Corrigendum to “Gender in obsessive–compulsive disorder: clinical and genetic findings” [Eur. Neuropsychopharmacol. 14/2 (2004) 105–113]

Background: There is increasing recognition that obsessive–compulsive disorder (OCD) is not a homogeneous entity. It has been suggested that gender may contribute to the clinical and biological heterogeneity of OCD. Methods: Two hundred and twenty patients (n=220; 107 male, 113 female) with DSM-IV OCD (age: 36.40±13.46) underwent structured interviews. A subset of Caucasian subjects (n=178), including subjects from the genetically homogeneous Afrikaner population (n=81), and of matched control subjects (n=161), was genotyped for polymorphisms in genes involved in monoamine function. Clinical and genetic data were statistically analyzed across gender. Results: Compared with females, males with OCD (1) had an earlier age of onset, and a trend toward having more tics and worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis I comorbidity, and (3) in the Caucasian group, were more likely to have the high activity T allele of the EcoRV variant of the monoamine oxidase A (MAO-A) gene compared to controls, and (4) in the Afrikaner subgroup, were more frequently homozygous for the G allele at the G861C variant of the 5HT_1Dβ gene than controls. Females with OCD (1) reported more sexual abuse during childhood than males, (2) often noted changes in obsessive–compulsive symptoms in the premenstrual/menstrual period as well as during/shortly after pregnancy, and with menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for the low activity C allele of the EcoRV variant of the MAO-A gene compared to controls, with this allele also more frequent in female patients than controls. Conclusion: This study supports the hypothesis that gender contributes to the clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of genetic susceptibility to OCD may be present. Further work is, however, needed to delineate the mechanisms that are responsible for mediating the effects of gender.     

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.     

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive-compulsive disorder in males.

BACKGROUND: Mounting evidence suggests the involvement of the dopamine system in the pathophysiology of obsessive-compulsive disorder. METHOD: The relationship of the dopamine D(2) receptor (DRD2) TaqI A, and catechol-O-methyl-transferase (COMT) NlaIII High/Low activity polymorphism to obsessive-compulsive disorder (OCD) was examined in a sample of 150 patients and 150 controls. RESULTS: OCD patients did not show significant differences in genotype distribution and allele frequency for polymorphisms investigated relative to controls. However, when the sample was stratified by gender, there was a trend to a significant predominance of the DRD2 A2A2 genotype (p=0.049), and a higher frequency of the DRD2 A2 allele (p=0.020) and low-activity COMT allele (p=0.035) in male OCD patients compared to male controls. In addition, we observed an association of the DRD2 A2A2 genotype in patients with an early onset of disease (相似文献   

Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder.

There is increasing evidence that the aetiology of obsessive-compulsive disorder (OCD) has a marked genetic component, although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. This study investigated the role of attractive candidate genes in the serotonergic and dopaminergic pathways in the development of OCD. The distribution of selected polymorphic variants in the serotonin receptor type 2A and 1Dbeta (5-HT(2A), 5-HT(1Dbeta)), dopamine transporter (DAT), dopamine receptor type 4 (DRD4) and monoamine-oxidase A (MAO-A) genes were analysed in 71 OCD cases and 129 control individuals in the genetically homogeneous Afrikaner population, by means of case-control association studies. Although no statistically significant genotypic or allelic associations were detected, the data yielded interesting preliminary results that warrant further discussion and investigation.     

Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder.

Family studies suggest an interrelationship between Gilles de la Tourette Syndrome (GTS) and some forms of obsessive-compulsive disorder (OCD). Some authors consider GTS to be part of a serotonergically mediated cluster of OCD spectrum disorders. The present study was undertaken to compare measures of psychopathology, personality and blood serotonin between GTS and OCD (without tics), and to investigate whether an OCD spectrum hypothesis is supported for GTS. Fifteen GTS without OCD subjects, 21 tic with (+) OCD subjects, 15 OCD without tic subjects and 26 controls (all without serotonergic medication) were evaluated with self-rated and clinician-rated measures of psychopathology and personality. Whole blood serotonin (5-HT) and platelet monoamine oxidase activity (MAO) was measured, and Spearman's correlations were calculated between whole blood 5-HT, MAO and rating scale scores within the entire sample and within subgroups. There were main effects of OCD on anxiety, obsessive-compulsive, neuroticism and extraversion scores. There were main effects of tics on depression, obsessive-compulsive, trait anxiety and neuroticism scores, and on platelet MAO. There were interaction effects on platelet MAO, 5-HT, Yale-Brown Obsessive-Compulsive Rating Scale severity, trait anxiety and Eysenck Personality Questionnaire neuroticism scores. Platelet MAO activity was elevated in tic-free OCD subjects when compared to tic + OCD, GTS without OCD and controls. Whole blood 5-HT was lowered in tic + OCD patients in comparison to GTS without OCD and tic-free OCD subjects. Whole blood 5-HT and obsessive-compulsive severity were negatively correlated within OCD without tic patients and MAO and Leyton Obsessive Inventory scores were negatively related within GTS without OCD patients. The biochemical data of this study suggest that in tic + OCD and in tic-free OCD patients, 5-HT dysregulations play a role, but not necessarily in pure GTS. Serotonergic dysregulations within tic + OCD and tic-free OCD patients are distinct, suggesting differences in underlying pathophysiology. The finding that obsessions and compulsions can be associated with either 5-HT hypofunctionality or hyperfunctionality reveals a major weakness in the OCD spectrum theory, i.e. that the associations between obsessive-compulsive behaviours and 5-HT abnormalities are less specific than suggested by the original obsessive-compulsive spectrum model.     

