Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review

This review (2021) explores the use of ketamine to treat Anorexia Nervosa (AN). The ability of ketamine to induce neuroplasticity, neurogenesis and synaptogenesis is discussed in relation to AN. Furthermore, the known antidepressant effects of ketamine may be beneficial to people with AN as depression is often experienced comorbidly.

Abstract

“Anorexia nervosa (AN) is a highly complex disorder to treat, especially in severe and enduring cases. Whilst the precise aetiology of the disorder is uncertain, malnutrition and weight loss can contribute to reductions in grey and white matter of the brain, impairments in neuroplasticity and neurogenesis and difficulties with cognitive flexibility, memory and learning. Depression is highly comorbid in AN and may be a barrier to recovery. However, traditional antidepressants are often ineffective in alleviating depressive symptoms in underweight patients with AN. There is an urgent need for new treatment approaches for AN. This review gives a conceptual overview for the treatment of AN with ketamine. Ketamine has rapid antidepressant effects, which are hypothesised to occur via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis. This article provides an overview of the use of ketamine for common psychiatric comorbidities of AN and discusses particular safety concerns and side effects. Potential avenues for future research and specific methodological considerations are explored. Overall, there appears to be ample theoretical background, via several potential mechanisms, that warrant the exploration of ketamine as a treatment for adults with AN.”

Authors: Johanna L. Keeler, Janet Treasure, Mario F. Juruena, Carol Kan & Hubertus

Summary

Review

Anorexia nervosa is a complex disorder to treat, especially in severe and enduring cases. Ketamine may be a potential treatment option for AN, and it has rapid antidepressant effects via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis.

1. Introduction: An Overview of Ketamine

Ketamine is an n-methyl-D-aspartate (NMDA) receptor antagonist that can be administered via several routes with varying bioavailabilities. Its area under the curve, peak plasma concentration and time to peak plasma concentration differ depending on the administration route and dosage.

Ketamine is rapidly metabolised by the liver and excreted renally through urine and faeces. Its main metabolic pathway is N-demethylation to an active metabolite norketamine by CYP3A4.

Ketamine was first used in 1964 at the University of Michigan. It was classified as a dissociative anaesthetic and had fast peak plasma concentrations.

Ketamine is rapidly metabolised by the liver and excreted renally through urine and faeces. Its main metabolic pathway is N-demethylation to an active metabolite norketamine by CYP3A4.

Ketamine was first used in 1964 to treat depression at the University of Michigan. It was later approved by the FDA to treat depression in children, adults and the elderly, and was later used in psychiatric settings for the treatment of depression, anxiety disorders, alcohol and substance use disorder and post-traumatic stress disorder.

The phenomenology of ketamine treatment includes the set (person factors) and setting (situational factors) of the experience, which can be optimised by providing patients with sitters, a calm and relaxing environment with minimal stimuli and bright light, and guided attention inwards.

Ketamine has antidepressant effects across all administration routes, although intravenous, intramuscular and subcutaneous administration have the most adverse events. Oral, SC, IM and intranasal ketamine are more convenient than IV ketamine and can be used in everyday clinical care.

2. Materials and Methods

A literature search was conducted in the electronic databases MEDLINE and PubMed until 15 September 2021 to synthesise a theoretical rationale for the use of ketamine in the treatment of anorexia nervosa.

3. The Neurobiological and Psychological Effects of Ketamine

When administered at subanaesthetic doses, ketamine produces dissociative and mild psychological effects within 15 min. These effects resolve within 90 min, and the antidepressant effects persist for a week in some patients.

Ketamine is an NMDA receptor antagonist that paradoxically stimulates glutamate transmission at low doses. This increases brain-derived neurotrophic factor (BDNF) release, which in turn stimulates the mammalian target of rapamycin (mTOR) via Atk (protein kinase B) and ERK signalling.

Ketamine increases synaptogenesis, neurogenesis and downregulates stress-induced inflammation in the hippocampus and medial prefrontal cortex. These effects are thought to contribute to its sustained antidepressant effects.

Ketamine has been shown to attenuate stress-induced inflammatory responses in rats. These effects have been replicated in humans, with some studies finding an association between the anti-inflammatory and antidepressant properties of subanaesthetic ketamine administration.

4. Anorexia Nervosa

Anorexia nervosa (AN) is characterised by dietary restriction and weight loss behaviours, leading to significantly low weight. The prognosis is often poor, with estimates of relapse including 59% at nine years of illness and 30% at 15 years of illness.

