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.

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.

Translation and linguistic validation of the Swedish recovering quality of life (ReQoL) - A brief research report.

In research and among clinicians, the focus has shifted from mainly symptom reduction and increasing functionality to a more recovery-oriented focus. Although there are instruments measuring recovery, there has been a lack of instruments sensitive enough to measure the quality of life for people with severe mental health disorders. Therefore, this study aimed to obtain a Swedish version of the Recovering Quality of Life (ReQoL) questionnaire adhering to best practice guidelines using various steps of translation, linguistic validation, and cognitive debriefing. The cognitive debriefing was conducted with seven participants, and all felt the items in the questionnaire were relevant to their health, apprehensible, and easy to complete. However, some issues were raised regarding wording and the concepts behind certain items. All feedback was considered, and some items were revised in response to criticism after continuous discussions. A Swedish version of ReQoL now exists, and although there is a need for ReQoL in different clinical research settings in Sweden, further research is required to psychometrically test the construct validity as well as reliability of the Swedish version in Sweden.

Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive-compulsive disorder: effects on cognition after 12 months.

PURPOSE: The aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive-Compulsive Disorder (OCD). METHODS: Eight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure. RESULTS: At 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25-34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility. CONCLUSIONS: DBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis.

BACKGROUND: Deep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle, and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS. METHODS: In a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study combined individual patient's stimulation parameters at 12- and 24-month follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation. RESULTS: The individual electric stimulation fields by stimulation in the BNST were similar at both the 12- and 24-month follow-up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe), and the anterior commissure. A statistical significant correlation (p < 0.05) between clinical effect measured by the Yale-Brown Obsessive Compulsive Scale and stimulation was found at the 12-month follow-up in the ventral ALIC and anteromedial GPe. CONCLUSIONS: Many of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc, and BNST may perhaps be considered to be stimulation of the same target.

Deep Brain Stimulation in the Bed Nucleus of Stria Terminalis in Obsessive-Compulsive Disorder-1-Year Follow-up.

BACKGROUND: Deep brain stimulation (DBS) is under investigation as a treatment for therapy-refractory obsessive-compulsive disorder (OCD). As a crucial part of the anxiety circuit, the bed nucleus of stria terminalis (BNST) has been proposed as a target for DBS in OCD. Here, we investigate clinical outcomes and safety of DBS in the BNST in a series of 11 participants with severe therapy-refractory OCD. METHODS: Eleven consecutive participants diagnosed with refractory OCD were treated with BNST DBS and completed follow-up. The primary outcome was a change in scores of the Yale Brown Obsessive Compulsive Scale (YBOCS) at 1 year after surgery. Secondary outcomes included changes in scores of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Global Assessment of Functioning. RESULTS: At baseline, the mean ± SD YBOCS score was 33 ± 3.0, MADRS score was 29 ± 4.5, and GAF score was 49 ± 5.4. One year after DBS, mean ± SD YBOCS score was 20 ± 4.8 (38% improvement (range 10%-60%) P < 0.01), MADRS score was 21 ± 5.8 (27% improvement, range 4%-74%, P < 0.01), and Global Assessment of Functioning score was 55 ± 6.5 (12% improvement, range 4%-29%, P < 0.05). Of the 11 participants, 6 were considered responders (decrease in YBOCS ≥35%) and 4 partial responders (decrease in YBOCS 25%-34%). Surgical adverse events included 1 case of skin infection leading to reimplantation. The most common transient stimulation-related side effects were anxiety and insomnia. CONCLUSIONS: BNST DBS is a promising therapy in severe therapy-refractory OCD. Our results are in line with previous publications regarding effect and safety profile. Nevertheless, DBS for OCD remains an investigational therapy and should therefore be performed in multidisciplinary clinical studies.

Deep brain stimulation for refractory obsessive-compulsive disorder (OCD): emerging or established therapy?

A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.

Deep brain stimulation for obsessive-compulsive disorder: Knowledge and concerns among psychiatrists, psychotherapists and patients.

BACKGROUND: Deep brain stimulation (DBS) is under investigation for severe obsessive-compulsive disorder (OCD) resistant to other therapies. The number of implants worldwide is slowly increasing. Therefore, it is of importance to explore knowledge and concerns of this novel treatment among patients and their psychiatric healthcare contacts. This information is relevant for scientific professionals working with clinical studies for DBS for this indication. Especially, for future study designs and the creation of information targeting healthcare professionals and patients. The aim of this study was to explore the knowledge and concerns toward DBS among patients with OCD, psychiatrists, and cognitive behavioral therapists. METHODS: The study was conducted through web-based surveys for the aimed target groups -psychiatrist, patients, and cognitive behavioral therapists. The surveys contained questions regarding previous knowledge of DBS, source of knowledge, attitudes, and concerns towards the therapy. RESULTS: The main source of information was from scientific sources among psychiatrists and psychotherapists. The patient's main source of information was the media. Common concerns among the groups included complications from surgery, anesthesia, stimulation side effects, and the novelty of the treatment. Specific concerns for the groups included; personality changes mentioned by patients and psychotherapists, and ethical concerns among psychiatrists. CONCLUSION: There are challenges for DBS in OCD as identified by the participants of this study; source and quality of information, efficacy, potential adverse effects, and eligibility. In all of which the current evidence base still is limited. A broad research agenda is needed for studies going forward.

