Deep Brain Stimulation (DBS) in anorexia nervosa.|
|- candidate number||12881|
|- NTR Number||NTR3469|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||10-jun-2012|
|- Secondary IDs||40930 MEC AMC|
|- Public Title||Deep Brain Stimulation (DBS) in anorexia nervosa.|
|- Scientific Title||Deep Brain Stimulation in patients with Chronic Treatment Refractory Anorexia Nervosa: A Pilot Study.|
|- hypothesis||Anorexia Nervosa (AN) is a serious condition and forms a major public health problem. The disorder affects biological, psychological as well as social functioning, affects mainly young people, tends to take on a chronic course in a considerable percentage of patients, has a high mortality rate and although there are many different treatment approaches, up to date, there is no evidence based treatment for AN.
AN is possibly the most homogenous of all psychiatric disorders. There is a narrow age of onset, a stereotypic presentation of symptoms and course, and relative gender specificity. AN patients show similarities with obsessive-compulsive disorder (OCD) patients (Altman e.a. 2009; Kaye e.a. 2006; Godart e.a. 2003; Speranza e.a. 2001). Individuals with AN are preoccupied with food and eating rituals to the point of obsession. They have a distorted body image and compulsively over-exercise. AN patients are characterised by obsessive-compulsive personality traits that manifest predominantly in maladaptive preoccupation with food, weight and body shape. Furthermore, patients with AN have elevated rates of lifetime diagnoses of comorbid anxiety (obsessive compulsive) and depressive disorders.
Numerous observers have documented the importance of the mesolimbic reward system in the pathophysiology of anorexia nervosa.
Deep Brain Stimulation (DBS) is an innovative and promising approach for the treatment of patients with therapy-refractory reward-related psychiatric disorders (Bewernick e.a. 2010; Denys 2009; Schlaepfer e.a. 2008; Okun e.a. 2007; Greenberg e.a. 2006; Sturm e.a. 2003) by modulating the reward-circuitry in the brain.
The department of psychiatry of the Academical Medical Centre (AMC) Amsterdam is one of the few centers in Europe performing DBS for complex psychiatric disorders. Currently, our center has experience in obsessive-compulsive disorder, addiction and major depressive disorder. In all these disorders, DBS targets reward related brain areas such as the nucleus accumbens and the ventral striatum.
We propose to introduce DBS for anorexia nervosa based on:
1. Our clinical experience with DBS of the NAc region as a safe, reversible and effective treatment for therapy-refractory reward-related psychiatric disorders;
2. The literature on the important role of the reward neurocircuitry in the pathophysiology of anorexia nervosa;
3. The existing knowledge of/experience with animal models of anorexia nervosa and human imaging studies on anorexia nervosa.
We hypothesize that treating treatment refractory anorexia nervosa patients with DBS in the area of the NAc and ALIC will result in clinically significant weight restoration and assosciated comorbidities and complications and significant improvement of anorexia nervosa symptoms reflected by scores on the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS).
|- Healt Condition(s) or Problem(s) studied||Eating disorders, Anorexia, Deep brain stimulation|
|- Inclusion criteria||1. Primary diagnosis: Anorexia Nervosa (restricting or purging type; 307.1) according to the DSM-IV criteria based on a psychiatric interview;|
2. Illness duration > 5 years, chronic AN;
3. Disabling severity with substantial functional impairment according to the DSM-IV criterion C and a Global Assessment of Function (GAF) score of 45 or less;
4. The level of impairment must have been persistent for at least 2 years;
5. Treatment refractoriness, defined as lack of response to two or more typical modes of treatment, such as psychotherapy and psychopharmacology;
6. Weight <85% of ideal body weight (and/or BMI < 17,5);
7. Age: 18-65 years old;
8. Written informed consent;
9. Able to fully understand the consequences of the procedure;
10. Dutch or English speaking and able to answer the study questions;
11. Capable to make his or her own choice without coercion.
|- Exclusion criteria||1. Unstable physical condition (severe electrolyte disturbances, cardiac failure, other physical conditions due to underweight in which surgery/aneasthesia is contraindicated). The use of anticoagulants must be able to be stopped before surgery;|
2. Treatable underlying cause of anorexia/underweight;
3. Parkinson’s disease, dementia, epilepsy;
4. Schizophrenia/ history of psychosis, bipolar disorder, major depressive disorder;
5. Alcohol or substance abuse (including benzodiazepines) during last 6 months;
6. Current Tic disorder;
7. Antisocial personality disorder;
8. Participation in a SPECT study in the year prior to this study;
9. Standard MRI scan exclusion criteria (pregnancy, pacemaker and metals contraindicated for MRI except for the DBS implantation and stimulator itself);
10. The use of dopaminergic medication.
|- mec approval received||no|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-sep-2012|
|- planned closingdate||1-sep-2016|
|- Target number of participants||6|
|- Interventions||The intervention of this study will be Deep Brain Stimulation (DBS) in the ventral limb of the capsula interna. Deep Brain stimulation is an adjustable, reversible, non-destructive intervention using a surgically implanted medical device to deliver carefully controlled electrical pulses to precisely targeted areas of the brain. The stimulation can be programmed and adjusted non-invasively by a trained physician to maximize symptom control and minimize side effects. The ventral limb of the capsula interna has been chosen because both animal and human studies indicate that this location is promising for DBS treatment of anorexia nervosa and because this location has shown to be safe in DBS studies among humans with other psychiatric/reward-related disorders such as OCD, depression, and addiction. |
|- Primary outcome||Treatment effects will be established using within-subject analyses comparing baseline characteristics with patient reports during the optimization phase (T1 and T2), during periods when the stimulator is ‘on’ and periods when the stimulator is ‘off’, (T3 and T4), during the acute treatment period and at the end of the maintenance treatment period (T5).
