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Biomedical subjects

G Kirov

Publications and source records attributed to G Kirov.

At least 55 records · Page 3Linked to original sources
PubMed1998

Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response.

Serotonin (5-HT) neurotransmitter receptors are targeted by atypical antipsychotic drugs. We hypothesized that genetic variation in these receptors may affect clinical response to the drugs targeting them. This hypothesis has been tested by several studies in which the correlation between polymorphic variants in the 5-HT2A receptor gene and clinical response to the atypical antipsychotic clozapine was investigated. The results of these studies either found association between 5-HT2A genetic variants and clozapine response or found differences in the same direction which did not reach statistical significance. Meta-analysis of these studies including 373 patients who responded to the treatment and 360 non-responders showed association between two 5-HT2A polymorphisms, 102-T/C and His452Tyr, and clozapine response. Statistical analysis of extreme responders showed a clearer association of the 102-T/C with clozapine response. These results reinforce the hypothesis and strengthen the candidacy of these receptors as important therapeutic targets.

Alleles↗
PubMed1998

Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 and epsilon 2 alleles may influence the age of onset of depressive illness. Depressive illness of late onset is also a risk factor for Alzheimer's disease (AD), and there is some evidence that the ApoE epsilon 2 allele is associated with depressive symptomatology in AD. Depressive symptomatology in AD may thus share common genetic risk factors with late-onset depressive illness. METHODS: The frequency of the epsilon 2 and epsilon 4 alleles of ApoE and their effects on age of onset of disease in three independent groups of subjects, with depressive illness, with AD, and controls, were compared in a defined population from Southeast London. RESULTS: The frequency of the ApoE epsilon 2 allele was significantly lower in the depressive illness group compared with the control group and was associated with a later mean age at onset. Subjects with depressive symptomatology in AD had a higher frequency of the ApoE epsilon 2 allele and had a significantly later age of onset of depressive illness compared with the nondepressed AD group. CONCLUSIONS: The presence of the ApoE epsilon 2 allele in AD is found to be highly associated with depressive symptomatology, and it is proposed that this subgroup represents the presence of delayed depressive illness and that there are common genetic risk factors between AD and depressive illness.

Age of Onset↗
PubMed1998

Thyroid disorders in lithium-treated patients.

BACKGROUND: Little is known about the rate of thyroid disorders prior to lithium treatment, and which patients have a higher risk for developing such disorders during such treatment. METHOD: Assessment of the thyroid histories and laboratory results of 209 lithium-treated patients with affective disorders from one catchment area. RESULTS: Six female patients had thyrotoxicosis before starting lithium, a rate of 4.9%. Twenty patients developed hypothyroidism during the treatment: 3.4% of all males and 14.9% of all females. Female patients over the age of 50 were more likely to develop early lithium-induced hypothyroidism. CONCLUSIONS: (1) Female patients with affective disorders might have an increased rate of thyrotoxicosis. (2) Lithium-induced hypothyroidism might develop earlier in female patients over the age of 50. LIMITATIONS: Retrospective design of the study. CLINICAL RELEVANCE: (1) The thyroid status of patients with affective disorders might be more relevant than is appreciated. (2) Guidelines for thyroid tests in lithium-treated patients should reflect the different risks conferred by age and gender.

Adult↗
PubMed1998

Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine.

Clozapine is a potent atypical antipsychotic which binds to a variety of neurotransmitter receptors including serotonin (5-HT) receptors. However, the precise neurochemical site of clozapine's therapeutic action is unknown. We hypothesize that genetic variation in the neurotransmitter receptors to which the drug binds may influence clozapine response. To test this hypothesis we genotyped a novel -1438-G/A polymorphism detected in the promoter region, and a His452Tyr polymorphism described in the coding region of the 5-HT2A receptor gene in two independent samples of clozapine-treated patients including responders and non-responders. Although the strong association between these polymorphisms and clozapine response observed in the first sample (sample I) was not statistically significant in the second sample (sample II), the results in both samples were in the same direction. Homozygosity for the allele G-1438 was higher among non-responders (56% in sample I, 43% in sample II) than in responders (28% in sample I and 32% in sample II) in both samples. Similarly, the frequency of allele Tyr452 was higher in non-responders (11% in sample I, 16% in sample II) than in responders (6% in sample I and 10% in sample II). A combined analysis of both samples showed association between both polymorphisms and clozapine response. These results provide further evidence suggesting that genetic variation at 5-HT2A receptors may influence clozapine response and strengthen the candidacy of these receptors as important therapeutic targets.

