Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: A preliminary investigation.

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

Longitudinal study of gut microbiome in obsessive-compulsive disorder.

INTRODUCTION: Patients with obsessive-compulsive disorder (OCD) often have limited exposure to a diverse environment and perform repetitive compulsions such as excessive cleaning and washing, which could lead to altered gut microbiome. Therefore, longitudinal studies that investigate changes in gut microbiome before and after cognitive behavioral therapy based on exposure and response prevention (ERP) are warranted. METHODS: All study participants (N = 64) underwent a structured psychiatric diagnostic interview prior to inclusion. Nutritional intake was assessed with a comprehensive food frequency questionnaire. Stool samples were collected from OCD patients before ERP (n = 32) and 1 month after completion of ERP (n = 15), as well as from healthy controls (HCs; n = 32). Taxonomic and functional analyses were performed using data from microbiome whole genome sequencing. RESULTS: Patients with OCD at baseline reported consuming significantly less fiber than HCs (R2  = .12, F(2, 59) = 5.2, p ≤ .01). There were no significant differences in α- and ß-diversity indices, or taxonomic dissimilarities at the species level between patients with OCD and HCs, or within patients before and after ERP. Functional profiling based on gut microbial gene expression was grouped into 56 gut-brain modules with neuroactive potential. None of the gut-brain modules differed significantly in expression between patients with OCD at baseline and HCs or within patients before and after ERP. CONCLUSIONS: The diversity, composition, and functional profile of the gut microbiome in patients with OCD did not differ significantly from HCs and remained stable over time, despite behavioral changes.

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation.

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

Effectiveness of Internet-based cognitive-behavioural therapy for obsessive-compulsive disorder (OCD-NET) and body dysmorphic disorder (BDD-NET) in the Swedish public health system using the RE-AIM implementation framework.

Objectives: Therapist-guided internet-delivered cognitive behaviour therapy (ICBT) is an efficacious treatment for obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD), but it is unclear if the results obtained in controlled trials can be reproduced in clinical settings. We evaluated the implementation of ICBT for OCD (OCD-NET) and BDD (BDD-NET) in the Swedish public health system. Methods: Consecutive referrals to an outpatient psychiatric clinic providing ICBT, with a primary diagnosis of OCD or BDD, were included in the study. Four hundred and thirty-four participants started OCD-NET and 163 started BDD-NET. The primary outcome measures were the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the Y-BOCS for BDD (BDD-YBOCS), respectively. Participants were assessed before treatment, weekly during treatment, and after treatment. The study used the RE-AIM implementation framework, and the elements of reach, effectiveness, adoption, and implementation for the evaluation. Results: Intention to treat analysis of the OCD-NET sample (n = 434) showed a significant decrease in OCD symptoms from pre-treatment to post-treatment (mean reduction = -8.77 [95 % CI -9.48 to -8.05] p < .001, d = 1.94 [95 % CI 1.75 to 2.13]). Forty-nine percent (95 % CI 43 % to 56 %) of the participants in OCD-NET were classified as treatment responders and 21 % (95 % CI 16 % to 27 %) were in remission. Participants in BDD-NET (n = 163) also showed a significant decrease in BDD symptoms from pre-post treatment (mean reduction = -11.37 [95 % CI -12.9 to -9.87] p < .001, d = 2.07 [95 % CI 1.74 to 2.40]) and 69 % (95 % CI 58 % to 79 %) of the participants were classified as treatment responders and 48 % (95 % CI 38 % to 58 %) were in full or partial remission. Eighty-seven percent of the participants in OCD-NET and 78 % in BDD-NET were treatment completers and participants in both treatment groups reported a high treatment satisfaction at post treatment (OCD-NET = 87 %, BDD-NET = 79 %). The most reported negative effects attributed to the treatments were transient experiences of unpleasant feelings (52 %) and anxiety (50 %). The implementation also influenced treatment delivery and dramatically decreased the mean number of patients waiting to receive face-to-face treatment at the clinic. Conclusions: Our results indicate that OCD-NET and BDD-NET are suitable treatments for implementation in a Swedish public health service.

Empirically Defining Treatment Response and Remission in Obsessive-Compulsive Disorder Using the Obsessive-Compulsive Inventory-Revised.

In clinical trials of obsessive-compulsive disorder (OCD), clinical outcomes are generally measured using lengthy clinician-administered interviews. However, in routine clinical practice, many clinicians lack the time to administer such instruments. This study evaluated cutoffs for treatment response and remission in OCD using the self-rated Obsessive-Compulsive Inventory-Revised (OCI-R). Data from 349 patients in three clinical trials of cognitive-behavioral therapy for OCD were pooled for analysis. The OCI-R was compared to gold-standard criteria for response and remission based on the clinician-administered Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impression Scale. The results showed that a ≥40% reduction on the OCI-R was the optimal cutoff for treatment response, with a sensitivity of 0.72 and a specificity of 0.79. For remission status, the optimal cutoff was ≤8 points on the OCI-R, with a sensitivity of 0.57 and specificity of 0.83. Results from additional analyses using the 12-item version of the OCI were similar. These cutoffs provide a simple and time-efficient way to help determine treatment response and remission in OCD when the administration of clinician-administered instruments is unfeasible.

