Inference-Based Cognitive Behavioral Therapy versus Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder: A Multisite Randomized Controlled Non-Inferiority Trial.

INTRODUCTION: Although cognitive behavioral therapy (CBT) effectively treats obsessive-compulsive disorder (OCD), many patients refuse CBT or drop out prematurely, partly because of anxiety regarding exposure and response prevention (ERP) exercises. Inference-based cognitive behavioral therapy (I-CBT) focuses on correcting distorted inferential thinking patterns, enhancing reality-based reasoning, and addressing obsessional doubt by targeting underlying dysfunctional reasoning, without incorporating an ERP component. We hypothesized that I-CBT would be non-inferior to CBT. Additionally, we hypothesized that I-CBT would be more tolerable than CBT. METHODS: 197 participants were randomly assigned to 20 sessions CBT or I-CBT and assessed at baseline, posttreatment, and 6 and 12 months' follow-up. The primary outcome was OCD symptom severity measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; non-inferiority margin: 2 points). The secondary outcome, treatment tolerability, was assessed using the Treatment Acceptability/Adherence Scale (TAAS). A linear mixed-effects model was used to assess the non-inferiority of the primary outcome and superiority of secondary outcomes. RESULTS: Statistically significant within-group improvements in the primary and secondary outcomes were observed in both treatments. No statistically significant between-group differences in Y-BOCS were found at any assessment point, but the confidence intervals exceeded the non-inferiority threshold, making the results inconclusive. The estimated mean posttreatment TAAS score was significantly higher in the I-CBT group than in the CBT group. CONCLUSION: While both CBT and I-CBT are effective for OCD, whether I-CBT is non-inferior to CBT in terms of OCD symptom severity remains inconclusive. Nevertheless, I-CBT offers better tolerability and warrants consideration as an alternative treatment for OCD.

Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study.

BACKGROUND: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. METHODS: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. RESULTS: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. CONCLUSIONS: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

European clinical guidelines for Tourette syndrome and other tic disorders: summary statement.

In 2011 a working group of the European Society for the Study of Tourette syndrome (ESSTS) developed the first European Guidelines for Tourette syndrome (TS) published in the ECAP journal. After a decade ESSTS now presents updated guidelines, divided into four sections: Part I: assessment, Part II: psychological interventions, Part III: pharmacological treatment and Part IV: deep brain stimulation (DBS). In this paper, we summarise new developments described in the guidelines with respect to assessment and treatment of tics. Further, summary findings from a recent survey conducted amongst TS experts on these same topics are presented, as well as the first European patient representative statement on research. Finally, an updated decision tree is introduced providing a practical algorithm for the treatment of patients with TS. Interestingly, in the last decade there has been a significant shift in assessment and treatment of tics, with more emphasis on non-pharmacological treatments.

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment.

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive Remediation Therapy Does Not Enhance Treatment Effect in Obsessive-Compulsive Disorder and Anorexia Nervosa: A Randomized Controlled Trial.

BACKGROUND: Guideline-recommended therapies are moderately successful in the treatment of obsessive-compulsive disorder (OCD) and anorexia nervosa (AN), leaving room for improvement. Cognitive inflexibility, a common trait in both disorders, is likely to prevent patients from engaging in treatment and from fully benefiting from existing therapies. Cognitive remediation therapy (CRT) is a practical augmentation intervention aimed at ameliorating this impairing cognitive style prior to disorder-specific therapy. OBJECTIVE: To compare the effectiveness of CRT and a control treatment that was not aimed at enhancing flexibility, named specialized attention therapy (SAT), as add-ons to treatment as usual (TAU). METHODS: In a randomized controlled multicenter clinical trial, 71 adult patients with OCD and 61 with AN were randomized to ten twice-weekly sessions with either CRT or SAT, followed by TAU. Patients were evaluated at baseline, post-CRT/SAT, and after 6 and 12 months, with outcomes being quantified using the Yale-Brown Obsessive Compulsive Scale for OCD and the Eating Disorder Examination Questionnaire for AN. RESULTS: Across study groups, most importantly CRT+TAU was not superior to control treatment (SAT)+TAU in reducing OCD and AN pathology. Contrary to expectations, SAT+TAU may have been more effective than CRT+TAU in patients being treated for OCD. CONCLUSIONS: CRT did not enhance the effect of TAU for OCD and AN more than SAT. Unexpectedly, SAT, the control condition, may have had an augmentation effect on TAU in OCD patients. Although this latter finding may have been due to chance, the effect of SAT delivered as a pretreatment add-on intervention for adults with OCD and AN merits future efforts at replication.

