Patient adherence as a predictor of acute and long-term outcomes in concentrated exposure treatment for difficult-to-treat obsessive-compulsive disorder.

BACKGROUND: Exposure and response prevention (ERP) is considered the first-line psychotherapy for obsessive-compulsive disorder (OCD). Substantial research supports the effectiveness of ERP, yet a notable portion of patients do not fully respond while others experience relapse. Understanding poor outcomes such as these necessitates further research. This study investigated the role of patient adherence to ERP tasks in concentrated exposure treatment (cET) in a sample who had previously not responded to treatment or relapsed. METHOD: The present study included 163 adults with difficult-to-treat OCD. All patients received cET delivered during four consecutive days. Patients' treatment adherence was assessed using the Patient EX/RP Adherence Scale (PEAS-P) after the second and third day of treatment. OCD severity was evaluated at post-treatment, 3-month follow-up, and 1-year follow-up by independent evaluators. RESULTS: PEAS-P scores during concentrated treatment were associated with OCD-severity at post-treatment, 3-month follow-up, and 1-year follow-up. Moreover, PEAS-P scores predicted 12-month OCD severity adjusting for relevant covariates. Adherence also predicted work- and social functioning at 1-year follow-up. CONCLUSIONS: These results indicate that ERP adherence during the brief period of cET robustly relates to improvement in OCD symptoms and functioning in both the short and long term. Assessing adherence might identify patients at risk of poor outcomes, while improving adherence may enhance ERP for treatment resistant patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656342.

Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

The Bergen 4-day treatment for social anxiety disorder: a pilot study.

BACKGROUND: Few studies have examined the use of concentrated and intensified cognitive behaviour therapy for treating social anxiety disorder (SAD). The aim of this study was to examine the feasibility of the Bergen 4-Day Treatment (B4DT) for treating SAD. METHODS: This study adopted an open trial design without a control group. Thirty consecutively referred patients who were diagnosed with SAD were treated and assessed at pre-treatment, at post-treatment, and at the 3-month follow-up. The Liebowitz Social Anxiety Scale was used to assess symptoms of SAD; the Generalized Anxiety Disorder-7 scale was used to assess anxiety symptoms; and the Patient Health Questionnaire-9 was used to assess symptoms of anxiety and depression. The Client Satisfaction Questionnaire-8 was administered posttreatment. RESULTS: Overall, patients reported a high level of satisfaction with the B4DT. Large effect sizes were observed for symptoms of SAD (d = 1.94-2.66) and for the secondary outcomes, i.e., generalized anxiety (d = 0.86-0.99) and depression (d = 0.62-0.83). The remission rate was 55.2% at follow-up, while the treatment response rate was 89.7%. CONCLUSIONS: The B4DT is a promising treatment approach for patients with SAD. In the future, controlled trials should be performed to compare the efficacy of this treatment approach with standard outpatient treatment. Practical consequences, policy implications, and suggestions for future research are discussed herein.

White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

The effectiveness and acceptability of the Bergen 4-day treatment for adolescents with OCD: a replication and extension.

BACKGROUND: B4DT is a concentrated treatment format with prolonged sessions of exposure and ritual prevention (ERP) delivered over four consecutive days. Two previous open trials demonstrated promising results of the Bergen 4-day treatment (B4DT) for adolescents with obsessive-compulsive disorder (OCD). The aim of the current study was to replicate the initial results with a new sample of adolescents and different therapists at different sites across Norway. METHODS: Forty-three youths participated in treatment program. At pretreatment, posttreatment, and the three-month follow-up, OCD symptoms were assessed using the CY-BOCS interview, while the GAD-7 and PHQ-9 were administered to rate general anxiety symptoms and depressive symptoms. Acceptability and patient satisfaction with the treatment were rated with the CSQ-8. RESULTS: All symptoms were significantly reduced at posttreatment and follow-up. At posttreatment, 36 patients (85.71%) were defined as responders, while 29 patients (69.05%) achieved remission. At the three-month follow-up, 36 patients (92.3%) were defined as responders, while 33 patients (84.62%) were in remission. CSQ-8 scores indicated that the patients were highly satisfied with the treatment. CONCLUSIONS: The B4DT was successfully replicated in a new sample at different sites across Norway, which indicates that this treatment is generalizable, effective and acceptable to adolescents with OCD.

