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Biomedical subjects

J de Leon

Publications and source records attributed to J de Leon.

At least 19 recordsLinked to original sources
PubMed2007

No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample.

This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy-Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene.

Case-Control Studies↗
PubMed2007

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients.

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

Adolescent↗
PubMed2006

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing.

Limited information is available on the frequency of the many CYP2D6 alleles found in African-Americans. DNA was isolated and genetic testing was performed on samples from 222 African-Americans, healthy controls (n=131), and psychiatric patients (n=91). Each DNA was tested for CYP2D6 alleles *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14, *15, *17, *18, *19, *20, *25, *26, *29, *30, *31, *35, *36, *37, *40, *41 and *43 and 8 multiple copy alleles (*1xn, *2xn, *4xn, *41xn, *2Lxn, *17xn, *35xn and *10xn) using the AmpliChip CYP450 prototype microarray assay, along with allele-specific-PCR and PCR restriction fragment length polymorphism methods. No significant difference was noted between controls and psychiatric patients in any CYP2D6 allele frequencies. Three subjects were genotyped as poor metabolizers (1.4%; 0.0-2.9%, 95% confidence intervals (CI)), and 10 were classified as ultrarapid metabolizers (4.5%; 1.8-7.2%, 95% CI). A new CYP2D6 allele (*58) and two new duplicated CYP2D6 alleles (*17xn and *2Lxn) not previously reported were also identified. The frequency of the CYP2D6 overexpression in African-Americans may represent a greater therapeutic challenge than its deficiency based on these results. The most common alleles found in African-Americans including CYP2D6*1, *17 and *41 need to be investigated more closely for race-specific allelic variations and the mechanism responsible for differences in allele function more closely examined. The diversity of CYP2D6 alleles suggests that nucleotide arrays or similar methods are needed to efficiently test for the most prominent/relevant CYP2D6 alleles in humans.

Adolescent↗
PubMed2005

Risperidone half-life in a patient taking paroxetine -- a case report.

This case report further establishes the inhibitory effects of paroxetine on risperidone (R) metabolism in a patient whose R was discontinued due to side effects. Baseline through levels in ng/ml were 33 for R, 9 for 9-hydroxyrisperidone (9-OHR) and 42 for the total moiety. The fourth morning after R discontinuation, levels were 4 for R, 1 for 9-OHR and 5 for the total moiety. The estimated half-lives were 23.8 hours for R, 22.8 hours for 9-OHR and 23.5 hours for the total moiety.

Adult↗
PubMed2004

New GABAA receptor alpha5 subunit gene polymorphism that may confound genotyping.

We report the discovery of a new GABAA receptor alpha5 subunit gene polymorphism close to the polymorphism described by Glatt et al. (GT)5GCGTGC(GT)21. This new polymorphism is of great importance, because it means that non-denaturing acrylamide gels used to separate the different alleles of the polymorphism described by Glatt et al. cannot distinguish an allele with the sequence: (GT)4GCGTGC(GT)n from another allele with the sequence: (GT)4(GCGT)4GC(GT)(n-6). These gel fragments are separated by size, which would be the same in these two cases. An alternative would be to use an analysis method that can detect base changes, for instance, single strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE).

Base Sequence↗
PubMed2003

Dimensions of suicidal behavior according to patient reports.

Five factor analyses with limitations explored the Suicidal Intent Scale (SIS) subscales reflecting suicidal behavior dimensions. This larger sample study conducts an exploratory factor analysis of the SIS. Two large samples of suicide attempters (N= 435 and N= 252) from a general hospital were studied. The validity of SIS subscales obtained from the factor analysis was investigated by examining the association between the subscales and clinical variables. There were two factors: expected lethality and planning. In both samples, male gender and depression tended to be associated with higher scores in both subscales (small to medium effect sizes). Hospitalization was associated with higher scores in both SIS subscales (medium to large effects) suggesting that these subscales were reasonably good predictors of suicide attempt severity. Clinicians assessing patient reports to establish the severity of suicide attempts need to ask questions regarding both dimensions: expected lethality and planning.