Psychiatric comorbidity is common in eating disorder patients, including mood disorders, anxiety disorders, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder and substance use disorder.

Patients with AN often report symptoms of anxiety disorders, and AN is associated with a higher risk of suicide. Comorbid depression is linked to poor outcomes in patients, particularly those with severe-enduring AN (SE-AN), whereby patients with comorbid depression are six times more likely to remain unrecovered at a 22-year follow-up.

Genetic studies suggest that AN and some psychiatric comorbidities may share an aetiology, but psychopharmacological drugs often show little efficacy in terms of weight gain in AN. New approaches, such as ketamine, may alleviate ED symptoms.

5. The Use of Ketamine in Commonly Comorbid Psychiatric Disorders 5.1. Depression

Patients with treatment-resistant depression who have failed two antidepressants may benefit from esketamine nasal spray therapy. In research, intravenous (IV) ketamine elicits a rapid antidepressant response in major depressive disorder and treatment-resistant depression, and can be used to treat all symptoms of depression, including suicidality. Additionally, improvements in aspects of memory and learning have been found in patients with depression after ketamine treatment.

Esketamine has fewer psychotomimetic effects than R-ketamine, but these effects can have transformative psychological effects akin to those elicited from other psychedelic experiences. Additionally, acute doses of ketamine can improve cognitive function.

5.2. Obsessive-Compulsive Disorder

A systematic review of 11 studies found that intravenous ketamine improved obsessive-compulsive symptomatology, and the effects were prolonged if augmented with cognitive behavioural therapy.

5.3. Autism Spectrum Disorder (ASD)

The evidence for using ketamine to treat the core symptoms of ASD is preliminary. One randomised controlled pilot study found no specific effects of ketamine on the clinician- and self-reported measures of autism, but a single case study found a dramatic reduction in the core symptoms of ASD.

5.4.1. Generalised Anxiety Disorder and Social Anxiety Disorder

Several studies have demonstrated the efficacy of ketamine for the treatment of anxiety disorders, including generalised anxiety disorder and social anxiety disorder. However, no studies have examined intranasal esketamine for anxiety disorders, nor have they paired ketamine with adjunctive therapy, which is a potential area for future research.

5.4.2. Post-Traumatic Stress Disorder

Ketamine may be used to treat PTSD by targeting the fear response associated with a trauma-related stimulus and promoting fear extinction via mTORC1 signalling.

Ketamine has shown promising results in treating PTSD in humans, especially chronic PTSD. It has also been shown to improve the length of the clinical response to a mindfulness-based extinction and reconsolidation cognitive therapy.

5.5. Substance and Alcohol Use Disorders

Ketamine has been shown to improve cravings, motivations to quit, physiological reactions to withdrawal and reduce or completely abolish the self-administration of drugs/alcohol. It is often administered alongside psychotherapy, termed “ketamine psychedelic therapy” (KPT), which allows patients to fully take advantage of a hyperplastic brain state.

6.1.1. Serotonin

Serotonin, a monoamine neurotransmitter, is produced in the gastrointestinal tract and brainstem, and regulates many functions including food intake, body weight control, mood, cognition, learning and memory. There are many 5-HT receptors, but the 5-HT1A and 5-HT2A receptor families are of most interest in the context of AN.

The dietary restriction associated with AN may lead to a depletion of tryptophan, a chemical precursor to 5-HT, and changes in serotonin signalling in limbic pathways and structures.

Ketamine may have antidepressant effects due to its effects on 5-HT, showing some similarities to traditional SSRIs. This may be due to the hippocampal NMDA receptor inhibition and AMPA receptor activation.

6.1.2. Dopamine

Dopamine is a neurotransmitter important in reward processing. It is most important for wanting processes, and thus is a large feature in theories of addiction.

A number of studies have noted alterations in the dopaminergic reward system in AN, which may contribute to increased levels of anxiety and harm avoidance. Treatment should focus on developing associations with recovery goals and egosyntonic aspects of the disorder rather than simply on food cues.

Ketamine has been found to modulate brain circuits related to reward and motivation. It is possible that using psychological approaches within a window of ketamine-induced neuroplasticity may instigate changes in reward functioning and reward-related associations with disordered cues.

