Benedetta Monzani

Population-Based, Multigenerational Family Clustering Study of Obsessive-compulsive Disorder

IMPORTANCE Controlled family studies have consistently found that obsessive-compulsive disorder (OCD) aggregates in families but have typically relied on samples recruited from specialist clinics. Furthermore, previous studies could not disentangle genetic from environmental factors contributing to the observed familiality. OBJECTIVE To provide unbiased estimates of familial risk for and heritability of OCD at the population level. DESIGN AND SETTING Population-based, multigenerational, case-control family and twin studies using the Swedish National Patient Register, Multi-Generation Register, and Twin Register. PARTICIPANTS All individuals diagnosed as having OCD between January 1, 1969, and December 31, 2009 (n = 24 768) and all their available first-, second-, and third-degree relatives, as well as nonbiological relatives and matched general population control subjects. Twins (n = 16 383) were included from the population-based Twin Register. MAIN OUTCOME AND MEASURE The risk for OCD among relatives of OCD probands. RESULTS The risk for OCD among relatives of OCD probands increased proportionally to the degree of genetic relatedness. The risk for first-degree relatives was significantly higher than that for second- and third-degree and nonbiological relatives. Second-degree relatives had higher risk for OCD than third-degree relatives. Relatives at similar genetic distances had similar risks for OCD, despite different degrees of shared environment. Separate twin modeling analyses confirmed that familial risk for OCD was largely attributable to additive genetic factors (47%; 95% CI, 42%-52%), with no significant effect of shared environment. Nonbiological relatives (spouses or partners who have at least 1 child together) also had an elevated risk for OCD (odds ratio, 2.61; 95% CI, 1.99-3.42). Early-onset probands (3907 individuals; mean age, 13.7 years) had slightly (nonsignificantly) higher familial risk than the total sample, although this was substantially lower than previously reported. There were no significant sex differences in the familial pattern or heritability estimates. CONCLUSIONS AND RELEVANCE Obsessive-compulsive disorder clusters in families primarily due to genetic factors. Nonshared environmental factors are at least as important. The quest for candidate genes, nonshared environmental risk factors, and their possible correlation or interaction should continue. The finding of possible assortative mating in OCD is intriguing and should be investigated further.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data

Importance Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, −3.62; 95% CI, −0.81 to −6.43; P = .01; d = −0.25) but not from pretreatment to midtreatment (mean difference, −1.66; 95% CI, −4.92 to 1.60; P = .32; d = −0.14) or from pretreatment to follow-up (mean difference, −2.98, 95% CI, −5.99 to 0.03; P = .05; d = −0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Cognitive-behavioural therapy with post-session d-cycloserine augmentation for paediatric obsessive-compulsive disorder: pilot randomised controlled trial

A partial N-methyl-D-aspartate agonist, D-cycloserine, enhances fear extinction when given before or shortly after exposure to feared stimuli in animals. In this pilot double-blind placebo-controlled trial (trial number: ISRCTN70977225), 27 youth with obsessive-compulsive disorder were randomised to either 50 mg D-cycloserine or placebo administered immediately after each of ten cognitive-behavioural therapy (CBT) sessions, primarily consisting of exposure and ritual prevention. Both groups improved significantly and maintained their gains at 1-year follow-up, with no significant advantage of D-cycloserine over placebo at any time point. The effects of CBT may not be augmented or accelerated when D-cycloserine is administered after sessions.

Evidence for a genetic overlap between body dysmorphic concerns and obsessive-compulsive symptoms in an adult female community twin sample.

Body dysmorphic disorder (BDD) is thought to be etiologically related to obsessive–compulsive disorder (OCD) but the available evidence is incomplete. The current study examined the genetic and environmental sources of covariance between body dysmorphic and obsessive–compulsive symptoms in a community sample of adult twins. A total of 2,148 female twins (1,074 pairs) completed valid and reliable measures of body dysmorphic concerns and obsessive–compulsive symptoms. The data were analyzed using bivariate twin modeling methods and the statistical programme Mx. In the best‐fitting model, the covariation between body dysmorphic and obsessive–compulsive traits was largely accounted for by genetic influences common to both phenotypes (64%; 95% CI: 0.50–0.80). This genetic overlap was even higher when specific obsessive–compulsive symptom dimensions were considered, with up to 82% of the phenotypic correlation between the obsessing and symmetry/ordering symptom dimensions and dysmorphic concerns being attributable to common genetic factors. Unique environmental factors, although influencing these traits individually, did not substantially contribute to their covariation. The results remained unchanged when excluding individuals reporting an objective medical condition/injury accounting for their concern in physical appearance. The association between body dysmorphic concerns and obsessive–compulsive symptoms is largely explained by shared genetic factors. Environmental risk factors were largely unique to each phenotype. These results support current recommendations to group BDD together with OCD in the same DSM‐5 chapter, although comparison with other phenotypes such as somatoform disorders and social phobia is needed.