Botulinum neurotoxin treatment in jerky and tremulous functional movement disorders: a double-blind, randomised placebo-controlled trial with an open-label extension.

OBJECTIVE: To study the effect of botulinum neurotoxin (BoNT) treatment in jerky and tremulous functional movement disorders (FMD). METHODS: Patients with invalidating, chronic (>1 year) symptoms were randomly assigned to two subsequent treatments with BoNT or placebo every 3 months with stratification according to symptom localisation. Improvement on the dichotomised Clinical Global Impression-Improvement scale (CGI-I) (improvement vs no change or worsening) at 4 months, assessed by investigators blinded to the allocated treatment was the primary outcome. Subsequently all patients were treated with BoNT in a ten month open-label phase. RESULTS: Between January 2011 and February 2015 a total of 239 patients were screened for eligibility of whom 48 patients were included. No difference was found on the primary outcome (BoNT 16 of 25 (64.0%) vs Placebo 13 of 23 patients (56.5%); proportional difference 0.075 (95% CI -0.189 to 0.327; p=0.77). Secondary outcomes (symptom severity, disease burden, disability, quality of life and psychiatric symptoms) showed no between-group differences. The open-label phase showed improvement on the CGI-I in 19/43 (44.2%) of remaining patients, with a total of 35/43 (81.4%) improvement compared with baseline. CONCLUSIONS: In this double-blind randomised controlled trial of BoNT for chronic jerky and tremulous FMD, we found no evidence of improved outcomes compared with placebo. Motor symptoms improved in a large proportion in both groups which was sustained in the open-label phase. This study underlines the substantial potential of chronic jerky and tremulous FMD patients to recover and may stimulate further exploration of placebo-therapies in these patients. TRIAL REGISTRATION NUMBER: NTR2478.

Effects of comorbidity on Tourette's tic severity and quality of life.

OBJECTIVE: The aim of this study is to gain more insight in the differential contributions of anxiety, depression and obsessive-compulsive (OC) symptom severity to quality of life (QoL) and tic severity in adults with Tourette Disorder (TD). METHODS: Self-reported OC symptom, anxiety and depression severity measures were used to investigate their predictive value on QoL and Tic severity in adult TD patients (N = 187), using correlation, regression, and mediation analyses. RESULTS: Tic severity has no effect on QoL. Depression severity directly reduces QoL, whereas anxiety and OC symptom severity have an indirect effect on QoL, mediated by depression severity. OC symptom severity directly affects tic severity, whereas depression and anxiety severity do not have a direct effect on tic or OC severity. Finally, anxiety severity indirectly impacts tic severity, with OC symptom severity functioning as a mediator. CONCLUSION: In line with and extending previous studies, these findings indicate that OC symptom severity directly influences tic symptom severity whereas depression severity directly influences QoL in TD. Results imply that to improve QoL in TD patients, treatment should primarily focus on diminishing OC and depressive symptom severity rather than focusing on tic reduction.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial.

BACKGROUND: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. METHODS/DESIGN: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. DISCUSSION: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. TRIAL REGISTRATION: Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.

Design and methods of the 'monitoring outcomes of psychiatric pharmacotherapy' (MOPHAR) monitoring program - a study protocol.

BACKGROUND: At many outpatient departments for psychiatry worldwide, standardized monitoring of the safety of prescribed psychotropic drugs is not routinely performed in daily clinical practice. Therefore it is unclear to which extent the drugs used by psychiatric outpatients are prescribed effectively and safely. These issues warrant structured monitoring of medication use, (pre-existing) co-morbidities, effectiveness and side effects during psychiatric outpatient treatment. Improvement of monitoring practices provides an opportunity to ensure that somatic complications and adverse drug effects are detected and dealt with in a timely manner. Structural support for data collection and follow-up tests seems essential for improvement of monitoring practices in psychiatric outpatients. The implementation of a structured somatic monitoring program as part of routine clinical practice, as we describe in this study protocol, may be a solution. METHODS: In order to address these issues, we developed the innovative program 'Monitoring Outcomes of Psychiatric Pharmacotherapy (MOPHAR)'. MOPHAR is an infrastructure for implementation of standardized routine outcome monitoring (ROM; including standardized monitoring of treatment effect), monitoring of adverse psychotropic medication effects in psychiatric outpatients, encompassing both somatic adverse effects (e.g. metabolic disturbances) and subjective adverse effects (e.g. sedation or sexual side effects) and medication reconciliation. DISCUSSION: In the MOPHAR monitoring program, a nurse performs general and psychotropic drug-specific somatic screenings and provides the treating mental health care providers with more and better information on somatic monitoring for treatment decisions. Given our experience regarding implementation of the MOPHAR program, we expect that the MOPHAR program is feasible and beneficial for patients in any MHS organisation. This paper describes the objectives, target population, setting and the composition and roles of the treatment team. It also indicates what measurements are performed at which time points during outpatient treatment in the MOPHAR monitoring program, as well as the research aspects of this project. TRIAL REGISTRATION: MOPHAR research has been prospectively registered with the Netherlands Trial Register on 19th of November 2014. ( NL4779 ).

