Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

Sleep architecture modifications after double chronotherapy: A case series of bipolar depressed inpatients.

The aim of this study is to objectively evaluate sleep architecture changes of depressed bipolar subjects treated with chronoterapeutics. Eleven depressed bipolar inpatients received 3 cycles of Total Sleep Deprivation, followed by daily light therapy sessions for one week. Polysomnography was performed before and after the treatment. Depressive symptoms significantly reduced, and sleep architecture changed with significant differences in N2% and N3% and REM density. Change in N3% was also positively correlated to depressive symptoms reduction. Although, previous studies reported sleep architecture changes after chronoterapeutics in unipolar depression, this is the first study to demonstrate changes also in bipolar depressed subjects.

Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: a pilot study.

Objectives: We performed a randomized single-blinded study to assess the superiority of the combination strategy of repetitive Transcranial Magnetic Stimulation (rTMS) and Bright Light Therapy (BLT) over rTMS treatment alone in reducing depressive symptoms in treatment-resistant depression (TRD).Methods: We enrolled 80 inpatients with a diagnosis of TRD. All patients were randomly assigned into two groups: group A was treated with rTMS, compared to group B treated with a combination of rTMS and BLT. Depressive symptoms were weekly assessed (T0, T1, T2, T3) through the 17-item Hamilton depression rating scale (HDRS-17).Results: rANOVA (F=2.766, p=0.043) and post-hoc in HDRS-17 showed significant better scores in favour of group B every week (p<0.025, T1: 22.075 vs 17.200; T2: 16.100 vs 12.775; T3: 12.225 vs 8.900).Conclusions: The antidepressant effect of rTMS was enhanced and accelerated by its combination with BLT in treating resistant depression.KEYPOINTSAlmost one third of depressed patients does not respond to antidepressants; emerging neuromodulation and chronobiological techniques are effective antidepressant augmentation treatments.The aim of this study was to assess the superiority of the combination strategy of Light Therapy and TMS over TMS treatment alone in a group of treatment resistant depressed patients.The implication of this study in clinical practice is that a safe, low risk and cost-effective treatment, as Light Therapy, improves and accelerates the antidepressant effect of TMS.

Planning functioning and impulsiveness in obsessive-compulsive disorder.

Planning ability (PA) is a key aspect of cognitive functioning and requires subjects to identify and organise the necessary steps to achieve a goal. Despite the central role of executive dysfunction in patients with obsessive-compulsive disorder (OCD), deficits in PA have been investigated leading to contrasting results. Given these inconsistencies, the main aim of our work is to give a deeper and clearer understanding of PA in OCD patients. Moreover, we are interested in investigating the relationship between PAs and impulsivity traits and other clinical variables. Sixty-eight OCD patients and 68 healthy controls (HCs) matched for sex and age were assessed through the Stocking of Cambridge (SoC), a computerised version of the Tower of London. We examined planning sub-components for each difficulty levels (from 2 to 5 minimum moves). Our results showed that OCD patients needed longer initial thinking time than HCs during the execution of low demanding tasks (i.e. 2 and 3 moves), while the accuracy level between the two groups did not significantly differ. OCD patients required longer initial thinking time also during high demanding tasks (i.e., 4 and 5 moves), but in this case their accuracy was significantly worse than HCs' one. We did not find any association between impulsivity and PAs. Our results supported the hypothesis that OCD patients were not able to retain in memory the planned sequence and they had to reschedule their movements during the execution. Thus, future studies should deepen the interrelation between working memory and PA to better understand the influence between these two cognitive functions and their interaction with clinical variables in OCD patients.

Effects of gender and executive function on visuospatial working memory in adult obsessive-compulsive disorder.

