ArticlesSubcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial
Introduction
Anorexia nervosa has a mortality of 6–11% and is among the most challenging psychiatric disorders to treat.1, 2, 3 With an estimated prevalence of 0·3–0·9%, it is typically diagnosed in female young adults aged 15–19 years, and is among the most common psychiatric disorders in this age group.4, 5, 6 Anorexia nervosa is characterised by a refusal to maintain a healthy body weight, a persistent fear of gaining weight, a relentless drive for thinness, and preoccupations with body image and self-perception.7 Psychological factors, such as perfectionism, anxiety, affective dysregulation, and reward processing abnormalities, have been proposed as prominent perpetuating, and causal, factors in the disorder.8, 9, 10
Treatment strategies used currently are aimed at the acute and chronic stages of the illness. Acute care entails medical stabilisation (such as the correction of electrolyte abnormalities or cardiac problems) in severely underweight and metabolically unstable patients. Rapid fluctuations in weight, severe restriction, and bingeing and purging behaviour are associated with serious medical complications, which can lead to cardiac arrhythmias and musculoskeletal and neurological symptoms.11 Intensive treatment, in inpatient or outpatient settings, focuses on behavioural change and on addressing underlying and disease-maintaining factors.12 Anorexia nervosa is usually a chronic illness, with a waxing and waning course. Up to 20% of patients derive no sustained benefit from available treatment programmes and are at risk for premature death.13 Despite decades of investigation, the factors associated with mortality and progression to chronic illness are poorly understood.
The circuitry and biology of anorexia nervosa are areas of active investigation, with most disease models focused on structures that underlie pathological mood, anxiety, reward, body perception, and interoception.14 Much of this work is driven by neuroimaging, which has been used to show both structural and functional differences between patients with anorexia nervosa and healthy controls.15, 16, 17 The most consistent features are parietal area hypometabolism and limbic circuit dysfunction, including increased activity and decreased 5-HT2A binding in the subcallosal area, a region that is known to be important in mood regulation, which emphasises the importance of perceptual and mood disturbances in the disorder.17, 18, 19, 20
Deep brain stimulation (DBS) is a neurosurgical procedure that has been used for more than 25 years to modulate the activity of dysfunctional brain circuits. It has proved effective and safe in patients with Parkinson's disease and essential tremor and its use has now been extended to other circuit-based neuropsychiatric disorders, such as major depression, obsessive–compulsive disorder, Tourette's syndrome, and Alzheimer's disease.21, 22, 23, 24, 25 DBS is a non-lesional and adjustable procedure that exerts its effect both locally and remotely, across monosynaptically and polysynaptically linked networks.26, 27
We selected the subcallosal cingulate as a target for DBS in anorexia nervosa because: imaging studies show similar patterns of activity in the subcallosal cingulate region and in its afferent and efferent projections in patients with anorexia nervosa as are seen in patients with depression;14, 17, 18, 26, 28 anorexia nervosa and mood and anxiety disorders are often comorbid, with similar anatomical structures and circuits implicated14, 29 (results of several studies have also shown that treatment of weight alone in patients with anorexia nervosa leads to faster relapse, whereas treatment of comorbid mood and anxiety symptoms is associated with improved outcomes and more complete and long-lasting recovery, suggesting that these are important symptoms to target);30, 31, 32, 33, 34 and subcallosal cingulate DBS improves symptoms in patients with treatment-refractory depression and reverses cerebral metabolic abnormalities in dysfunctional limbic circuits.26 With the evidence of shared symptoms and circuitry, we postulated that subcallosal cingulate DBS could also be helpful in anorexia nervosa. We designed this pilot, phase 1 trial to assess the safety and potential effects of this approach in six patients with chronic, treatment-refractory anorexia nervosa.
Section snippets
Patients and study design
Inclusion and exclusion criteria for this study are listed in panel 1. Patients were identified through the eating disorders programme at Toronto General Hospital (Toronto, ON, Canada) and through community referrals to the study. Our intent was to offer this procedure only to patients who might be expected to continue with a chronic illness or die a premature death because of the severity of their illness. No established, consensus operational criteria exist to identify treatment-refractory
Results
Six patients were enrolled in this pilot trial (table 1). All patients were female and had a mean age at surgery of 38 years (SD 11). All patients met DSM-IV-TR criteria35 for anorexia nervosa, with an average age at diagnosis of 20 years, and a mean duration of illness of 18 years (SD 11) before DBS surgery. Five patients had a history of recurrent acute hospital admissions for medical stabilisation, with four of these patients having had ten or more admissions. After study enrolment, all
Discussion
DBS in this group of six patients with chronic and treatment-refractory anorexia nervosa was generally safe. All our patients had longstanding, life-threatening disease; five had a history of emergency admissions to intensive care, and four had needed to be surgically fed in the past. At 9 months no deaths, strokes, infections, or serious device-related complications had occurred (table 2). One unanticipated adverse event was a seizure that followed device programming, which occurred in the
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