Presence and Predictive Value of Obsessive-Compulsive Symptoms in Anxiety and Depressive Disorders.

OBJECTIVE: Obsessive-compulsive symptoms (OCS) co-occur frequently with anxiety and depressive disorders, but the nature of their relationship and their impact on severity of anxiety and depressive disorders is poorly understood. In a large sample of patients with anxiety and depressive disorders, we assessed the frequency of OCS, defined as a Young Adult Self-Report Scale-obsessive-compulsive symptoms score >7. The associations between OCS and severity of anxiety and/or depressive disorders were examined, and it was investigated whether OCS predict onset, relapse, and persistence of anxiety and depressive disorders. METHODS: Data were obtained from the third (at 2-year follow-up) and fourth wave (at 4-year follow-up) of data collection in the Netherlands Study of Anxiety and Depression cohort, including 469 healthy controls, 909 participants with a remitted disorder, and 747 participants with a current anxiety and/or depressive disorder. RESULTS: OCS were present in 23.6% of the total sample, most notably in those with current combined anxiety and depressive disorders. In patients with a current disorder, OCS were associated with severity of this disorder. Moreover, OCS predicted (1) first onset of anxiety and/or depressive disorders in healthy controls (odds ratio [OR], 5.79; 95% confidence interval [CI], 1.15 to 29.14), (2) relapse in those with remitted anxiety and/or depressive disorders (OR, 2.31; 95% CI, 1.55 to 3.46), and (3) persistence in patients with the combination of current anxiety and depressive disorders (OR, 4.42; 95% CI, 2.54 to 7.70) within the 2-year follow-up period Conclusions: OCS are closely related to both the presence and severity of anxiety and depressive disorders and affect their course trajectories. Hence, OCS might be regarded as a course specifier signaling unfavorable outcomes. This specifier may be useful in clinical care to adapt and intensify treatment in individual patients.

No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia: A Double-Blind, Randomized Controlled Trial.

PURPOSE/BACKGROUND: D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the effectiveness of adding 125 mg of DCS to exposure therapy (before or directly after the first 6 treatment sessions) in patients with panic disorder with agoraphobia and (2) the effectiveness of DCS augmentation preceding exposure relative to DCS augmentation directly postexposure. METHODS/PROCEDURES: Fifty-seven patients were allocated to 1 of 3 medication conditions (placebo and pre-exposure and postexposure DCS) as an addition to 6 exposure sessions within a 12-session exposure and response prevention protocol. The primary outcome measure was the mean score on the "alone" subscale of the Mobility Inventory (MI). FINDINGS/RESULTS: No differences were found in treatment outcome between DCS and placebo, administered either pre-exposure or postexposure therapy, although at 3-month follow-up, the DCS postexposure group compared with DCS pre-exposure, exhibited greater symptom reduction on the MI-alone subscale. Ancillary analyses in specific subgroups (responders vs nonresponders, early vs late responders, severely vs mildly affected patients) did not reveal any between-group DCS versus placebo differences. Finally, the study did not find an effect of DCS relative to placebo to be specific for successful exposure sessions. IMPLICATIONS/CONCLUSIONS: This study does not find an effect of augmentation with DCS in patients with severe panic disorder and agoraphobia administered either pretreatment or directly posttreatment sessions. Moreover, no preferential effects are revealed in specific subgroups nor in successful exposure sessions. Yet, a small effect of DCS administration postexposure therapy cannot be ruled out, given the relatively small sample size of this study.

Age-Specific Prevalence of Hoarding and Obsessive Compulsive Disorder: A Population-Based Study.