Deep brain stimulation in the bed nucleus of the stria terminalis and medial forebrain bundle in a patient with major depressive disorder and anorexia nervosa.

Deep brain stimulation (DBS) may be considered in severe cases of therapy-refractory major depressive disorder (MDD). However, DBS for MDD is still an experimental therapy. Therefore, it should only be administered in clinical studies driven by multidisciplinary teams, including surgeons with substantial experience of DBS in the treatment of other conditions.

[Deep brain stimulation for psychiatric disorders]. / Djup hjärnstimulering vid psykiska sjukdomar visar lovande resultat - Men behandlingen är fortfarande experimentell.

Deep brain stimulation for psychiatric disorders Deep brain stimulation is an established treatment for movement disorders. It has been proven to be a safe method; only minor complications have been reported in larger studies. New indications for deep brain stimulation are under investigation; among them major depressive disorder and obsessive-compulsive disorder. Deep brain stimulation for severe and therapy-resistant major depressive disorder and obsessive compulsive-disorder shows promising results. However, the experience of deep brain stimulation in psychiatric disorders is limited. Several potential target areas for stimulation have been presented; which are the most effective is still an open question. Deep brain stimulation in psychiatric disorders is a highly experimental treatment and should only be performed by a multidisciplinary team with extensive experience with deep brain stimulation in other conditions.

A systematic review of psychiatric indications for deep brain stimulation, with focus on major depressive and obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation is a treatment under investigation for a range of psychiatric disorders. It has shown promising results for therapy-refractory obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Other indications under investigation include Tourette's syndrome, anorexia nervosa and substance use disorders. AIMS: To review current studies on psychiatric indications for deep brain stimulation (DBS), with focus on OCD and MDD. METHOD: A systematic search was carried out in MEDLINE, and the literature was searched to identify studies with DBS for psychiatric disorders. The identified studies were analysed based on patient characteristics, treatment results and adverse effects of DBS. RESULTS: A total of 52 papers met the inclusion criteria and described a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in six different anatomical targets, while nine studies presented 100 patients with DBS for MDD in five different targets. CONCLUSION: DBS may show promise for treatment-resistant OCD and MDD but the results are limited by small sample size and insufficient randomized controlled data. Deep brain stimulation for OCD has received United States Food and Drug Administration approval. Other psychiatric indications are currently of a purely experimental nature.

A cry for help, do not omit the signs. Dermatitis artefacta--psychiatric problems in dermatological diseases (a review of 5 cases).

BACKGROUND: Dermatitis artefacta (DA) is a dermatologicopsychiatric illness that is a conscious self-infliction of lesions to accessible regions of the body. The lesions usually do not resemble those of any know skin disease and there are no specific diagnostic tests to recognize them. This makes dermatitis artefacta a very slow, challenging and expensive disease to diagnose. CASE REPORT: We present 5 different clinical cases of dermatitis artefacta treated in the Department of Dermatology, Venereology and Allergology, Medical University of Gdansk in 2011. Detailed anamnesis and physical examination were performed at the day of admission. All patients had biochemical and hematological blood tests, skin biopsies and swabs for bacteriological examination, and photographs were taken. Psychiatric consultation was recommended in all cases. Clinical symptoms before diagnosis lasted from 1 to 10 years. The female-to-male ratio is 1:0.7, with age range of 57-62 years. Of our patients, only 2 refused a psychiatric consultation. Three out of 5 patients denied self-mutilation (2 of those 3 patients finally admitted to self-manipulations). Lesions were usually within the reach of the dominant hand. Two patients have other personality disorders. In 4/5 cases visible improvement after treatment with occlusive dressings were observed. CONCLUSIONS: We discuss and attempt to depict issues associated with collaboration between dermatologists and psychiatrists, reasons for poor recognition of the disease, very long diagnosis and high costs. To conclude, we found that close collaboration between dermatologists and psychiatrists is important in diagnosing and treating DA patients.

A retrospective study of 12 cases of pyoderma gangrenosum: why we should avoid surgical intervention and what therapy to apply.

Lesions of skin are ubiquitous in the medical field. The varying etiopathologies with similar presentation can pose a misleading picture, especially when faced with less common skin diseases. Furthermore, the misdiagnosis can cause detrimental effects on the patient's morbidity and mortality, which was seen in the case series study we performed on pyoderma gangrenosum. The history of 12 patients were analyzed in reference to the course of the disease, accompanying diseases, clinical picture, histopathological examination, surgical intervention before diagnosis, and treatment. Within this group of 12 patients, five were exposed to surgical interventions before diagnosis of pyoderma gangrenosum. The 5 patients were all exposed to prolonged aggravation of the disease process, followed by remission after proper diagnosis and treatment therapy. This study was done to improve the knowledge of surgeons about pyoderma gangrenosum considering the frequency of skin lesion cases in the surgical practice. Knowledge of the disease is essential to diagnose pyoderma gangrenosum in early stages to avoid interventions that may prolong or worsen the outcome. Surgical interventions in these patients should be avoided before proper diagnosis. The key to a better prognosis of pyoderma gangrenosum patients is often in the hands of surgeons.