Deep Brain Stimulation (DBS) in anorexia nervosa.

Rationale:

Anorexia nervosa (AN) is a severe psychiatric condition

with high rates of morbidity, comorbidity and mortality.

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, exercising) 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.



Objective:

Pilot study 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 fMRI, EEG changes, and neuropsychological

functioning.



Study design:

Pilot study consisting of treatment with deep brain

stimulation targeted at the anterior limb of the capsula

interna (ALIC), with an initial 3-9 months optimization

phase, followed by a 12 months maintenance phase.



Study population:

Six patients (age range 25-65 years) with chronic

treatment refractory anorexia nervosa, defined as meeting

the diagnostic criteria for AN continuously in minimally the

previous 10 years and not having achieved remission with

two or more typical modes of treatment.



Intervention:

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 are the change in body

weight/BMI, score change from baseline on the Yale-

Brown-Cornell Eating Disorder Scale (YBC-EDS) and score

change from baseline on the Eating Disoder Quality of Life

(EDQOL). Secondary outcome measurements include score

change from baseline on the Eating Disorder Inventory

(EDI-II), the Eating Disorder Examination Questionnaire

(EDE-Q), and the Nederlandse Vragenlijst voor Eetgedrag

(NVE). Furthermore, functional effects and safety of DBS

will be explored by neuroimaging (fMRI), electro-

encephalography (EEG) and neuropsychological

evaluation.

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 and 3-4% of 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 substudies are considered safe in

patients with DBS.

Countries of recruitment: The Netherlands.

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 vALIC will result in clinically significant weight

restoration and associated comorbidities and

complications and significant improvement of anorexia

nervosa symptoms reflected by scores on the Yale-Brown-

Cornell Eating Disorder Scale (YBC-EDS).

T-1:Preoperative phase;

T0: Surgery phase;

T1: Start optimization phase (DBS off);

T2: End optimization phase (DBS on)

T3: Maintenance phase (26 weeks);

T4: End of maintenance phase (52 weeks) = end of study;

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.