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The experience of doubt, the lack of confidence in one's perceptions, internal states, memory and attention, can be due to the variability in occurrence of a phenomenon or can be driven by the internal experience of uncertainty based on subjective evaluation of the environment. Although the experience of some doubt is adaptive in normal cognitive functioning, excessive doubt can significantly impair decision-making and in extreme cases give rise to psychopathology. Although neuroimaging studies have provided some insight into the network of brain areas that is engaged when decision-making involves uncertainty, it remains unclear if dysfunction in these areas also gives rise to the experience and pathological expression of doubt. This study examined the neural correlates of doubt using neuroimaging during the performance of a forced-choice perceptual decision-making task under varying levels of uncertainty in participants who reported either low or high doubt. Participants reporting high doubt exhibited increased activation in the bilateral inferior parietal lobule (IPL) during perceptual decision-making which was not observed in participants who reported low doubt. Furthermore, activity in the IPL in high doubt participants was associated with clinical measures of doubt and showed functional connectivity differences between the high and low doubt groups. The findings of the current study suggest a key role of the IPL and provide a network of brain regions that may play a role in the experience and expression of doubt., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Prior research has shown that onset or exacerbation of OCD is associated with menstruation, pregnancy, and the post-partum period. However, the underlying cause is unclear. The goal of this study was to assess whether pregnancy and birth complications were associated with OCD symptoms exacerbation, among women with established OCD. Two-hundred and five (n=205) women with OCD retrospectively reported information on their physical and mental health during their first pregnancy. Over a third of the sample (34%) reported an exacerbation in their OCD symptoms. History of pregnancy and birth complications in the first pregnancy were similar between women who did and did not experience symptom exacerbation, with the exception of gestational diabetes, which was significantly more common among women who experienced exacerbation (7% vs 1%, p=0.03). In a multivariable logistic regression model, gestational diabetes remained significantly associated with exacerbation of OCD symptoms (OR=8.44 [95% CI 1.37-77.27]; p=0.03), even after adjusting for maternal age, OCD severity and treatment, premenstrual OCD symptom increase, stress during pregnancy, and major depression or anxiety disorder diagnosis during pregnancy. We discuss potential explanations for this link. These findings should be treated as hypothesis-generating and need to be replicated in a larger, prospective study., Competing Interests: Conflict of Interest Declarations of interest: none

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10 -7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data., (Published by Elsevier B.V.)

Obsessive-compulsive disorder (OCD) is a polygenic neuropsychiatric disorder characterized by repetitive thoughts and behaviors that cause distress. The pathogenic repeat expansion [GGGGCC] n found at the C9orf72 locus is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and has also been documented in patients with psychosis and schizophrenia. Furthermore, obsessions and compulsions have been identified in patients diagnosed with ALS and/or FTD and carrying the pathogenic repeat expansion. Here, we performed genetic screening for the C9orf72 repeat expansion on 573 patients diagnosed with OCD. None of the patients were found to carry the expansion. The results show that patients with OCD do not commonly carry the pathogenic repeat expansion and therefore should not be routinely screened. OCD and psychotic patients who do test positive for the C9orf72, however, should be closely observed for the later development of FTD and ALS., (Published by Elsevier B.V.)

Compared to studies in adults, there have been few studies of hoarding in children and adolescents with obsessive-compulsive disorder (OCD). In the current study, we evaluated OCD clinical features, Axis I disorders, and social reciprocity scores in 641 children and adolescents with OCD, of whom 163 (25%) had hoarding compulsions and 478 did not. We found that, as a group, youth with hoarding had an earlier age at onset and more severe lifetime OCD symptoms, poorer insight, more difficulty making decisions and completing tasks, and more overall impairment. The hoarding group also had a greater lifetime prevalence of panic disorder, specific phobia, Tourette disorder, and tics. As measured with the Social Reciprocity Scale, the hoarding group had more severe deficits in parent-rated domains of social communication, social motivation, and restricted interests and repetitive behavior. In a multivariable model, the overall social reciprocity score, age at onset of OCD symptoms, symmetry obsessions, and indecision were independently related to hoarding in these children and adolescents with OCD. These features should be considered as candidate risk factors for the development of hoarding behavior in pediatric OCD.

