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.

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.

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.

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.

Is Therapeutic Drug Monitoring Relevant for Antidepressant Drug Therapy? Implications From a Systematic Review and Meta-Analysis With Focus on Moderating Factors.

Inter-individual differences in antidepressant drug concentrations attained in blood may limit the efficacy of pharmacological treatment of depressive disorders. Therapeutic drug monitoring (TDM) enables to determine drug concentrations in blood and adjust antidepressant dosage accordingly. However, research on the underlying assumption of TDM, association between concentration and clinical effect, has yielded ambiguous results for antidepressants. It has been proposed that this ambiguity may be caused by methodological shortcomings in studies investigating the concentration-effect relationship. Guidelines recommend the use of TDM in antidepressant treatment as expert opinion. This reflects the lack of research, particularly systematic reviews and meta-analyses of randomized controlled trials, on the relationship between concentration and effect as well as on the benefits of the use of TDM in clinical practice. In this study, a systematic review and meta-analysis of randomized controlled trials has been performed to investigate the relationship between antidepressant concentration, efficacy, and side effects. It is the first meta-analytical approach to this subject and additionally considers methodological properties of primary studies as moderators of effect in quantitative analysis. Our results identified methodological shortcomings, namely the use of a flexible dose design and the exclusion of concentrations in lower- or subtherapeutic ranges, which significantly moderate the relationship between antidepressant concentration and efficacy. Such shortcomings obscure the evidence base of using TDM in clinical practice to guide antidepressant drug therapy. Further research should consider these findings to determine the relationship between concentration and efficacy and safety of antidepressant treatments, especially for newer antidepressants. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246149, identifier: CRD42021246149.

Effectiveness of Individual Cognitive-Behavioral Therapy and Predictors of Outcome in Adult Patients with Obsessive-Compulsive Disorder.

INTRODUCTION: Cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) has proven its efficacy in randomized controlled trials (RCTs). OBJECTIVE: To test generalizability to routine care settings, we conducted an effectiveness study to provide naturalistic outcome data and their predictors. METHODS: Pre-post changes in symptoms and impairment as well as response rates were determined in a naturalistic OCD sample (intention-to-treat, ITT, n = 393). Patients received individual CBT for OCD adopting an exposure-based, non-manualized treatment format. Linear and logistic regression analyses were applied to identify associations of sociodemographic and clinical variables with symptom change. RESULTS: Effect size in ITT patients amounted to d = 1.47 in primary outcome (Yale-Brown Obsessive-Compulsive Scale, Y-BOCS). Remission rates were 46.3% (ITT), 52.0% (completers), and 18.2% (non-completers). The rates of treatment response without remission, no change, and deterioration in the ITT sample were 13.2, 38, and 3%, respectively. Initial symptom severity, comorbid personality disorder, and unemployment were associated with a poorer outcome, and previous medication with a better outcome. Comorbid depressive and anxiety disorders as well as other clinical or sociodemographic variables showed no effects on symptom change. CONCLUSIONS: Outcomes in this large observational trial in a naturalistic setting correspond to available RCT findings suggesting that CBT for OCD should be strongly recommended for dissemination in routine care. Targets for further research include early prediction of non-response and development of alternative treatment strategies for patients who respond insufficiently.

Mechanisms of exposure and response prevention in obsessive-compulsive disorder: effects of habituation and expectancy violation on short-term outcome in cognitive behavioral therapy.

BACKGROUND: Exposure and response prevention is effective and recommended as the first choice for treating obsessive-compulsive disorders (OCD). Its mechanisms of action are rarely studied, but two major theories make distinct assumptions: while the emotional processing theory assumes that treatment effects are associated with habituation within and between exposure sessions, the inhibitory learning approach highlights the acquisition of additional associations, implying alternative mechanisms like expectancy violation. The present study aimed to investigate whether process variables derived from both theories predict short-term outcome. METHOD: In a university outpatient unit, 110 patients (63 female) with OCD received manual-based cognitive-behavioral therapy with high standardization of the first two exposure sessions. Specifically, therapists repeated the first exposure session identically and assessed subjective units of distress as well as expectancy ratings in the course of exposure sessions. Based on these data, individual scores for habituation and distress-related expectancy violation were calculated and used for prediction of both percentage change on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and remission status after 20 therapy sessions. RESULTS: In a multiple regression model for percentage change, within-session habituation during the first exposure was a significant predictor, while in a logistic regression predicting remission status, distress-related expectancy violation during the first exposure revealed significance. A path model further supported these findings. CONCLUSIONS: The results represent first evidence for distress-related expectancy violation and confirm preliminary findings for habituation, suggesting that both processes contribute to treatment benefits of exposure in OCD, and both mechanisms appear to be independent.

