Elsevier

The Lancet

Volume 381, Issue 9875, 20–26 April 2013, Pages 1361-1370
The Lancet

Articles
Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial

https://doi.org/10.1016/S0140-6736(12)62188-6Get rights and content

Summary

Background

Anorexia nervosa is characterised by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder. Deep brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results. We aimed to assess the safety of DBS to modulate the activity of limbic circuits and to examine how this might affect the clinical features of anorexia nervosa.

Methods

We did a phase 1, prospective trial of subcallosal cingulate DBS in six patients with chronic, severe, and treatment-refractory anorexia nervosa. Eligible patients were aged 20–60 years, had been diagnosed with restricting or binge-purging anorexia nervosa, and showed evidence of chronicity or treatment resistance. Patients underwent medical optimisation preoperatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation. Patients were followed up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit. Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals. This trial is registered with ClinicalTrials.gov, number NCT01476540.

Findings

DBS was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious. Other related adverse events were panic attack during surgery, nausea, air embolus, and pain. After 9 months, three of the six patients had achieved and maintained a BMI greater than their historical baselines. DBS was associated with improvements in mood, anxiety, affective regulation, and anorexia nervosa-related obsessions and compulsions in four patients and with improvements in quality of life in three patients after 6 months of stimulation. These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder.

Interpretation

Subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory anorexia nervosa.

Funding

Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.

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

References (63)

  • AM Lozano et al.

    Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression

    Biol Psychiatry

    (2008)
  • BH Bewernick et al.

    Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression

    Biol Psychiatry

    (2010)
  • D Guardia et al.

    Spatial orientation constancy is impaired in anorexia nervosa

    Psychiatry Res

    (2012)
  • V Delvenne et al.

    Brain hypometabolism of glucose in anorexia nervosa: a PET scan study

    Biol Psychiatry

    (1995)
  • V Delvenne et al.

    Brain hypometabolism of glucose in anorexia nervosa: normalization after weight gain

    Biol Psychiatry

    (1996)
  • S Kojima et al.

    Comparison of regional cerebral blood flow in patients with anorexia nervosa before and after weight gain

    Psychiatry Res

    (2005)
  • PF Sullivan

    Mortality in anorexia nervosa

    Am J Psychiatry

    (1995)
  • H Tanaka et al.

    Outcome of severe anorexia nervosa patients receiving inpatient treatment in Japan: an 8-year follow-up study

    Psychiatry Clin Neurosci

    (2001)
  • J Arcelus et al.

    Mortality rates in patients with anorexia nervosa and other eating disorders—a meta-analysis of 36 studies

    Arch Gen Psychiatry

    (2011)
  • HW Hoek

    Incidence, prevalence and mortality of anorexia nervosa and other eating disorders

    Curr Opin Psychiatry

    (2006)
  • HW Hoek et al.

    Review of the prevalence and incidence of eating disorders

    Int J Eat Disord

    (2003)
  • CM Bulik et al.

    Anorexia nervosa: definition, epidemiology, and cycle of risk

    Int J Eat Disord

    (2005)
  • Diagnostic and statistical manual of mental disorders, 4th edn, text revision (DSM-IV-TR)

    (2000)
  • KA Halmi et al.

    Predictors of treatment acceptance and completion in anorexia nervosa: implications for future study designs

    Arch Gen Psychiatry

    (2005)
  • M Strober et al.

    The association of anxiety disorders and obsessive compulsive personality disorder with anorexia nervosa: evidence from a family study with discussion of nosological and neurodevelopmental implications

    Int J Eat Disord

    (2007)
  • DK Katzman

    Medical complications in adolescents with anorexia nervosa: a review of the literature

    Int J Eat Disord

    (2005)
  • J Morris et al.

    Anorexia nervosa

    BMJ

    (2007)
  • HC Steinhausen

    The outcome of anorexia nervosa in the 20th century

    Am J Psychiatry

    (2002)
  • WH Kaye et al.

    Neurocircuity of eating disorders

    Curr Top Behav Neurosci

    (2011)
  • R Uher et al.

    Medial prefrontal cortex activity associated with symptom provocation in eating disorders

    Am J Psychiatry

    (2004)
  • UF Bailer et al.

    Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness

    Neuropsychopharmacology

    (2004)
  • Cited by (232)

    View all citing articles on Scopus
    View full text