6.2. Neuroplasticity and Neuromorphology

Neuropsychological studies of AN indicate reduced neuroplasticity, with decreased cognitive flexibility, memory and learning. Malnutrition, chronic stress and the presence of psychiatric comorbidities can lead to reductions in BDNF and hippocampal volume, together with increases in proinflammatory cytokines.

Stress-induced depression-like behaviours in rodents are associated with increased levels of proinflammatory cytokines and decreased levels of BDNF and neurogenesis. Comorbidities may contribute to neuroinflammation in AN.

In the acute stages of acute malnutrition, grey and white matter volume decreases by 4% to 5%, and the loss of white matter is more pronounced in adolescents. However, the volumes increase following weight restoration.

Chronic malnutrition, traumatic events and chronic social stress associated with living with AN may contribute to neuroinflammation and impaired neuroplasticity and neurogenesis. However, there is little research investigating neurogenesis in human patients with AN, and many questions remain.

Ketamine has been shown to increase glutamate release, which is associated with increased BDNF, neurogenesis and synaptic plasticity. Ketamine may also mitigate the effects of chronic stress on the brain.

6.3. Neuropsychology

Patients with AN often have difficulties in several aspects of cognition, including memory, learning and cognitive flexibility. These difficulties may be related to reduced neuroplasticity and hippocampal function, and may be precipitating or maintaining factors in the difficulty in engaging with psychological therapies.

Ketamine has several qualities that are likely to address the difficulties in several aspects of neuropsychology in AN, including its effects on memory, its ability to facilitate extinction learning, and its ability to block the reconsolidation of trauma-related memories.

Individuals with eating disorders often experience social anxiety. Ketamine has been reported to increase social functioning and reduce rejection sensitivity in patients with depression, which facilitates a therapeutic bond.

Ketamine can induce feelings of lightness and floating, and may have an additional therapeutic impact for patients with eating disorders by promoting flexibility, ego dissolution, detachment from one’s internal dialogue and openness to experiences.

To date, there have been few studies investigating the therapeutic use of ketamine for AN. All studies found reductions in the main outcome measures, including depression scores, suicidality and eating disorder psychopathology.

In all studies, no severe side effects were reported beyond those expected, but there have been no well-controlled feasibility studies using a large sample.

7.2. Side Effects and Safety Concerns

There are specific safety concerns when investigating pharmacological interventions for AN. Liver enzyme abnormalities, high doses of ketamine, and prolonged ketamine abuse are associated with liver injury and hepatotoxicity, and upper and lower urinary tract dysfunctions are common in recreational ketamine users.

Cardiac complications/abnormalities are a notable feature of AN, and can be caused by self-induced vomiting, hypokaemia, prolonged QT intervals, bradycardia/tachycardia, congestive heart failure and hypotension. Ketamine administration is associated with transient increases in the blood pressure and heart rate.

Ketamine has several side effects, including dissociation, sedation, nausea and vomiting, dysgeusia and hypoesthesia. Patients with comorbid PTSD should be closely monitored and the Clinician Administered Dissociative States Scale should be administered.

Ketamine can induce psychotic episodes in people with schizophrenia, and may cause nausea, vomiting and dysgeusia.

8. Future Perspectives

People with eating disorders often have concerns around pharmacological interventions, but also report wanting medication to alleviate anxiety, eating disorder thoughts, poor concentration and sleep problems. A recent survey investigated views on psychedelic drugs as a treatment for eating disorders, and highlighted the need for collaboration with service users.

Future studies should aim to establish a safety profile for ketamine in eating disorders through well-controlled feasibility and pilot studies. Long follow-up periods should be implemented and other metrics of improvement should be considered instead of weight gain.

Ketamine-assisted therapy generally follows a three-stage process: preparation, dosing and integration. Specific therapeutic strategies may work well with ketamine, such as compassion-based meditation exercises, yoga, cognitive bias modifications and exposure therapies.

9. Conclusions

Current treatment options for AN show limited efficacy, and addressing severe-enduring cases presents a particular challenge to clinicians and researchers. Ketamine may be an effective treatment for AN, but further studies are required to establish its efficacy, acceptability and safety.

Funding: J.K. acknowledges a Medical Research Council stipend, H.H. and J.T. acknowledge salary support from the NIHR Maudsley Biomedical Research Centre for Mental Health.

M.J. has received honoraria for speaking from Janssen, Lundbeck, EMS, Neurocentrx and Daiichi Sankyo, and C.K. has received salary from EMS.