Adult↗
PubMed2001

A prospective study of the paradoxical relationship between impulsivity and lethality of suicide attempts.

BACKGROUND: Biological studies suggest that lower serotonergic activity is associated with both greater suicide lethality and impulsive personality traits. These results may lead to the conclusion that impulsivity in the attempt should be associated with greater lethality. However, Klerman's review of epidemiologic suicide studies suggests an inverse relationship between impulsivity and lethality. This seemingly paradoxical relationship between impulsivity and lethality has not been explored in large representative clinical samples of suicide attempts. METHOD: During 1996 to 1998, 478 individuals who attempted suicide were studied in a general hospital in Madrid, Spain. Impulsivity was measured as described in the literature by combining 2 items of Beck's Suicidal Intent Scale (active preparation for attempt and degree of premeditation). Lethality of the attempt was assigned 1 of 4 levels according to the need for medical and/or psychiatric treatment. RESULTS: More than half of the attempts were impulsive (55%; 95% confidence interval [CI], 51% to 59%), approximately one fourth of the attempts had an intermediate level of impulsivity (28%; 95% CI, 24% to 32%), and approximately one sixth of the attempts were not impulsive (17%, 95% CI, 13% to 21%). There was an inverse association between the impulsivity and lethality of the suicide attempt (chi2 = 62.639, df = 6, p < .0001). The most impulsive attempts tended to result in less morbidity, while the less impulsive attempts tended to be more lethal. CONCLUSION: If the inverse relationship between impulsivity and lethality is replicated in other large and representative samples, new studies will be needed to clarify the complex interactions between the clinical dimensions (lethality, impulsivity as a state, and impulsivity as a personality trait) and the biological correlates (particularly serotonergic function) of suicidal behavior.

Adult↗
PubMed2000

A simple high performance liquid chromatographic method for the quantification of total cotinine, total 3'-hydroxycotinine and caffeine in the plasma of smokers.

A simple isocratic HPLC procedure has been developed for the quantification of caffeine and the nicotine metabolites cotinine, 3'-hydroxycotinine, cotinine glucuronide and 3'-hydroxycotinine glucuronide in the plasma of smokers. The glucuronide conjugates were determined indirectly via initial basic hydrolysis of the analyte sample followed by quantification of the resulting deconjugation product. Plasma was basified, extracted with dichloromethane, evaporated, the residue dissolved water and an aliquot part was analyzed by HPLC. The method utilized a Partisil-10 SCX cation-exchange column and an isocratic mobile phase of sodium phosphate buffer: methanol (92:8 v/v, 0.1 M, adjusted to pH 4.8 with triethylamine) at a flow rate of 1.5 ml/min. UV detection was at 254 nm. All solutes were separated with good resolution, and quantification was determined using an internal standard of N,N-diethylnicotinamide. The retention times were: caffeine 5.1 min, 3'-hydroxycotinine 7.2 min, N,N-diethylnicotinamide 9.5 min, and cotinine 15.5 min. Detection limits for caffeine, 3'-hydroxycotinine, cotinine, and total cotinine were 10 ng/ml; the detection limit for total 3'-hydroxycotinine was 20 ng/ml. The inter-day and intra-day variations for all analytes were between 1 and 8%. This analytical method is suitable for the determination of caffeine and nicotine metabolite levels in large numbers of clinical samples.

Caffeine↗
PubMed2000

Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness.

