Guaraci Requena

Epigenetic evidence for involvement of the oxytocin receptor gene in obsessive-compulsive disorder.

AbstractBackground Obsessive–compulsive disorder (OCD) is a chronic neurodevelopmental disorder that affects up to 3% of the general population. Although epigenetic mechanisms play a role in neurodevelopment disorders, epigenetic pathways associated with OCD have rarely been investigated. Oxytocin is a neuropeptide involved in neurobehavioral functions. Oxytocin has been shown to be associated with the regulation of complex socio-cognitive processes such as attachment, social exploration, and social recognition, as well as anxiety and other stress-related behaviors. Oxytocin has also been linked to the pathophysiology of OCD, albeit inconsistently. The aim of this study was to investigate methylation in two targets sequences located in the exon III of the oxytocin receptor gene (OXTR), in OCD patients and healthy controls. We used bisulfite sequencing to quantify DNA methylation in peripheral blood samples collected from 42 OCD patients and 31 healthy controls. ResultsWe found that the level of methylation of the cytosine-phosphate-guanine sites in two targets sequences analyzed was greater in the OCD patients than in the controls. The higher methylation in the OCD patients correlated with OCD severity. We measured DNA methylation in the peripheral blood, which prevented us from drawing any conclusions about processes in the central nervous system.ConclusionTo our knowledge, this is the first study investigating DNA methylation of the OXTR in OCD. Further studies are needed to evaluate the roles that DNA methylation and oxytocin play in OCD.

Randomized, Double-Blind, Placebo-Controlled Trial of N -Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder

OBJECTIVE To evaluate the efficacy of serotonin reuptake inhibitor (SRI) augmentation with N-acetylcysteine (NAC), a glutamate modulator and antioxidant medication, for treatment-resistant obsessive-compulsive disorder (OCD). METHODS We conducted a randomized, double-blind, placebo-controlled, 16-week trial of NAC (3,000 mg daily) in adults (aged 18-65 years) with treatment-resistant OCD, established according to DSM-IV criteria. Forty subjects were recruited at an OCD-specialized outpatient clinic at a tertiary hospital (May 2012-October 2014). The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores. To evaluate the variables group, time, and interaction effects for Y-BOCS scores at all time points, we used nonparametric analysis of variance with repeated measures. Secondary outcomes were the severity scores for anxiety, depression, specific OCD symptom dimensions, and insight. RESULTS Both groups showed a significant reduction of baseline Y-BOCS scores at week 16: the NAC group had a reduction of 4.3 points (25.6 to 21.3), compared with 3.0 points (24.8 to 21.8) for the placebo group. However, there were no significant differences between groups (P = .92). Adding NAC was superior to placebo in reducing anxiety symptoms (P = .02), but not depression severity or specific OCD symptom dimensions. In general, NAC was well tolerated, despite abdominal pain being more frequently reported in the NAC group (n [%]: NAC = 9 [60.0], placebo = 2 [13.3]; P < .01). CONCLUSIONS Our trial did not demonstrate a significant benefit of NAC in reducing OCD severity in treatment-resistant OCD adults. Secondary analysis suggested that NAC might have some benefit in reducing anxiety symptoms in treatment-resistant OCD patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01555970.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

