Association of serotonin receptor 2a haplotypes with obsessive-compulsive disorder and its treatment response in Iranian patients: a genetic and pharmacogenetic study.
ABSTRACT: Introduction:Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder causing intrusive thoughts or repetitive behaviors. Serotonin reuptake inhibitors are used for OCD treatment, but 40%-60% of patients do not respond to them adequately. In this study, the associations of serotonin receptor 2a polymorphisms rs6311 and rs6313 with OCD, its familial form and fluvoxamine treatment response in Iranian population were investigated. Patients and methods:Association analyses were conducted in 293 OCD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR and 245 controls. Pharmacotherapy was defined as 12 weeks of treatment with fluvoxamine (150-300 mg). Treatment response was considered as >25% reduction in Yale-Brown Obsessive Compulsive Scale score. Genotyping was performed by means of PCR-RFLP. Results:The results showed no association of rs6311 or rs6313 with OCD, but their haplotypes had different distribution patterns in cases and controls. Moreover, rs6313 was associated with the familial form of OCD in females significantly (P=0.005) under the recessive genetic model. Moreover, rs6311-rs6313 haplotypes were associated with fluvoxamine treatment response in OCD patients with more AC and less AT in responders. Conclusion:HTR2A haplotypes are associated with OCD and its treatment response with a fluvoxamine in Iranian patients. Furthermore, the observed association of rs6313 with the familial form of OCD in females suggests different genetic background of OCD familial and non-familial forms, which needs further investigation.
Project description:Anorexia nervosa (AN), bulimia nervosa (BN), and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN, and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. Additionally, few if any studies have interrogated postmortem brain tissue for evidence of eQTLs associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN, and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a non-psychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, e.g., eating disorders (ED; N=15), and obsessive-compulsive disorder/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and non-psychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared to controls and OCD cases compared to controls, respectively (FDR < 5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain datasets. Gene expression data from the dorsolateral prefrontal cortex (DLPFC) from postmortem tissue on 133 subjects - 15 eating disorder (ED) patients, 16 obessive compulsive disorder (OCD) patients, and 102 non-psychiatric controls - run on the Illumina HumanHT-12 v3 microarray
Project description:Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive-compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95-associated protein 3 (SAPAP3/DLGAP3) is a post-synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family-based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS.
Project description:To identify predictors and moderators of outcome in the first Pediatric OCD Treatment Study (POTS I) among youth (N = 112) randomly assigned to sertraline, cognitive behavioral therapy (CBT), both sertraline and CBT (COMB), or a pill placebo.Potential baseline predictors and moderators were identified by literature review. The outcome measure was an adjusted week 12 predicted score for the Children's Yale Brown Obsessive Compulsive Scale (CY-BOCS). Main and interactive effects of treatment condition and each candidate predictor or moderator variable were examined using a general linear model on the adjusted predicted week 12 CY-BOCS scores.Youth with lower obsessive-compulsive disorder (OCD) severity, less OCD-related functional impairment, greater insight, fewer comorbid externalizing symptoms, and lower levels of family accommodation showed greater improvement across treatment conditions than their counterparts after acute POTS treatment. Those with a family history of OCD had more than a sixfold decrease in effect size in CBT monotherapy relative to their counterparts in CBT without a family history of OCD.Greater attention is needed to build optimized intervention strategies for more complex youth with OCD. Youth with a family history of OCD are not likely to benefit from CBT unless offered in combination with an SSRI.Treatment of Obsessive Compulsive Disorder (OCD) in Children, http://www.clinicaltrials.gov, NCT00000384.
Project description:Attention-deficit/hyperactivity disorder (ADHD) has been found to be highly comorbid in children and adolescents with obsessive-compulsive disorder (OCD). Some have proposed, however, that obsessive anxiety may cause inattention and executive dysfunction, leading to inappropriate ADHD diagnoses in those with OCD. If this were the case, these symptoms would be expected to decrease following successful OCD treatment. The present study tested this hypothesis and evaluated whether ADHD symptoms at baseline predicted OCD treatment response. Obsessive-compulsive and ADHD symptoms were assessed in 50 youth enrolled in a randomized controlled trial investigating selective serotonin reuptake inhibitor and cognitive behavioral treatment. Repeated-measures analysis of variance (RMANOVA) revealed that ADHD symptoms at baseline do not significantly predict treatment outcome. A multivariate RMANOVA found that OCD treatment response moderated change in inattention; participants who showed greater reduction in OCD severity experienced greater reduction in ADHD-inattentive symptoms, while those with less substantial reduction in obsessions and compulsions showed less change. These findings suggest that children and adolescents with OCD and inattention may experience meaningful improvements in attention problems following OCD treatment. Thus, in many youth with OCD, inattention may be inherently tied to obsessions and compulsions. Clinicians may consider addressing OCD in treatment before targeting inattentive-type ADHD.
