Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. OBJECTIVE: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. METHODS: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. RESULTS: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. CONCLUSIONS: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

Does "thinking about thinking" interfere with memory? An experimental memory study in obsessive-compulsive disorder.

Neuropsychological assessments of participants with obsessive-compulsive disorder (OCD) indicate impaired verbal memory if to be remembered material has to be organized. People with OCD also tend to focus their attention on their thoughts (heightened cognitive self-consciousness). We tested the hypothesis that cognitive self-consciousness causes verbal memory deficits by provoking a division of attention between study task and thoughts. Thirty-six participants with OCD, 36 matched healthy controls and 36 participants with major depressive disorder (MDD) learned under proactive interference in three study conditions: single-task condition, condition with heightened cognitive self-consciousness and condition with an external secondary task. Memory was impaired in the cognitive self-consciousness condition compared to both other conditions. Independent of condition, participants with OCD showed a reduced memory performance compared to healthy controls, but did not differ from participants with MDD. Our results are in line with the hypothesis that cognitive self-consciousness causes memory impairment.

Predicting therapy outcome in patients with early and late obsessive-compulsive disorder (EOCD and LOCD).

BACKGROUND: Increasing attention has been given to subtyping OCD with respect to different clinical profiles, response to drug treatments, comorbidity and age of onset. There are a number of studies looking at predictors of treatment outcome in OCD, but so far not for OCD subtypes. METHOD: Prediction of outcome after cognitive-behavioural therapy was evaluated in 63 inpatients with early obsessive-compulsive disorder (EOCD < or = 12 years of age) and 191 patients with late obsessive-compulsive disorder (LOCD > 15 years of age). RESULTS: For EOCD patients factors predicting a good outcome included high motivation and high initial Y-BOCS scores. Factors associated with a bad outcome were higher age at assessment, a longer duration of psychiatric inpatient treatment before assessment and a low level of social functioning (BSS). For LOCD patients living in a stable relationship, high motivation and completing treatment predicted a favourable therapy outcome, while a low level of psychological functioning (BSS) and a longer duration of inpatient psychiatric treatment before assessment were associated with an undesirable therapy outcome. CONCLUSIONS: Subtyping OCD patients according to age of onset seems to be a promising avenue towards improving and developing more specified treatment programs.

Symptom-specific EEG power correlations in patients with obsessive-compulsive disorder.

Neurophysiological studies in patients with obsessive-compulsive disorder (OCD) consistently revealed frontal alterations of cortical activity but otherwise showed inhomogeneous results, conceivably due to variable subgroups with diverse pathomechanisms involved. The aim of this study was to investigate quantitative electroencephalography (EEG) in patients with OCD as compared to healthy controls and to correlate neurophysiological data with clinical variables. EEGs were digitally recorded from 18 unmedicated patients (8 male, mean age 32.4+/-11.8 years, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) 15.3+/-7.9) and 18 matched healthy controls, and analysed quantitatively. The mean frequency of EEG background activity and absolute power in delta, theta, alpha and beta frequency bands were calculated. Mean frequency of background activity was significantly lower in patients as compared to controls (-1.44/s, p<0.01), predominantly for the frontal electrode positions. Power spectra revealed increased delta- and decreased alpha-/beta-power in the group of patients (p<0.05, patients vs. controls). Correlation analyses showed significant positive correlations of EEG-power with the Y-BOCS sub-scores "obsessions", and negative correlations with the sub-scores "compulsions" (Spearman's correlations, r(s)=+0.48 to +0.70, and -0.47 to -0.6, respectively, p<0.05). The data provide evidence of a dysfunction of frontal cortical activity in patients with OCD. The opposite correlations of neurophysiological data and clinical features, i.e. obsessions and compulsions, are suggestive of pathophysiological differences based on the presence of the respective cardinal symptoms of OCD.

Implicit sequence learning in obsessive-compulsive disorder: further support for the fronto-striatal dysfunction model.

BACKGROUND: Obsessive-compulsive disorder (OCD) is conceived as a disease that implicates dysfunctions in fronto-striatal brain systems. According to this model, performance deficits observed in patients with lesions in these brain areas are hypothesized to be present also in OCD patients. Implicit procedural learning, which refers to the acquisition of motor or nonmotor skills by practice, is one candidate function to test this prediction. METHODS: The serial reaction time task was used to assess implicit sequence learning of 33 patients with a diagnosis of OCD and 27 healthy control participants. In addition, explicit (i.e., conscious) knowledge of the sequence was determined. A subgroup of 24 patients was reassessed after intensive cognitive-behavioral psychotherapy. RESULTS: Implicit sequence learning was significantly reduced in the OCD group by 41%, while explicit learning and verbal abilities were unaffected. The deficit remained stable across time, although symptoms remitted substantially. Depressive symptoms did not account for the finding. Partial explicit knowledge of the sequence was not a predictor of the amount of implicit learning. CONCLUSIONS: Reduced implicit learning appears to be a dissociable trait of OCD patients. The results confirm previous findings and add supportive evidence for the fronto-striatal dysfunction model of OCD.

P300 subcomponents in obsessive-compulsive disorder.

Hyperactivity in the frontal cortex, leading to acceleration of attentional and cognitive processes, is discussed as pathogenetic factor in obsessive-compulsive disorder (OCD), as supported by findings of neuroimaging studies. This dysfunction in patients with OCD could be reflected by the auditory event-related P300 component, since one subcomponent of the P300, the so-called P3a, is mainly generated in frontal regions. The P300 of 21 patients with OCD free of medication and 21 age- and sex-matched healthy controls was studied, and dipole source analysis was used, allowing the separation of the subcomponents P3a and P3b with high reliability. No difference concerning the P3a between OCD and healthy subjects was found. OCD patients, however, showed a larger P3b amplitude and a shorter P3b latency (only right hemisphere) as well as a shorter reaction time to target tones as the healthy controls. Since the P3b, generated mainly in the temporo-parietal junction, is related to attentional and higher cognitive functions, whereas the P3a is more related to unspecific orienting reactions, the P3b abnormalities found in these patients could be an electrophysiological correlate of overfocussed attention and faster cognitive processes in OCD, possibly due to higher arousal and noradrenergic function. Regarding the findings with small P300 amplitudes and long latencies in most of the other psychiatric patients, it is remarkable that OCD is one of the few psychiatric diseases being characterized by larger P3b amplitudes and shorter latencies.