Neurocircuit models of obsessive-compulsive disorder: limitations and future directions for research

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

Factor structure of the Dimensional Yale-Brown Obsessive-Compulsive Scale in a large sample of adults with obsessive-compulsive disorder

Objectives: Although the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a widely used instrument for assessing different obsessive-compulsive symptom dimensions, its factor structure has never been studied in a Brazilian population. Thus, we aimed to assess the goodness-of-fit indexes and factor loadings of two higher-order models of the DY-BOCS using confirmatory factor analysis (CFA) in a large obsessive-compulsive disorder (OCD) sample. Methods: We tested two CFA models in a sample of 955 adults with OCD who had been assessed with the DY-BOCS in a cross-sectional multi-site study. The first model encompassed the symptom checklist (present or absent), whereas the second focused on items related to severity scores. Results: Both models presented adequate goodness-of-fit indexes. The comparative fit index, Tucker-Lewis index, and omega were > 0.9, while the root mean square error of approximation was ≤ 0.06 for both models. Factor loadings for each item of each dimension are presented and discussed. Conclusion: Higher-order factor models showed adequate goodness-of-fit indexes, indicating that they appropriately measured OCD dimensions in this Brazilian population.

Predictors of gaming disorder in children and adolescents: a school-based study

Objective: To determine whether psychiatric and gaming pattern variables are associated with gaming disorder in a school-based sample. Methods: We analyzed data from the Brazilian High-Risk Cohort for Psychiatric Disorders, a community sample aged 10 to 18, using questionnaires on gaming use patterns. We applied the Gaming Addiction Scale to diagnose gaming disorder and the Development and Well-Being Behavior Assessment for other diagnoses. Results: Out of 407 subjects, 83 (20.4%) fulfilled the criteria for gaming disorder. More role-playing game players were diagnosed with gaming disorder that any other genre. Gaming disorder rates increased proportionally to the number of genres played. Playing online, being diagnosed with a mental disorder, and more hours of non-stop gaming were associated with higher rates of gaming disorder. When all variables (including age and gender) were considered in a logistic regression model, the number of genres played, the number of non-stop hours, the proportion of online games, and having a diagnosed mental disorder emerged as significant predictors of gaming disorder. Conclusion: Each variable seems to add further risk of gaming disorder among children and adolescents. Monitoring the length of gaming sessions, the number and type of genres played, time spent gaming online, and behavior changes may help parents or guardians identify unhealthy patterns of gaming behavior.

Population neuroscience: challenges and opportunities for psychiatric research in low- and middle-income countries

Objective: Population neuroscience is an emerging field that combines epidemiology and neuroscience to study how genes and the environment shape typical and atypical brain functioning. The objective of this study was to review key studies on population neuroscience from low- and middle-income countries (LMICs) and to identify potential gaps vis-à-vis studies conducted in high-income countries. Methods: We conducted a systematic review to search for longitudinal cohort studies investigating the development of psychiatric disorders in children and adolescents in LMICs. We performed an electronic search in the EMBASE and MEDLINE databases from inception to July 5th, 2019. Results: We found six cohorts from four countries that met our search criteria: three cohorts from Brazil, one from China, one from South Africa, and one from Mauritius. Relevant examples of findings from these studies are reported. Conclusion: Our results demonstrate the impact of the valuable science output these cohort designs promote, allowing LMICs to have a share in frontline global psychiatry research. National and international funding agencies should invest in LMIC population neuroscience in order to promote replication and generalization of research from high-income countries.

Pharmacological and behavioral treatment for trichotillomania: An updated systematic review with meta-analysis.

