Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response.

Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.

Reduced neural response to reward and pleasant pictures independently relate to depression.

BACKGROUND: Multiple studies have found a reduced reward positivity (RewP) among individuals with major depressive disorder (MDD). Event-related potential studies have also reported blunted neural responses to pleasant pictures in MDD as reflected by the late positive potential (LPP). These deficits have been interpreted broadly in terms of anhedonia and decreased emotional engagement characteristic of depression. METHODS: In the current study, a community-based sample of 83 participants with current MDD and 45 healthy individuals performed both a guessing task and a picture viewing paradigm with neutral and pleasant pictures to assess the RewP and the LPP, respectively. RESULTS: We found that both RewP and LPP to pleasant pictures were reduced in the MDD group; moreover, RewP and LPP were both independent predictors of MDD status. Within the MDD group, a smaller RewP predicted impaired mood reactivity in younger but not older participants. Smaller LPP amplitudes were associated with increased anhedonia severity in the MDD group. CONCLUSIONS: These data replicate and merge separate previous lines of research, and suggest that a blunted RewP and LPP reflect independent neural deficits in MDD - which could be used in conjunction to improve the classification of depression.

Neural Response to Rewards, Stress and Sleep Interact to Prospectively Predict Depressive Symptoms in Adolescent Girls.

Blunted reward processing both characterizes major depressive disorder and predicts increases in depressive symptoms. However, little is known about the interaction between blunted reward processing and other risk factors in relation to increases in depressive symptoms. Stressful life events and sleep problems are prominent risk factors that contribute to the etiopathogenesis of depression and have been linked to reward dysfunction; these factors may interact with reward dysfunction to predict increased depressive symptoms. In a large sample of 8- to 14-year-old adolescent girls, the current study examined how blunted reward processing, stressful life events, and sleep problems at baseline interacted to predict increases in depressive symptoms 1 year later. Reward processing was indexed by the reward positivity (RewP), an event-related potential elicited during a simple monetary reward paradigm (i.e., Doors task). Two-way interactions confirmed that a blunted RewP predicted increased depressive symptoms at (a) high levels of stress but not average or low levels of stress, and (b) high and average levels of sleep problems but not low levels of sleep problems. Finally, a 3-way interaction confirmed that a blunted RewP predicted increased depressive symptoms at high levels of stress and sleep problems but not average or low levels of stress and sleep problems. Thus, adolescents characterized by low reward response (i.e., blunted RewP) were at an increased risk of developing depressive symptoms if they experienced increased stressful life events or sleep problems; moreover, risk was greatest among adolescents characterized by all 3.

A brief, computerized intervention targeting error sensitivity reduces the error-related negativity.

Research has identified the neural response to errors (the error-related negativity; ERN) as a marker of current anxiety, as well as risk for future anxiety. Previous work found that traditional cognitive behavioral therapy approaches do not impact the ERN. However, none of these approaches directly target the psychological constructs linked to an increased ERN (e.g., error sensitivity). In the current study, we examine the extent to which a brief, computerized intervention ("Treating the ERN"; i.e., TERN) might impact the ERN by reducing error sensitivity. Results suggest that TERN reduced the ERN and that the impact of the intervention was larger amongst individuals with an increased baseline ERN. This study is an important first step in the development of a novel intervention approach that directly targets error sensitivity, and thereby the ERN.

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder.

BACKGROUND: Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. METHODS: The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). RESULTS: Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. CONCLUSIONS: Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.

The Utility of Event-Related Potentials in Clinical Psychology.

Event-related potentials (ERPs) are direct measures of brain activity that can be leveraged for clinically meaningful research. They can relate robustly both to continuous measures of individual difference and to categorical diagnoses in ways that clarify similarities and distinctions between apparently related disorders and traits. ERPs can be linked to genetic risk, can act as moderators of developmental trajectories and responses to stress, and can be leveraged to identify those at greater risk for psychopathology, especially when used in combination with other neural and self-report measures. ERPs can inform models of the development of, and risk for, psychopathology. Finally, ERPs can be used as targets for existing and novel interventions and prevention efforts. We provide concrete examples for each of these possibilities by focusing on programmatic research on the error-related negativity and anxiety, and thus show that ERPs are poised to make greater contributions toward the identification, prediction, treatment, and prevention of mental disorders.

Performance monitoring in obsessive-compulsive disorder: a temporo-spatial principal component analysis.