Alleles↗
PubMed1998

Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder.

Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines. An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme. A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population. We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed chi 2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: chi 2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder.

Alleles↗
PubMed1998

Linkage analysis between bipolar affective disorder and markers on chromosome X.

Since 1969, several classical linkage studies suggested an X-chromosome locus for bipolar affective disorder. However, methods using highly polymorphic DNA markers have provided conflicting evidence for linkage, and an X-chromosomal locus for bipolar disorder remains controversial. More recently, Pekkarinen et al. (1995) found a maximum LOD score of 3.54 at the marker DXS994 in a large bipolar Finnish kindred. In the present study, we attempted to replicate this finding using 43 families multiply affected by bipolar affective disorder. These families were selected for the absence of male-to-male transmission of the disease, and were genotyped for two microsatellte markers, DXS1227 and DXS1062 (which is about 2 cM telomeric to DXS994). Linkage to this region was excluded either using a two-point lod score method with two plausible genetic models, or by a model-free lod score analysis which does not require specification of a particular mode of transmission. We conclude that there is no evidence of a common major gene for bipolar affective disorder at Xq25-q27 in our set of families.

Bipolar Disorder↗
PubMed1998

Religious faith after psychotic illness.

Religion can play an important role in the lives of psychiatric patients. We assessed how often a psychotic illness can lead to a change in the strength of religious faith and how commonly religion is used for coping with such illnesses in a sample of consecutively admitted patients. 52 patients with psychosis were interviewed regarding their religious beliefs after their index admission. 69.4% of the patients were religious, and 11 (22.4%) stated that religion was the most important part of their lives. 30.4% of the sample described that there had been an increase in their religiousness after the onset of illness. 61.2% of patients were using their religion for coping with the illness. Such patients had a better insight into their illness and were more compliant with antipsychotic medication. We conclude that the experience of a psychotic illness is likely to lead to an increase in religious beliefs. Such beliefs are commonly used for coping with the illness and some patients attach a great importance to them.

Adaptation, Psychological↗
PubMed1998

Randomised controlled trial of compliance therapy. 18-month follow-up.

BACKGROUND: A randomised controlled trial was conducted in an acute treatment setting to examine the effectiveness of compliance therapy, a brief pragmatic intervention targeting treatment adherence in psychotic disorders, based on motivational interviewing and recent cognitive approaches to psychosis. METHOD: Seventy-four patients with psychotic disorders according to DSM-III-R criteria recruited from consecutive admissions to an acute in-patient unit, received 4-6 sessions of either compliance therapy or non-specific counselling, and were followed-up over 18 months. The principal outcome measures were observer-rated compliance, attitudes to treatment, insight and social functioning. RESULTS: Significant advantages were found for the compliance therapy group post-treatment on measures of insight, attitudes to treatment and observer-rated compliance which were retained over the follow-up period. Global social functioning improved relatively more over time in the compliance therapy group compared with the control group. Survival in the community prior to readmission was significantly longer in the compliance therapy group. CONCLUSIONS: The results support the effectiveness of compliance therapy in improving functioning and community tenure after an acute psychotic episode.

Acute Disease↗
PubMed1998

Cost-effectiveness evaluation of compliance therapy for people with psychosis.

BACKGROUND: Non-compliance rates with antipsychotic medication can be high, and the personal and societal costs are considerable. A new psychological intervention, compliance therapy seeks to improve compliance and patient outcomes and reduce treatment costs. METHOD: A randomised controlled study examined the cost-effectiveness of compliance therapy compared to non-specific counselling over 18 months for 74 people with psychosis admitted as inpatients at the Maudsley Hospital. Bivariate and multivariate analyses were conducted to test for differences and to explore inter-patient cost variations. RESULTS: Compliance therapy is more effective and is no more expensive. Consequently, compliance therapy is more cost-effective than non-specific counselling at six, 12 and 18 months. CONCLUSIONS: There are compliance, outcome and cost-effectiveness arguments in favour of compliance therapy in preference to non-specific counselling.

