Search PubMed⌕ Search

Biomedical subjects

R Kerwin

Publications and source records attributed to R Kerwin.

At least 37 records · Page 2Linked to original sources
PubMed1997

5-HT2A receptor and bipolar affective disorder: association studies in affected patients.

The aim of this study was to investigate the possible involvement of genetic variation in serotonin receptors in the aetiology of bipolar affective disorder. The 5-HT2A receptor gene was systematically screened for genetic variants by single strand conformation polymorphism (SSCP) methods in subjects with bipolar affective disorder. Four polymorphisms (two structural changes, Thr25Asn and His4 M52Tyr, and two silent polymorphisms, 102-T/C and 516-C/T) which had previously been found in patients with schizophrenia and control subjects were detected. No novel polymorphisms were found in patients with bipolar affective disorder. These polymorphisms were genotyped in a sample of 129 patients and 252 controls of German origin and 176 patients and 182 controls of British origin. No strong associations were found between any of these polymorphisms and bipolar affective disorder. Genetic variation at the 5-HT2A receptor gene does not play a major role in the pathogenesis of the disorder.

Alleles↗
PubMed1997

Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder.

OBJECTIVE: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression. METHOD: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin. RESULTS: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed. CONCLUSIONS: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder.

Alleles↗
PubMed1995

Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients.

We have examined the hypothesis that a variable number of tandem repeats in the third cytoplasmic loop of the dopamine D4 receptor influences clinical response to clozapine using a sample of 189 schizophrenic patients. Alleles of the 48-bp repeat, which range from two to ten copies in the normal human population, were analysed by the polymerase chain reaction using genomic DNA as template. Association between these alleles and response to clozapine was tested using the difference in pre- and post-treatment GAS scores as a measure of response. We found no statistically significant variation between genotypic groups and response by analysis of variance. We conclude that the variation of the number of 48-bp repeats alone does not determine response to clozapine. Larger studies are underway to determine if there is a more subtle relationship with sequence variation within the repeats or at other polymorphic sites within the gene that may provide evidence for a component of clozapine's action being at D4 receptors.

Alleles↗
PubMed1995

Schizophrenia and the androgen receptor gene: report of a sibship showing co-segregation with Reifenstein syndrome but no evidence for linkage in 23 multiply affected families.

Crow et al. [1993: Am J Med Genet (Neuropsychiatr Genet) 48:159-160] have reported excess sharing of alleles by male sibling pairs with schizophrenia, at a triplet repeat marker within the androgen receptor gene, indicating that mutations at or near this gene may be a risk factor for males. In this report, we describe a pair of male siblings concordant for both schizophrenia and Reifenstein syndrome, which is caused by a mutation in this gene. This provides support for the hypothesis that the androgen receptor may contribute to liability to develop schizophrenia. Because of this, we have examined a collection of 23 pedigrees multiply affected by schizophrenia for linkage to the androgen receptor. We have found no evidence for linkage by both the LOD score and affected sibling-pair methods, under a range of genetic models with a broad and narrow definition of phenotype, and when families with male-to-male transmission are excluded. However, because of the small number of informative male-male pairs in our sample, we cannot confirm or refute the excess allele sharing for males reported by Crow.

Adolescent↗
PubMed1995

Association between clozapine response and allelic variation in 5-HT2A receptor gene.

We report allelic association between a polymorphism (T102C) within the coding region of the 5-HT2A gene (HTR2A, 13q14-21) and response to clozapine in schizophrenic patients. Homozygosity for the C102 allele was more frequent (30/57, 53%) among patients who did not respond to clozapine than in those who responded (23/92, 25%). This finding is evidence that allelic variation of genes which encode neurotransmitter receptors can influence clinical response to antipsychotic drugs.

Alleles↗
PubMed1995

Decreased expression of AMPA receptor messenger RNA and protein in AIDS: a model for HIV-associated neurotoxicity.

HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA and protein of the GluR-A flop subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor in cerebellar Purkinje cells. Although Purkinje cells are relatively resistant to loss, the observed disturbance of AMPA receptors may contribute to the neurotoxic process in other vulnerable brain regions and clinically to the development of dementia.

AIDS Dementia Complex↗
PubMed1995

Cytochrome P4502D6 genotype does not determine response to clozapine.

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.

Alleles↗
PubMed1995

Effect of clozapine on d-fenfluramine-evoked neuroendocrine responses in schizophrenia and its relationship to clinical improvement.

BACKGROUND: Clozapine is an effective antipsychotic that has high affinity for serotonin type 2 (5-HT2) receptors. The importance of 5-HT antagonism in the overall clinical efficacy of clozapine is unclear. Using a neuroendocrine strategy we tested the hypothesis that clinical response to clozapine is related to alteration in 5-HT function. METHOD: Ten treatment-resistant schizophrenic subjects were treated with clozapine for a mean of 10.3 (s.e. 0.9) weeks; d-fenfluramine (DFEN) challenge tests were performed before and after treatment with concurrent clinical ratings (BPRS, SAPS, SANS) made at the time of testing. RESULTS: All patients showed clinical improvement following treatment with clozapine. In addition, clozapine produced a significant attenuation of prolactin (PRL) and cortisol (CRT) response to DFEN challenge. Change in symptom ratings correlated significantly with reduction in PRL response to DFEN challenge. CONCLUSIONS: These data show that functional alterations occur in the 5-HT system following response to clozapine and lend support to studies suggesting that 5-HT is an important component to the spectrum of action of clozapine.

Adult↗