A Burden of Rare Copy Number Variants in Obsessive-Compulsive Disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2,248 deeply phenotyped OCD cases and 3,608 unaffected controls from Sweden and Norway. We found that in general cases carry an elevated burden of large (>30kb, at least 15 probes) CNVs (OR=1.12, P=1.77×10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P=2.58×10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR=1.19, P=3.08×10-4), particularly deletions impacting loss-of-function intolerant genes (pLI>0.995, OR=4.12, P=2.54×10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60×10-3). In cases where sufficient clinical data were available (n=1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P<0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P=0.02). The results demonstrate a contribution of large, rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

Does the use of polymethyl-methacrylate cement after intralesional curettage of giant cell tumors of appendicular bone guarantee reduced local recurrence rates? A retrospective analysis.

PURPOSE: Polymethyl-methacrylate cement (PMMA) is often used as bone defect reconstruction material after surgical removal of giant cell tumors. The purpose of this study was to investigate if the application of PMMA improves the local recurrence rates for giant cell tumors (GCT) of appendicular bone treated with intralesional curettage. METHODS: A retrospective analysis of all appendicular GTCs treated at two major Danish sarcoma centres between the 1st of January 1998 and December 31st 2013; minimum follow-up of 3.0 years (median: 8.9; 1.3-18.7 years). Kaplan-Meier survival model, log-rank and multivariate Cox regression were used to calculate and compare local recurrence rates. p-values <0.05 were considered statistically significant. RESULTS: 102 patients (M59/F43), median age 31Y (11-84) were included in this study. The overall 3-years local recurrence-rate was 19.9% (95%CI: 11.9-27.9%); 91% had occurred within 3 years. In patients treated with intralesional curettage (n = 64), the 3-years recurrence-rate was 30.6% (95%CI: 18.8-42.4%), compared to 2.6% (95%CI: 0.0-7.8%) in patients treated with wide resection or amputation (n = 38), p < .001. The 3-years recurrence-rate for patients treated with intralesional curettage and reconstruction using PMMA was 29.0% (95%CI: 12.6-45.4%) and without PMMA: 31.8% (95%CI: 15.2-48.4%), p = .83. CONCLUSION: We found that the use of PMMA for bone defect reconstruction after intralesional curettage of GTCs in the appendicular skeleton did not ensure a reduced risk of local recurrence.

The Bergen 4-day treatment for panic disorder: adapting to COVID-19 restrictions with a hybrid approach of face-to-face and videoconference modalities.

BACKGROUND: The Bergen 4-day treatment (B4DT) is a concentrated exposure-based therapy that has been shown to be effective in the treatment of anxiety disorders. The current study sought to examine the effectiveness of B4DT for panic disorder (PD), when delivered with a combination of face-to-face sessions and videoconferencing. METHODS: Treatment was delivered to 50 patients from April 2020 to May 2021. Because of regulations during the pandemic, a significant portion of the treatment was conducted via videoconference. The primary outcome measure was the clinician-rated Panic Disorder Severity Scale (PDSS), and secondary measures included patient-rated symptoms of panic disorder, agoraphobia, generalized anxiety, depression, and treatment satisfaction. Changes in symptom levels over time were estimated using multilevel models. RESULTS: Patients showed a significant reduction in clinician-rated symptoms of panic disorder (Measured by PDSS) from before treatment to post treatment (d = 2.18) and 3-month follow-up (d = 2.01). At three months follow-up 62% of patients were classified as in remission, while 70% reported a clinically significant response. We also found a reduction in symptoms of depression and generalized anxiety, and the patients reported high satisfaction with the treatment. CONCLUSION: The current study suggests that B4DT delivered in a combination of videoconference and face-to-face meetings may be a useful treatment approach. As the study is uncontrolled, future studies should also include more strictly designed investigations.