Hyperactive performance monitoring is a robust finding in obsessive-compulsive disorder (OCD). Patients show increased amplitudes of the error-related negativity (ERN) and correct-related negativity (CRN). Recently, two temporo-spatial factors were shown to contribute to both ERPs in healthy individuals. In the present study, it was investigated whether the factor structure underlying ERN and CRN is similar in OCD and which factors differ between groups. A principal component analysis (PCA) was employed to investigate the temporo-spatial factor structure of ERN and CRN. Twenty-six OCD patients and 26 healthy controls conducted a flanker task. EEG data were analyzed as conventional ERP components and as factor scores derived from temporo-spatial PCA. ERP results showed expected increases in ERN and CRN amplitudes in OCD patients. For both groups, the PCA confirmed the assumed factor structure of a central and a fronto-parietal factor contributing to ERN and CRN. Factor scores of both factors were differently affected by response correctness in OCD. Alterations in factor scores indicate increased activity in both an outcome-independent monitoring process and an error-sensitive process, contributing to overactive performance monitoring in OCD.

Heart rate and heart rate variability in obsessive-compulsive disorder: Evidence from patients and unaffected first-degree relatives.

Altered heart rate (HR) and heart rate variability (HRV) are common observations in psychiatric disorders. Yet, few studies have examined these cardiac measures in obsessive-compulsive disorder (OCD). The current study aimed to investigate HR and HRV, indexed by the root mean square of successive differences (RMSSD) and further time domain indices, as putative biological characteristics of OCD. Electrocardiogram was recorded during a five-minute resting state. Group differences between patients with OCD (n = 96), healthy participants (n = 112), and unaffected first-degree relatives of patients with OCD (n = 47) were analyzed. As potential moderators of group differences, we examined the influence of age and medication, respectively. As results indicated, patients with OCD showed higher HR and lower HRV compared to healthy participants. These group differences were not moderated by age. Importantly, subgroup analyses showed that only medicated patients displayed lower HRV compared to healthy individuals, while HR alterations were evident in unmedicated patients. Regarding unaffected first-degree relatives, group differences in HRV remained at trend level. Further, an age-moderated group differentiation showed that higher HRV distinguished relatives from healthy individuals in young adulthood, whereas at higher age lower HRV was indicative of relatives. Both the role of familial risk and medication in HRV alterations need further elucidation. Pending future studies, alterations in HR and potentially HRV might serve as useful indices to characterize the pathophysiology of OCD.

Affective evaluation of errors and neural error processing in obsessive-compulsive disorder.

Even though overactive error monitoring, indexed by enhanced amplitudes of the error-related negativity (ERN), is a potential biomarker for obsessive-compulsive disorder (OCD), the mechanisms underlying clinical variations in ERN amplitude remain unknown. To investigate whether ERN enhancement in OCD results from altered error evaluation, we examined the trial-wise valence evaluation of errors and its relation to the ERN in 28 patients with OCD and 28 healthy individuals. Electroencephalogram was recorded during an affective priming paradigm in which responses in a go/no-go task were followed by valence-based word categorization. Results indicated that errors were followed by faster categorization of negative than positive words, confirming that negative valence is assigned to errors. This affective priming effect was reduced in patients with OCD, while go/no-go performance was comparable between groups. Notably, this reduction amplified with increasing symptom severity. These results suggest attenuated affective error evaluation in OCD, possibly resulting from interfering effects of anxiety. There was no evidence for a trial-level association between valence evaluation and ERN, implying that ERN amplitude does not reflect valence assignment to errors. Consequently, altered error monitoring in OCD may involve alterations in possibly distinct processes, with weaker assignment of negative valence to errors being one of them.

Associations of neural error-processing with symptoms and traits in a dimensional sample recruited across the obsessive-compulsive spectrum.

The error-related negativity (ERN), a neural response to errors, has been associated with several forms of psychopathology and assumed to represent a neural risk marker for obsessive-compulsive disorder (OCD) and anxiety disorders. Yet, it is still unknown which specific symptoms or traits best explain ERN variation. This study investigated performance-monitoring in participants (N = 100) recruited across a spectrum of obsessive-compulsive characteristics (n = 26 patients with OCD; n = 74 healthy participants including n = 24 with low, n = 24 with medium, and n = 26 with high OC-characteristics). Several compulsivity- and anxiety-associated characteristics were assessed and submitted to exploratory principal axis factor analysis. Associations of raw measures and derived factors with ERN and correct-related negativity (CRN) were examined. Patients with OCD showed increased ERN amplitudes compared to healthy participants. The ERN was associated with a variety of traits related to anxiety and negative affect. Factor analysis results revealed a most prominent association of the ERN with a composite measure of anxiety and neuroticism, whereas the CRN was specifically associated with compulsivity. Results support differential associations for the ERN and CRN and demonstrate that a dimensional recruitment approach and use of composite measures can improve our understanding of characteristics underlying variation in neural performance monitoring.