Executive functioning in body dysmorphic disorder and obsessive-compulsive disorder.

OBJECTIVE: To assess executive functions (EFs) in patients with body dysmorphic disorder (BDD) and obsessive-compulsive disorder (OCD) compared with healthy controls. METHODS: Adults diagnosed with BDD (n = 26) or OCD (n = 29) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and healthy controls (n = 28) underwent validated and computerized neuropsychological tests, spatial working memory (SWM), intra-extra-dimensional set shifting (IED), and stop signal task (SST), from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Test performance was compared between groups, and correlated with standardized symptom severity of BDD and OCD. Significance level was set to P < .05. RESULTS: There were no statistically significant between-group differences on key outcome measures in SWM, IED, or SST. There was a weak positive correlation between symptom severity and test errors on SWM and IED in both OCD and BDD groups; increased clinical severity was associated with more errors in these tests. Furthermore, there was a negative correlation between symptom severity and SST in the BDD group. CONCLUSIONS: Patients with BDD or OCD did not differ from healthy control subjects in terms of test performance; however, there were several statistically significant correlations between symptom severity and performance in those with BDD or OCD. More studies on EFs in BDD and OCD are required to elucidate if there are differences in EFs between these two disorders.

Empirically Defining Treatment Response and Remission in Body Dysmorphic Disorder Using a Short Self-Report Instrument.

Determining response or remission status in body dysmorphic disorder (BDD) usually requires a lengthy interview with a trained clinician. This study sought to establish empirically derived cutoffs to define treatment response and remission in BDD using a brief self-report instrument, the Appearance Anxiety Inventory (AAI). Results from three clinical trials of BDD were pooled to create a sample of 123 individuals who had received cognitive-behavioral therapy for BDD, delivered via the Internet. The AAI was compared to gold-standard criteria for response and remission in BDD, based on the clinician-administered Yale-Brown Obsessive Compulsive Scale, modified for BDD (BDD-YBOCS), and evaluated using signal detection analysis. The results showed that a ≥ 40% reduction on the AAI best corresponded to treatment response, with a sensitivity of 0.71 and a specificity of 0.84. A score ≤ 13 at posttreatment was the optimal cutoff in determining full or partial remission from BDD, with a sensitivity of 0.75 and a specificity of 0.88. These findings provide benchmarks for using the AAI in BDD treatment evaluation when resource-intensive measures administered by clinicians are not feasible.

Gut Microbiota in Psychiatric Disorders: A Systematic Review.

OBJECTIVE: This systematic review sought to comprehensively summarize gut microbiota research in psychiatric disorders following PRISMA guidelines. METHODS: Literature searches were performed on databases using keywords involving gut microbiota and psychiatric disorders. Articles in English with human participants up until February 13, 2020, were reviewed. Risk of bias was assessed using a modified Newcastle-Ottawa Scale for microbiota studies. RESULTS: Sixty-nine of 4231 identified studies met the inclusion criteria for extraction. In most studies, gut microbiota composition differed between individuals with psychiatric disorders and healthy controls; however, limited consistency was observed in the taxonomic profiles. At the genus level, the most replicated findings were higher abundance of Bifidobacterium and lower abundance of Roseburia and Faecalibacterium among patients with psychiatric disorders. CONCLUSIONS: Gut bacteria that produce short-chain fatty acids, such as Roseburia and Faecalibacterium, could be less abundant in patients with psychiatric disorders, whereas commensal genera, for example, Bifidobacterium, might be more abundant compared with healthy controls. However, most included studies were hampered by methodological shortcomings including small sample size, unclear diagnostics, failure to address confounding factors, and inadequate bioinformatic processing, which might contribute to inconsistent results. Based on our findings, we provide recommendations to improve quality and comparability of future microbiota studies in psychiatry.

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

[Deep brain stimulation can break vicious circle in obsessive-compulsive disorder]. / Djup hjärnstimulering kan bryta ond cirkel vid tvångssyndrom.

Obsessive-compulsive disorder (OCD), characterized by repetitive intrusive thoughts and ritualized behaviors, is a highly debilitating disorder with an estimated lifetime prevalence of about 2 %. Approximately 10 % of these patients have severe symptoms despite having received all available treatments, thus considered treatment refractory. Deep brain stimulation (DBS), a reversible, safe and adaptive method widely used for movement disorders, enables specific targeting of deep brain structures of relevance in OCD. About 60% of the patients with treatment refractory OCD show ameliorated symptoms and improved quality of life with DBS. Taking ethical aspects into consideration DBS is a viable option for patients with treatment refractory OCD though further studies are needed to fully understand and individualize this treatment.