Objective: To determine the association between personality domains and 11-year cognitive decline in a sample from a population-based study., Method: Data from Waves 3 (1993-1996) and 4 (2003-2004) of the Baltimore cohort of the Epidemiologic Catchment Area (ECA) study were used for analyses. The sample included 561 adults (mean age ± SD: 45.2 ± 10.78 years) who completed the NEO Personality Inventory-Revised prior to Wave 4. Participants also completed the Mini-Mental State Examination (MMSE) and immediate and delayed word recall tests at Wave 3, and at Wave 4, 10.9 ± 0.6 years later., Results: In models adjusted for baseline cognitive performance, demographic characteristics, medical conditions, depressive symptoms, and psychotropic medication use, each 10-point increase in Neuroticism T-scores was associated with a 0.15-point decrease in MMSE scores (B = -0.15, 95% confidence interval [CI]: -0.30, -0.01), whereas each 10-point increase in Conscientiousness T-scores was associated with a 0.18-point increase on the MMSE (B = 0.18, 95% CI: 0.04, 0.32) and a 0.21-point increase in immediate recall (B = 0.21, 95% CI: 0.003, 0.41) between baseline and follow-up., Conclusion: Findings suggest that greater Neuroticism is associated with decline, and greater Conscientiousness is associated with improvement in performance on measures of general cognitive function and memory in adults. Further studies are needed to determine the extent to which personality traits in midlife are associated with clinically significant cognitive outcomes in older adults, such as mild cognitive impairment and dementia, and to identify potential mediators of the association between personality and cognitive trajectories., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date., Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios., Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%)., Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: Certain personality and behavioral traits (e.g., type A and type D) have been reported to be associated with development and progression of coronary heart disease (CHD), but few have examined the relationship using a comprehensive assessment of personality along with a structured assessment of psychiatric disorders., Methods: Based on participants (age: 47.3 ± 12.8; female: 62.6%) of the Baltimore Epidemiologic Catchment Area follow-up study, we examined the relationship between the 5 major domains of personality traits (neuroticism, extraversion, openness, agreeableness, and conscientiousness) and incident CHD between Wave III (1993-1996) and Wave IV (2004-2005)., Results: Incident CHD developed in 65 participants during the follow-up. Those with incident CHD had lower on openness (44.06 ± 9.29 vs. 47.18 ± 8.80; p = 0.007) and extraversion (45.98 ± 9.25 vs. 49.12 ± 8.92; p = 0.007) scores than those without. Logistic regression models revealed an inverse association (OR = 0.73; 95% CI = 0.54-0.98) between openness factor z-scores and incident CHD after adjusting for putative confounding factors, including DSM III-R Major Depressive Disorder., Conclusion: High openness appears to be an independent protective factor for incident CHD in the community. Future studies should examine behavioral and pathophysiologic mechanisms underlying this association., (Copyright © 2014 Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome., Methods: We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ., Results: We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10(-5); adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value .007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication., Conclusions: We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The aim of this study is to determine whether neurocognitive performance distinguishes individuals with compulsive hoarding (CH) from those with obsessive-compulsive disorder (OCD). Compared to control subjects, OCD patients and CHs scored significantly worse on the Serial Reaction Time Task suggesting disturbed implicit memory in both patient groups. On the Iowa Gambling Task, an overall learning progression difference over time was found between the CHs, OCD group, and control subjects, suggesting differences in decision-making between the groups. The groups did not differ in performance on the Stop Signal Reaction Time Task (motor inhibition). This study found evidence for impaired implicit memory in CHs, but also in OCD patients, albeit less severe. There was evidence that OCD patients learned more slowly on a decision-making task than CHs and control subjects. This latter finding provides some evidence to suggest that CH and OCD have, at least on this one measure, differing cognitive substrates., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Over the past several decades, the relationship between personality traits and heart disease has interested clinicians and researchers alike., Objective: The authors investigated personality disorders (PDs) and PD dimensional traits as prospective risk factors for incident cardiovascular disease (CVD) in the Baltimore Epidemiologic Catchment Area (ECA) follow-up study., Method: In 1981, 244 community residents were examined for DSM-III PDs, and PD dimensional traits and were followed for incident CVD by 2004., Results: Logistic-regression models with or without adjustment for potential confounders revealed that Cluster B PD and PD dimensional traits at baseline were consistently associated with increased risk of incident CVD by 2004. Post-hoc analysis also revealed that Cluster B PD and traits also predict CVD mortality., Conclusion: Cluster B PDs and dimensional traits may be independent risk factors for incident CVD in the community.

Purpose: We had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time., Methods: We genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods., Results: We saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B (GRIN2B), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study., Conclusions: Following up weaker signals can significantly improve linkage signals even after relatively small increases in information content. Our results on chromosome 12p support GRIN2B as a candidate gene for bipolar disorder that needs further investigation.

Background: Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions., Methods: Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales., Results: After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01)., Conclusions: Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD.

Background: Individuals with obsessive-compulsive disorder (OCD) frequently have other psychiatric disorders. This study employed latent class analysis (LCA) to explore whether there are underlying clinical constructs that distinguish "OCD-related" subgroups., Methods: The study included 450 subjects, case and control probands and their first-degree relatives, and LCA was used to derive empirically based subgroups of 10 disorders: OCD, obsessive-compulsive personality disorder (OCPD), recurrent major depressive disorder (RMDD), separation anxiety disorder, panic disorder or agoraphobia (PD/AG), tic disorders (TD), generalized anxiety disorder (GAD), somatoform disorders (hypochondriasis or body dysmorphic disorder), pathologic skin picking or nail biting (PSP/NB), and eating disorders (EDs). The derived classes were compared on several clinical variables., Results: The best fitting model is a four-class structure: minimal disorder, predominant RMDD and GAD, "highly comorbid," and PD/AG and TD. The nature and number of disorders represented suggests that the first classes are distributed ordinarily on a dimension of severity, and the fourth class is qualitatively distinct. Support for this structure is based on the number of disorders, age at onset of OCD, neuroticism, and extraversion., Conclusions: In this OCD enriched sample, LCA identified four classes of disorder. These classes appear to conform to two subgroups that may prove useful in investigating the etiology of OCD.

