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R W Kerwin

Publications and source records attributed to R W Kerwin.

At least 19 recordsLinked to original sources
PubMed2007

No association between ADRA2A polymorphisms and schizophrenia.

There is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.

Adult↗
PubMed2004

Serotonergic polymorphisms and psychotic disorders in populations from North Spain.

There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P < or = 0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

Adult↗
PubMed2004

Pharmacogenomics--can genetics help in the care of psychiatric patients?

Psychiatric patients demonstrate varied responses to treatment. Consequently, treatment strategies are trial-and-error, which has a negative effect on prognosis and compliance. The aim of pharmacogenomic research is to enable customised drug treatment by identifying variations within multiple candidate genes (those encoding drug-targeted neurotransmitter receptors, transporters and metabolic enzymes) that are likely to confer the inter-individual differences in drug response and development of drug-induced side effects. Pharmacogenetic and pharmacogenomic research to date has identified genetic polymorphisms of dopamine (DA) and serotonin (5-HT) receptor subtypes, the serotonin transporter (5-HTT) and metabolic enzymes (cytochrome P450 [CYP] family) as important contributors to the variability in response to psychiatric drugs and the development of drug-induced side effects such as tardive dyskinesia and weight gain. It is anticipated that technological and methodological advances will provide further candidate genes and refine association analyses of existing candidates, enabling pharmacogenomic research to move towards future treatment regimes that are catered to the individual.

Cytochrome P-450 Enzyme System↗
PubMed2003

Advances in the pharmacogenetic prediction of antipsychotic response.

Pharmacogenetics (investigation of a limited number of genes) and pharmacogenomic (investigation of large number of genes and their expression) strategies are being used for the identification of genetic factors contributing to response variability. Whereas pharmacogenomic investigation is producing a wealth of information that will take several years to analyse and translate into clinical advantages, pharmacogenetic research has already produced some interesting results such as the identification of metabolic polymorphisms that may be important for therapeutic doses and side-effects, and the identification of response-related mutations in drug targets. Preliminary studies have also shown that pharmacogenetic information can be used for the pre-treatment prediction of treatment response. It is expected that over the next decade these advances are introduced into clinical practice and will help to tailor psychiatric treatment to the patient's individual needs.

Antipsychotic Agents↗
PubMed2003

GABAergic inhibitory mechanisms for repetition-adaptivity in large-scale brain systems.

Molecular mechanisms for systems level adaptivity of brain activation are largely unknown but a key role for active inhibition by gamma-aminobutyric acid (GABA) is plausible. We used functional magnetic resonance imaging to contrast the modulatory effects on brain adaptivity to task repetition and task difficulty of two GABAergic drugs, lorazepam and flumazenil. In a working memory paradigm, occipitotemporal regions clearly demonstrated attenuation of activation as a function of within-session task repetition or practice in data acquired following placebo, but this spatiotemporal pattern of repetition adaptivity was abolished by both lorazepam and flumazenil. However, in other brain systems flumazenil enhanced repetition adaptivity compared to placebo: in frontal cortex, flumzenil induced attenuation of signal related to task repetition and in hippocampus it exaggerated normal enhancement of signal with repetition. In contrast, there were no significant effects of either flumazenil or lorazepam on areas of frontal cortex which normally demonstrated significant neurocognitive load response or adaptivity to task difficulty. We argue that repetition adaptivity of large-scale brain systems is regulated by GABAergic inhibitory mechanisms and that expression of repetition adaptivity in a given brain system may show an "inverted-U" form of relationship with pharmacologically manipulable levels of GABAergic inhibitory tone.

Adult↗
PubMed2003

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

Adult↗
PubMed2002

An RT-PCR study of 5-HT(6) and 5-HT(7) receptor mRNAs in the hippocampal formation and prefrontal cortex in schizophrenia.

5-Hydroxytryptamine (5-HT; serotonin) 5-HT(6) receptors (5-HT(6)R) and 5-HT(7) receptors (5-HT(7)R) have been implicated in schizophrenia and as targets of atypical antipsychotic drugs. We have studied the expression of these receptors in the hippocampal formation and dorsolateral prefrontal cortex (DLPFC) of 17 subjects with schizophrenia and 17 controls using reverse transcription-polymerase chain reaction (RT-PCR) with cyclophilin co-amplification. In schizophrenia, 5-HT(6)R mRNA was decreased in the hippocampal formation, and 5-HT(7)R mRNA was decreased in the dorsolateral prefrontal cortex. The mRNAs were unchanged in rats treated for 2 weeks with haloperidol, chlorpromazine, risperidone, olanzapine or clozapine. Regional decreases in 5-HT(6)R and 5-HT(7)R expression in schizophrenia may contribute to the overall serotonergic alterations which occur in the disorder, in part through their interactions with other neurotransmitter systems including glutamate and acetylcholine.

