Predicting heterogeneous treatment effects of an Internet-based depression intervention for patients with chronic back pain: Secondary analysis of two randomized controlled trials.

Background: Depression is highly prevalent among individuals with chronic back pain. Internet-based interventions can be effective in treating and preventing depression in this patient group, but it is unclear who benefits most from this intervention format. Method: In an analysis of two randomized trials (N = 504), we explored ways to predict heterogeneous treatment effects of an Internet-based depression intervention for patients with chronic back pain. Univariate treatment-moderator interactions were explored in a first step. Multilevel model-based recursive partitioning was then applied to develop a decision tree model predicting individualized treatment benefits. Results: The average effect on depressive symptoms was d = -0.43 (95 % CI: -0.68 to -0.17; 9 weeks; PHQ-9). Using univariate models, only back pain medication intake was detected as an effect moderator, predicting higher effects. More complex interactions were found using recursive partitioning, resulting in a final decision tree with six terminal nodes. The model explained a large amount of variation (bootstrap-bias-corrected R2 = 45 %), with predicted subgroup-conditional effects ranging from di = 0.24 to -1.31. External validation in a pilot trial among patients on sick leave (N = 76; R2 = 33 %) pointed to the transportability of the model. Conclusions: The studied intervention is effective in reducing depressive symptoms, but not among all chronic back pain patients. Predictions of the multivariate tree learning model suggest a pattern in which patients with moderate depression and relatively low pain self-efficacy benefit most, while no benefits arise when patients' self-efficacy is already high. If corroborated in further studies, the developed tree algorithm could serve as a practical decision-making tool.

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.

Lack of speeded disengagement from facial expressions of disgust in remitted major depressive disorder: Evidence from an eye-movement study.

Acute major depression is characterized by specific abnormalities in the way emotional material is attended to. In late stages of stimulus processing, clinically depressed and dysphoric individuals show difficulties to disengage attention from emotionally negative material. It is unclear, however, whether aberrant disengagement is a transitory attentional phenomenon tied to depressive symptoms, or whether it constitutes a more stable disposition that outlast the symptomatic episode. To address this issue, the current study examined 39 currently euthymic individuals previously affected by major depression (RMD) and 40 healthy control participants reporting no lifetime psychopathology (ND). We used a gaze-contingent eye tracking paradigm designed to separately assess the attentional components of engagement and disengagement when viewing facial expressions of sadness, disgust and happiness. Never-depressed healthy participants, but not remitted euthymic individuals, showed speeded disengagement from facial expressions of disgust. We propose that the lack of this distinct acceleration in previously depressed but fully remitted individuals might reflect an attentional disposition that carries over to euthymic phases of the disease. On the other hand, a tendency to disengage quickly from areas in the visual field that convey social disdain could potentially act as a protective, possibly mood-stabilizing bias in resilient 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.

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.

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.

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.

Systematic evaluation of the 'efficacy-effectiveness gap' in the treatment of depression with venlafaxine and duloxetine.

OBJECTIVE: Evidence of larger drug effects in highly standardized studies (efficacy) compared to clinical routine (effectiveness) is discussed as efficacy-effectiveness gap. This study aimed to quantify effect size differences of RCTs and non-RCTs in the treatment of depression with venlafaxine and duloxetine and to identify effect modifying predictors. METHODS: A comprehensive systematic review and meta-analysis was conducted, including all prospective trials, which evaluated the treatment effects of duloxetine or venlafaxine in patients with depression. The primary outcome was the pre-post effect size after acute therapy, which were compared between RCTs and non-RCTs. Moreover, an exploratory analysis of predictors in a mixed meta-regression model within an information-theoretic approach was performed. RESULTS: 171 RCTs and 74 non-RCTs were included. The pre-post effect size differed significantly between RCTs and non-RCTs (-3.04 vs. -2.62, Δ = 0.41, p = 0.012, high heterogeneity). Study characteristics were very similar between RCTs and non-RCTs. Most important variables to predict effect sizes were 'depression severity', 'dose' and 'number of participants'. CONCLUSION: Despite differences in effect sizes between RCTs and non-RCTs, study design is not clearly an important predictor for the effect sizes. Our results question the common assumption that non-RCTs are generally better suited to describe a drug's effectiveness in clinical practice than RCTs. Future studies and their reporting should put more emphasis on the description of external validity, in order to allow better assessments of clinical relevance.

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.

Dwelling on verbal but not pictorial threat cues: An eye-tracking study with adult survivors of childhood interpersonal violence.

OBJECTIVE: Previous studies have found evidence of an attentional bias for trauma-related stimuli in posttraumatic stress disorder (PTSD) using eye-tracking (ET) technlogy. However, it is unclear whether findings for PTSD after traumatic events in adulthood can be transferred to PTSD after interpersonal trauma in childhood. The latter is often accompanied by more complex symptom features, including, for example, affective dysregulation and has not yet been studied using ET. The aim of this study was to explore which components of attention are biased in adult victims of childhood trauma with PTSD compared to those without PTSD. METHOD: Female participants with (n = 27) or without (n = 27) PTSD who had experienced interpersonal violence in childhood or adolescence watched different trauma-related stimuli (Experiment 1: words, Experiment 2: facial expressions). We analyzed whether trauma-related stimuli were primarily detected (vigilance bias) and/or dwelled on longer (maintenance bias) compared to stimuli of other emotional qualities. RESULTS: For trauma-related words, there was evidence of a maintenance bias but not of a vigilance bias. For trauma-related facial expressions, there was no evidence of any bias. CONCLUSIONS: At present, an attentional bias to trauma-related stimuli cannot be considered as robust in PTSD following trauma in childhood compared to that of PTSD following trauma in adulthood. The findings are discussed with respect to difficulties attributing effects specifically to PTSD in this highly comorbid though understudied population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Getting it just right: A reevaluation of OCD symptom dimensions integrating traditional and Bayesian approaches.