A twin study of body dysmorphic concerns.

BACKGROUND Dysmorphic concern refers to an excessive preoccupation with a perceived or slight defect in physical appearance. It lies on a continuum of severity from no or minimal concerns to severe concerns over ones appearance. The present study examined the heritability of dysmorphic concerns in a large sample of twins. METHOD Twins from the St Thomas UK twin registry completed a valid and reliable self-report measure of dysmorphic concerns, which also includes questions about perceived body odour and malfunction. Twin modelling methods (female twins only, n=3544) were employed to decompose the variance in the liability to dysmorphic concerns into additive genetic, shared and non-shared environmental factors. RESULTS Model-fitting analyses showed that genetic factors accounted for approximately 44% [95% confidence intervals (CI) 36-50%] of the variance in dysmorphic concerns, with non-shared environmental factors and measurement error accounting for the remaining variance (56%; 95% CI 50-63%). Shared environmental factors were negligible. The results remained unchanged when excluding individuals reporting an objective medical condition/injury accounting for their concern in physical appearance. CONCLUSIONS Over-concern with a perceived or slight defect in physical appearance is a heritable trait, with non-shared environmental factors also playing an important role in its causation. The results are relevant for various psychiatric disorders characterized by excessive concerns in body appearance, odour or function, including but not limited to body dysmorphic disorder.

Understanding the covariation of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms: A population-based adult twin study

Chronic tic disorders (TD), attention‐deficit/hyperactivity‐disorder (ADHD), and obsessive‐compulsive disorder (OCD) frequently co‐occur in clinical and epidemiological samples. Family studies have found evidence of shared familial transmission between TD and OCD, whereas the familial association between these disorders and ADHD is less clear. This study aimed to investigate to what extent liability of tics, attention‐deficit/hyperactivity, and obsessive‐compulsive symptoms is caused by shared or distinct genetic or environmental influences, in a large population‐representative sample of Swedish adult twins (n = 21,911). Tics, attention‐deficit/hyperactivity, and obsessive‐compulsive symptoms showed modest, but significant covariation. Model fitting suggested a latent liability factor underlying the three phenotypes. This common factor was relatively heritable, and explained significantly less of the variance of attention‐deficit/hyperactivity symptom liability. The majority of genetic variance was specific rather than shared. The greatest proportion of total variance in liability of tics, attention‐deficit/hyperactivity, and obsessive‐compulsive symptoms was attributed to specific non‐shared environmental influences. Our findings suggest that the co‐occurrence of tics and obsessive‐compulsive symptoms, and to a lesser extent attention‐deficit/hyperactivity symptoms, can be partly explained by shared etiological influences. However, these phenotypes do not appear to be alternative expressions of the same underlying genetic liability. Further research examining sub‐dimensions of these phenotypes may serve to further clarify the association between these disorders and identify more genetically homogenous symptom subtypes.

A Pilot Randomized Controlled Trial of Cognitive-Behavioral Therapy for Adolescents With Body Dysmorphic Disorder