Animals↗
PubMed2002

IQ in childhood psychiatric attendees predicts outcome of later schizophrenia at 21 year follow-up.

OBJECTIVE: Preschizophrenic children who merit psychiatric referral are claimed to have a particularly malevolent illness when the psychosis develops later. The 21 years outcome of a sample of such children was investigated. METHOD: Fifty-one children who attended psychiatric services, and were later diagnosed as having schizophrenia, were followed up a mean of 21 years later. Baseline childhood demographic, clinical and putative aetiological characteristics were identified from the case notes. Follow-up assessment evaluated clinical symptoms, social functioning and service utilization. The predictive value of baseline factors on outcome was examined. RESULTS: Outcome was poor, and seven (14%) of the subjects were deceased. Childhood IQ was strongly predictive of social outcome (F=5.1, P=0.01) and service utilization (F=5.2, P=0.01), but not clinical symptoms. No other factors predicted outcome. CONCLUSION: Low childhood IQ had an unfavourable impact on social outcome and service utilization once schizophrenia developed.

Age of Onset↗
PubMed2001

Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia.

A dysfunctional glutamatergic system has been implicated in the pathophysiology of schizophrenia. The group III metabotropic glutamate receptor (mGluR) types 7 and 8 presynaptically inhibit glutamate release, thereby modulating glutamatergic transmission in the brain. We conducted association studies to investigate the novel Tyr433Phe (mGluR7) variant and the 2846-C/T (mGluR8) polymorphism in schizophrenia. Both variants, present at high frequencies, failed to demonstrate any significant association with schizophrenia (mGluR7 [Tyr433Phe] allele: P=0.33; genotype: P=0.63; mGluR8 [2846-C/T] allele: P=0.72; genotype: P=0.63).

Adult↗
PubMed2001

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.

1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action.

Animals↗
PubMed2001

RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia.

5-HT(2C) receptor (5HT(2C)R, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT(2C)R RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT(2C)R gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT(2C-MNI) and 5-HT(2C-VDI). Screening of the 5-HT(2C)R gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT(2C-INI) is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT(2C)R-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.

Animals↗
PubMed2001

Applications of pharmacogenetics in psychiatry: personalisation of treatment.

In spite of the lack of epidemiological information, pharmacogenetic research has produced evidence of the relationship between genes and treatment response. Genetic variants of metabolic enzymes are related to toxic reactions; polymorphisms in genes coding for drug-targeted neurotransmitter receptors influence therapeutic efficacy. Also, recent studies have shown that response to antipsychotic drugs can be predicted by looking at the individual's pharmacogenetic profile. In addition to providing the first evidence that treatment response can be predicted by looking at a core of key genes, these studies illustrate the feasibility of individualisation of psychiatric treatment.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Genetic strategies for the personalization of antipsychotic treatment.

Pharmacogenetic research into complex traits, such as response to antipsychotic treatment has proved a difficult task. Nevertheless, investigation of drug metabolic enzymes has revealed polymorphisms in specific cytochrome P450 genes responsible for treatment-induced toxic reactions. However, the picture becomes more complicated when drug target sites are investigated in search of genetic influence. Most antipsychotic drugs are multitarget, denoting a complex mechanism of action. Although individual genes have been reported to influence antipsychotic response, no single gene can account for the variability observed in treatment response. Current investigations focus on single gene variants that may be associated with particular side effects or symptoms as well as contributing to general response. The scope of this article is to review recent advances of pharmacogenetic research on antipsychotic drugs and the strategies under development for the individualization of treatment.

Antipsychotic Agents↗
PubMed2001

Pharmacogenetics for the individualization of psychiatric treatment.

Drug treatment of psychiatric disorders is troubled by severe adverse effects, low compliance and lack of efficacy in about 30% of patients. Pharmacogenetic research in psychiatry aims to elucidate the reasons for treatment failure and adverse reactions. Genetic variations in cytochrome P450 (CYP) enzymes have the potential to directly influence the efficacy and tolerability of commonly used antipsychotic and antidepressant drugs. The activity of psychiatric drugs can also be influenced by genetic alterations affecting the drug target molecule. These include the dopaminergic and serotonergic receptors, neurotransmitter transporters and other receptors and enzymes involved in psychiatric disorders. Association studies investigating the relation between genetic polymorphisms in metabolic enzymes and neurotransmitter receptors on psychiatric treatment outcome provide a step towards the individualization of psychiatric treatment through enabling the selection of the most beneficial drug according to the individual's genetic background.

Antipsychotic Agents↗