The Bergen 4-day treatment for panic disorder: implementation in a rural clinical setting.

INTRODUCTION: The Bergen 4-Day Treatment (B4DT) is a concentrated treatment with individually tailored exposure exercises. The format has shown promising results in the treatment of panic disorder. AIM: The aim of the current study was to investigate the effectiveness of the B4DT in a large sample in a rural clinical setting. METHOD: Fifty-eight patients with panic disorder were consecutively included using an open trial design. The primary outcome measure was the Panic Disorder Severity Scale. The Generalized Anxiety Disorder-7 and the Patient Health Questionnaire-9 were used as secondary outcome measures. Assessments were conducted at pretreatment, posttreatment, and 3-month follow-up. Treatment satisfaction was measured at posttreatment using the Client Satisfaction Questionnaire-8. RESULTS: There was a significant reduction in symptoms of panic disorder from pre- to posttreatment (d = 3.36) and from pretreatment to follow-up (d = 3.63). At posttreatment and follow-up, 72.4% and 81.0% of patients, respectively, were classified as in remission. Patients reported high treatment satisfaction, and there were significant reductions in symptoms of generalized anxiety and depression. CONCLUSION: The results from the current study replicated the findings from previous studies using a larger sample size. The findings indicate that the B4DT is a promising treatment format for panic disorder. The study also demonstrated that the treatment format can be successfully implemented in new rural clinics.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Right Prefrontal Cortical Thickness Is Associated With Response to Cognitive-Behavioral Therapy in Children With Obsessive-Compulsive Disorder.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is considered a first-line treatment for obsessive-compulsive disorder (OCD) in pediatric and adult populations. Nevertheless, some patients show partial or null response. The identification of predictors of CBT response may improve clinical management of patients with OCD. Here, we aimed to identify structural magnetic resonance imaging (MRI) predictors of CBT response in 2 large series of children and adults with OCD from the worldwide ENIGMA-OCD consortium. METHOD: Data from 16 datasets from 13 international sites were included in the study. We assessed which variations in baseline cortical thickness, cortical surface area, and subcortical volume predicted response to CBT (percentage of baseline to post-treatment symptom reduction) in 2 samples totaling 168 children and adolescents (age range 5-17.5 years) and 318 adult patients (age range 18-63 years) with OCD. Mixed linear models with random intercept were used to account for potential cross-site differences in imaging values. RESULTS: Significant results were observed exclusively in the pediatric sample. Right prefrontal cortex thickness was positively associated with the percentage of CBT response. In a post hoc analysis, we observed that the specific changes accounting for this relationship were a higher thickness of the frontal pole and the rostral middle frontal gyrus. We observed no significant effects of age, sex, or medication on our findings. CONCLUSION: Higher cortical thickness in specific right prefrontal cortex regions may be important for CBT response in children with OCD. Our findings suggest that the right prefrontal cortex plays a relevant role in the mechanisms of action of CBT in children.

The Bergen 4-day treatment for panic disorder: replication and implementation in a new clinic.

BACKGROUND: Bergen 4-day treatment (B4DT) is a concentrated exposure-based treatment (cET), where the patient receives concentrated, individually tailored cognitive behavioral therapy (CBT) during four consecutive days. Previous findings have indicated that B4DT could be a promising treatment for panic disorder (PD). AIM: The aim of the present study was to evaluate the implementation of B4DT for panic disorder with- and without agoraphobia, at a new clinic. This is the first replication study for B4DT on panic disorder. METHOD: Thirty consecutively recruited patients with PD were included in an open trial design. Assessment of symptoms of panic disorder were measured with Panic Disorder Severity Scale (PDSS), while symptoms of generalized anxiety were assessed by Generalized Anxiety Disorder-7 (GAD-7) and depressive symptoms by Patient Health Questionnaire (PHQ-9) pre-treatment, post-treatment and at 3-month follow-up. Treatment satisfaction was measured with Client Satisfaction Questionnaire (CSQ-8) post-treatment. RESULTS: The results showed a significant reduction in symptom severity from pre-treatment to post-treatment (d = 4.32), and at 3-month follow-up (d = 4.91). The proportion of patients classified as fulfilling the criteria for remission was 80.0% at post-treatment and 86.7% at follow up. There was a significant reduction in symptoms of depression and generalized anxiety. Treatment satisfaction was high and none of the patients dropped out. CONCLUSION: The current study replicated the results from the original study and indicate that the treatment can be successfully implemented at new clinics. B4DT may be a promising treatment for panic disorder and comorbid symptoms of generalized anxiety and depression. Larger and more controlled studies are needed to establish the efficacy of B4DT for panic disorder.