The free-viewing matrix task: A reliable measure of attention allocation in psychopathology.

Aberrant attention allocation has been implicated in the etiology and maintenance of a range of psychopathologies. However, three decades of research, relying primarily on manual response-time tasks, have been challenged on the grounds of poor reliability of its attention bias indices. Here, in a large, multisite, international study we provide reliability information for a new eye-tracking-based measure of attention allocation and its relation to psychopathology and age. Data from 1567 participants, across a wide range of psychiatric diagnoses and ages, were aggregated from nine sites around the world. Of these, 213 participants also provided retest data. Acceptable overall internal consistency and test-retest reliability were observed among adult participants (Cronbach's alpha = 0.86 and r(213) = 0.89, respectively), as well as across all examined psychopathologies. Youth demonstrated lower internal consistency scores (Cronbach's alpha = 0.65). Finally, the percent dwell time index derived from the task statistically differentiated between healthy participants and participants diagnosed with social anxiety disorder, major depression, and post-traumatic stress disorder. These results potentially address a long-standing reliability crisis in this research field. Aberrant attention allocation patterns in a variety of psychiatric disorders may be targeted with the hope of affecting symptoms. The attention allocation index derived from the matrix task offers reliable means to measure such cognitive target engagement in clinical contexts.

Event-related potential studies of emotion regulation: A review of recent progress and future directions.

Event-related potentials (ERPs) bring many strengths to the study of emotion regulation, including: direct measurement of neural activity, high temporal resolution, affordability and suitability to a wide range of participants. Research using ERPs to study emotion regulation began approximately two decades ago, but has grown exponentially over the last 10 years. Here, we highlight progress in this body of work throughout the past decade, as well as emerging themes, novel approaches and paradigms that will likely shape the field in the coming years. While standardized picture sets are still the most commonly used stimuli in these studies, new types of stimuli (e.g., mental imagery, autobiographical memories) have become increasingly common throughout the past decade, with the potential for improved ecological validity. Cognitive reappraisal is still seen by many as the gold standard of emotion regulation, yet mixed findings suggest that its utility might be better understood by taking into account the type of stimuli and context to which it is applied. Moreover, other emotion regulation techniques, particularly for the upregulation of positive emotion (e.g., savoring), have been relatively unexamined in the ERP literature to-date, as have associations between controlled, lab-based measures of emotion generation and regulation in everyday life (e.g., as assessed using ambulatory techniques). In sum, the past decade has seen progress in a more granular understanding of emotion regulation, with ongoing and future work aimed at increasing understanding of the boundary conditions of emotion regulation; novel techniques and emotion regulation's application to everyday life.

Depression reduces neural correlates of reward salience with increasing effort over the course of the progressive ratio task.

BACKGROUND: Depressive disorders have been associated with altered effort-cost decision making (ECDM) in behavioral investigations, such as a decreased willingness to expend effort for reward attainment. However, little is known about neural mechanisms implicated in altered ECDM. METHODS: The study investigates neural correlates of reward attainment during a progressive ratio task in participants with a current depressive disorder (n = 65) and never-depressed healthy individuals (n = 44). On each trial, participants completed an increasing number of button presses to attain a fixed monetary reward, indicated by an auditory reward signal. Participants could decide to quit the task anytime (breakpoint). EEG was recorded during the task and P300 amplitudes were examined in response to the auditory signal of reward attainment. RESULTS: There was no difference in breakpoint, as both groups completed comparable numbers of button presses. In contrast, results from mixed-effects models of trial-level ERP responses indicated depression-related effects on P300 amplitudes over the course of the task. Generally, the reward-locked P300 increased with ascending effort expenditure; however, compared to healthy participants, individuals with current depression were characterized by an attenuated trajectory of the reward-locked P300, pointing towards decreased reactivity to reward attainment with increasing effort. LIMITATIONS: Sample size and reward magnitude were possibly not large enough to detect differences in breakpoint. CONCLUSIONS: The results of the current study demonstrate that the investigation of reward-related P300 trajectory may represent an informative novel addition to the progressive ratio task, which could help shed light on depression-related alterations in motivation and ECDM.

Non-invasive brain stimulation modulates neural correlates of performance monitoring in patients with obsessive-compulsive disorder.

