Biomedical subjects

F M Macciardi

Publications and source records attributed to F M Macciardi.

11 recordsLinked to original sources

PubMed2001

Polymorphism of the serotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index in women with bulimia nervosa.

BACKGROUND: Preclinical research has shown that the serotonin-1B receptor has important modulatory effects on feeding behavior and thus body weight. In the current study, we examined whether genetic variation of the serotonin-1B receptor was associated with minimum and maximum lifetime body mass indices (BMIs) in a sample of women with bulimia nervosa (BN). METHODS: Ninety-eight women with BN were genotyped based on the G861C polymorphism of the serotonin-1B receptor gene (HTR1B). Minimum and maximum lifetime BMIs were compared across the three genotypic groups using analysis of variance. RESULTS: There was a highly significant difference in minimum lifetime BMI across the three genotypic groups (p =.001). Both the G/C and C/C genotypes were associated with significantly lower minimum lifetime BMIs than was the G/G genotype. Maximum lifetime BMI was not significantly different across groups. These results were not attributable to different lifetime rates of anorexia nervosa across the three genotypic groups. CONCLUSIONS: These preliminary findings suggest a possible association between HTR1B genetic polymorphism and minimum lifetime BMI in women with BN. These findings may shed light on why, in response to dieting, some BN patients achieve lower BMIs, whereas others have a natural limitation to their weight loss. Pending replication in a larger sample, these findings point to a possible genetic factor of fundamental importance to the BN population.

Adolescent↗

PubMed2001

Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.

The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-HT1A (HTR1A) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding.

Adult↗

PubMed2001

Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for TD which is in part attributed to their ability to block the serotonin-2A (5-HT(2A)) receptor. 5-HT(2A) receptors were also identified in the basal ganglia; a brain region that plays a critical role in antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT(2A) receptor gene (HTR2A) in relation to the TD phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal Involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated. In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.

Adult↗

PubMed2000

Pharmacogenetics of antipsychotic treatment: lessons learned from clozapine.

The reintroduction of clozapine, the prototype of atypical antipsychotics, in the late 1980s has led to significant advances in the pharmacological management of schizophrenia. Since then, there has been a rapid development of novel "atypical" antipsychotic agents that have been pharmacologically modeled, to a certain extent, after their predecessor clozapine. As with all antipsychotics, there is variability among individuals in their response to these "atypical" drugs. Pharmacogenetics can provide a foundation for understanding this interindividual variability in antipsychotic response. This review first provides a rationale for the pharmacogenetic investigation of this variable trait. Studies of pharmacokinetic and pharmacodynamic factors of antipsychotic therapy are considered in the development of this rationale. Next, the molecular genetic techniques used to study this interindividual variation in response are described. This is followed by a review and discussion of the published studies examining genetic factors involved in clozapine response. From this, several recommendations for future pharmacogenetic investigations of antipsychotic response are proposed. Although still in its early stages, psychiatric pharmacogenetics should provide a basis for individualized pharmacotherapy of schizophrenia, and may also lead to the development of newer, more efficacious antipsychotic agents.

Antipsychotic Agents↗

PubMed2000

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.

Adult↗

PubMed1999

Chromosome 4 Workshop Summary: Sixth World Congress on Psychiatric Genetics, Bonn, Germany, October 6-10, 1998.

This report summarizes the findings presented at the Chromosome 4 Workshop of the Sixth World Congress on Psychiatric Genetics (October 1998, Bonn, Germany). Chromosome 4 linkage and association results for several psychiatric phenotypes including bipolar affective disorder, schizophrenia, alcoholism, and mental retardation are reviewed. In bipolar affective disorder, positive linkage results for markers on 4q35 were reported by three independent groups. In addition, findings in bipolar disorder were reported for markers spanning 4p14-16, and of particular interest are the results that coincide with the original Blackwood et al. [1996: Nat Genet 12:427-430] region at 4p16. For schizophrenia, modest positive results were reported for 4q31, as well as for marker D4S2917 at a region of 4q close to the centromere. Chromosome 4 continues to demonstrate interesting results in alcoholism, particularly in the region of the alcohol dehydrogenase gene cluster; however, it is not clear how to interpret the contrast in the susceptibility versus protective loci that are being reported in this region.