Personality measures after gamma ventral capsulotomy in intractable OCD

Background: Neurosurgeries such as gamma ventral capsulotomy (GVC) are an option for otherwise intractable obsessive‐compulsive disorder (OCD) patients. In general, clinical and neuropsychological status both improve after GVC. However, its consequences on personality traits are not well‐studied. The objective of this study was to investigate personality changes after one year of GVC in intractable OCD patients. Methods: The personality assessment was conducted using the Revised NEO Personality Inventory (NEO PI‐R) and Cloningers Temperament and Character Inventory (TCI) in 14 intractable OCD patients before and one year after GVC. Comparisons of personality features between treatment responders (n = 5) and non‐responders (n = 9) were performed. Multiple linear regression was also used for predicting changes in clinical and global functioning variables. Results: Overall, no deleterious effect was found in personality after GVC. Responders had a reduction in neuroticism (p = 0.043) and an increase in extraversion (p = 0.043). No significant changes were observed in non‐responders. Increases in novelty seeking and self‐directedness, and decreases in persistence and cooperativiness predicted OCD symptom improvement. Similary, improvement in functioning was also predicted by hgher novelty seeking and self‐directedness after GVC, whereas better functioning was also associated with lower reward dependence and cooperativeness after surgery. Conclusions: The pattern of changes in personality traits after GVC was generally towards that observed in nonclinical population, and does not raise safety concerns. HighlightsNo deleterious effect was found in personality after GVC in OCD patients.Personality changes were observed in the responders but not in non‐responders.Changes in personality predicted improvement in OCD symptom and global functioning.

Cord blood concentrations of leptin, zinc-α2-glycoprotein, and adiponectin, and adiposity gain during the first 3 mo of life

OBJECTIVES Adipose tissue development starts in intrauterine life and cytokines are involved in this process. Therefore, understanding the role of cytokines in the fat mass gain of infants is crucial to prevent obesity later in life. Furthermore, recent evidence indicates a sex-specific link between cytokines and adipose tissue development. The objective of this study was to assess sex-specific relationships of cord blood concentrations of the cytokines leptin, zinc-α2-glycoprotein (ZAG), and adiponectin with infant adiposity during the first 3 mo of life. METHODS This was a prospective cohort study of 104 mother-infant pairs that were selected from a maternity hospital in Sao Paulo, Brazil. Cord blood leptin, ZAG, and adiponectin were determined by enzyme-linked immunosorbent assays. The body composition of the infants was assessed monthly by air displacement plethysmography. A multiple linear regression analysis was conducted with the average fat mass gain from birth to the third month of life as the outcome and cord blood leptin, ZAG, and adiponectin as the variables of interest. RESULTS Leptin was inversely associated with fat mass gain in the first 3 mo of life (P = 0.003; adjusted R2 = 0.09). There were inverse associations of leptin (P = 0.021), ZAG (P = 0.042), and maternal body mass index (P = 0.04) with fat mass gain in girls (adjusted R2 = 0.29) but fat mass gain in boys was positively associated with gestational age (P = 0.01; adjusted R2 = 0.15). CONCLUSIONS The results of this study suggest that adiposity programming is sex-specific, which highlights the need to investigate the different metabolic mechanisms that are involved in adipogenesis.

Adaptive treatment strategies for children and adolescents with Obsessive-Compulsive Disorder: A sequential multiple assignment randomized trial

OBJECTIVE This sequential multiple assignment randomized trial (SMART) tested the effect of beginning treatment of childhood OCD with fluoxetine (FLX) or group cognitive-behavioral therapy (GCBT) accounting for treatment failures over time. METHODS A two-stage, 28-week SMART was conducted with 83 children and adolescents with OCD. Participants were randomly allocated to GCBT or FLX for 14 weeks. Responders to the initial treatment remained in the same regimen for additional 14 weeks. Non-responders, defined by less than 50% reduction in baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, were re-randomized to either switch to or add the other treatment. Assessments were performed at baseline, 7, 14, 21, and 28 weeks. RESULTS Among the 43 children randomized to FLX who completed the first stage, 15 (41.7%) responded to treatment and 21 non-responders were randomized to switch to (N = 9) or add GCBT (N = 12). Among the 40 children randomized to GCBT who completed the first stage, 18 (51.4%) responded to treatment and 17 non-responders were randomized to switch to (N = 9) or add FLX (N = 8). Primary analysis showed that significant improvement occurred in children initially treated with either FLX or GCBT. Each time point was statistically significant, showing a linear trend of symptom reduction. Effect sizes were large within (0.76-0.78) and small between (-0.05) groups. CONCLUSIONS Fluoxetine and GCBT are similarly effective initial treatments for childhood OCD considering treatment failures over time. Consequently, provision of treatment for childhood OCD could be tailored according to the availability of local resources.