BACKGROUND: Trichotillomania (TTM) is a difficult-to-treat psychiatric condition with no first-line medications approved by the Food and Drug Administration. Individuals with TTM often feel that clinicians know little about this disorder. Here, we present an updated meta-analysis of randomized controlled trials (RCTs) examining treatments for TTM. METHODS: Pubmed, PsychINFO, Embase, and CENTRAL were searched with the terms "Trichotillomania OR Hair Pulling Disorder" to identify randomized controlled clinical trials evaluating treatments for TTM. RESULTS: Twenty-four trials involving 26 comparisons and 857 participants were included in this meta-analysis. Behavioral therapy with habit-reversal training components (BT-HRT) demonstrated a large benefit compared to control conditions (standardized mean difference [SMD] [95% CI] = -1.22 [-1.71, -0.73], p < .0001) for improving TTM symptoms. Clomipramine (SMD [95% CI] = -0.71 [-1.38, -0.05], p = .036), N-acetylcysteine (SMD [95% CI] = -0.75 [-1.36, -0.13], p = .017) and olanzapine (SMD [95% CI] = -0.94 [-1.77, -0.12], p = .025) demonstrated significant benefits compared to placebo in RCTs. CONCLUSIONS: BT-HRT has demonstrated the largest treatment effects and has the strongest evidence base for reducing TTM symptoms. In contrast, several pharmacological agents have demonstrated efficacy in single randomized clinical trials that would benefit from replication. Additional trials are needed to identify other effective medications for TTM and determine the relative efficacy of available agents.

Theoretical models of Obsessive-Compulsive Disorder (OCD): a perspective on future approaches

Obsessive-Compulsive disorder (OCD) is a common psychiatric condition that leads to significant impairment in everyday life. Advancements in neurobiological investigations contributed to a better understanding of pathophysiological mechanisms behind OCD, leading to the understanding that current models employed to conceptualize OCD are not adequate and might be a significant factor in precluding further advancements in how OCD is treated. In this paper, we will use OCD as a model to discuss the limitations of the current diagnostic systems in Psychiatry and to present the novel perspectives based on neurobiological findings that might lead to considerable advancements in treatments for OCD.

No evidence of attentional bias toward angry faces in patients with obsessive-compulsive disorder

Objective: Although attentional bias (AB) toward angry faces is well established in patients with anxiety disorders, it is still poorly studied in obsessive-compulsive disorder (OCD). We investigated whether OCD patients present AB toward angry faces, whether AB is related to symptom severity and whether AB scores are associated with specific OCD symptom dimensions. Method: Forty-eight OCD patients were assessed in clinical evaluations, intelligence testing and a dot-probe AB paradigm that used neutral and angry faces as stimuli. Analyses were performed with a one-sample t-test, Pearson correlations and linear regression. Results: No evidence of AB was observed in OCD patients, nor was there any association between AB and symptom severity or dimension. Psychiatric comorbidity did not affect our results. Conclusion: In accordance with previous studies, we were unable to detect AB in OCD patients. To investigate whether OCD patients have different brain activation patterns from anxiety disorder patients, future studies using a transdiagnostic approach should evaluate AB in OCD and anxiety disorder patients as they perform AB tasks under functional neuroimaging protocols.

Treatments used for obsessive-compulsive disorder-An international perspective.

OBJECTIVE: The objective of this study was to characterise international trends in the use of psychotropic medication, psychological therapies, and novel therapies used to treat obsessive-compulsive disorder (OCD). METHODS: Researchers in the field of OCD were invited to contribute summary statistics on the characteristics of their samples. Consistency of summary statistics across countries was evaluated. RESULTS: The study surveyed 19 expert centres from 15 countries (Argentina, Australia, Brazil, China, Germany, Greece, India, Italy, Japan, Mexico, Portugal, South Africa, Spain, the United Kingdom, and the United States) providing a total sample of 7,340 participants. Fluoxetine (n = 972; 13.2%) and fluvoxamine (n = 913; 12.4%) were the most commonly used selective serotonin reuptake inhibitor medications. Risperidone (n = 428; 7.3%) and aripiprazole (n = 415; 7.1%) were the most commonly used antipsychotic agents. Neurostimulation techniques such as transcranial magnetic stimulation, deep brain stimulation, gamma knife surgery, and psychosurgery were used in less than 1% of the sample. There was significant variation in the use and accessibility of exposure and response prevention for OCD. CONCLUSIONS: The variation between countries in treatments used for OCD needs further evaluation. Exposure and response prevention is not used as frequently as guidelines suggest and appears difficult to access in most countries. Updated treatment guidelines are recommended.

Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder.

For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions. It was against this backdrop that gamma knife capsulotomy (GKC) for OCD was developed. In this paper, we review the history of this stereotactic radiosurgical procedure, from its inception to recent advances. We perform a systematic review of the existing literature and also provide a narrative account of the evolution of the procedure, detailing how the procedure has changed over time, and has been shaped by forces of evidence and innovation. As the procedure has evolved and adverse events have decreased considerably, favorable response rates have remained attainable for approximately one-half to two-thirds of individuals treated at experienced centers. A reduction in obsessive-compulsive symptom severity may result not only from direct modulation of OCD neural pathways but also from enhanced efficacy of pharmacological and psychological therapies working in a synergistic fashion with GKC. Possible complications include frontal lobe edema and even the rare formation of delayed radionecrotic cysts. These adverse events have become much less common with new radiation dose and targeting strategies. Detailed neuropsychological assessments from recent studies suggest that cognitive function is not impaired, and in some domains may even improve following treatment. We conclude this review with discussions covering topics essential for further progress of this therapy, including suggestions for future trial design given the unique features of GKC therapy, considerations for optimizing stereotactic targeting and dose planning using biophysical models, and the use of advanced imaging techniques to understand circuitry and predict response. GKC, and in particular its modern variant, gamma ventral capsulotomy, continues to be a reliable treatment option for selected cases of otherwise highly refractory OCD.

Obsessive-Compulsive Personality Symptoms Predict Poorer Response to Gamma Ventral Capsulotomy for Intractable OCD.

Gamma ventral capsulotomy (GVC) is a radiosurgical procedure which aims to create lesions in the ventral part of the anterior limb of the internal capsule (ALIC). It has been used as a treatment option for patients with intractable obsessive-compulsive disorder (OCD) who do not respond to several first-line treatments attempts. However, changes in personality disorder symptoms after GVC have not been investigated. The aims of this study are to investigate changes in personality disorder symptoms after GVC and to search for baseline personality disorder symptoms that may predict clinical response to GVC. Fourteen treatment-intractable OCD patients who underwent GVC completed the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) at baseline and one year after the procedure. Wilcoxon signed-rank test was performed to investigate personality disorder symptom changes before and after surgery. Linear regression models were utilized to predict treatment response, using baseline personality disorder symptoms as independent variables. We did not observe any quantitative changes in personality disorder symptoms after GVC, compared with baseline. Higher severity of obsessive-compulsive personality disorder symptoms at baseline was correlated with worse treatment response after GVC for OCD (ß = -0.085, t-value = -2.52, p-value = 0.027). These findings advocate for the safety of the GVC procedure in this specific population of intractable OCD patients, in terms of personality disorder symptom changes. They also highlight the importance of taking into account the severity of obsessive-compulsive personality disorder symptoms when GVC is indicated for intractable OCD patients.

Obsessive-compulsive symptoms in children with first degree relatives diagnosed with obsessive-compulsive disorder

Objective: A first-degree relative affected by obsessive-compulsive disorder (OCD) and obsessive-compulsive symptoms (OCS) in childhood is an important risk factor for developing the disorder in adulthood. The relationship between a family history of OCD and the presence of OCS and its correlates in childhood is not well established. Methods: A total of 66 children whose parents or siblings have been diagnosed with OCD were assessed for the presence of OCS and clinical correlates. Results: Three children (4.5%) were reported to have received an OCD diagnosis and another 26 (39.4%) were identified as having OCS. Children with OCS had higher rates of coercive behavior and came from families with lower socioeconomic status. Contamination/cleaning dimension symptoms in the proband were associated with OCS in the assessed children. Conclusion: OCS are frequent among family members of individuals with OCD and are associated with socioeconomic status, coercive behaviors and proband contamination/cleaning symptoms. Future longitudinal studies should test the risk of developing OCD in association with these characteristics.

