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R W Kerwin

Publications and source records attributed to R W Kerwin.

At least 91 records · Page 5Linked to original sources
PubMed1995

A risk-benefit assessment of risperidone in schizophrenia.

The atypical antipsychotic risperidone combines dopaminergic and serotonergic antagonism. This results in a drug that is both clinically effective, reducing positive and negative symptoms of schizophrenia, and has a low incidence of adverse effects. At a dosage of 4 to 8 mg/day, risperidone is comparable to 10 mg/day of haloperidol. This dosage has a low incidence of extrapyramidal adverse effects and is nonsedative, although it may cause orthostatic hypotension. There is no current evidence for specific biochemical and haematological abnormalities associated with risperidone. Although the clinical benefits appear to outweigh the risks, this drug continues to be a relatively expensive treatment option in the UK. There is therefore a need for a formal cost-utility assessment of risperidone and for comparisons between this drug and other atypical neuroleptics.

Antipsychotic Agents↗
PubMed1994

AMPA glutamate receptors and their flip and flop mRNAs in human hippocampus.

AMPA-preferring glutamate receptor genes gluR1-4 undergo alternative splicing into flip and flop mRNA isoforms. In the rodent hippocampus, gluR1 and gluR2 isoforms are differentially expressed. We have studied their distribution in human hippocampus. As in the rat, flop isoforms predominate over flip in dentate gyrus, whereas gluR1 flip is prominent only in CA3. In contrast to the rat, flop mRNAs are clearly present in CA3. At a cellular level, pyramidal neurones express moderate amounts of each isoform. In several hippocampal fields, scattered non-pyramidal cells--putatively interneurones and glia--show abundant expression. The findings are supported by immunocytochemical detection of gluR1 and gluR2/3. As the four encoded isoforms have distinct properties, their differential expression within the hippocampus, and between species, should be taken into account when considering the roles of AMPA receptors in normal and abnormal brain states.

Adult↗
PubMed1994

Stereotypy, schizophrenia and dopamine D2 receptor binding in the basal ganglia.

Animal models suggest a relationship between disturbed striatal dopaminergic function and stereotyped behaviour. Several studies show increased stereotypy in schizophrenic patients compared to normal controls. We investigated the performance of 12 antipsychotic-drug-free schizophrenic patients, and 15 healthy control subjects on a neuropsychological measure of stereotypy--the two-choice guessing task--and correlated this with in vivo striatal dopamine D2 receptor binding, as measured by 123I-iodobenzamide single photon emission tomography. Patients and controls did not differ with respect to the measures of stereotypy derived from the task. However, there was a significant correlation between one of these measures (RR Information) and the degree of striatal D2 receptor binding asymmetry in the patient group only. In view of research connecting striatal and frontal lesions with stereotypy in animals and cognitive inflexibility in humans, these data could suggest a similar disturbance underlying the phenomenon in schizophrenia.

Adolescent↗
PubMed1994

Regional cerebral blood flow (rCBF) in schizophrenia during verbal memory activation: a 99mTc-HMPAO single photon emission tomography (SPET) study.

Regional cerebral blood flow (rCBF) was investigated in a group of medicated DSM-III-R schizophrenic patients and age, sex and handedness matched normal volunteers using a split-dose 99mTc-HMPAO Single Photon Emission Tomography (SPET) protocol. Measures were taken during the performance of a verbal memory task aimed at activating the left medial temporal lobe, a region repeatedly suggested to be structurally abnormal in schizophrenia. In normal subjects, the performance of the task was associated with significant rCBF increases in the left medial temporal, left inferior frontal and anterior cingulate cortices, and right cerebellum. Despite their significantly poorer performance on the memory task, the degree of medial temporal activation measured in the schizophrenic patients was not significantly different from that found in the control group. This finding suggests that memory deficits in schizophrenia do not necessarily imply failure to activate the left medial temporal lobe as assessed by 99mTc-HMPAO SPET.

Adult↗
PubMed1994

D2 dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients. An 123I-IBZM single photon emission computerised tomography study.

We used SPECT to examine striatal D2 receptor binding in 20 antipsychotic-free DSM-III-R schizophrenic patients and 20 age- and sex-matched normal controls. Dynamic single-slice SPECT, at a slice chosen to include the basal ganglia, began immediately following intravenous injection of 185 MBq of 123I-IBZM. A semiquantitative approach was used to generate indices of specific D2 receptor binding in the basal ganglia. There was no overall elevation of D2 receptor binding between patients and controls. A male sex-specific left lateralised asymmetry of striatal D2 receptor binding was found in the patient group. Age-dependent decline of striatal D2 receptors was confirmed in controls, but not in patients. These results suggest that alterations in striatal D2 receptor distribution and density do occur in schizophrenia, and possibly reflect wider disruptions in prefrontal-striatal-limbic circuits.

Adolescent↗
PubMed1994

Functional neuroimaging and pharmacogenetic studies of clozapine's action at dopamine receptors.

The factors that influence response to neuroleptic drugs are poorly understood. These factors may include clinical variables such as length of illness before treatment, age at onset, and the presence of negative symptoms; and pharmacologic factors such as rates of drug metabolism. For example, pharmacodynamic differences in therapeutic response to haloperidol have been observed between Chinese and Caucasian patients. Response rates may also reflect clinical heterogeneity, although familiality, history of obstetric trauma, or ventricular enlargement have been not shown to be significant factors. It is also possible that genetic differences in receptors that are targets for these drugs may influence response.

Adult↗
PubMed1993

Expression of alternatively-spliced glutamate receptors in human hippocampus.

