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Biomedical subjects

S Kapur

Publications and source records attributed to S Kapur.

At least 91 records · Page 5Linked to original sources
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

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

Adolescent↗
PubMed1999

D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET.

The advent of a number of new antipsychotics has been paralleled by efforts to better delineate their mechanisms of action and, in doing so, further our understanding of schizophrenia and its pathophysiology. Technological advances, such as positron emission tomography (PET), have proven to be powerful tools in this process, allowing us to evaluate in vivo models based primarily on in vitro evidence. Combined serotonin-2/dopamine-2 (5-HT2/D2) antagonism represents one such model, and we now have PET evidence available that can be extrapolated to our understanding and clinical use of both conventional and novel antipsychotics.

Amoxapine↗
PubMed1999

Phosphorus balance and prostate cancer.

Prostatic diseases affect men over the age of 45 and increase in frequency with age so that by the eighth decade more than 90% of men have Benign Prostatic Hyperplasia, (BPH), of which some progress to Carcinoma of Prostate (CaP). CaP, the most common malignancy in men, is also the second most common cause of death in men. Over the last three decades the mortality rate for CaP has steadily increased. There, however, are scant clues to the aetiology/pathogenesis of CaP. As treatment failures of advanced carcinoma continue to frustrate clinicians, emphasis has recently been focused on possible preventive strategies. Several studies support the view that higher levels of 1,25-(OH)2D, the active metabolite of vitamin D, reduce the risk of BPH and CaP. Men with high serum levels of 1,25-(OH)2D have a reduced risk of poorly differentiated and clinically advanced CaP. Hypercalcemic activity of 1,25-(OH)2D or its analogues, however, thwart their use for therapy in humans. Incidentally, a low dietary intake of phosphorus has been reported to increase serum levels of 1,25-(OH)2D. In addition, dietary fructose reduces plasma phosphate levels by 30 to 50% for more than 3 hr. Fruit intake has, indeed, been shown to be associated with reduced risk of CaP, particularly the advanced type. These observations, taken together, support that dietary determinants of hypophosphatemia, leading to increased plasma levels of 1,25-(OH)2D, could reduce the risk of ageing men to develop prostatic diseases, both BPH and/or carcinoma of Prostate.

Humans↗
PubMed1999

Chlamydia trachomatis infection in pregnancy: risk factor for an adverse outcome.

A cohort of 122 pregnant women attending the hospital antenatal clinic in northern India were studied to determine the prevalence of genital chlamydial infection, and any adverse effect on the pregnancy. Endocervical swabs were taken at > 12 weeks of pregnancy and cultured for Chlamydia trachomatis. Twenty-six (21.3%) pregnant women were found to be infected with C. trachomatis. The mean age, gravidity and parity were significantly higher (25.03 vs 23.6 years, 1.88 vs 1.72 and 0.92 vs 0.68 respectively [P < 0.005]) in women from whom C. trachomatis was isolated. Follow-up was possible in 87 women who delivered in the hospital. There was increased incidence of still-birth, prematurity and low birth-weight in the C. trachomatis-positive women (16.6% vs 5.7%, 26.6% vs 18.4% and 26.6% vs 23.0%), and these differences were statistically significant (P < 0.5, P < 0.5 and P < 0.05 respectively). The results suggest a definite need for C. trachomatis screening on a wider scale, both in different risk groups of asymptomatic antenatal women and in neonates, to confirm these findings.

Adolescent↗
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

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

Clinical outcome of patients infected with hepatitis C virus infection on survival after primary liver transplantation under tacrolimus.

The outcome of hepatitis C virus (HCV) infection on patient and graft survival after orthotopic liver transplantation (OLT) has been controversial. An earlier experience with a higher dose of tacrolimus (>/=0.1 mg/kg/d intravenously and >/=0.2 mg/kg/d orally) was associated with a worse clinical outcome in patients infected with HCV. The clinical outcome of 183 liver transplant recipients with end-stage liver disease (ESLD) secondary to HCV infection (HCV group) was compared with a contemporary cohort of 556 patients with HCV infection who underwent transplantation for nonviral, nonmalignant ESLD (control group). All patients were prospectively screened for anti-HCV antibodies and HCV RNA by reverse-transcriptase polymerase chain reaction. All OLT patients were receiving low-dose tacrolimus immunosuppression. Cumulative patient survival rates for the HCV group were 80% after 1 year and 75% after 3 years compared with rates of 84% and 78%, respectively, in the control group (P = .452). Primary graft survival rates at the same time intervals for the HCV group and the control group were 72% and 77.5% at 1 year and 67% and 72% at 3 years, respectively (P = .144). The incidence of re-transplantation (re-OLT) in the HCV group and the control group was 12.6% and 10.4%, respectively (P = .42). Chronic HCV infection as an indication for OLT with a lower dose of tacrolimus immunosuppression (</=0.05 mg/kg/d intravenously and </=0.1 mg/kg/d orally) is associated with a similar patient and graft survival as those without HCV infection.

Adult↗
PubMed1998

Mapping neural interactivity onto regional activity: an analysis of semantic processing and response mode interactions.

