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Obsessive-compulsive disorder (OCD) is a debilitating developmental neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), finding strong evidence that de novo likely gene disrupting and predicted damaging missense variants contribute to OCD risk. Together, these de novo damaging variants are enriched in OCD probands (RR 1.52, p=0.0005). We identified two high-confidence risk genes, each containing two de novo damaging variants in unrelated probands:CHD8 (Chromodomain Helicase DNA Binding Protein 8)andSCUBE1 (Signal Peptide, CUB Domain And EGF Like Domain Containing 1). Based on our data, we estimate that 34% of de novo damaging variants seen in OCD contribute to risk, and that de novo damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring de novo damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly autism spectrum disorders. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways related to immune response.SIGNIFICANCE STATEMENTDecades of genetic studies in obsessive-compulsive disorder (OCD) have yet to provide reproducible, statistically significant findings. Following an approach that has led to tremendous success in gene discovery for several neuropsychiatric disorders, here we report findings from DNA whole-exome sequencing of patients with OCD and their parents. We find strong evidence for the contribution of spontaneous, or de novo, predicted-damaging genetic variants to OCD risk, identify two high-confidence risk genes, and detect significant overlap with genes previously identified in autism. These results change the status quo of OCD genetics by identifying novel OCD risk genes, clarifying the genetic landscape of OCD with respect to de novo variation, and suggesting underlying biological pathways that will improve our understanding of OCD biology.

After 12 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy with inadequate response, 10 patients received clomipramine and 11 received quetiapine as augmentation agents of the SSRI. The primary outcome measure was the difference between initial and final scores of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), rated in a blinded fashion, and the score of clinical global improvement (CGI-I). Statistical analyses were performed using nonparametric tests to evaluate treatment efficacy and the difference between treatment groups. Percentile plots were constructed with YBOCS scores from the clomipramine and quetiapine groups. Considering response a ≥35% reduction in the initial Y-BOCS score plus a rating of ‘much improved’ or ‘very much improved’ on CGI-I, four of eleven quetiapine patients and one out of ten clomipramine patients were classified as responders. The mean final Y-BOCS score was significantly lower than baseline in the quetiapine augmentation group (P = 0.023), but not in the clomipramine augmentation group (P = 0.503). The difference between groups showed a trend towards significance only at week 4, the mean Y-BOCS score being lower for those receiving quetiapine (P = 0.052). A difference between groups was also observed at week 4 according to percentile plots. These results corroborate previous findings of quetiapine augmentation efficacy in obsessive-compulsive disorder (OCD). Clomipramine augmentation did not produce a significant reduction in Y-BOCS scores. Higher target maximum dosages might have yielded different results.

ResumenObjetivoEn este estudio se investiga la influencia de la edad de inicio de los síntomas obsesivos-compulsivos (SOC) sobre las enfermedades psiquiátricas coexistentes, y trata de establecer un valor de corte para la edad de inicio.MétodosTrescientos treinta pacientes con TOC se seleccionaron y entrevistaron consecutivamente usando las siguientes entrevistas estructuradas: Escala Obsesiva Compulsiva Yale-Brown; Escala Global de Gravedad de Tics de Yale y Entrevista Clínica Estructurada del DSM-IV. Los datos se analizaron por análisis en racimo y de regresión.ResultadosLa edad menor de inicio de la enfermedad se asoció con una mayor probabilidad de coexistencia de trastornos de tics, ansiedad, somatomorfo, de la alimentación y del control de impulsos. La mayor duración de la enfermedad se asoció con menos posibilidades de tener tics. El sexo femenino se asoció con trastornos de ansiedad, de la alimentación y del control de impulsos. Los trastornos de tics se asociaron con trastornos de ansiedad y trastorno de déficit de atención/hiperactividad (TDAH). No se encontró ningún valor de corte de la edad de inicio de la enfermedad para dividir claramente la muestra en subgrupos homogéneos. Sin embargo, los análisis en racimo revelaron que comenzaban a surgir diferencias a los 10 años y eran más pronunciadas a los 17 años, lo que indica que éstos son los mejores valores de corte de esta muestra.ConclusionesEn pacientes con TOC, la edad de inicio se asocia con patrones específicos de enfermedades coexistentes. Las diferencias más notables se obtienen analizando la edad de inicio como valor absoluto.