Visuospatial working memory (VSWM) is the ability of the brain to transiently store and manipulate visual information. VSWM deficiencies have been reported in obsessive-compulsive disorder (OCD), but not consistently, perhaps due to variability in task design and clinical patient factors. To explore this variability, this study assessed effects of the design factors task difficulty and executive organizational strategy and of the clinical factors gender, OCD symptom dimension, and duration of illness on VSWM in OCD. The CANTAB spatial working memory, spatial recognition memory, delayed matching to sample, and stop signal tasks were administered to 42 adult OCD patients and 42 age- and sex-matched healthy controls. Aims were to detect a possible VSWM deficit in the OCD sample, to evaluate influences of the above task and patient factors, to determine the specificity of the deficit to the visuospatial subdomain, and to examine effects of sustained attention as potential neurocognitive confound. We confirmed previous findings of a VSWM deficit in OCD that was more severe for greater memory load (task difficulty) and that was affected by task strategy (executive function). We failed to demonstrate significant deficits in neighboring or confounding neurocognitive subdomains (visual object recognition or visual object short-term memory, sustained attention). Notably, the VSWM deficit was only significant for female patients, adding to evidence for sexual dimorphism in OCD. Again as in prior work, more severe OCD symptoms in the symmetry dimension (but no other dimension) significantly negatively impacted VSWM. Duration of illness had no significant effect on VSWM. VSWM deficits in OCD appear more severe with higher task load and may be mediated through poor task strategy. Such deficits may present mainly in female patients and in (male and female) patients with symmetry symptoms.

Evaluating effect of symptoms heterogeneity on decision-making ability in obsessive-compulsive disorder.

AIMS: Despite having a univocal definition, obsessive-compulsive disorder (OCD) shows a remarkably phenotypic heterogeneity. The published reports show impaired decision-making in OCD patients, using tasks such as the Iowa Gambling Task (IGT). We wanted to verify the hypothesis of an IGT worse performance in a large sample of OCD patients and healthy control (HC) subjects and to examine the relation between neuropsychological performance in IGT and the OCD symptoms heterogeneity. METHODS: Binary data from the Yale-Brown Obsessive Compulsive Scale collected on a large sample of OCD patients were analyzed using a multidimensional item response theory model to explore the underlying structure of data, thus revealing latent factors. Factor scores were categorized into quartiles. Then, for each factor, we identified patients respectively with the highest versus lowest score. We evaluated whether symptom dimensions affect the probability of a correct answer over time generalized, during IGT performance, fitting a generalized linear mixed model. RESULTS: We found a general deficit in ambiguous decision-making in OCD compared to HC. Moreover, our findings suggested that OCD symptoms heterogeneity affects decision-making learning abilities during IGT. In fact, while 'Symmetry' and 'Washing' patients showed a learning curve during the task, other subgroups did not. CONCLUSIONS: Our study confirmed previous findings suggesting that OCD is characterized by a deficit in decision-making under uncertainty. Moreover, our study gave evidence about biological specificity for each symptom dimension in OCD. Data were discussed in the context of the somatic marker hypothesis, which was hypothesized to be reduced in OCD patients.

Low baseline startle in anorexia nervosa patients.

This study examined baseline startle magnitude, using eye blink response and skin conductance response in anorexia nervosa patients. Twenty female in-patients with anorexia nervosa and an equal number of female healthy controls were tested. Baseline startle response was assessed during blank screens while four startling loud sounds (a 116 dB, 1s, 250 Hz tone) were delivered with a time interval ranging from 35 to 55 s. It was investigated if BMI and state anxiety correlated with physiological responses. The clinical sample showed a lower baseline startle reflex measured with both indices, than healthy controls. Across the whole sample, a single regression model partially explained the relationship between BMI and baseline skin conductance response.

Executive functioning in anorexia nervosa patients and their unaffected relatives.