Neuroimaging studies of cognition have typically been designed to identify brain regions that are active during a cognitive process. However, identifying how brain regions interact may be equally important. In a recent study we found that the pattern of activation associated with a semantic task differed depending on how subjects made a response, suggesting that there was an interaction between the neural systems underlying response mode and semantic processing (J. M. Jennings et al., 1997, NeuroImage 5, 229-239). This result raises two important questions, which we examined here: (1) How did the regions underlying semantic performance influence one another, or interact, to produce a different pattern of activation in each case? (2) What can be learned about the neurobiology of semantic processing when different regions are identified as a function of response? We addressed these questions using structural equation modeling. This technique produced functional network models representing the effect of different regions on each other during the semantic task for each response. A common network of regions associated with semantic processing was observed and included the left inferior frontal and left superior temporal cortices, with other regions brought into that network depending on response (e.g., right middle frontal). Moreover, changes in the influences among these regions across response condition predicted the pattern of activation found previously. These results show how an arbitrary response can affect the neural pathways associated with a cognitive process, likely due to the parallel and reentrant organization of the brain, and emphasize the importance of examining functional connections when studying cognition.

Adult↗
PubMed1998

Task-independent effect of time on rCBF.

Positron emission tomography was used to identify brain regions that showed general increase or decrease in regional cerebral blood flow (rCBF) across time that was task-independent. Twelve male subjects were scanned eight times: the first and last scans were taken while subjects performed a baseline fixation task and the middle six scans were taken while subjects performed a visuomotor activation task. To determine whether there was a consistency across different studies in the regions that showed this time-related change in rCBF two additional datasets were analyzed. There were similarities across all three studies in the regions that showed a monotonic task-independent change in activity. In all three studies there was a general bilateral decrease in rCBF of occipital and temporal areas across scans that might be related to habituation in the visual domain. Increases in rCBF were found in anterior cingulate, postcentral gyrus, and precentral gyrus across studies. It is likely that these changes reflect motor learning and motor program retrieval. This implies that, unless the experimenter controls for time-dependent changes in brain activity, the interpretation of task-related changes in rCBF may be confounded by these monotonic changes in rCBF. We present analytic strategies to identify experimental effects that are independent of nonspecific time effects, which can be used when it is not possible to control these effects through counterbalancing the experimental design. Nonspecific confounds are particularly relevant in functional MRI studies in which the number of scans acquired per study is much larger.

Adult↗
PubMed1998

A new framework for investigating antipsychotic action in humans: lessons from PET imaging.

With a decade of neuroreceptor imaging of antipsychotics behind us, this article attempts to synthesise what has been learnt about the mechanism of action of antipsychotics using these techniques. The data show that: (i) the 'typical' antipsychotics bind mainly to the dopamine D2 receptor, and that 60-80% D2 occupancy may provide optimal antipsychotic response with little extrapyramidal side effects; (ii) all the clinically available 'atypical' antipsychotics show a higher occupancy of the 5-HT2 than D2 receptors; (iii) however, these 'atypical' antipsychotics differ in their D2 occupancy. The D2 occupancy of risperidone is within the typical range (i.e. > 60%) while that of clozapine is clearly lower (< 60%); (iv) antipsychotics with combined 5-HT2/D2 antagonism lose some of their 'atypical' properties if used in doses where their D2 occupancy is too high (> 80%). Based on these data a framework is suggested wherein antipsychotics may be classified on the basis of their D2 and 5-HT2 occupancy in patients at steady state while taking clinically relevant doses. Within this framework typical antipsychotics are classified as 'high-D2', resperidone as 'high-D2 high-5HT2' and clozapine as a 'low-D2 high-5HT2' antipsychotic. The justification, limitations and the value of this framework in understanding and investigating newer antipsychotics is discussed.

Antipsychotic Agents↗
PubMed1998

Neuroanatomical correlates of human reasoning.

One of the important questions cognitive theories of reasoning must address is whether logical reasoning is inherently sentential or spatial. A sentential model would exploit nonspatial (linguistic) properties of representations whereas a spatial model would exploit spatial properties of representations. In general terms, the linguistic hypothesis predicts that the language processing regions underwrite human reasoning processes, and the spatial hypothesis suggests that the neural structures for perception and motor control contribute the basic representational building blocks used for high-level logical and linguistic reasoning. We carried out a [(15)O] H(2)O PET imaging study to address this issue. Twelve normal volunteers performed three types of deductive reasoning tasks (categorical syllogisms, three-term spatial relational items, and three-term nonspatial relational items) while their regional cerebral blood flow pattern was recorded using [(15)O] H(2)O PET imaging. In the control condition subjects semantically comprehended sets of three sentences. In the deductive reasoning conditions subjects determined whether the third sentence was entailed by the first two sentences. The areas of activation in each reasoning condition were confined to the left hemisphere and were similar to each other and to activation reported in previous studies. They included the left inferior frontal gyrus (Brodmann area 45, 47), a portion of the left middle frontal gyrus (Brodmann area 46), the left middle temporal gyrus (Brodmann areas 21, 22), a region of the left lateral inferior temporal gyrus and superior temporal gyrus (Brodmann areas 22, 37), and a portion of the left cingulate gyrus (Brodmann areas 32, 24). There was no significant right-hemisphere or parietal activation. These results are consistent with previous neuroimaging studies and raise questions about the level of involvement of classic spatial regions in reasoning about linguistically presented spatial relations.

Adult↗
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↗