Prevalence, clinical correlates and maternal psychopathology of deliberate self-harm in children and early adolescents: results from a large community study

Objectives: Little is known about the prevalence and correlates of deliberate self-harm (DSH) in children from low- and middle-income countries. We investigated the prevalence of DSH and its clinical and maternal psychopathological associations in Brazilian children (n=2,508, ages 6-14y) in a community-based study. Methods: Participants of the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders (HRC) and their mothers were assessed in structured interviews. Current (last month) and lifetime DSH were estimated, including analysis stratified by age groups. Logistic regressions were performed to investigate the role of the children's clinical diagnoses and maternal psychopathology on DSH prevalence estimates, adjusting for potential confounding factors. Results: The prevalence of current DSH was 0.8% (children 0.6%, adolescents 1%) and lifetime DSH was 1.6% (1.8% and 1.5%, respectively). Current and lifetime DSH were more frequent in children with depression, attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), even in multiple models accounting for demographic variables and co-occurring psychiatric disorders. Maternal anxiety disorder was strongly associated with current and lifetime DSH in offspring; whereas current DSH, specifically in young children, was associated with maternal mood disorder. Conclusion: Diagnoses of depression, ADHD and ODD were consistently associated with DSH, as was having a mother with anxiety disorder.

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 Cloninger's 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.

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.

Specific and social fears in children and adolescents: separating normative fears from problem indicators and phobias

Objective: To distinguish normative fears from problematic fears and phobias. Methods: We investigated 2,512 children and adolescents from a large community school-based study, the High Risk Study for Psychiatric Disorders. Parent reports of 18 fears and psychiatric diagnosis were investigated. We used two analytical approaches: confirmatory factor analysis (CFA)/item response theory (IRT) and nonparametric receiver operating characteristic (ROC) curve. Results: According to IRT and ROC analyses, social fears are more likely to indicate problems and phobias than specific fears. Most specific fears were normative when mild; all specific fears indicate problems when pervasive. In addition, the situational fear of toilets and people who look unusual were highly indicative of specific phobia. Among social fears, those not restricted to performance and fear of writing in front of others indicate problems when mild. All social fears indicate problems and are highly indicative of social phobia when pervasive. Conclusion: These preliminary findings provide guidance for clinicians and researchers to determine the boundaries that separate normative fears from problem indicators in children and adolescents, and indicate a differential severity threshold for specific and social fears.

Socioeconomic Disadvantage Moderates the Association between Peripheral Biomarkers and Childhood Psychopathology.

BACKGROUND: Socioeconomic disadvantage (SED) has been consistently associated with early life mental health problems. SED has been shown to impact multiple biological systems, including the regulation of neurotrophic proteins, immune-inflammatory and oxidative stress markers, which, conversely, have been reported to be relevant to physiological and pathological neurodevelopment This study investigated the relationship between SED, different domains of psychopathology, serum levels of interleukin-6 (IL6), thiobarbituric acid-reactive substance (TBARS) and brain-derived neurotrophic factor (BDNF). We hypothesized that a composite of socioeconomic risk would be associated with psychopathology and altered levels of peripheral biomarkers. In addition, we hypothesized that SED would moderate the associations between mental health problems, IL6, TBARS and BDNF. METHODS AND FINDINGS: Using a cross-sectional design, we measured the serum levels of IL6, TBARS and BDNF in 495 children aged 6 to 12. We also investigated socio-demographic characteristics and mental health problems using the Child Behaviour Checklist (CBCL) DSM-oriented scales. SED was evaluated using a cumulative risk model. Generalized linear models were used to assess associations between SED, biomarkers levels and psychopathology. SED was significantly associated with serum levels of IL6 (RR = 1.026, 95% CI 1.004; 1.049, p = 0.020) and TBARS (RR = 1.077, 95% CI 1.028; 1.127, p = 0.002). The association between SED and BDNF was not statistically significant (RR = 1.031, 95% CI 0.997; 1.066, p = 0.077). SED was also significantly associated with all CBCL DSM-oriented scales (all p < 0.05), whereas serum biomarkers (i.e. IL6, TBARS, BDNF) were associated with specific subscales. Moreover, the associations between serum biomarkers and domains of psychopathology were moderated by SED, with stronger correlations between mental health problems, IL6, TBARS, and BDNF being observed in children with high SED. CONCLUSIONS: In children, SED is highly associated with mental health problems. Our findings suggest that this association may be moderated via effects on multiple interacting neurobiological systems.