Formal genetic studies suggested a substantial genetic influence for anorexia nervosa (AN), but currently results are inconsistent. The use of the neurocognitive endophenotype approach may facilitate our understanding of the AN pathophysiology. We investigated decision-making, set-shifting and planning in AN patients (n=29) and their unaffected relatives (n=29) compared to healthy probands (n=29) and their relatives (n=29). The Iowa Gambling Task (IGT), the Tower of Hanoi (ToH) and the Wisconsin Card Sorting Test (WCST) were administered. Concordance rates and heritability indices were also calculated in probands/relatives. Impaired performance on the IGT and the WCST were found in both AN probands and their relatives, although planning appeared to be preserved. The IGT heritability index suggested the presence of genetic effects that influence this measure. No evidence for genetic effects was found for the WCST. The results suggest the presence of a shared dysfunctional executive profile in women with AN and their unaffected relatives, characterized by deficient decision-making and set-shifting. Concordance analysis strongly suggests that these impairments aggregate in AN families, supporting the hypothesis that they may constitute biological markers for AN. Decision-making impairment presents a moderate heritability, suggesting that decision-making may be a candidate endophenotype for AN.

Motor inhibition and cognitive flexibility in eating disorder subtypes.

Anorexia Nervosa (AN) and Bulimia Nervosa (BN) are complex Eating Disorders (EDs). Even if are considered two different diagnostic categories, they share clinical relevant characteristics. The evaluation of neurocognitive functions, using standardized neuropsychological assessment, could be a interesting approach to better understand differences and similarities between diagnostic categories and clinical subtypes in EDs thus improving our knowledge of the pathophisiology of EDs spectrum. This study explored cognitive flexibility and motor inhibition in patients with AN considering both Restricter and Binge/Purge subtypes, patients with BN and healthy comparisons subjects (HC). Intra-Extra Dimentional Set shifting Test and Stop Signal Task, selected from CANTAB battery, were administered to analyzed set-shifting and motor inhibition respectively. AN patients showed a deficient motor inhibition compared to HC, while no evidence for impaired motor inhibition was found in BN patients; a significant relationship between commission errors in the Stop Signal Task and attentional impulsiveness was found. Moreover, no difference in set-shifting abilities was found comparing all clinician groups and HC. So our results indicated no cognitive impairment in these two cognitive functions in BN patients, while AN and BN showed different performances in motor inhibition. A similar cognitive profile was found in other obsessive compulsive spectrum disorders. Finally, the paper suggests a new interactive approach for the study of cognitive profile in psychiatric disorders; it might be more useful since it is more closely related to the executive functions complexity.

Executive dysfunctions in obsessive-compulsive patients and unaffected relatives: searching for a new intermediate phenotype.

BACKGROUND: Evidence in literature suggests that neurocognitive deficits may represent suitable intermediate-phenotype candidates for the dissection of obsessive-compulsive disorder (OCD) genetic heterogeneity. The aim of this study was to search for possible OCD neurocognitive endophenotypes by assessing decision-making, planning, and mental flexibility profiles in OCD probands, healthy control subjects (HC), and their respective relatives. METHODS: The sample consisted of 35 pairs of OCD probands without other Axis I comorbidities and unaffected first-degree relatives and 31 pairs of HC subjects without a known family history of OCD and their relatives. Neuropsychological assessment was performed using the Iowa Gambling Task (IGT), the Tower of Hanoi (ToH), and the Wisconsin Card Sorting Test (WCST). RESULTS: Obsessive-compulsive disorder patients showed impairments in decision making, planning, and mental flexibility, given that OCD probands performed significantly poorer than HC probands at the IGT, the ToH, and the WCST. Obsessive-compulsive disorder relatives performed poorer at these tests than HC probands and relatives. Symptom severity was found to have no influence on neurocognitive performance. Analysis of proband/relative concordance in task performance was performed for each task. A significant overall difference was found when comparing the percentages of the different concordance profiles of our OCD and HC samples with regard to IGT and ToH performance. No significant difference was found in the WCST. CONCLUSIONS: Executive dysfunctions may qualify as a suitable endophenotype candidate for OCD. Concordance rates in neuropsychological task performance suggest that decision-making and planning deficits aggregate in these families and therefore might be a heritable component of OCD.

Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

No association between obsessive-compulsive disorder and the 5-HT(1Dbeta) receptor gene.

OBJECTIVE: Serotonin abnormalities may be involved in the etiopathogenesis of obsessive-compulsive disorder (OCD). The silent G-to-C substitution at nucleotide 861 of the coding region of the 5-HT(1Dbeta) receptor gene may be associated with liability to OCD. The aim of this study was to investigate this association in an Italian OCD study group. METHOD: Genotyping for 5-HT(1Dbeta) was performed for 79 nuclear families of probands with OCD. The transmission/disequilibrium test was used to determine transmission of the alleles from parents to offspring. RESULTS: Of the 79 families, 48 were informative for the analysis, i.e., both parents were genotyped for 5-HT(1Dbeta), and at least one parent was heterozygous. No preferential transmission of either allele of the 5-HT(1Dbeta) gene was observed. CONCLUSIONS: These data do not support a role for the 5-HT(1Dbeta) receptor gene in conferring susceptibility to OCD.

Obsessive compulsive disorder among idiopathic focal dystonia patients: an epidemiological and family study.

BACKGROUND: A disturbed function of striato-thalamo-cortical circuitry is hypothesized to underlie idiopathic focal dystonia (IFD) and obsessive compulsive disorder (OCD), two severe and disabling neurologic and psychiatric disorders. Previous studies on small samples showed either higher obsessionality scores or higher frequency of OCD in dystonic patients than in normal control subjects. The aim of this study was to evaluate the frequency and familial loading of OCD in a population of patients with IFD. METHODS: We evaluated OCD diagnosis and family history in 76 patients affected by IFD. RESULTS: Of our subjects 19.7% satisfied DSM-IV criteria for OCD diagnosis and had a family morbidity risk for OCD of 13.8%, significantly higher than that found in the general population. CONCLUSIONS: Our results support the hypothesis of a common pathologic background for OCD and IFD, at least in a subgroup of IFD, indicating basal ganglia dysfunction.

Anticipation of age at onset of obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder.

Anticipation of age at onset has been observed in several neuropsychiatric disorders. Recent studies have associated anticipation with the presence of unstable DNA and have suggested that trinucleotide repeats may be the main cause in some of these diseases. However, several selection biases may mimic the presence of such an effect. In this study we evaluated the presence of this effect in 40 families of probands with obsessive-compulsive disorder (OCD) compared with affected subjects in the parental generation. We controlled for ascertainment biases by taking into account the age at interview of probands. Using a different recruitment strategy, we controlled for anticipation in a sub-sample of offspring of 13 OCD patients, affected with OC spectrum disorders. While the younger generation showed a significantly earlier age at onset than the parental generation, no effect of age at interview was observed. Drawing on the results, we hypothesised that the presence of anticipation in OCD and OC spectrum disorders could be due to a specific genetic effect (unstable DNA), as it has been hypothesised for other disorders showing this effect.

Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism.

The determination of a genetic basis for obsessive-compulsive disorder (OCD) depends on how phenotypic boundaries are defined. Although a hypothesis for serotonin dysfunction in OCD has been advanced, no genes specifically responsible for serotonin regulation have as yet been definitively related to the etiology of OCD. The phenotypic variability of OCD could be at the basis of the failure of molecular biology investigations to find any genes involved in the liability to the disorder. Obsessive and compulsive contents can aggregate in OCD patients differently; multifactorial description may therefore be able to account for OCD phenotypic variance. Using principal component analysis, we derived five factors from 13 main contents of the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and considered them as quantitative phenotypes to evaluate their possible association with an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR). A trend toward positive association between the fifth factor, including counting and repeating rituals, and 5-HTTLPR was found. However, only considering the subgroup of patients with tic codiagnosis, we found a significantly higher score for the fifth factor for patients with L/L genotype with respect to L/S and S/S genotypes.