The influence of cytochrome P450 2D6 (CYP2D6) genetic variability was examined in psychiatric inpatients by evaluating adverse drug events (ADEs), hospital stays, and total costs over a 1-year period in an extension of a previously published brief report. One hundred consecutive psychiatric patients from Eastern State Hospital in Lexington, Kentucky, were genotyped for CYP2D6 expression. ADEs were evaluated by a neurologic rating scale, modified Udvalg for Kliniske Undersogelser Side Effect Rating Scale, or chart review. Information on total hospitalization days and total costs were gathered for a 1-year period. Forty-five percent of the patients received medications that were primarily dependent on the CYP2D6 enzyme for their elimination. When the analysis was restricted to just those patients in each group receiving medication heavily dependent on the CYP2D6 enzyme, the following were observed: (1) a trend toward greater numbers of ADEs from medications as one moved from the group with ultrarapid CYP2D6 activity (UM) to the group with absent CYP2D6 activity (PM); (2) the cost of treating patients with extremes in CYP2D6 activity (UM and PM) was on average $4,000 to $6,000 per year greater than the cost of treating patients in the efficient metabolizer (EM) and intermediate metabolizer (IM) groups; and (3) total duration of hospital stay was more pronounced for those in CYP2D6 PM group. Variance of hospital stays and costs calculated from these preliminary data suggests that 1,500 to 2,000 patients must be evaluated over at least a 1-year period to determine whether the CYP2D6 genetic variation significantly alters the duration of hospital stay and costs.

Antipsychotic Agents↗
PubMed1999

Diurnal variability of orofacial dyskinetic movements.

OBJECTIVE: Instrumental methods to measure tardive dyskinesia (TD) have been introduced in the last few years to try to eliminate the differences in inter-rater reliability. After eliminating variations attributed to the use of different raters, it is clear that TD frequently shows fluctuations in severity contributing to a low test-retest reliability. In the present study the diurnal variability of dyskinetic movements was explored by a computerized technique using digital imaging processing to measure orofacial movements. METHOD: Ten patients with persistent tardive dyskinesia were assessed three times a day once a week for four consecutive weeks. RESULTS: Four patients had significant diurnal variations in the severity of dyskinetic movements and six did not have significant variations. The period of time between waking and the assessment, the severity of dyskinetic movements, and smoking were significantly different between these two groups. CONCLUSION: Diurnal variations, particularly in relation to sleeping and smoking patterns, may need to be taken into account during longitudinal studies of tardive dyskinesia.

Adult↗
PubMed1999

Double-blind study of clozapine dose response in chronic schizophrenia.

OBJECTIVE: This study explored the relative efficacy of three different doses of clozapine. METHOD: Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses. RESULTS: Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day. CONCLUSIONS: Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.

Antipsychotic Agents↗
PubMed1999

A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.

BACKGROUND: The limited available information on plasma risperidone levels shows a stable relationship between daily doses of risperidone and total plasma concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450 2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not expected to be clinically significant. One case report suggests that CYP3A participates in the metabolism of risperidone. METHOD: A case series of 13 risperidone patients (the initial case and 12 new cases) who were genotyped for CYP2D6 were followed, and another 20 risperidone patients from a case-control study for the CYP2D6 genotype were reviewed. RESULTS: The CYP2D6 poor metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the case-control study), did not appear to tolerate risperidone well. Drugs affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at least a 2-fold decrease or increase in plasma risperidone levels. CONCLUSION: The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.

Adolescent↗
PubMed1998

First episode in bipolar disorder: misdiagnosis and psychotic symptoms.

BACKGROUND: This study explores factors that can influence other psychotic diagnoses in the first episode of a DSM-III-R bipolar disorder. METHODS: It includes all 163 bipolar in-patients and out-patients in the state of Alava, North of Spain (Basque country) from February 1994 to May 1996. Patients were divided into two non-overlapping groups: unstable diagnoses, bipolars with an initial diagnosis of schizophrenia (or other psychosis), and stable diagnoses of bipolar disorder. RESULTS: A logistic regression analysis using marital status, age at onset and mood incongruent psychotic symptoms found that the latter was the only independent factor significantly associated with an unstable diagnosis.

Adult↗