Overactive performance monitoring, as reflected by enhanced neural responses to errors (the error-related negativity, ERN), is considered a biomarker for obsessive-compulsive disorder (OCD) and may be a promising target for novel treatment approaches. Prior research suggests that non-invasive brain stimulation with transcranial direct current stimulation (tDCS) may reduce the ERN in healthy individuals, yet no study has investigated its efficacy in attenuating the ERN in OCD. In this preregistered, randomized, sham-controlled, crossover study, we investigated effects of tDCS on performance monitoring in patients with OCD (n = 28) and healthy individuals (n = 28). Cathodal and sham tDCS was applied over the presupplementary motor area (pre-SMA) in two sessions, each followed by electroencephalogram recording during a flanker task. Cathodal tDCS reduced the ERN amplitude compared to sham tDCS, albeit this effect was only marginally significant (p = .052; mean difference: 0.86 µV). Additionally, cathodal tDCS reduced the correct-response negativity and increased the error positivity. These neural modulations were not accompanied by behavioral changes. Moreover, we found no evidence that the tDCS effect was more pronounced in the patient group. In summary, our findings indicate that tDCS over the pre-SMA modulates neural correlates of performance monitoring across groups. Therefore, this study represents a valuable starting point for future research to determine whether repeated tDCS application induces a more pronounced ERN attenuation and normalizes aberrant performance monitoring in the long term, thereby potentially alleviating obsessive-compulsive symptoms and providing a psychophysiological intervention strategy for individuals who do not benefit sufficiently from existing interventions.

Neural correlates of emotional reactivity predict response to cognitive-behavioral therapy in obsessive-compulsive disorder.

BACKGROUND: Examining predictive biomarkers to identify individuals who will likely benefit from a specific treatment is important for the development of targeted interventions. The late positive potential (LPP) is a neural marker of attention and elaborated stimulus processing, and increased LPP responses to negative stimuli are characteristic of pathological anxiety. The present study investigated whether LPP reactivity would prospectively predict response to cognitive-behavioral therapy (CBT), the first-line treatment for obsessive-compulsive disorder (OCD). METHODS: To this end, the LPP in response to negative as compared to neutral pictures was examined in 45 patients with OCD, who underwent CBT in a naturalistic outpatient setting. LPP amplitudes were used as predictors of symptom reduction after CBT. RESULTS: We found that higher LPP amplitudes to negative relative to neutral stimuli were predictive of lower self-reported OCD symptoms after completion of CBT, controlling for pre-treatment symptoms. Further, LPP reactivity was negatively correlated with self-reported habitual use of suppression in everyday life. LIMITATIONS: Some participants had already begun treatment at the time of study participation. Overall, results need further replication in larger samples and standardized therapy settings. CONCLUSIONS: The current findings suggest that patients with increased emotional reactivity benefit more from CBT, possibly through less avoidance of anxiety-provoking stimuli during exposure with response prevention, a crucial component in CBT for OCD. Although its clinical utility still needs to be evaluated further, the LPP constitutes a promising candidate as a prognostic marker for CBT response in OCD.

Reduced electrocortical responses to pleasant pictures in depression: A brief report on time-domain and time-frequency delta analyses.

BACKGROUND: The late positive potential (LPP) to pleasant content is an electrocortical indicator of blunted emotional reactivity in depression. A reduced time-frequency delta power has never been investigated in clinical samples. The present study examined time-frequency delta in depression and at investigated whether the combination of time-domain and time-frequency data would explain additional variance in the depression status. METHODS: The study was a secondary analysis of data collected during a passive viewing task of pleasant and neutral pictures in a community-based sample of 75 participants with a current depressive disorder and 42 controls. A time-frequency analysis on event-related changes within delta frequency band was conducted. RESULTS: Cluster-based statistics revealed a centro-parietal increase in delta power to pleasant relative to neutral pictures in the control group but not within the depression group. Moreover, a fronto-centro-parietal reduction in delta power to pleasant pictures emerged in depression relative to controls. Both a smaller LPP and delta power to pleasant pictures were related to depression status. The combination of LPP and delta power explained a greater amount of variance compared to the model where LPP was entered as the only predictor of depression status. CONCLUSIONS: These data suggest that delta power might be a promising electrocortical correlate of the hypoactivation of the approach-related motivational system in depression. Additionally, a blunted delta and LPP might reflect unique processes related to depression. A combination of these measures can be leveraged together to enhance clinical utility and to shed light on the underlying mechanisms associated with depression.