Project description:The aim of the study is to identify the global messenger RNA (mRNA) and long noncoding RNA (lncRNA) expression profiling in peripheral blood from thirty patients with Obsessive Compulsive Disorders (OCD) and thirty paired normal controls. Overall design: We quantified the gene transcripts in peripheral blood from thirty patients with OCD and thirty normal controls by the method of Microarray using Aglilent G3 lncRNA v4.04×180K.
Project description:Obsessive-compulsive disorder (OCD) is associated with emotion regulation impairments, namely the frequent use of maladaptive strategies such as suppression and the decreased use of reappraisal strategies. Additionally, these patients exhibit elevated stress levels. Since stress exposure affects emotion regulation abilities, stress might influence the relationship between obsessive-compulsive symptoms and emotion regulation. In this study, we explored the effects of stress and obsessive-compulsive symptoms on emotion regulation in a sample of healthy and OCD individuals. We used self-reported psychometric scales to measure stress levels, obsessive-compulsive symptoms, and emotion reappraisal and suppression skills. We applied multiple regression and mediation analyses. Our results demonstrated that increased reappraisal scores were associated with higher suppression scores. Additionally, elevated stress values predicted increased scores for suppression and decreased scores for reappraisal. Furthermore, the reappraisal abilities resulted from a combination of a direct effect of obsessive-compulsive symptoms and an indirect effect of obsessive-compulsive symptoms mediated by stress. The reliance on suppression strategies and the difficulty in using reappraisal approaches are explained by stress levels and are not directly explained by obsessive-compulsive symptoms. This study highlights the necessity of targeting stress in current therapy-based treatments for OCD.
Project description:Evidence from twin and family studies supports a genetic etiology for obsessive-compulsive disorder (OCD). The purpose of this study was to test whether a major gene is implicated in a proportion of families with OCD. Complex segregation analyses of 153 families (80 case and 73 control), ascertained in the Johns Hopkins OCD Family Study, provided strong evidence for a major gene. A Mendelian-dominant model, with significant sex effects and with residual familial effects, best explained the observed data. Stratification of the sample by the sex of probands provided further evidence of heterogeneity with respect to familial aggregation. Segregation analyses of 86 families with a female proband and of the 67 families with a male proband suggested that a Mendelian-dominant model with familial residual effects was the most parsimonious model explaining the inheritance of OCD in both subgroups.
Project description:The existence of neuropsychological deficits has been implicated in obsessive-compulsive disorder (OCD), particularly memory, attention, and executive functions. However, few studies have focused on neuropsychological deficits in the relatives of OCD patients. The aim of this study was to investigate cognitive deficits in OCD patients and their parents.Forty patients with OCD, 48 parents of these patients, and 87 healthy controls completed a neuropsychological testing battery.Both OCD patients and their parents showed impairments in delayed verbal memory and delayed visual memory. Furthermore, they performed worse than healthy controls in problem-solving ability.Our study demonstrated familial aggregation of delayed memory deficits and impaired problem-solving ability, which may be the potential neuropsychological endophenotypes of hereditary susceptibility to OCD.
Project description:OBJECTIVE:To review progress in understanding pediatric obsessive-compulsive disorder (OCD). The focus is on the frontal-striatal-thalamic model of OCD, neurobiological and genetic studies of the disorder, and their influence on recent advances in treatment. METHOD:Computerized literature searches were conducted with the key words "obsessive-compulsive disorder" in conjunction with "pediatric," "genetics," and "imaging." RESULTS:Neuroimaging studies find evidence to support the frontal-striatal-thalamic model. Genetic and neurochemical studies also implicate glutamate in the pathological finding of OCD. This has led to the application of glutamate-modulating agents to treat OCD. CONCLUSIONS:Studies of pediatric OCD have led to a refined frontal-striatal-thalamic model of pathogenesis and are having an evidence-based impact on treatment. Despite this progress, fully explanatory models are still needed that would allow for accurate prognosis and the development of targeted and efficacious treatments.
Project description:Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.