The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2.

Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

[Effects of nasal continuous positive airway pressure short-term treatment on C-reactive protein and intercellular adhesion molecule-1 in patients with obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To investgate the effects of nasal continuous positive airway pressure (nC-PAP) short-term treatment on the serum level of C-reactive protein (CRP) and intercellular adhesion molecule-1 in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. METHODS: Twenty patients with OSAHS ( AHI > or = 15 ) and 15 controls (AHI < 15) were recruited. After polysomnography (PSG), the venous blood was collected from all subjects to investigate CRP and ICAM-1. The effects of short-term treatment (4 d) of nCPAP on the serum levels of CRP and ICAM-1 were studied in patients with moderate and severe OSAHS. RESULTS: Before the treatment, there was a significant positive correlation between CRP and AHI in all subjects (r = 0.615, P < 0.001), a significant negative correlation between CRP and the mean nocturnal oxygen saturation (r = -0.682, P < 0.001), and a significant negative correlation between CRP and the lowest nocturnal SaO2 (r = -0.61, P < 0.001). There was a significant positive correlation between ICAM-1 and AHI in all subjects (r = 0.751, P < 0.001), a significant negative correlation between ICAM-1 and the mean nocturnal oxygen saturation (r = -0.68, P < 0.001), and a significant negative correlation between ICAM-1 and the lowest nocturnal oxygen saturation (r = -0.656, P < 0.001). There was a significant positive correlation between CRP and ICAM-1 (r = 0.437, P = 0.009). The levels of CRP and ICAM-1 were significantly higher in patients with moderate and severe OSAHS than in the controls (P < 0.01). nCPAP decreased the levels of CRP and ICAM-1 in patients with moderate and severe OSAHS (P < 0.01). CONCLUSION: Inflammatory reaction exists in OSAHS and can be palliated after nCPAP short-term treatment.

[The study of soluble P-selectin levels and it's correlation to the severity of coronary artery lesions in coronary heart disease].

OBJECTIVE: To investigate the difference of soluble P-selectin levels in different subtype of coronary heart disease and the relationship between soluble P-selectin levels with the severity of coronary artery lesions. METHODS: Enzyme linked immuoserbent assay (ELISA) was used to measure the plasma soluble P-selectin levels in 69 patients with angiocardiography documented coronary heart disease and 19 normal coronary arteries persons without angiocardiography detectable coronary artery disease (control group). The coronary artery lesions score was recorded according to single, double and triple-vessel lesions while the American College of Cardiology and the American Heart Association proposed type A, B, C lesion and Gensini scoring system. The relationships between plasma soluble P-selectin levels and the coronary artery score (the severity of coronary heart disease) were assessed. RESULTS: (1) The level of plasma soluble P-selectin was obviously higher in the coronary heart disease group than in the control group (180.6 +/- 60.5 ng/L vs. 145.3 +/- 21.7 ng/L, P<0.05). (2) The level of plasma soluble P-selectin was significantly higher in the acute coronary syndrome group (191.4 +/- 63.7 ng/L) than in the control group (145.3 +/- 21.7 ng/L, P< 0.01) and in the stable angina pectoris group (141.3 +/- 17.9 ng/L, P<0.01). (3) The level of plasma soluble P-selectin was high in multi-vessel coronary artery lesions group than in single-vessel group (190.1 +/- 64.2 ng/L vs. 157.2 +/- 43.4 ng/L, P < 0.05). The level of plasma soluble P-selectin was positively correlated with the Gensini score (r = 0.391, P = 0.001); the numbers of vessels lesions (rs = 0.349, P = 0.003); Type A, B and C lesions (rs = 0.358, P = 0.002). CONCLUSION: The positive correlation between the level of soluble P-selectin and the coronary artery score may indicate that soluble P-selectin levels might reflect the severity of coronary heart disease. The elevated soluble P-selectin level in acute coronary syndrome suggested the possible relation of P-selectin to the pathogenesis of acute coronary syndrome, which may save as a potential marker of plaque unstability.

[AT1 receptor autoantibodies and essential hypertension].

OBJECTIVE: To observe the relationship between AT1 receptor autoantibodies and clinical features in essential hypertension, and to compare the therapeutic effect of losartan between the positive and the negative group. METHODS: Clinical data were collected in patients with essential hypertension (n = 123). AT1 receptor autoantibodies were checked. Twenty-four patients from either AT1-positive or AT1-negative group were treated with losartan for 12 weeks. RESULTS: The average age in the positive group was significantly higher than that of the negative one (P = 0.023). Logistic regression analysis indicated that age was an independant risk factor of AT1 receptor autoantibody. Antihypertensive efficiency of losartan showed no obvious difference between the two groups. CONCLUSION: Positive response of AT1 receptor autoantibody is related only to age. Anti-hypertensive therapy with losartan in the positive group shows no advantage over the negative one, indicating that AT1 receptor autoantibodies possibly have no vascular activity in vivo.