Primary outcome measurements are:|
1. Physical outcome: Weight/BMI;
2. Psychological outcome: Score on the Yale-Brown-Cornell Eating Disorder Scale ( YBC-
EDS; Mazure e.a. 1994, Dutch translation by our department with back-translation to ensure conceptual equivalence).
|- Secondary outcome||Secondary outcome measurements include:|
1. Additional psychological outcome:
A. Eating behaviour measured by assessing the quantity, quality and choice of food;
B. Assessment of eating behaviour with the Eating Disorder Inventory (EDI-II; van Strien 2002), the Eating Disorder Examination (EDE; Dutch translation by Jansen 2000), and the Nederlandse Vragenlijst voor Eetgedrag (NVE; van Strien e.a. 1986).
2. Quality of life:
Secondary outcomes include social function and quality of life using the EQ-6D (Euroqol 6 Dimension), the WHO-QOL BREF (World Health Organisation – Quality of Life), the MOS SF36 (Medical Outcome Study Short Form), the SDS (Sheehan Disability Scale), and the Q-LES-Q (Quality of Life Enjoyment and Satisfaction Questionnaire), assessed at T0 (pre surgery), T1 (1 month after surgery), T2 (optimization phase), T3 (double blind phase), T4 (double blind phase) and T5 (maintenance phase).
Additionally, the functional aspects of DBS wil be explored in different ways. In this study, clinical outcome measures will be associated with:
1. Effects of DBS on cerebral perfusion in response to specific tasks using functional MRI;
2. Effects of DBS on striatal D2 receptor binding using IBZM SPECT;
3. Intracranial and extracranial EEG changes associated with DBS;
4. Changes in neuropsychological functioning in on-off situation.
|- Timepoints||T-1: Preoperative phase;|
T0: Surgery phase;
T1: Optimization phase (3-9 months);
T2+T3: Double blind phase/on-off phase (4-12 weeks);
T4: Maintenance phase (52 weeks);
T5: End of the study.
|- Trial web site||www.amcpsychiatrie.nl/research|
|- CONTACT FOR PUBLIC QUERIES|| M.S. Oudijn|
|- CONTACT for SCIENTIFIC QUERIES||Prof. dr. D. Denys|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Department of Psychiatry|
(Source(s) of Monetary or Material Support)
|Academic Medical Center (AMC)|
|- Brief summary||Rationale: |
Anorexia nervosa (AN) is a serious psychiatric condition with a high mortality rate. Many parallels between obsessive-compulsive disorder (OCD) and anorexia nervosa have been drawn with regard to symptomatology and pathophysiology. AN consists of obsessive (weight gain) and compulsive behaviours (dieting) that, similar to OCD, are related to a dysfunction of the mesolimbic reward system. It is conceivable that the significant relapse and failure rates of current anorexia nervosa treatments may be at least in part the result of this dysregulated reward system.
We hypothesize that in line with the positive outcome following deep brain stimulation (DBS) in OCD, modulating the reward circuitry in AN may provide 1) significant and sustained improvement in anorexia nervosa symptoms and associated comorbidities and complications and 2) effectively lessen relapse rates associated with the current anorexia treatments.
To demonstrate the efficacy, feasibility and safety of deep brain stimulation in patients with chronic, treatment-refractory anorexia nervosa. Additionally, the functional effects of deep brain stimulation will be explored by associating the clinical outcome parameters with intracranial and extracranial EEG changes, fMRI and SPECT, and neuropsychological functioning.
Pilot study consisting of treatment with deep brain stimulation, with an initial 3-9 months observational phase, followed by a double-blind crossover design with randomly assigned 2-week periods of active or sham stimulation, and an open twelve month maintenance phase.
Six patients (age range 18-65 years) with chronic treatment refractory anorexia nervosa, defined as meeting the diagnostic criteria for AN continuously in minimally the previous 5 years and not having achieved remission with two or more typical modes of treatment.
Treatment with bilateral deep brain stimulation targeted at the nucleus accumbens with stimulation at the ventral anterior limb of the capsula interna.
Main study parameters/endpoints:
Primary outcome measures will are the change in body weight/BMI and the score change from baseline on the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS). Secondary outcome measurements include score change from baseline on the Eating Disorder Inventory (EDI-II), the Eating Disorder Examination (EDE), and the Nederlandse Vragenlijst voor Eetgedrag (NVE). Furthermore, functional effects of DBS will be explored by intracranial and extracranial EEG, neuroimaging, neuropsychological evaluation and additional endocrinological measurements.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The greatest burden on the patient during this study is the intervention itself. Potential risks consist of the risks associated with the surgical procedures (i.e. a risk < 1% of intracranial haemorrhage or infection). Patients will be admitted to the hospital during the surgery phase. Changes in somatic condition and potential refeeding syndrome will be monitored closely. At several timepoints patients will be asked to come to the AMC to participate in clinical interviews, questionnaires, neuroimaging, and neuropsychological tests. The neuroimaging and neuropsychological ubstudies are considered safe in patients with DBS.
Countries of recruitment: The Netherlands.
|- Main changes (audit trail)|
|- RECORD||10-jun-2012 - 17-jun-2012|
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