Quantifying dimensional severity of obsessive-compulsive disorder for neurobiological research

Current research to explore genetic susceptibility factors in obsessive-compulsive disorder (OCD) has resulted in the tentative identification of a small number of genes. However, findings have not been readily replicated. It is now broadly accepted that a major limitation to this work is the heterogeneous nature of this disorder, and that an approach incorporating OCD symptom dimensions in a quantitative manner may be more successful in identifying both common as well as dimension-specific vulnerability genetic factors. As most existing genetic datasets did not collect specific dimensional severity ratings, a specific method to reliably extract dimensional ratings from the most widely used severity rating scale, the Yale-Brown Obsessive Compulsive Scale (YBOCS), for OCD is needed. This project aims to develop and validate a novel algorithm to extrapolate specific dimensional symptom severity ratings in OCD from the existing YBOCS for use in genetics and other neurobiological research. To accomplish this goal, we used a large data set comprising adult subjects from three independent sites: the Brazilian OCD Consortium, the Sunnybrook Health Sciences Centre in Toronto, Canada and the Hospital of Bellvitge, in Barcelona, Spain. A multinomial logistic regression was proposed to model and predict the quantitative phenotype [i.e., the severity of each of the five homogeneous symptom dimensions of the Dimensional YBOCS (DYBOCS)] in subjects who have only YBOCS (categorical) data. YBOCS and DYBOCS data obtained from 1183 subjects were used to build the model, which was tested with the leave-one-out cross-validation method. The models goodness of fit, accepting a deviation of up to three points in the predicted DYBOCS score, varied from 78% (symmetry/order) to 84% (cleaning/contamination and hoarding dimensions). These results suggest that this algorithm may be a valuable tool for extracting dimensional phenotypic data for neurobiological studies in OCD.

Dissecting the Yale-Brown Obsessive-Compulsive Scale severity scale to understand the routes for symptomatic improvement in obsessive-compulsive disorder

We aimed to investigate which items of the Yale-Brown Obsessive-Compulsive Severity Scale best discriminate the reduction in total scores in obsessive-compulsive disorder patients after 4 and 12 weeks of pharmacological treatment. Data from 112 obsessive-compulsive disorder patients who received fluoxetine (⩽80 mg/day) for 12 weeks were included. Improvement indices were built for each Yale-Brown Obsessive-Compulsive Severity Scale item at two timeframes: from baseline to week 4 and from baseline to week 12. Indices for each item were correlated with the total scores for obsessions and compulsions and then ranked by correlation coefficient. A correlation coefficient ⩾0.7 was used to identify items that contributed significantly to reducing obsessive-compulsive disorder severity. At week 4, the distress items reached the threshold of 0.7 for improvement on the obsession and compulsion subscales although, contrary to our expectations, there was greater improvement in the control items than in the distress items. At week 12, there was greater improvement in the time, interference, and control items than in the distress items. The use of fluoxetine led first to reductions in distress and increases in control over symptoms before affecting the time spent on, and interference from, obsessions and compulsions. Resistance did not correlate with overall improvement. Understanding the pathway of improvement with pharmacological treatment in obsessive-compulsive disorder may provide clues about how to optimize the effects of medication.

An Alternative Operational Risk Methodology for Regulatory Capital Calculation

The main objective of this work is to suggest a new method for calculation of regulatory capital required for operational risk as an alternative to the corresponding version advocated by the Basel Committee of Banking Supervision. Our method takes into account genuine dependence among the losses of possible risk units within a financial institution. Our proposal reduces the amount of regulatory capital suggested by Basel Committee, where the risk units are assumed to be perfectly positive-dependent. A simulation study is performed to compare both approaches. Finally, we discuss when Bayesian methods are preferable to the classical ones.