Rat glutamate receptors have been shown to be expressed as two developmentally regulated, alternatively spliced isoforms. We have investigated the expression of these isoforms of GluRA and GluRB in the human hippocampus. The expression pattern of the mRNAs coding for these subunits does not correspond to that in the rat hippocampus, both isoforms being preferentially expressed in the dentate gyrus and CA1 regions, with lower expression in CA3, with the exception of GluRB flop, where hybridization in CA3 is only lower than in dentate gyrus. Cloning of cDNA from human frontal cortex has also revealed that the two isoforms of human GluRB have virtual nucleotide sequence identity with the alternative exons in the rat, confirming the usefulness of oligonucleotides complementary to the rat cDNAs as probes for these receptor subunits in human neuropsychiatric disorders.

Alternative Splicing↗
PubMed1993

Antipsychotic medication, D2 dopamine receptor blockade and clinical response: a 123I IBZM SPET (single photon emission tomography) study.

The hypothesis that poor response to antipsychotic medication is due to inadequate occupancy of central D2 receptors was tested in vivo. We assessed striatal D2 dopamine receptor availability for binding with the specific ligand 123I IBZM by single photon emission tomography (SPET) in two groups of DSM-III-R diagnosed schizophrenic patients on typical antipsychotic medication, and a group of healthy controls (N = 20). Patients were characterized by clinical ratings as antipsychotic responders (N = 10) or non-responders (N = 8). Dynamic single slice SPET, at a slice chosen to include the basal ganglia, began immediately following intravenous injection of 185 MBq 123I IBZM. Semiquantitative analysis generated indices of D2 receptor availability for binding. There was no difference in striatal D2 receptor availability between the patient groups, both showing a similar degree of occupancy by antipsychotic medication compared to the control group. Thus, poor clinical response does not appear to be accounted for by differential blockade, or inadequate occupancy of striatal dopamine D2 receptors by antipsychotic medication.

Adult↗
PubMed1993

Schizophrenia: a neurodevelopmental perspective.

The role of aberrant neurodevelopment in the etiology of schizophrenia is reviewed in light of recent neuropathologic, neurochemical, and neuroimaging evidence of cerebral abnormalities in schizophrenic patients. There may exist some genetic defect in the control of brain development. Clinical epidemiologic surveys highlight the importance of obstetric complications, and prenatal exposure to influenza epidemics in contributing to these abnormalities. It is suggested that such environmental hazards and aberrations in the control of early brain development produce the neuronal phenotype that manifests as schizophrenia with early age of onset of symptoms associated with soft neurologic signs and is more common in young males.

Brain Chemistry↗
PubMed1992

Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia.

According to the dopamine hypothesis of schizophrenia, D2 receptor blockade is essential for a drug to have antipsychotic potency, and antipsychotic potency and D2 blockade are linearly related in vitro. To test this assumption in vivo, we have compared clinical response with central D2 dopamine receptor availability measured by 123I-iodobenzamide single photon emission tomography in two groups of schizophrenic patients. 6 patients were on typical antipsychotic drugs and 10 were on the atypical antipsychotic clozapine, including 2 patients from the first group. The patients on typical antipsychotics showed poor therapeutic response despite D2 receptor blockade. Significant clinical improvement occurred in all patients on clozapine, but at a lower level of D2 blockade by the drug. These findings suggest a more complex relation between D2 blockade and clinical efficacy than was previously thought.

Adult↗
PubMed1992

A developmental perspective on the pathology and neurochemistry of the temporal lobe in schizophrenia.

Neuropathological, neuroimaging, clinical and epidemiological evidence suggests that many cases of schizophrenia are developmental in origin. Dysplastic changes in the medial temporal lobes appear to be of particular importance. However, research implicating a neurodevelopmental origin for schizophrenia has proceeded largely in isolation from knowledge concerning the neurochemistry of the disorder. This paper attempts to integrate these disparate lines of research, and examines the role of trophic mechanisms in the formation of the hippocampus. Those neurotransmitters which have been most consistently found to be abnormal in the temporal lobes of schizophrenics (excitatory amino acids and CCK), are involved in the control of hippocampal development. We suggest that these neurotransmitter findings are the residue of abnormalities in their role as trophic factors in foetal or neonatal life, and that the latter contribute to the developmental aberrations considered fundamental to schizophrenia.

Adult↗
PubMed1992

Clozapine.

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Ambulatory Care↗
PubMed1991

Decreased hippocampal expression of a glutamate receptor gene in schizophrenia.

A striking and specific loss of the messenger RNA that encodes a non-N-methyl D-aspartate (non-NMDA) glutamate receptor was found in hippocampal tissue obtained at necropsy from 6 patients with schizophrenia, when compared to specimens from 8 controls without neurological or psychiatric signs or symptoms. These findings support suggestions of aberrant glutamatergic function in schizophrenia. Evidence that gene expression may be abnormal in schizophrenia, with decreased production of an excitatory neurotransmitter receptor, may have therapeutic as well as pathogenetic implications.

Adult↗
PubMed1990

Increased forskolin binding in the left parahippocampal gyrus and CA1 region in post mortem schizophrenic brain determined by quantitative autoradiography.

Using quantitative autoradiography of [3H]forskolin we have visualized the activated states of adenylate cyclase in the hippocampal formation bilaterally in sections from schizophrenic brain and age-matched controls. There is a generalized increase in binding in schizophrenic hippocampi, particularly in the CA1 region and parahippocampal gyrus. The effect is particularly marked in the left parahippocampal gyrus. These findings add some support to the notion of schizophrenia as a medial temporal lobe disorder and suggest novel substrates as therapeutic targets in schizophrenia.

Adenylyl Cyclases↗