Longitudinal changes in neurometabolite concentrations in the dorsal anterior cingulate cortex after concentrated exposure therapy for obsessive-compulsive disorder.

BACKGROUND: The dorsal anterior cingulate cortex (dACC) plays an important role in the pathophysiology of obsessive-compulsive disorder (OCD) due to its role in error processing, cognitive control and emotion regulation. OCD patients have shown altered concentrations in neurometabolites in the dACC, particularly Glx (glutamate+glutamine) and tNAA (N-acetylaspartate+N-acetyl-aspartyl-glutamate). We investigated the immediate and prolonged effects of exposure and response prevention (ERP) on these neurometabolites. METHODS: Glx and tNAA concentrations were measured using magnetic resonance spectroscopy (1H-MRS) in 24 OCD patients and 23 healthy controls at baseline. Patients received concentrated ERP over four days. A subset was re-scanned after one week and three months. RESULTS: No Glx and tNAA abnormalities were observed in OCD patients compared to healthy controls before treatment or over time. Patients with childhood or adult onset differed in the change over time in tNAA (F(2,40) = 7.24, É³2p= 0.27, p = 0.004): concentrations increased between one week after treatment and follow-up in the childhood onset group (t(39) = -2.43, d = -0.86, p = 0.020), whereas tNAA concentrations decreased between baseline and follow-up in patients with an adult onset (t(42) = 2.78, d = 1.07, p = 0.008). In OCD patients with versus without comorbid mood disorders, lower Glx concentrations were detected at baseline (t(38) = -2.28, d = -1.00, p = 0.028). Glx increased after one week of treatment within OCD patients with comorbid mood disorders (t(30) = -3.09, d = -1.21, p = 0.004). LIMITATIONS: Our OCD sample size allowed the detection of moderate to large effect sizes only. CONCLUSION: ERP induced changes in neurometabolites in OCD seem to be dependent on mood disorder comorbidity and disease stage rather than OCD itself.

Does Concentrated Exposure Treatment for Obsessive-Compulsive Disorder Improve Insomnia Symptoms? Results From a Randomized Controlled Trial.

Insomnia is a substantial problem in patients with obsessive-compulsive disorder (OCD). There is, however, a lack of studies investigating changes in concurrent symptoms of insomnia in OCD after concentrated treatment. A recent randomized controlled trial randomized participants to the Bergen 4-day treatment (B4DT, n = 16), or 12 weeks of unguided self-help (SH, n = 16), or waitlist (WL, n = 16). Patients from the SH- and WL-group who wanted further treatment after the 12 weeks were then offered the B4DT (total of 42 patients treated with the B4DT). There were no significant differences in symptoms of insomnia between the conditions at post-treatment, but a significant moderate improvement at 3-month follow-up for patients who received the B4DT. Insomnia was not associated with OCD-treatment outcome, and change in symptoms of insomnia was mainly related to changes in depressive symptoms. The main conclusion is that concentrated exposure treatment is effective irrespective of comorbid insomnia, and that insomnia problems are moderately reduced following treatment.

Treatment Adherence as Predictor of Outcome in Concentrated Exposure Treatment for Obsessive-Compulsive Disorder.

