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R B Zipursky

Publications and source records attributed to R B Zipursky.

At least 37 records · Page 2Linked to original sources
PubMed1999

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects.

OBJECTIVE: Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging. METHOD: Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest. RESULTS: Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions. CONCLUSIONS: This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.

Antipsychotic Agents↗
PubMed1999

Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia.

OBJECTIVE: Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

Adult↗
PubMed1999

Optimal haloperidol dosage in first-episode psychosis.

OBJECTIVE: To determine optimal doses of haloperidol for the treatment of a first episode of psychosis. METHOD: A 4-week prospective controlled clinical trial with "optimal dose" defined as the dose at which either of the following occurs: 1) significant improvement, defined as a 15% or greater decrease in scores on the Positive And Negative Syndrome Scale (PANSS), or 2) the onset of extrapyramidal symptoms. Beginning with 2 mg daily, haloperidol was increased weekly to 5 mg, 10 mg, and finally 20 mg daily until either 1) or 2) occurred. RESULTS: Optimal doses for the 36 subjects were 2 mg daily for 15 subjects, 5 mg daily for 11, 10 mg daily for 7, and 20 mg daily for 3. On average, subjects whose optimal dose was 2 mg daily showed the greatest improvement. Among the 27 subjects evidencing clinical response to treatment, 20 had plasma haloperidol levels below 5 ng/ml. CONCLUSION: Many people suffering a first psychotic episode respond to haloperidol doses well below levels in common use.

Adult↗
PubMed1998

An investigation of ethnic and gender differences in the pharmacodynamics of haloperidol.

The objective of this study was to examine neuroleptic effectiveness among Asians and Caucasians, and to investigate inter-ethnic pharmacodynamic differences. Asians and Caucasians suffering a first episode of psychosis were maintained on low oral doses of haloperidol (2 mg/day) for the first week of treatment. Doses were increased weekly until the optimal therapeutic dosage was achieved. This was defined as the point at which subjects: (a) experienced significant clinical improvement; or (b) developed extrapyramidal side effects. Plasma haloperidol and prolactin were measured at intake, at the end of first week of the treatment on haloperidol 2 mg/day, and at optimal therapeutic dosage. The average optimal dosage for Asians and Caucasians was equal. However, at the end of the first week of haloperidol at a fixed dose of 2 mg, Caucasian males had significantly lower plasma haloperidol levels than Asian males while no ethnic differences in haloperidol levels were found among females. There were no ethnicity or gender effects on plasma prolactin response after 1 week of treatment. Ethnicity and gender may affect haloperidol metabolism.

Adult↗
PubMed1998

Temporal horn enlargement is present in schizophrenia and bipolar disorder.

BACKGROUND: Ventricular enlargement and temporal lobe volume deficits have been demonstrated in patients with affective disorder as well as those with schizophrenia. This study compares quantitative measures of temporal lobe, hemispheric, and ventricular volumes in a group of patients with chronic schizophrenia and bipolar disorder and seeks to determine if the groups can be differentiated on the basis of measured brain abnormalities. METHODS: A series of coronal magnetic resonance imaging sections were acquired and analyzed for each of 22 patients with chronic schizophrenia, 14 patients with bipolar disorder, and 15 community volunteers. Eleven regions of interest for each brain were defined, which included temporal lobe, superior temporal gyrus, hemisphere, lateral ventricle, third ventricle, and temporal horn measures. Tissue measures were obtained by tracing, and cerebrospinal fluid measures were obtained by fluid-tissue thresholding using specialized computer software. RESULTS: Both patient groups had significantly larger temporal horn volumes in comparison with the control group both before and after correction for intracranial volume. The two patient groups did not differ from each other or controls on any other tissue or fluid measure. CONCLUSIONS: This study confirms the findings of increased temporal horn volume in patients with schizophrenia and suggests that this structural abnormality does not differentiate the structural neuropathology of schizophrenia from that of bipolar disorder.

Adult↗
PubMed1998

Functional network differences in schizophrenia: a rCBF study of semantic processing.

Studies of regional cerebral blood flow in patients with schizophrenia have led to the idea that dysfunctional neurocircuitry may play a role in patients' cognitive deficits. The present PET study was designed to explore this idea by comparing the functional neural networks associated with semantic processing for patients and normal controls through structural equation modeling (path analysis). The patients showed significantly different neural interactions among frontal regions, between the frontal and temporal cortices, and between the frontal lobe and anterior cingulate than controls. These discrepancies were especially striking given there were minimal group differences in task performance. Results suggest that schizophrenia involves a neural abnormality that is evident in functional networks during cognitive performance.

