entities: the cardinal feature of delusions of passivity (alien control).

Brain Mapping↗
PubMed1996

Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production.

Cellular origins of methylarginines are not precisely known but the presence of free methyl and dimethylarginines in the brain were reported. We have investigated the circulating concentrations of asymmetrical dimethylarginine NG,NG-dimethylarginine (ADMA), NG,NG-dimethylarginine (SDMA), nitrate and nitrite levels in drug naive first episode schizophrenic patients and matched control subjects. Three of those patients were treated with neurolepties for 3 months. Plasma ADMA levels increased significantly but nitrate levels were significantly low compared to control subjects. Drug treatment apparently lowered ADMA levels and increased nitrate levels in plasma. Methylation of arginine to methylarginines may have an important role in regulating signal transduction through the nitric oxide system in the brain, and suggest novel therapeutic targets.

Adult↗
PubMed1996

Tilarin in combination with astemizole.

This multicentre double-blind, placebo controlled study had a practical objective, based on the expectation that many patients with seasonal allergic rhinitis will be prescribed oral antihistamine monotherapy by their primary care physician, whereas allergy specialists are more likely to prescribe combination therapy including antiinflammatories. The specific question was, "Will the addition of nedocromil sodium 1% nasal spray to astemizole tablets improve control of symptoms of seasonal allergic rhinitis induced by ragweed pollen, as compared to astemizole therapy alone?'. Following a one-week baseline, planned to coincide with the start of the local ragweed pollen season, patients (aged 12-64) were randomly assigned to four weeks' double-blind test treatment with either nedocromil sodium 1% nasal spray four times daily (QID) + astemizole (n = 146) or placebo nasal spray + astemizole (n = 148) or double-dummy (nasal spray + capsules) placebo (n = 71). Patient diary cards were kept throughout the five weeks, and clinic visits were made before and after baseline and after one and four weeks' treatment. During the 10-day peak pollen period, the diary card rhinitis symptom summary score (0-4 severity scale) was significantly reduced in patients receiving either astemizole alone (p < 0.001) or the combination therapy (p < 0.001) as compared with placebo. Direct comparison of the active treatments further showed that symptoms were significantly less severe (p < 0.01) with the combined therapy than with astemizole alone, and this despite significantly greater reliance on permitted rescue medications (p < 0.05 for pseudoephedrine usage) in the astemizole group. Clinical assessments of rhinitis made during the peak pollen visit, after the first week of test treatment, were also significantly (p < 0.05 - p < 0.01) in favour of combined therapy with nedocromil sodium 1% nasal spray + astemizole rather than astemizole alone, and at the same time this preference was confirmed by physician (p = 0.011) and patient (p = 0.003) opinions of symptom control. In conclusion, this antiinflammatory + antihistamine treatment proved superior to antihistamine alone for effective management of allergic rhinitis. The combined therapy worked quickly and was well-tolerated, with no serious adverse events or untoward effects on blood or urine variables.

Administration, Intranasal↗
PubMed1996

The Camden schizophrenia surveys. II. High prevalence of schizophrenia in an inner London borough and its relationship to socio-demographic factors.

BACKGROUND: Investigation of the geographical distribution of schizophrenia and its relationship to socio-demographic factors is useful for planning services. METHOD: Individuals with schizophrenia (n = 980) were identified by key informants within an inner London borough and point prevalence calculated for broad, Feighner and DSM-III-R schizophrenia. The distribution of cases was tested for significant variation using the Poisson process model. Regression models using the Jarman-8 score and its component variables were tested for their ability to predict the prevalence of schizophrenia. RESULTS: A high point prevalence of schizophrenia (5.3 per 1000 resident population) was demonstrated. Case distribution showed a marked and significant variation associated with socio-demographic factors. The prediction of prevalence was more accurate for broad than for narrower definitions of schizophrenia; unemployment rate performed best. CONCLUSIONS: Unemployment rates and Jarman-8 scores may provide crude estimates for resource allocation in planning mental health services, highlighting the need for additional services in deprived inner city areas.

Adolescent↗
PubMed1995

Elevated platelet calcium mobilization and nitric oxide synthase activity may reflect abnormalities in schizophrenic brain.