Background: The treatment of choice for obsessive-compulsive disorder (OCD) is exposure and response prevention (EX/RP). Previous studies have demonstrated that treatment adherence predicts treatment outcome for patients with OCD, but there is little knowledge on its role in concentrated exposure treatment for OCD. Method: In the present study, 42 patients received EX/RP treatment using the Bergen 4-day format. Adherence was measured with the Exposure and Response Prevention Adherence Scale (PEAS, rated both by patients and therapists) after the second and third day. Treatment outcome (symptoms of OCD, depression, anxiety, work- and social functioning, and well-being) was assessed at 3-month follow-up. Results: At follow-up, 71.4% were in remission. High adherence was reported (mean score of 6 on a 1-7 scale). The combination of patient- and therapist rated adherence was significantly associated with treatment outcome whilst controlling for age, sex, and pre-treatment scores. Patients with higher degree of adherence reported less symptoms, higher functioning, and more well-being at follow-up. Conclusions: The results of the present study indicated that adherence in concentrated exposure treatment is significantly associated with a wide range of treatment outcomes for OCD.

Diffusion Tensor Imaging Before and 3 Months After Concentrated Exposure Response Prevention in Obsessive-Compulsive Disorder.

Background: Subtle differences in white matter microstructure have been found in obsessive-compulsive disorder (OCD) compared to controls using diffusion tensor imaging (DTI), but it is unclear if and how this change after treatment. The primary aim of this pre-registered study was to investigate white matter integrity between OCD patients and controls and changes after concentrated exposure and response prevention (ERP). Methods: Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and mean diffusivity (MD) were estimated using FMRIB Software Library (FSL). The images were registered to a study-specific template using a longitudinal pipeline based on full tensor information in DTI-TK. Voxel-based analysis was performed using tract-based spatial statistics (TBSS). Using SPSS, we compared the integrity in three bilateral regions of interest (ROI), the sagittal stratum, posterior thalamic radiation and cingulum, in 32 OCD patients and 30 matched healthy controls at baseline. Patients received a four-day concentrated ERP format. We investigated longitudinal changes in 26 OCD patients and 22 healthy controls at 3months follow-up using repeated-measures ANOVA. Exploratory t-tests were conducted for AD and MD. Secondary hypothesis used linear regression to investigate if baseline FA predict treatment outcome 3 months later, and if patients with illness onset before 18 years of age would show lower FA in sagittal stratum. Finally, we performed sensitivity analysis on medication and comorbidity influences on FA. Results: Three months after treatment, 77% of the patients were in remission. Contrary to our hypotheses, we did not find any significant differences in FA, RD, AD or MD between the groups before treatment, nor significant group by time effects in any of the ROI. None of the baseline FA measures significantly predicted treatment outcome. Illness onset before 18 years of age did not significantly predict FA in the sagittal stratum. Adjusting for medication or comorbid anxiety or mood disorder did not influence the results. Conclusions: Although concentrated ERP in OCD lead to high remission, we did not find significant long-term changes by DTI. Future studies will benefit from using larger sample sizes and multi-shell diffusion-weighted imaging when investigating white matter microstructure in OCD and underlying neurobiological mechanisms of treatment.

A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice.

Hemophilia A is a bleeding disorder resulting from deficient factor VIII (FVIII), which normally functions as a cofactor to activated factor IX (FIXa) that facilitates activation of factor X (FX). To mimic this property in a bispecific antibody format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting bispecific antibody (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant of 16 nM. Binding affinity with FIXa and FX in solution was much lower, with equilibrium dissociation constant values for FIXa and FX of 2.3 and 1.5 µM, respectively. In addition, the activity of Mim8 was dependent on stimulatory activity contributed by the anti-FIXa arm, which enhanced the proteolytic activity of FIXa by 4 orders of magnitude. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation, with potencies 13 and 18 times higher than a sequence-identical analogue of emicizumab. A similar potency difference was observed in a tail vein transection model in hemophilia A mice, whereas reduction of bleeding in a severe tail-clip model was observed only for Mim8. Furthermore, the pharmacokinetic parameters of Mim8 were investigated and a half-life of 14 days shown in cynomolgus monkeys. In conclusion, Mim8 is an activated FVIII mimetic with a potent and efficacious hemostatic effect based on preclinical data.

Disentangling Within- and Between-Person Effects During Response Inhibition in Obsessive-Compulsive Disorder.

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment. Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity. Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity. Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.