Clinical outcome in patients with bipolar I disorder, obsessive compulsive disorder or both

BACKGROUND: Bipolar disorder (BPD) is often comorbid with obsessive-compulsive (OCD) and other anxiety disorders, but the impact of such comorbidity on long-term outcome has not been evaluated systematically. METHODS: Extensive follow-up assessments were carried out at 4.3 years after index hospitalizations in a mixed BPD-OCD group (N=20) compared to matched groups with BPD (N=22) or OCD (N=20) alone. RESULTS: At follow-up, ratings of functional status were similar across groups. Rehospitalizations were similar among BPD-OCD and BPD subjects, but 2.9-times more frequent among comorbid than OCD patients. OCD symptoms averaged 150% more severe in OCD than comorbid subjects, and were not measured in BPD subjects. CONCLUSIONS: Despite potential sampling bias with previously hospitalized subjects, the findings suggest that comorbid BPD-OCD patients may be clinically more similar to BPD than OCD patients, and that BPD-OCD comorbidity may not negatively impact the long-term clinical outcome.     

Association study between the dopamine receptor D(4) gene and obsessive-compulsive disorder.

Pharmacological and neuroanatomical evidence suggest the involvement of the dopaminergic system in obsessive-compulsive disorder (OCD). Analysis of the 48-bp dopamine receptor D(4) (DRD4) gene polymorphism in a sample of 210 OCD patients and 202 healthy control subjects showed a significant association (chi(2)=27.5, df=6, p=0.0003). This difference was attributable to a lower frequency of allele 4R in OCD patients compared with the control group (chi(2)=9.33, p=0.0027). However, we did not replicate previous findings of an association between the 7R allele and OCD patients with tics. Finally, we analyzed a sub-sample of 86 OCD families. E-TDT analysis in 70 informative parents did not confirm the association observed in our case-control analysis. In conclusion, the current study cannot exclude an association between DRD4 gene and OCD in the largest sample analyzed. However, further studies will be required to confirm if the DRD4 gene is involved in the pathogenesis of this disorder.     

Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder

The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods.     

A family-based association study of the 5-HT-1Dbeta receptor gene in obsessive-compulsive disorder

Pharmacological studies have shown that sumatriptan, a selective ligand of the serotonin 5-HT-1Dbeta autoreceptor, modifies obsessive-compulsive disorder (OCD) symptoms. The current study analysed the G861C polymorphism of the 5-HT-1Dbeta gene in a sample of 72 trios. Genotyping data were analysed using the Family-Based Association Test (FBAT). We did not replicate the previously reported linkage disequilibrium between the G861 variant and OCD. However, a quantitative trait analysis, assessing severity of OCD symptoms and defined as YBOCS score, confirmed the finding that subjects with a preferential transmission of the G861 variant showed higher YBOCS Obsession scores compared to patients carrying the C861 allele. These preliminary findings may indicate that the 5-HT-1Dbeta receptor gene could be involved in the severity of obsession symptoms in OCD. However, it is important to perform the replication of these findings in larger sample sizes of informative families.     

Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder.

Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p < 0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.     

Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism?