Schizophrenia has a diverse nature of clinical symptoms and a number of hypotheses have been suggested to explain its aetiological basis. In this study we have examined two aspects of membrane function, receptor-activated calcium mobilization and calcium activated nitric oxide synthase activity in schizophrenic subjects. Thrombin induces mobilization of calcium ions from intracellular stores. The platelet response of drug naive schizophrenics was found to be significantly increased over a range of thrombin concentrations (0.01 to 0.60 U/ml) compared to control subjects. Possible involvement of nitric oxide (NO) in the aetiology of schizophrenia was investigated. NO has been functionally linked to both dopaminergic and glutamatergic systems both of which are strongly implicated in the biochemical pathology of schizophrenia. Nitric oxide synthase (NOS) activity was determined in platelets of controls, schizophrenic and panic disorder subjects. Enzyme activity was found to be significantly higher in platelets of drug naive schizophrenic subjects compared to controls, drug treated schizophrenics and panic disorder subjects. It is suggested that there is an imbalance of the calcium-induced L-arginine- nitric oxide pathway in platelets of schizophrenic subjects which may be modified by neuroleptic treatment. This imbalance may be mirrored in the central nervous system in particular at the NMDA receptor. It is possible that such a disturbance in the L-arginine-nitric oxide pathway may have pathological implications in the aetiology of schizophrenia.

Adult↗
PubMed1995

Depressive disorder due to craniopharyngioma.

Secondary causes of depression are legion, and must always be considered in patients presenting with features atypical of primary idiopathic depressive disorder. The case described is that of a middle-aged woman presenting initially with a major depressive disorder who was subsequently found to have a craniopharyngioma, leading to a revised diagnosis of mood disorder due to the tumour. Some features of the presentation might have led to earlier diagnosis had their localizing significance been recognized. Diencephalic lesions should always be considered in patients presenting with the hypersomnic-hyperphagic variant of depressive disorder.

Craniopharyngioma↗
PubMed1994

Population based study of fatigue and psychological distress.

OBJECTIVES: To determine the prevalence of fatigue in the general population and the factors associated with fatigue. DESIGN: Postal survey. SETTING: Six general practices in southern England. SUBJECTS: 31,651 men and women aged 18-45 years registered with the practices. MAIN OUTCOME MEASURES: Responses to the 12 item general health questionnaire and a fatigue questionnaire which included self reported measures of duration, severity, and causes of fatigue. RESULTS: 15,283 valid questionnaires were returned, giving a response rate of 48.3%, (64% after adjustment for inaccuracies in the practice registers). 2798 (18.3%) of respondents reported substantial fatigue lasting six months or longer. Fatigue and psychological morbidity were moderately correlated (r = 0.62). Women were more likely to complain of fatigue than men, even after adjustment for psychological distress. The commonest cited reasons for fatigue were psychosocial (40% of patients). Of 2798 patients with excessive tiredness, only 38 (1.4%) attributed this to the chronic fatigue syndrome. CONCLUSION: Fatigue is distributed as a continuous variable in the community and is closely associated with psychological morbidity.

Adolescent↗
PubMed1994

Elevated platelet phosphatidylinositol bisphosphate in mediated schizophrenics.

Levels of phosphatidyl inositol 4,5-bisphosphate (PIP2) have been measured in platelets from schizophrenic and healthy subjects by means of an immunoassay. Resting platelets from schizophrenic patients contained a significantly increased amount of PIP2 compared to controls. The agonist-stimulated hydrolysis of PIP2 in platelets from the schizophrenic group was also significantly greater than that in platelets from the control group. PIP2 plays an important role in cell signalling, and the observed abnormality may be reflected by an impairment in signal transduction via the inositol phospholipid pathway.

Adult↗
PubMed1994

Role of polyamines in the membrane pathology of schizophrenia. A study using fibroblasts from schizophrenic patients and normal controls.

The polyamines putrescine, spermine, and spermidine play a major role in the regulation of cell growth and differentiation, metabolic pathways, and on cell membrane functions in mammalian systems. It has recently been suggested that polyamines may be involved in the pathophysiology of schizophrenia. Moreover, several reports suggest that schizophrenia may be associated with a generalized cell membrane abnormality. In view of these findings, we measured polyamine levels in cultured skin fibroblasts from schizophrenic patients and normal control subjects. These was a significant increase in the levels of spermidine and in total polyamines in fibroblasts and spermine in the culture medium from schizophrenic patients. This preliminary report suggests that polyamines may play an important role in the membrane abnormalities that have been reported in schizophrenic patients.

Adult↗