Background: Obsessive-compulsive disorder (OCD) and tic disorders have phenomenological and familial-genetic overlaps. An OCD family study sample that excludes Tourette's syndrome in probands is used to examine whether tic disorders are part of the familial phenotype of OCD., Methods: Eighty case and 73 control probands and their first-degree relatives were examined by experienced clinicians using the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety version. DSM-IV psychiatric diagnoses were ascertained by a best-estimate consensus procedure. The prevalence and severity of tic disorders, age-at-onset of OCD symptoms, and transmission of OCD and tic disorders by characteristics and type of proband (OCD + tic disorder, OCD - tic disorder) were examined in relatives., Results: Case probands and case relatives had a greater lifetime prevalence of tic disorders compared to control subjects. Tic disorders spanning a wide severity range were seen in case relatives; only mild severity was seen in control relatives. Younger age-at-onset of OCD symptoms and possibly male gender in case probands were associated with increased tic disorders in relatives. Although relatives of OCD + tic disorder and OCD - tic disorder probands had similar prevalences of tic disorders, this result is not conclusive., Conclusions: Tic disorders constitute an alternate expression of the familial OCD phenotype.

Background: The familial relationship between obsessive-compulsive disorder (OCD) and "obsessive-compulsive spectrum" disorders is unclear. This study investigates the relationship of OCD to somatoform disorders (body dysmorphic disorder [BDD] and hypochondriasis), eating disorders (e.g., anorexia nervosa and bulimia nervosa), pathologic "grooming" conditions (e.g., nail biting, skin picking, trichotillomania), and other impulse control disorders (e.g., kleptomania, pathologic gambling, pyromania) using blinded family study methodology., Methods: Eighty case and 73 control probands, as well as 343 case and 300 control first-degree relatives, were examined by psychiatrists or Ph.D. psychologists using the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety version. Two experienced psychiatrists independently reviewed all diagnostic information and made final consensus diagnoses using DSM-IV criteria., Results: Body dysmorphic disorder, hypochondriasis, any eating disorder, and any grooming condition occurred more frequently in case probands. In addition, BDD, either somatoform disorder, and any grooming condition occurred more frequently in case relatives, whether or not case probands also had the same diagnosis., Conclusions: These findings indicate that certain somatoform and pathologic grooming conditions are part of the familial OCD spectrum. Though other "spectrum" conditions may resemble OCD, they do not appear to be important parts of the familial spectrum.

Background: Deletions of 1.5-2 MB of chromosome 22q11 have been previously associated with schizophrenia. The deleted region includes proximally the region harboring genes involved in DiGeorge and velocardiofacial syndromes. Distally, it includes the gene for catechol-O-methyl-transferase (COMT), an enzyme that catalyzes the O-methylation of catecholamine neurotransmitters, including dopamine, and which therefore is considered a candidate gene for schizophrenia., Methods: We address the issue of a direct involvement of the COMT gene in the development of schizophrenia by employing the first extensive mutational analysis of this gene in a sample of 157 schizophrenia patients and 129 healthy controls, using single-strand conformation polymorphism and chemical cleavage methodologies., Results: No mutations were found, but several sequence variants were identified, including the genetic polymorphism that underlies the high/low activity of the enzyme (a Val158-->Met change, which results in the creation of an NlaIII restriction site in the low-activity allele). The distribution of the NlaIII genotypes among subsets of schizophrenia patients was analyzed., Conclusions: The results presented here argue against a major role of COMT in schizophrenia in general (although a minor effect could not be excluded) and represent a first step toward a more refined delineation of the phenotype/genotype relationship between 22q11 microdeletions and schizophrenia susceptibility.

Five, healthy, adult, male research volunteers participated in up to four daily laboratory sessions while residing on a Clinical Research Unit. Two subjects were tested twice. Fifty milligrams of cocaine base was smoked one, two or four times each session with a 14-min interval between doses. Two subjects smoked cocaine placed in 'smoke-free' cigarettes, while the remaining subjects smoked cocaine placed in a modified tobacco pipe. Significant and biologically relevant cocaine venous blood levels were engendered most consistently using the modified tobacco pipe. Large, transient increases in heart rate, blood pressure and self-reported 'stimulated' scores were observed during single dosing sessions. During multiple dose sessions, cardiovascular activity either increased, returning to near baseline levels between doses, or were sustained, while reported 'stimulated' scores peaked after the first dose and were lower following subsequent doses. Both cardiovascular and subjective effects were greater on the ascending limb than on the descending limb of the cocaine blood level curve suggesting acute tolerance. Although preliminary, these results demonstrate the usefulness of this relatively simple procedure requiring subjects to smoke in the manner they are accustomed, and suggest the importance of further research in this area.