OBJECTIVE Body dysmorphic disorder (BDD) typically starts in adolescence, but evidence-based treatments are yet to be developed and formally evaluated in this age group. We designed an age-appropriate cognitive-behavioral therapy (CBT) protocol for adolescents with BDD and evaluated its acceptability and efficacy in a pilot randomized controlled trial. METHOD Thirty adolescents aged 12 to 18 years (mean = 16.0, SD = 1.7) with a primary diagnosis of BDD, together with their families, were randomly assigned to 14 sessions of CBT delivered over 4 months or a control condition of equivalent duration, consisting of written psycho-education materials and weekly telephone monitoring. Blinded evaluators assessed participants at baseline, midtreatment, posttreatment, and at 2-month follow-up. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale Modified for BDD, Adolescent Version (mean baseline score = 37.13, SD = 4.98, range = 24-43). RESULTS The CBT group showed a significantly greater improvement than the control group, both at posttreatment (time × group interaction coefficient [95% CI] = -11.26 [-17.22 to -5.31]; p = .000) and at 2-month follow-up (time × group interaction coefficient [95% CI] = -9.62 [-15.74 to -3.51]; p = .002). Six participants (40%) in the CBT group and 1 participant (6.7%) in the control condition were classified as responders at both time points (χ(2) = 4.658, p = .031). Improvements were also seen on secondary measures, including insight, depression, and quality of life at posttreatment. Both patients and their families deemed the treatment as highly acceptable. CONCLUSION Developmentally tailored CBT is a promising intervention for young people with BDD, although there is significant room for improvement. Further clinical trials incorporating lessons learned in this pilot study and comparing CBT and pharmacological therapies, as well as their combination, are warranted. CLINICAL TRIAL REGISTRATION INFORMATION Cognitive-Behaviour Therapy for Adolescents With Body Dysmorphic Disorder; http://www.isrctn.com/; ISRCTN67699666.

Aetiological overlap between obsessive–compulsive and depressive symptoms: a longitudinal twin study in adolescents and adults

Background Depression is commonly co-morbid with obsessive–compulsive disorder (OCD). However, it is unknown whether depression is a functional consequence of OCD or whether these disorders share a common genetic aetiology. This longitudinal twin study compared these two hypotheses. Method Data were drawn from a longitudinal sample of adolescent twins and siblings (n = 2651; Genesis 12–19 study) and from a cross-sectional sample of adult twins (n = 4920). The longitudinal phenotypic associations between OCD symptoms (OCS) and depressive symptoms were examined using a cross-lag model. Multivariate twin analyses were performed to explore the genetic and environmental contributions to the cross-sectional and longitudinal relationship between OCS and depressive symptoms. Results In the longitudinal phenotypic analyses, OCS at time 1 (wave 2 of the Genesis 12–19 study) predicted depressive symptoms at time 2 (wave 3 of the Genesis 12–19 study) to a similar extent to which depressive symptoms at time 1 predicted OCS at time 2. Cross-sectional twin analyses in both samples indicated that common genetic factors explained 52–65% of the phenotypic correlation between OCS and depressive symptoms. The proportion of the phenotypic correlation due to common non-shared environmental factors was considerably smaller (35%). In the adolescent sample, the longitudinal association between OCS at time 1 and subsequent depressive symptoms was accounted for by the genetic association between OCS and depressive symptoms at time 1. There was no significant environmental association between OCS and later depressive symptoms. Conclusions The present findings show that OCS and depressive symptoms co-occur primarily due to shared genetic factors and suggest that genetic, rather than environmental, effects account for the longitudinal relationship between OCS and depressive symptoms.

EFFECTS OF HOMEWORK COMPLIANCE ON COGNITIVE‐BEHAVIORAL THERAPY WITH D‐CYCLOSERINE AUGMENTATION FOR CHILDREN WITH OBSESSIVE COMPULSIVE DISORDER

The present study examined the effects of homework compliance on outcome from cognitive behavioral therapy (CBT) for children with obsessive‐compulsive disorder (OCD) and the extent to which these effects differ as a function of augmentation of CBT with D‐cycloserine (DCS).

Holistic versus detailed visual processing in body dysmorphic disorder: Testing the inversion, composite and global precedence effects

Individuals with Body Dysmorphic Disorder (BDD) are preoccupied with perceived defects in their appearance that are not visible to others. An excessive focus and processing of details has been proposed as a possible mechanism underlying this distorted self-image in BDD. The nature and extent of visuoperceptual abnormalities in BDD however require further investigation; specifically, it remains unclear whether feature-based processing in BDD is a result of a failure of holistic perceptual processes. The present study evaluated whether BDD is associated with an impairment in global processing. Twenty-five individuals with a primary diagnosis of BDD (15 unmedicated, 10 medicated) and 25 matched healthy controls were administered three robust behavioural tasks that test holistic encoding, namely the face inversion, the composite and the navon tasks. Overall, individuals in the BDD and control groups performed similarly in all aspects of holistic processing tested. Our findings suggest that the excessive focus on specific aspects of appearance in BDD may not be explained by impairments in the global encoding of visual information. Implications of these results and suggestions for future research on visual processing in BDD are discussed.