Adult↗
PubMed1998

MRI correlates of treatment response in first episode psychosis.

It is not known whether the magnitude of the structural brain abnormalities that underlie schizophrenia is a determinant of the extent to which patients respond to antipsychotic medication. This study was undertaken in order to explore this relationship. Twenty-six patients receiving treatment for a first episode of psychosis were involved in both a study measuring treatment response and a magnetic resonance imaging (MRI) study. In the treatment study, haloperidol dose was increased weekly beginning at 2 mg/day until patients showed evidence of a response or extrapyramidal symptoms. MRI scans were analyzed using a computerized volumetric approach to yield estimates of cerebrospinal fluid (CSF), gray-matter and white-matter volumes. Improvement in positive and negative symptoms after 1 week of treatment was significantly correlated with cortical gray-matter volumes. Those patients who were maintained on 2 mg/day of haloperidol had greater cortical gray-matter volume than those who were treated with higher doses. The severity of structural brain abnormalities at the onset of psychosis may contribute to individual variation in response to antipsychotic medication. It remains to be determined whether the degree to which particular domains of symptomatology can improve is related to the severity of structural brain pathology in specific brain regions.

Adolescent↗
PubMed1998

Cerebral gray matter volume deficits in first episode psychosis.

BACKGROUND: Structural brain differences including decreased gray matter and increased cerebrospinal fluid volumes have been observed in the brains of chronically ill patients with schizophrenia. We hypothesized that deficits in gray matter volume would be present in patients presenting with a first episode of nonaffective psychosis. METHODS: We used magnetic resonance imaging to compare the brains of 77 patients assessed as having a first episode of psychosis (meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, or psychotic disorder not otherwise specified) with those of 61 healthy controls matched for age, sex, race, and parental socioeconomic status. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and cerebrospinal fluid compartments using a computerized volumetric approach. These measures were corrected for the significant effects of intracranial volume and age prior to performing between-group comparisons. RESULTS: The first episode psychosis group had significantly smaller gray matter volume (t[136] = -2.2; P = .03) and greater cerebrospinal fluid volume (t[136] = 2.5; P = .02) than normal controls. In the patient group, gray matter volumes were positively correlated with estimates of IQ but not with age of onset, duration of illness, or measures of premorbid functioning. CONCLUSIONS: Deficits in gray matter volume are present in patients experiencing first episode nonaffective psychosis. The magnitude of these differences is smaller than has been described in more chronically ill patients.

Adolescent↗
PubMed1998

5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. CONCLUSIONS: Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Adult↗
PubMed1998

Pharmacotherapy of first-episode schizophrenia.

BACKGROUND: A growing interest in first-episode schizophrenia reflects the belief that this line of investigation will lead to further developments regarding schizophrenia's aetiology, course and outcome. METHOD: Evidence from more recent clinical trials involving first-episode schizophrenia is integrated with neuroimaging data, specifically positron emission tomography, to provide direction regarding pharmacotherapy. RESULTS: Individuals with a first episode of schizophrenia appear particularly responsive to pharmacotherapy, as well as quite sensitive to side-effects. At the same time, current clinical and receptor-binding data support the efficacy of low-dose neuroleptic treatment. CONCLUSIONS: Early and effective treatment of schizophrenia has been associated with better long-term outcome. Low-dose neuroleptic therapy is an effective treatment strategy and the diminished risk of side-effects with this approach may further enhance compliance and outcome.

Antipsychotic Agents↗
PubMed1997

Deficits in gray matter volume are present in schizophrenia but not bipolar disorder.

Studies using magnetic resonance (MR) imaging have provided strong evidence that patients with schizophrenia as a group have structural brain abnormalities, including enlarged ventricles and sulci as well as smaller cortical gray matter volumes. This study was undertaken to investigate whether the brain abnormalities found in schizophrenia could be distinguished from those seen in bipolar disorder. The MR scans of 23 patients with schizophrenia were compared to those of 17 healthy community volunteers and 14 patients with bipolar disorder. Images were processed using computer-based image processing techniques to generate quantitative measures of cerebrospinal fluid (CSF), gray matter and white matter volumes. Compared to the community volunteers, the schizophrenia group had larger total CSF volumes while the bipolar group had larger ventricles. Smaller cortical gray matter volumes were found in the schizophrenia group, but not in the bipolar group. The schizophrenia group had regional deficits in gray matter volumes in comparison with both the community volunteers and the bipolar group. These findings suggest that the brain tissue abnormalities found in schizophrenia and bipolar disorder may be distinguishable using MR imaging.

Adult↗
PubMed1997

Relationship between negative symptoms in chronic schizophrenia and neuroleptic dose, plasma levels and side effects.