Association of serum interleukin-6 with mental health problems in children exposed to perinatal complications and social disadvantage.

There is consistent evidence that inflammation is involved in mental disorders pathogenesis. Herein, using data from the High Risk Cohort Study for Psychiatric Disorders, we investigated the relationship between parental mood disorders (PMD), environmental factors, serum interleukin-6 (IL6) and mental health problems in children aged 6-12. We measured the serum levels of IL6 in 567 children. Information related to socio-demographic characteristics, mental health problems and multiple risk factors, as well as parent's psychiatric diagnosis, was captured. We evaluated two groups of environmental risk factors (i.e. perinatal complications and social disadvantage) using a cumulative risk model. Results showed that higher serum levels of IL6 were associated with PMD (RR=1.072, p=0.001), perinatal complications (RR=1.022, p=0.013) and social disadvantage (RR=1.024, p=0.021). There was an interaction between PMD and social disadvantage (RR=1.141, p=0.021), as the effect of PMD on IL6 was significantly higher in children exposed to higher levels of social disadvantage. Moreover, there was a positive correlation between IL6 and mental health problems (RR=1.099, p=0.026), which was moderated by exposure to perinatal complications or social disadvantage (RR=1.273, p=0.015 and RR=1.179, p=0.048, respectively). In conclusions, there is evidence of a differential inflammatory activation in children with PMD and exposure to environmental risk factors, when compared to matched peers. Systemic inflammation may be involved in the pathway linking familial risk and mental health problems.

Visuospatial Memory Improvement after Gamma Ventral Capsulotomy in Treatment Refractory Obsessive-Compulsive Disorder Patients.

Gamma ventral capsulotomy (GVC) radiosurgery is intended to minimize side effects while maintaining the efficacy of traditional thermocoagulation techniques for the treatment of refractory obsessive-compulsive disorder (OCD). Neuropsychological outcomes are not clear based on previous studies and, therefore, we investigated the effects of GVC on cognitive and motor performance. A double-blind, randomized controlled trial (RCT) was conducted with 16 refractory OCD patients allocated to active treatment (n=8) and sham (n=8) groups. A comprehensive neuropsychological evaluation including intellectual functioning, attention, verbal and visuospatial learning and memory, visuospatial perception, inhibitory control, cognitive flexibility, and motor functioning was applied at baseline and one year after the procedure. Secondary analysis included all operated patients: eight from the active group, four from the sham group who were submitted to surgery after blind was broken, and five patients from a previous open pilot study (n=5), totaling 17 patients. In the RCT, visuospatial memory (VSM) performance significantly improved in the active group after GVC (p=0.008), and remained stable in the sham group. Considering all patients operated, there was no decline in cognitive or motor functioning after one year of follow-up. Our initial results after 1 year of follow-up suggests that GVC not only is a safe procedure in terms of neuropsychological functioning but in fact may actually improve certain neuropsychological domains, particularly VSM performance, in treatment refractory OCD patients.