Previous research using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) suggests that the heterogeneous symptoms of obsessive-compulsive disorder (OCD) may reflect four underlying dimensions. However, past results vary substantially, which may be due to (a) the reliance on aggregated scores, (b) the common use of exploratory factor analyses, and (c) the exclusion of several symptoms. The present study tested the homogeneity of the original Y-BOCS categories using confirmatory factor analysis and modified categories where necessary. To test multidimensional models, data were further analyzed with Bayesian structural equation models, which better capture item heterogeneity in contrast to ordinary factor analysis. All analyses were run with two samples of patients with OCD allowing for cross-validation. Only a minority of the original Y-BOCS categories proved to be homogeneous. Modification yielded 10 homogeneous first-order factors, which can be reduced to four second-order factors: Incompleteness, Taboo Thoughts, Responsibility, and Contamination. This two-level factor model outperformed competing factor structures. The results corroborate the notion of four broader symptom dimensions in OCD, although the specific factor structure deviates from previous research. Differences presumably derive from using the full range of OCD symptoms and the combined exploratory and confirmatory approach with BSEM as a theoretically more appropriate analytical framework.

[Coercive Interventions in Psychiatry: Prevention and Patients' Preferences]. / Psychiatrische Zwangsmaßnahmen: Prävention und Präferenzen aus Patientenperspektive.

Objective This study explores patients' preferences and measures of prevention of coercive methods in psychiatric treatment. Methods Structured interviews of 90 patients with psychotic disorders were undertaken, most of whom had previously experienced coercive methods. Results Participants saw preventive potential in a wider availability of individual non-pharmacological therapy, improvement of staff professional competence and communication skills, high staff-to-patient ratios and retreat facilities. The majority of participants preferred forced medication and manual restraint in case of self-endangerment, and forced medication and mechanical restraint in the event of endangerment of others. Conclusion Patients' suggestions relating to prevention of coercion are in line with most expert's opinions. In case coercive methods are required, manual restraint and application of forced medication is accepted as the treatment of choice according to most patients in case of self-endangerment.

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.

Assessment of self-disorders in a non-clinical population: Reliability and association with schizotypy.

This study explores whether self-disorders occur and can be assessed reliably in a non-clinical sample, and whether the prevalence of these anomalies depends upon the degree of psychometrically defined schizotypy. Participants with either high (n=30) or low (n=20) schizotypy scores were interviewed using a modified version of the Examination of Anomalous Self-Experience (EASE). The degree to which interviewees experienced self-disorder symptoms was rated by the interviewer and an independent rater. Inter-rater reliability was calculated for each item, domain scores and the total score. For the total, sample most items (=66) showed substantial or perfect agreement (κ>0.61), with a few (=6) showing moderate agreement (κ>0.41). Reliability scores were only slightly lower when just the more homogeneous group of individuals with high Schizotypal Personality Questionnaire (SPQ) scores were examined. As expected, high SPQ scores were associated with a high level of self-disorders. In sum, the results suggest that self-disorders can be measured reliably in non-clinical samples and are particularly frequent in individuals with pronounced schizotypical traits.

Differential roles of the frontal and parietal cortices in the control of saccades.

Although externally as well as internally-guided eye movements allow us to flexibly explore the visual environment, their differential neural mechanisms remain elusive. A better understanding of these neural mechanisms will help us to understand the control of action and to elucidate the nature of cognitive deficits in certain psychiatric populations (e.g., schizophrenia) that show increased latencies in volitional but not visually-guided saccades. Both the superior precentral sulcus (sPCS) and the intraparietal sulcus (IPS) are implicated in the control of eye movements. However, it remains unknown what differential contributions the two areas make to the programming of visually-guided and internally-guided saccades. In this study we tested the hypotheses that sPCS and IPS distinctly encode internally-guided saccades and visually-guided saccades. We scanned subjects with fMRI while they generated visually-guided and internally-guided delayed saccades. We used multi-voxel pattern analysis to test whether patterns of cue related, preparatory and saccade related activation could be used to predict the direction of the planned eye movement. Results indicate that patterns in the human sPCS predicted internally-guided saccades but not visually-guided saccades in all trial periods and patterns in the IPS predicted internally-guided saccades and visually-guided saccades equally well. The results support the hypothesis that the human sPCS and IPS make distinct contributions to the control of volitional eye movements.

Neural correlates of impaired volitional action control in schizophrenia patients.

Slowed initiation of volitional but not visually guided saccades indicates impaired volitional action control in schizophrenia patients (SZ). The present study aimed at identifying neural correlates of this specific deficit. Fourteen SZ and 13 healthy control participants (HC) underwent functional magnetic resonance imaging while performing volitional and visually guided saccades. SZ showed increased latencies in volitional but not in visually guided saccades. Brain activation during volitional saccades compared to visually guided saccades was increased in SZ compared to HC in several areas: the supplementary eye fields, suggesting inefficient production of volitional saccades; the prefrontal cortex, pointing to altered top down control on complex eye movements; and the left middle temporal area, suggesting changes in early sensory and attention processing during the volitional control of saccades in SZ.