Glutathione Levels and Compulsivity
Condition: Anorexia Nervosa; Compulsive Behavior
MeSH terms: Anorexia; Anorexia Nervosa; Compulsive Behavior
Study type: Interventional

Summary: 
      The investigators will examine whether compulsivity in those who score above-average (but
      below clinical cut-off) on an eating disorder questionnaire can be altered by 9 days of
      N-acetyl cysteine (NAC). N-acetyl cysteine has been shown to be of some benefit in
      individuals with other compulsive disorders, such as trichotillomania and addiction, so this
      research investigates whether a short period of time taking N-acetyl cysteine changes
      compulsivity, measured using cognitive tasks and questionnaires.
    

Detailed description: 
      Anorexia nervosa is a psychiatric disorder with a high mortality rate and for which there is
      very little evidence for pharmacological interventions of value. The picture is similar in
      bulimia nervosa, with a high mortality rate and with mixed outcomes from studies testing
      Selective Serotonin Reuptake Inhibitors (SSRIs). It is possible to conceptualise eating
      disorders as akin to compulsive disorders, especially noting that repetitive weighing,
      calorie counting and compulsive exercise and compensatory mechanisms might fit into a
      hypothetic obsessive-compulsive spectrum (OC spectrum). Some disorders on this OC spectrum
      are associated with oxidative stress. This may also be true in eating disorders: it has
      recently been found in a meta-analysis that there is evidence of increased oxidative stress
      markers in AN.

      Glutathione is the main cellular anti-oxidant in mammals and it is possible to increase
      glutathione levels (and thus potentially combat oxidative stress) with a dietary supplement
      called N-Acetyl Cysteine (NAC). NAC is an acetylated form of the naturally occurring amino
      acid cysteine, and is converted to cysteine in the body. Cysteine is a key precursor of
      glutathione. Oral administration of cysteine itself does not increase brain glutathione
      levels because cysteine is poorly absorbed from the gastro-intestinal tract. However NAC is
      bioavailable and thus administration of it does increase glutathione in the brain.

      Using NAC to increase glutathione levels has been shown to be beneficial in some compulsive
      disorders such as addictions, Obsessive-Compulsive Disorder (OCD) and related disorders such
      as trichotillomania in preliminary studies. There have been positive indications for use and
      evidence in pathological gambling, trichotillomania, OCD and cocaine addiction. However, NAC
      has not to our knowledge ever been considered for the treatment of eating disorders. This
      research therefore aims to investigate whether increasing glutathione can reduce
      neuropsychological markers of compulsivity in a group at risk for eating disorders.

      The researchers have chosen to use a female non-patient group which is thought to be highly
      compulsive, but which will also be without the possible confounds of medication (as in OCD or
      addiction disorders) and without malnutrition (as in clinical eating disorders). Those
      recruited will be females, because there is evidence that there may be different risk factors
      and thus mechanisms underlying the development of eating disorders in males and females, such
      that recruiting both might produce a confound. The investigators have also chosen to use a
      short duration of NAC administration. This not only allows the use of a cross-over design
      without fears of high attrition rates and non-compliance, but it also will allow the
      detection of subtle and early changes in compulsivity. The hypothesis is thus that
      improvements will be seen in tasks measuring compulsivity, and also potentially in tasks
      which measure related constructs such as impulsivity, habit-based learning, and delay
      discounting. The researchers do not expect improvement in self-report symptom questionnaires.
      However, a possible future study would be a randomized clinical trial looking at increasing
      glutathione in a clinical group over time and how it affects clinical symptomatology.

      The questionnaires chosen will identify eating disorder symptom levels (the Eating Attitudes
      Test - 26 (EAT-26) is a validated way of doing this) and look at compulsive starvation using
      the self-starvation scale (Godier & Park 2015). The Structured Clinical Interview for the
      Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) will be used to rule out
      those with a current Axis I diagnosis including an eating disorder, to prevent the
      complications of starvation and medication in this initial pilot study. The Eysenck
      Personality Questionnaire (EPQ) will be used to ascertain personality traits, and the
      National Adult Reading Test (NART) will be used to estimate Intelligence Quotient (IQ).

      The rationale for choosing the tasks was based on the hypothesis that compulsivity may be
      improved by increasing glutathione levels. Thus, the tasks chosen are designed to pick up
      differences in different facets of compulsivity. The Wisconsin Card Sorting Task (WCST) is
      able to quantitatively measure set shifting, which is known to be impaired in eating
      disorders (Roberts et al. 2007) and is a facet of compulsivity. The Affective Go/No go picks
      up on attention bias within the umbrella of compulsivity; and the Attention Switching task
      picks up the ability to switch attention between different task demands, within the same
      compulsivity umbrella. The Cambridge Gambling Task is a good measure of disadvantageous
      decision making within the umbrella of impulsivity (which is thought to be orthogonally
      related to, rather than opposite to, compulsivity) (Fineberg et al. 2014). The sequential
      learning task has been used in OCD, where it is able to disentangle goal-directed learning
      from habitual learning based on two computational algorithms. The hypothesis is that
      compulsivity is related to a disturbance in goal-directed learning, with habit learning
      preferred leading to rigid behaviours (Gillan & Robbins 2014) (Voon et al. 2015). Thus it
      will be useful to see if more goal-directed and less habit learning occurs after increases in
      glutathione levels. The delay discount task measures the ability to ignore delays in time
      when considering reward value, which is relevant in eating disorders as often delay
      discounting is reduced so performance is better (Steinglass et al. 2012). This has an
      interesting interaction with impulsivity as it seems almost to be opposite to it, yet
      anorexic patients have shown a better performance. Thus this task might be useful as an
      exploratory measure. The Facial Expression Recognition Task (FERT) is very sensitive to early
      changes in emotional biases after only small pharmacological changes, and as the profile of
      individuals high eating disorder symptoms is different in this task compared to healthy
      controls (Jones et al. 2008) - it can operate as a positive control to identify if increased
      glutathione is having any effect on general emotional biases, even if it is not on
      compulsivity.

      Because the aim of the study is to see whether NAC may lower compulsivity by increasing
      glutathione levels, a researcher will take a small venous blood sample (5mls) and a saliva
      sample prior to testing in both arms of the study to check to what to what extent NAC
      treatment elevates glutathione levels over placebo. Participants who do not wish to give
      blood will not be excluded but asked to provide a saliva sample only. Blood and saliva will
      be rendered acellular by centrifugation and stored until assay in the University Departments
      of Chemistry and Pharmacology. Once assayed any remaining sample will be discarded according
      to Standard Operating Procedures for sample disposal.
    

Intervention name(s): N-acetyl cysteine; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Acetylcysteine