Adult↗
PubMed1997

No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene.

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

Adult↗
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

Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's disease.

We examined a deletion/insertion promoter polymorphism of the serotonin transporter gene, which confers an approximately 40% reduction in expression of the protein, in 196 subjects with late onset Alzheimer's disease (AD) and 271 controls. The frequency of the 484 bp low activity allele was elevated in the subjects with AD (p = 0.004), and an excess of the low activity genotype (30%) was also found in comparison with the controls (20%) (chi 2 = 7.16; p = 0.03). This association was unrelated to the age of the subjects or controls, or to epsilon 4 alleles of the ApoE gene. The odds ratio for the effect of the homozygous low activity genotype was 1.7 (95% CI 1.08-2.67), with a population attributable risk of 33% (95% CI 5-54%). These findings indicate that the low activity allele of the serotonin transporter is a risk factor for late onset AD.

Age of Onset↗
PubMed1997

Toxic shock syndrome and necrotizing fasciitis complicating neglected sacrococcygeal pilonidal sinus disease: report of a case.

PURPOSE: This study was conducted to report the rare combination of necrotizing fasciitis and toxic shock syndrome, which both complicated neglected sacrococcygeal pilonidal sinus disease. METHODS: A case report is presented. RESULTS: We describe the rare case of a previously healthy adult male patient who developed necrotizing fasciitis and toxic shock syndrome associated with Streptococcus pyogenes and Bacteroides fragilis. Patient's response to emergency surgery followed by repeated debridements of necrotic tissue, together with aggressive fluid resuscitation, broad-spectrum antibiotic coverage, and hyperbaric oxygenation was good. CONCLUSION: This case serves again as a clear reminder that neglected pilonidal sinus disease can lead to unusual and life-threatening consequences.

Bacteroides Infections↗
PubMed1997

The molecular genetics of schizophrenia: progress so far.

In 1988, a report of a genetic linkage between schizophrenia and markers on chromosome 5 caused considerable excitement. Many hoped that a cause for schizophrenia had been found. Unfortunately, subsequent results failed to replicate the finding, and there was little progress in the molecular understanding of the disorder over the next five years. However, within the past two years, there have been reports of positive linkages on chromosome arms 22q and 6p that, unlike previous reports, have received support from several teams. Here, we review the evidence for these linkages, as well as findings from association studies that have not yet received as much independent confirmation.

Adolescent↗
PubMed1996

Linkage studies in bipolar affective disorder with markers on chromosome 21.

Straub et al. (1994: Nature Genet. 8. 291-296) have suggested that a susceptibility gene for bipolar affective disorder is located at chromosome 21q22.3, on the basis of linkage analysis in one large family. This result has been supported by Gurling et al. (1995: Nature Genet. 10, 8-9) who also found some evidence for linkage to this region under locus heterogeneity. In order to investigate the validity of these results and to estimate how broadly applicable they are, we performed a linkage study between bipolar affective disorder and two DNA markers (D21S171 and PFKL) from 21q22.3 using 60 bipolar pedigrees from three European centres and Brazil. The most positive result obtained was a maximised admixture lod score of 1.2 for the marker PFKI, under the assumption of locus heterogeneity, dominant transmission and a diagnostic classification which included recurrent unipolar depression. However, since lod scores obtained for both markers were substantially negative overall, we conclude that there is no common major gene for bipolar affective disorder at 21q22.3. It remains possible that a gene of major effect in this region operates in a minority of families.

Bipolar Disorder↗
PubMed1996

Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine.

Clozapine is an atypical antipsychotic with affinity for a broad range of receptors, including serotonin (5-HT) and dopamine receptors. It is successful in treating about 60% of patients refractory to other antipsychotic drugs. Since genetic variation in clozapine's neurotransmitter receptor targets may affect clinical response through altering drug binding or receptor expression, we have studied a His452Tyr polymorphism in the 5-HT2A receptor (HTR2A) in a sample of 153 schizophrenic patients undergoing clozapine treatment and 178 normal controls. An association was found between the allele Tyr452 and poor clinical response.

Alleles↗
PubMed1996

The serotonin transporter is a potential susceptibility factor for bipolar affective disorder.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

Alleles↗