Purpose.This study investigates the influence of age at onset of OCS on psychiatric comorbidities, and tries to establish a cut-off point for age at onset.Methods.Three hundred and thirty OCD patients were consecutively recruited and interviewed using the following structured interviews: Yale-Brown Obsessive Compulsive Scale; Yale Global Tic Severity Scale and the Structured Clinical Interview for DSM-IV. Data were analyzed with regression and cluster analysis.Results.Lower age at onset was associated with a higher probability of having comorbidity with tic, anxiety, somatoform, eating and impulse–control disorders. Longer illness duration was associated with lower chance of having tics. Female gender was associated with anxiety, eating and impulse–control disorders. Tic disorders were associated with anxiety disorders and attention-deficit/hyperactivity disorder. No cut-off age at onset was found to clearly divide the sample in homogeneous subgroups. However, cluster analyses revealed that differences started to emerge at the age of 10 and were more pronounced at the age of 17, suggesting that these were the best cut-off points on this sample.Conclusions.Age at onset is associated with specific comorbidity patterns in OCD patients. More prominent differences are obtained when analyzing age at onset as an absolute value.

Introduction: Although obsessions and compulsions comprise the main features of obsessive-compulsive disorder (OCD), many patients report that their compulsions are preceded by a sense of “incompleteness” or other unpleasant feelings such as premonitory urges or a need perform actions until feeling “just right.” These manifestations have been characterized as Sensory Phenomena (SP). The current study presents initial psychometric data for a new scale designed to measure SP.Methods: Seventy-six adult OCD subjects were probed twice. Patients were assessed with an open clinical interview (considered as the “gold standard”) and with the following standardized instruments: Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders, Yale-Brown Obsessive-Compulsive Scale, Dimensional Yale-Brown Obsessive-Compulsive Scale, Yale Global Tic Severity Scale, Beck Anxiety Inventory, and Beck Depression Inventory.Results: SP were present in 51 OCD patients (67.1%). Tics were present in 16 (21.1%) of the overall sample. The presence of SP was significantly higher in early-onset OCD patients. There were no significant differences in the presence of SP according to comorbidity with tics or gender. The comparison between the results from the open clinical interviews and the University of São Paulo Sensory Phenomena Scale (USP-SPS) showed an excellent concordance between them, with no significant differences between interviewers. The inter-rater reliability between the expert raters for the USP-SPS was high, with K=.92. The Pearson correlation coefficient between the SP severity scores given by the two raters was .89.Conclusion: Preliminary results suggest that the USP-SPS is a valid and reliable instrument for assessing the presence and severity of SP in OCD subjects.

ObjectivesStudying defensive styles is typically associated with dynamic theory and therapy. The present study was designed to examine the efficacy of adding two individual sessions of Motivational Interviewing (MI) and Thought Mapping (TM) to cognitive-behavioral group therapy (CBGT) to promote changes in the use of defense mechanisms among obsessive-compulsive disorder (OCD) patients.MethodsForty outpatients meeting OCD DSM-IV criteria were randomly assigned to either a MI+TM group or a control group, before 12 weekly CBGT sessions. To evaluate changes in defense mechanisms, the Defense Style Questionnaire (DSQ) was administered before and after treatment.ResultsThe use of the mature defense mechanisms increased in the MI+TM group at post-treatment, and there were significant differences in the decrease of use of the neurotic defense mechanisms. In addition, patients who achieved full remission differed in the use of the immature defense mechanisms. The control group presented no significant decrease in the use of any defense mechanisms.ConclusionsThese findings suggest that adding two individual sessions of MI and TM to CBGT can facilitate changes in use of defense mechanisms in OCD adult outpatients, as measured by a specific instrument.