Impaired differential learning of fear versus safety signs in obsessive-compulsive disorder.

Pavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict treatment outcomes in patients, and whether they are etiologically relevant for OCD.

Identifying CBT non-response among OCD outpatients: A machine-learning approach.

Objectives: Machine learning models predicting treatment outcomes for individual patients may yield high clinical utility. However, few studies tested the utility of easy to acquire and low-cost sociodemographic and clinical data. In previous work, we reported significant predictions still insufficient for immediate clinical use in a sample with broad diagnostic spectrum. We here examined whether predictions will improve in a diagnostically more homogeneous yet large and naturalistic obsessive-compulsive disorder (OCD) sample. Methods: We used sociodemographic and clinical data routinely acquired during CBT treatment of n = 533 OCD subjects in a specialized outpatient clinic. Results: Remission was predicted with 65% (p = 0.001) balanced accuracy on unseen data for the best model. Higher OCD symptom severity predicted non-remission, while higher age of onset of first OCD symptoms and higher socioeconomic status predicted remission. For dimensional change, prediction achieved r = 0.31 (p = 0.001) between predicted and actual values. Conclusions: The comparison with our previous work suggests that predictions within a diagnostically homogeneous sample, here OCD, are not per se superior to a more diverse sample including several diagnostic groups. Using refined psychological predictors associated with disorder etiology and maintenance or adding further data modalities as neuroimaging or ecological momentary assessments are promising in order to further increase prediction accuracy.

Long-Term Stability of Benefits of Cognitive Behavioral Therapy for Obsessive Compulsive Disorder Depends on Symptom Remission During Treatment.

Background: Cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) and may afford stable long-term improvements. It is not clear, however, how stability or symptom recurrence can be predicted at the time of termination of CBT. Method: In a 1-year follow-up intention-to-treat study with 120 OCD patients receiving individual CBT at a university outpatient unit, we investigated the predictive value of international consensus criteria for response only (Y-BOCS score reduction by at least 35%) and remission status (Y-BOCS score ≤ 12). Secondly, we applied receiver-operating characteristic (ROC) curves in order to find an optimal cut-off score to classify for deterioration and for sustained gains. Results: Response only at post-treatment increased the likelihood of deterioration at follow-up compared to remission at an odds ratio of 8.8. Moreover, ROC curves indicated that a post-treatment score of ≥ 13 differentiated optimally between patients with and without symptom deterioration at follow-up assessment. The optimal cut-off score to classify for any sustained gains (response, remission, or both) at follow-up relative to baseline was 12. Importantly, previous findings of generally high long-term symptom stability after treatment in OCD could be replicated. Conclusion: The findings highlight the clinical importance of reaching remission during CBT, and suggest that a recently published expert consensus for defining remission has high utility.

Decomposing mechanisms of abnormal saccade generation in schizophrenia patients: Contributions of volitional initiation, motor preparation, and fixation release.

Clinical and theoretical models suggest deficient volitional initiation of action in schizophrenia patients. Recent research provided an experimental model of testing this assumption using saccade tasks. However, inconsistent findings necessitate a specification of conditions on which the deficit may occur. The present study sought to detect mechanisms that may contribute to poor performance. Sixteen schizophrenia patients and 16 healthy control participants performed visually guided and two types of volitional saccade tasks. All tasks varied as to whether the initial fixation stimulus disappeared (fixation stimulus offset) or continued during saccade initiation, and whether a direction cue allowed motor preparation of the specific saccade. Saccade latencies of the two groups were differentially affected by task type, fixation stimulus offset, and cueing, suggesting abnormal volitional saccade generation, fixation release, and motor preparation in schizophrenia. However, substantial performance deficits may only occur if all affected processes are required in a task.