The negative symptoms of schizophrenia are often difficult to distinguish from the side effects of antipsychotic medication. In this study, we tried to clarify this issue by studying a group of patients in a clinic setting where a wide range of antipsychotic doses were being prescribed. Thirty-one patients meeting DSM-III-R criteria for schizophrenia or schizoaffective disorder were studied. Clinical ratings were carried out to assess the positive and negative symptoms of schizophrenia, parkinsonism, akathisia and tardive dyskinesia. Plasma levels were also measured for the majority of patients. Antipsychotic plasma levels were found to be highly correlated with dose. Antipsychotic dose and plasma levels were not correlated with the severity of negative symptoms, akathisia or parkinsonism. However, the severity of positive symptoms and tardive dyskinesia were positively correlated with both dose and plasma level. These findings do not support the hypothesis that higher doses of antipsychotic medication are associated with more severe negative symptoms.

Adult↗
PubMed1997

A longitudinal magnetic resonance imaging study of brain changes in adolescents with anorexia nervosa.

OBJECTIVE: To assess whether the cerebral gray and white matter volume deficits described in patients with anorexia nervosa (AN) are fully reversible with weight rehabilitation. DESIGN: A prospective cohort study using magnetic resonance imaging to examine the brains of female adolescents after weight recovery from AN. SETTING: An adolescent eating disorder program located in a tertiary care children's hospital. PARTICIPANTS: Of 13 patients who underwent a previous magnetic resonance imaging study at a low weight, 6 patients were weight recovered and underwent rescanning. All brain measures were corrected for the effects of intracranial volume and age, based on a regression analysis of a group of 34 healthy female control subjects. Scans from the patients with AN were also compared with scans from an age-matched subset of 16 healthy female controls. MAIN OUTCOME MEASURES: White matter volumes, gray matter volumes, and cerebrospinal fluid volumes in the weight-recovered AN group. RESULTS: Quantitative analysis showed that white matter and ventricular cerebrospinal fluid volumes changed significantly (P = .03 for both) on weight recovery from AN. The weight-recovered patients had significant gray matter volume deficits (P = .01) and elevated cerebrospinal fluid volumes (P = .005) compared with those of the age-matched controls. They no longer had significant (P = .30) white matter volume deficits. CONCLUSION: The finding of persistent gray matter volume deficits in patients who have recovered their weight after AN suggests an irreversible component to the structural brain changes associated with AN, in addition to a component that resolves on weight recovery.

Adolescent↗
PubMed1997

Cerebral gray matter volume deficits after weight recovery from anorexia nervosa.

BACKGROUND: Structural changes have been observed in the brains of low-weight patients with anorexia nervosa (AN), including increased cerebrospinal fluid (CSF) volumes and decreased gray matter and white matter volumes. We hypothesized that subjects who are weight-recovered from AN would show elevated CSF volumes and reduced gray matter volumes compared with controls. METHODS: We used magnetic resonance imaging to compare the brains of 12 subjects who are weight-recovered from AN (time since weight recovery, 1-23 years) with those of 18 healthy control subjects and 13 low-weight patients with AN. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and CSF compartments by means of a computerized volumetric approach. Brain measures were corrected for the significant effects of intracranial volume and age, based on regression analysis of a larger group of 30 healthy female controls. RESULTS: Tests showed that the weight-recovered group had significantly greater CSF volumes and smaller gray matter volumes than the control group. By comparison with low-weight patients, the weight-recovered subjects had significantly smaller CSF volumes and significantly larger gray matter and white matter volumes. In the weight-recovered group, neither the CSF elevations nor gray matter deficits were correlated with the length of time since weight recovery. CONCLUSIONS: The persistent gray matter volume deficits in subjects who are weight-recovered from AN suggest that there may be an irreversible component to the brain changes associated with the illness. The neuropathological features of this irreversible component have yet to be characterized.

Adolescent↗
PubMed1997

Patterns of content, contextual, and working memory impairments in schizophrenia and nonamnesic alcoholism.

This study used tests of content memory (item recognition of words and abstract designs), context memory (order recognition of verbal and nonverbal items), and working memory (recognition at a short retention interval) to examine patterns of performance in 27 schizophrenic patients, 52 chronic alcoholic patients, and 66 healthy control participants. When performance was age- and IQ-adjusted the schizophrenia group was significantly impaired in item and order recognition of verbal and nonverbal material; the alcoholic group was impaired only in order recognition for both material types. Item- and order-recognition deficits in the schizophrenia group were greatest at the shortest retention intervals, a pattern previously observed in patients with Parkinson's disease, suggesting a prominence of a working memory deficit in schizophrenia.

Adult↗