OBJECTIVE: Little is known about the age-specific prevalence of hoarding and obsessive compulsive symptoms (OCS), particularly in older age groups. The objectives of this study were to estimate the age-specific prevalence, severity, and relationships between hoarding and OCS in males and females using a large population-based sample. METHODS: We assessed the age-specific prevalence rates of hoarding disorder (HD) and OC disorder (OCD) in males and females (at various age ranges between 15 and 97 years) from the Netherlands Twins Register (N = 15,194). Provisional HD and OCD diagnoses were made according to Diagnostic and Statistical Manual of Mental Health Disorders, 5th Edition, criteria using self-report measures. We also assessed hoarding and OCS severity in the various age groups and explored specific hoarding and OCS patterns (e.g., difficulty discarding, excessive acquisition, clutter, checking, washing, perfectionism, and obsessions) with age. RESULTS: Prevalence of provisional HD diagnoses (2.12%) increased linearly by 20% with every 5 years of age (z = 13.8, p < 0.0001) and did not differ between males and females. Provisional OCD diagnoses were most common in younger individuals and in individuals over age 65. Co-occurring OCD increased hoarding symptom severity (coefficient: 4.5; SE: 0.2; 95% CI: 4.1-4.9; t = 22.0, p < 0.0001). Difficulty discarding for HD and checking behaviors for OCD appeared to drive most increases in these diagnoses in older ages. CONCLUSION: Increased prevalence and severity of HD with age appears to be primarily driven by difficulties with discarding. Increases in OCD prevalence with older age were unexpected and of potential clinical relevance.

Psychiatric and social outcome after deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: The aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease (PD). METHODS: We randomly assigned patients to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized psychiatric and social questionnaires were assessed at baseline and after 12 months. RESULTS: No differences were found between GPi DBS and STN DBS on psychiatric evaluation. Within-group comparisons showed small but statistically significant changes on several measures in both groups. Descriptive statistics indicated slight changes in social functioning. Marital satisfaction of patients and partners remained relatively stable after GPi and STN DBS. CONCLUSIONS: We found neither differences in psychiatric and social outcome between GPi DBS and STN DBS nor any relevant within-group differences. The decision for GPi DBS or STN DBS cannot be based on expected psychiatric or social effects.

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Standards of care for obsessive-compulsive disorder centres.

In recent years, many assessment and care units for obsessive-compulsive disorder (OCD) have been set up in order to detect, diagnose and to properly manage this complex disorder, but there is no consensus regarding the key functions that these units should perform. The International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) together with the Obsessive Compulsive and Related Disorders Network (OCRN) of the European College of Neuropsychopharmacology (ECNP) and the Anxiety and Obsessive Compulsive Disorders Section of the World Psychiaric Association (WPA) has developed a standards of care programme for OCD centres. The goals of this collaborative initiative are promoting basic standards, improving the quality of clinical care and enhance the validity and reliability of research results provided by different facilities and countries.

Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder.

BACKGROUND: Recent studies have shown that response inhibition is impaired in patients with obsessive-compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive-compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive-compulsive disorder and their unaffected siblings. METHODS: Forty-one unmedicated patients with obsessive-compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho-physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. RESULTS: Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow-up dynamic causal modeling suggests a bottom-up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top-down in patients with obsessive-compulsive, and in both directions in siblings. CONCLUSIONS: Our findings suggest that amygdala activation in obsessive-compulsive disorder interferes differently with the task-related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive-compulsive disorder.

Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Updated meta-analysis of classical fear conditioning in the anxiety disorders.

The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty-four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders.

Genetic and environmental contributions to stability in adult obsessive compulsive behavior.

This study investigates the relative contribution of genetic and environmental factors to the stability of obsessive-compulsive (OC) symptoms in an adult population-based sample. We collected data from twin pairs and their siblings, using the Padua Inventory Revised Abbreviated, from the population-based Netherlands Twin Register (NTR) in 2002 (n = 10.134) and 2008 (n = 15.720). Multivariate twin analyses were used to estimate the stability of OC symptoms as a function of genetic and environmental components. OC symptoms were found to be highly stable, with a longitudinal phenotypic correlation of 0.63. Longitudinal broad sense heritability was found to be 56.0%. Longitudinal correlations for genetic (r = 0.58 for additive, r = 1 for non-additive genetic factors) and non-shared environment (r = 0.46) reflected stable effects, indicating that both genes and environment are influencing the stability of OC symptoms in adults. For the first time, evidence is reported for non-additive genetic effects on the stability of OC symptoms. In conclusion, this study showed that OC symptoms are highly stable across time in adults, and that genetic effects contribute mostly to this stability, both in an additive and non-additive way, besides non-shared environmental factors. These data are informative with respect to adult sample selection for future genetic studies, and suggest that gene-gene interaction studies are needed to further understand the dominance effect found in this study.