Error-Related Brain Activity in Patients With Obsessive-Compulsive Disorder and Unaffected First-Degree Relatives: Evidence for Protective Patterns.

Background: Indicators of increased error monitoring are associated with obsessive-compulsive disorder (OCD), as shown in electroencephalography and functional magnetic resonance imaging studies. As most studies used strictly controlled samples (excluding comorbidity and medication), it remains open whether these findings extend to naturalistic settings. Thus, we assessed error-related brain activity in a large, naturalistic OCD sample. We also explored which activity patterns might qualify as vulnerability endophenotypes or protective factors for the disorder. To this aim, a sample of unaffected first-degree relatives of patients with OCD was also included. Methods: Participants (84 patients with OCD, 99 healthy control participants, and 37 unaffected first-degree relatives of patients with OCD) completed a flanker task while blood oxygen level-dependent responses were measured with functional magnetic resonance imaging. Aberrant error-related brain activity in patients and relatives was identified. Results: Patients with OCD showed increased error-related activity in the supplementary motor area and within the default mode network, specifically in the precuneus and postcentral gyrus. Unaffected first-degree relatives showed increased error-related activity in the bilateral inferior frontal gyrus. Conclusions: Increased supplementary motor area and default mode network activity in patients with OCD replicates previous studies and might indicate excessive error signals and increased self-referential error processing. Increased activity of the inferior frontal gyrus in relatives may reflect increased inhibition. Impaired response inhibition in OCD has been demonstrated in several studies and might contribute to impairments in suppressing compulsive actions. Thus, increased inferior frontal gyrus activity in the unaffected relatives of patients with OCD may have contributed to protection from symptom development.

Error-related activity of the sensorimotor network contributes to the prediction of response to cognitive-behavioral therapy in obsessive-compulsive disorder.

BACKGROUND: Although cognitive behavioral therapy is a highly effective treatment for obsessive-compulsive disorder (OCD), yielding large symptom reductions on the group level, individual treatment response varies considerably. Identification of treatment response predictors may provide important information for maximizing individual treatment response and thus achieving efficient treatment resource allocation. Here, we investigated the predictive value of previously identified biomarkers of OCD, namely the error-related activity of the supplementary motor area (SMA) and the sensorimotor network (SMN, postcentral gyrus/precuneus). METHODS: Seventy-two participants with a primary diagnosis of OCD underwent functional magnetic resonance imaging (fMRI) scanning while performing a flanker task prior to receiving routine-care CBT. RESULTS: Error-related BOLD response of the SMN significantly contributed to the prediction of treatment response beyond the variance accounted for by clinical and sociodemographic variables. Stronger error-related SMN activity at baseline was associated with a higher likelihood of treatment response. CONCLUSIONS: The present results illustrate that the inclusion of error-related SMN activity can significantly increase treatment response prediction quality in OCD. Stronger error-related activity of the SMN may reflect the ability to activate symptom-relevant processing networks and may thus facilitate response to exposure-based CBT interventions.

Hypermethylation of the oxytocin receptor gene (OXTR) in obsessive-compulsive disorder: further evidence for a biomarker of disease and treatment response.

Obsessive-compulsive disorder (OCD) has recently been linked to increased methylation levels in the oxytocin receptor (OXTR) gene, and OXTR hypermethylation has predicted a worse treatment response to cognitive-behavioural therapy (CBT). Furthermore, OCD is associated with childhood trauma and stressful life events, which have both been shown to affect OXTR methylation. Here, we aimed to replicate findings of increased OXTR methylation as a predictor of disease and worse treatment response in an independent sample that received treatment within the public health care system. In addition, we aimed to extend previous findings by examining associations between OXTR hypermethylation, environmental stressors, OCD diagnosis, and treatment response. Methylation levels at two CpGs within OXTR exon III were compared between n = 181 OCD patients and n = 199 healthy controls using linear regression analysis. In a subsample of OCD patients (n = 98) with documented treatment data, we examined associations between methylation and treatment response to CBT. Childhood adversity and stressful life events were assessed using Childhood Trauma Questionnaire and Life Experience Survey, respectively. OCD patients exhibited significant hypermethylation at CpG site cg04523291 compared to controls, and increased methylation was associated with impaired treatment response. Moreover, hypermethylation at cg04523291 was associated with stressful life events in OCD patients, and with childhood adversity in controls. Yet, there were no significant mediation effects. In conclusion, we replicated the association between OXTR hypermethylation and OCD in the largest sample, so far. Furthermore, our findings support the role of OXTR methylation as a promising biomarker for treatment response in OCD.