Alcoholism↗

PubMed1998

Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.

Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A-1438 A-->G polymorphism in the putative promoter and a silent T-->C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T-->C. 102 allele: chi 2 = 0.02; 1 df, p = .90; genotype: chi 2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: chi 2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: chi 2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: chi 2 = 3.46, 2 df, p = .18; chi 2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.

Adult↗

PubMed1998

Chromosome 4 workshop.

The largest cluster of positive results, considering both bipolar and schizophrenia, occurs in the 4p region that includes D4S394 and DRD5. Four groups report at least weakly positive linkage analyses this region for bipolar disorder, and two groups find weak positive allelic association with schizophrenia in the region, although at separate markers. On the other hand, at least five groups do not find evidence for linkage of bipolar disorder to this area of 4p. The pattern on 4q is less clear, with a mixture of negative and small positive results in either bipolar or schizophrenia families. Additional allelic association and TDT studies of 4p markers in bipolar disorder and in schizophrenia might be able to narrow the focus of the 4p investigations. The dopamine D5 receptor gene has seductive qualities as a candidate gene because of the pharmacology of psychotic disorders. It would be helpful to have additional markers developed close to or in the recoding region of DRD5 in order to have the extra information at the DNA level provided by haplotype analysis. Chromosome 4 susceptibility loci may figure prominently in alcoholism, although a great deal of work remains to be done. With just two groups reporting here, only a limited assessment of the overall effect of the ADH cluster and the GABA cluster is possible. However, these loci have merit as candidate genes, and thus further work on the current and additional families is clearly indicated.

Alcoholism↗

PubMed1996

No evidence for association of dopamine D2 receptor variant (Ser311/Cys311) with major psychosis.

We investigated a variant of the dopamine D2 receptor gene (Ser311/Cys311 substitution) in Caucasian patients with schizophrenia (n = 273), delusional disorder (n = 62), bipolar I affective disorder (n = 63), and controls (n = 255). No evidence for association between the receptor variant and any of the diseases was found, even when patients with younger age-of-onset (< 25 years) were compared with controls. Furthermore, in a subgroup of schizophrenia patients whom we assessed for negative symptoms, those with the Cys allele did not differ from the remainder of the group. Also, the bipolar affective disorder patients with psychotic features did not show evidence for association with the receptor variant. Thus, our results do not provide evidence for an association between this D2 receptor variant and schizophrenia, or delusional disorder, or bipolar affective disorder.

Adult↗

PubMed1996

Psychosis and genes with trinucleotide repeat polymorphism.

Abnormal expansion of genes with trinucleotide repeat (TNR) polymorphism has been found in a number of neuropsychiatric disorders. These disorders and the major psychoses, schizophrenia and bipolar affective disorder, appear to share an interesting phenomenon: genetic anticipation. Because TNR expansion correlates with anticipation, these unstable DNA sites are considered important candidate loci for the major psychoses. We investigated genes with TNR polymorphisms, including B1, B33, B37, and the N-cadherin gene, in unrelated Caucasian North American and Italian schizophrenics (n = 53 to 74), and matched controls. Also, unrelated Caucasian North American patients with bipolar I affective disorder were screened for the B33 and N-cadherin genes (n = 49 and 63, respectively). No unusually long alleles that would suggest abnormal expansion of the TNR were observed for any of these genes. Also, no statistically significant results were found in tests for genetic association between any of these genes and schizophrenia. For B37, a trend toward a difference in allele counts between schizophrenics and controls was observed. However, no clear evidence for a role of these TNR-containing genes in schizophrenia or bipolar affective disorders was found.

Bipolar Disorder↗

PubMed1995

Association study of dopamine D3 receptor gene and schizophrenia.

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied.

Alleles↗