Ultrarapid drug metabolism mediated by CYP2D6 is associated with inheritance of alleles with duplicated or amplified functional CYP2D6 genes. However, genotyping for duplicated CYP2D6 alleles only explains a fraction (10-30%) of the ultrarapid metabolizer phenotypes observed in Caucasian populations. Using a sample of CYP2D6 duplication-negative ultrarapid metabolizer subjects and selected control subjects with extensive metabolism, we examined parts of the CYP2D7 pseudogene, and the promoter region and 5'-coding sequence of CYP2D6 for polymorphisms possibly associated with the ultrarapid metabolizer phenotype. In an initial screening of 17 subjects (13 ultrarapid metabolizers and four extensive metabolizers), we identified three DNA variants in the 5'-end of the CYP2D7 pseudogene and 29 variants in the 5'-end of the CYP2D6 gene. Five variants were then selected for examination in a larger sample of subjects having the ultrarapid metabolizer (n = 27) or extensive metabolizer phenotype (n = 77). Subsequent statistical analyses of allele, genotype and estimated haplotype distributions showed that the 31A allele of the 31G > A (Val(II)Met) polymorphism was significantly more frequent in ultrarapid metabolizer subjects than in extensive metabolizer subjects (P = 0.04). Also, estimation of haplotype frequencies suggested that one of the haplotypes with the 31A variant was significantly more frequent among the ultrarapid metabolizers compared with the extensive metabolizers (P = 0.03). The average metabolic ratio was significantly lower in subjects possessing the 31A allele compared with subjects homozygous for the 31G allele (P = 0.02). We also observed a nonsignificant over-representation of the G-allele of a - 1584 C > G promoter polymorphism in the ultrarapid metabolizer group. Since our results are based on a relatively low number of subjects, further studies on larger samples and functional analyses of the polymorphisms detected are necessary to determine the role of the 31G > A and - 1584C > 6 variants in CYP2D6 duplication-negative ultrarapid metabolizer subjects.     

Transmission disequilibrium analysis of the functional 5-HT3A receptor variant C178T in early-onset obsessive compulsive-disorder

The 5-HT(3) receptor is unique among the serotonin receptors in that it is a ligand-gated ion channel. Dysfunction of the serotonin system is thought to contribute to the pathogenesis of obsessive-compulsive disorder (OCD). Apart from the standard treatment with serotonin reuptake inhibitors and behavioural therapy, a 5-HT(3) receptor antagonist has recently been shown to benefit some OCD patients, suggesting the 5-HT(3) receptor as a serotonergic candidate gene in the polygenic aetiology of OCD. A functional regulatory variant of the 5-HT(3A) receptor influences 5-HT(3) receptor expression, serotonin metabolites in cerebrospinal fluid, and amygdala reactivity. We therefore assessed whether this C178T variant influences the risk of developing OCD. In a family-based approach employing the transmission disequilibrium test, we analysed a unique sample of 75 children and adolescents with OCD, as well as their biological parents. We found no evidence for a preferential transmission of either allele to the patients--the estimated transmission rate for the C allele was 0.51 (95% CI 0.36-0.65). This argues against an involvement of the 5-HT(3A) receptor in the polygenic aetiology of early-onset OCD.     

Frequency of cytochrome P450 2C9 mutant alleles in a Korean population

AIMS: To determine the frequencies of CYP2C9 variants in the Korean population and compare them with the frequencies in other ethnic populations. METHODS: Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was carried out in 574 Korean subjects by PCR and restriction fragment length pattern analysis. RESULTS: Thirteen of 574 subjects (2.3%) were heterozygous for CYP2C9*3 (Ile359Leu), but no subjects with a CYP2C9*2 allele or homozygous for CYP2C9*3 were identified. The allele frequency of CYP2C9*3 in Korean subjects (0.0113, 95% CI 0.0066-0.0193) was similar to that of other East Asian populations, but was considerably lower than that of Caucasian populations. CONCLUSIONS: CYP2C9*3 seems to be an allelic variant related to the functional polymorphism of CYP2C9, but this variant is rarely seen among Koreans compared with Caucasians. Routine genotyping of the CYP2C9*2 allele is considered to be unnecessary in Korean and East Asians, because this allele appears to be extremely rare or absent in these populations.     

Human CYP1B1 Leu432Val gene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese; oestradiol hydroxylase activity; and distribution in prostate cancer cases and controls

Cytochrome P4501B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones, including 17beta-oestradiol (E2) and testosterone. We report a significant difference in the allele frequencies of two point mutations in the coding region of the CYP1B1 gene among Caucasian (n = 189), African-American (n = 52) and Chinese (Linxian) (n = 109) populations. A (C to G) transversion at position 1666 in exon 3, which results in an amino acid substitution of Leu432 to Val, was present in African-Americans with an allele frequency for Va1432 of 0.75, in Caucasians of 0.43, and in Chinese of 0.17. A (C to T) transition at position 1719 in exon 3, with no amino acid change (Asp449), appeared to be closely linked with the Val432 variant. Results using human lung microsomal preparations from individuals with the CYP1B1Val/Val and CYP1B1Leu/Leu genotypes indicate that Val432 variant may be a high activity allele and thus may contribute to the interindividual differences in CYP1B1 activity. Because CYP1B1 is involved in hormone and carcinogen metabolism, and given the disparate rates of prostate cancer among ethnic groups, we also evaluated the association of the CYP1B1 Leu432Val polymorphism with prostate cancer risk in a pilot case-control study. Among Caucasians, 34% of men with cancer (n = 50) were homozygous for the Val432 polymorphism, while only 12% of matched control subjects (n = 50) had this genotype. These preliminary data indicate that genetic polymorphisms in CYP1B1 might play an important role in human prostate carcinogenesis.     

Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study

This double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 wk of risperidone augmentation of serotonin reuptake inhibitor (SRI) treatment in adult subjects with treatment-resistant obsessive-compulsive disorder (OCD) (failure of at least two SRI trials). Sixteen adult treatment-resistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone (n=10) (0.5-3.0 mg/d) or placebo (n=6) following at least 12 wk of SRI treatment. Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression - Improvement (CGI-I) score of 1 or 2 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease >/=25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this.     

Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials.

Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 - 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.     

AN INTERIM ANALYSIS OF A DOUBLE-BLIND SHAM-CONTROLLED STUDY ON THE ACUTE EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION IN OBSESSIVE-COMPULSIVE DISORDER

We describe the interim analysis of a double-blind sham controlled quasi-randomized study on the acute effects of transcranial direct current stimulation (tDCS) for individuals with obsessive-compulsive disorder (OCD). Twenty OCD patients were assigned to receive a single session of sham (n=10) or active (2mA) tDCS (n=10) for 30 minutes, with the cathode placed over the central supplementary motor area (SMA) and the anode on the supraorbital region. Assessments of outcome were made at baseline and one hour following tDCS using: a dot-probe task comprising images illustrating different OCD-related scenarios, the Positive and Negative Affect Schedule (PANAS), and the Yale-Brown Obsessive-Compulsive Challenge Scale (YBOCCS; a measure of symptoms in the preceding hour). Active and sham tDCS groups did not differ in terms of age, gender, medication use and baseline severity of OCD, depression and anxiety symptoms. Though a significant time-effect (before vs. after tDCS) was observed on YBOCCS, PANAS and dot-probe scores, there was no interaction between groups. However, exploratory analyses revealed that sham tDCS led to a significant decrease in OCD symptoms in the past hour, while active tDCS failed to do so. Although we did not observe acute effects of tDCS on OCD symptoms, this interim analysis suggests that inhibition of the SMA may interfere with sham response in OCD, probably through increasing vigilance towards OCD-related environmental stimuli.     

Single nucleotide polymorphisms in the CYP2J2 and CYP2C8 genes and the risk of hypertension

CYP2J2 and CYP2C8 metabolize arachidonic acid (AA) to cis-epoxyeicosatrienoic acids (EETs), which play a central role in regulating renal tubular fluid-electrolyte transport and vascular tone. We hypothesized that functionally relevant polymorphisms in the CYP2J2 or CYP2C8 genes influence hypertension risk. We examined associations between CYP2J2*7 (G-50 T promoter) and CYP2C8*3 (Arg139Lys and Lys399Arg, which are in 100% linkage disequilibrium) polymorphisms and hypertension in a biethnic population from Tennessee. CYP2J2*7 variant allele frequency was significantly higher in African-Americans versus Caucasians (14.1% versus 7.7%, P=0.01), irrespective of hypertension status. When analysed separately by race, the genotype distribution of the CYP2J2*7 variant allele was not significantly different among African-Americans with/without hypertension, but was significantly different among Caucasians with/without hypertension (P=0.03). Indeed, the odds ratio of having hypertension attributable to carrying the CYP2J2*7 variant allele adjusted for age, gender, body mass index and family history was 0.39 (95% confidence interval 0.17-0.89) among Caucasians, suggesting a protective effect. Additional subgroup analyses revealed a significantly lower CYP2J2*7 variant allele frequency in hypertensive versus normotensive Caucasian males (5.6% versus 12.5%, P=0.02) and in hypertensive versus normotensive Caucasians without a family history of hypertension (1.5% versus 11.0%, P=0.03). With respect to the CYP2C8*3 variant, genotype distribution and allele frequencies were similar between normotensive and hypertensive subjects. This study provides evidence for an association between CYP2J2*7 genotype and hypertension in Caucasian males and Caucasians without a family history of hypertension, but suggests no association between CYP2C8*3 genotype and hypertension. Confirmation of these findings in additional populations is warranted.