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• ¹Internal Medicine & Addiction Medicine, Waban, MA, United States
• ²Consultant-Ketogenic Diet Therapy LLC, Elm Grove, WI, United States
• ³Innovative Psychiatry, South Windsor, CT, United States
• ⁴Center for Neural Sciences, New York University, New York, NY, United States
• ⁵The Neuroscience Institute, NYU Langone Medical Center, New York, NY, United States
• ⁶Center of Excellence in Eating and Weight Disorders, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Background: Chronic anorexia nervosa is a tragic disease with no known effective pharmacological or behavioral treatment. We report the case of a 29 year-old woman who struggled with severe and enduring anorexia nervosa for 15 years, and experienced a complete recovery following a novel treatment of adopting a ketogenic diet followed by ketamine infusions. Her remission has persisted for over 6 months.

Case Presentation: At age 14.5, the patient embarked on an effort to “eat healthy.” She quickly lost control of the dieting, developed associated compulsions and obsessions about food, body dissatisfaction, emotional lability, and lost nearly 13.6 kilograms (30 pounds). She was hospitalized for 6 weeks, and while she regained some weight, she did not attain full weight restoration. For 15 years, she continued to eat in a restrictive manner, exercise compulsively, and have intermittent periods of alcohol dependence. Nevertheless, she always hoped to get well, and at age 29, she began a novel treatment for anorexia nervosa.

Conclusions: This is the first report of a ketogenic diet used specifically for the treatment of anorexia nervosa, followed by a short series of titrated IV ketamine infusions leading to complete remission of severe and enduring anorexia nervosa, with weight restoration, and sustained cessation of cognitive and behavioral symptoms, for 6 months. Although these treatments were used sequentially the relationship between these modalities, and possible synergy, is unclear, and deserves further study. Complete and sustained remission of chronic anorexia nervosa is quite rare, and the novel use of a ketogenic diet and IV ketamine treatment in this potentially lethal condition suggests avenues for further research, and hope for patients and their families.

Introduction

Anorexia nervosa (AN) is a severe disorder characterized by self-starvation, hyperactivity, anxiety, body dissatisfaction, and emotional dysregulation that usually begins in early puberty, and affects females more frequently than males. When weight restoration is the only criteria measured, rates of 60% recovery are often noted, but when cognitive recovery is included, the results are more discouraging (1–3). Severe and enduring anorexia nervosa refers to cases that have persisted for at least 3 years, and are resistant to intervention. It is a tragic disorder with no consistently effective pharmacological or behavioral treatments. The mortality rate is estimated to be ten times higher than that of the general female population, due to medical complications of self-starvation, and suicide (4). We report a case of severe and chronic AN treated successfully by adopting a ketogenic (KG) diet for 3 months followed by a series of intravenous ketamine infusions.

Emerging data suggest that disturbances in lipid signaling may underlay some of the core pathology of anorexia nervosa (5–7) and that chronic starvation may promote a type of metabolic hibernation in patients (8) that requires normalization of lipid signals to resume premorbid metabolic and central nervous system functions. A KG diet is a high fat, low carbohydrate medical diet, that leads to increased fatty acid oxidation for cellular energy, which in turn results in increased ketone body production. Ketones are produced in the liver whenever fat metabolism increases over carbohydrate metabolism; such as fasting, post-exercise, neonatal period, and KG diet, as well as during pathological states such as starvation or uncontrolled diabetes mellitus (9). Ketones easily pass the blood brain barrier and become the brains’ major energy source. This change in metabolic fuel from glucose to ketones leads to a myriad of changes in central nervous system neurotransmitters such as adenosine and gamma-aminobutyric acid (GABA), as well as neuropeptides such as leptin, adiponectin, and growth hormone-releasing peptides (10). As far as we know, this is the first publication describing the use of a KG diet for patients with AN.

In addition to dietary disturbances and potential metabolic disturbances, psychiatric symptoms such as anxiety, obsessive-compulsive disorder, depression, and addiction are frequently observed among individuals with AN (11). Ketamine has emerged as a novel treatment for treatment-resistant mood disorders, particularly those with suicidal ideation (12, 13). As far as we are aware, there is only one published study of ketamine infusions for AN, and it was encouraging (14).

We report the case of a 29 year-old woman, with chronic severe AN who had an excellent response to adopting a ketogenic diet and undergoing ketamine infusions.

Case Presentation and Clinical Assessment

The patient was a 29 years old single woman, diagnosed with AN at age 14.5, and intermittent alcohol dependence beginning at age 18. She was not in active psychiatric treatment, although she saw a supportive therapist episodically and attended Alcoholic Anonymous meetings at least once/month. She had been abstinent for 15 months, and was eating with many restrictions—preferring to eat by herself and use a napkin rather than a plate, eating only ice cream for days at a time, and excessively using non-nutritive low calorie sweeteners. She exercised daily and compulsively, usually spending 2 h at the gym. Her weight had been stable at 56.8 kg (125 lbs) for several years. Recognizing she was living a very limited life, she decided to try a novel treatment, and worked closely with an internist who was knowledgeable about eating disorders, who is the first author.

The patient was the product of a normal pregnancy and delivery and raised in an upper middle class home by parents who are both attorneys. Her older sister was very concerned with her own appearance. Family history was significant for a paternal grandmother who was obsessed with “being very slender” all her life, though was never given a psychiatric diagnosis. The patient’s mother was diagnosed with an anxiety disorder and was prescribed citalopram.

At an early age, the patient was identified as athletic, artistic, and excelled academically. Her parents noted that she had “compulsive tendencies’ such as “grinding erasers” and wanting her possessions to be lined up symmetrically, but this never reached the level of clinical concern.

At age 14.5, while at a sleep-away camp, she began a diet, with the aim of “eating healthier” with other girls in her bunk. When summer ended, she continued her diet. Her parents slowly became aware of a change in her mood and behavior, from a happy child to a sullen and angry teenager. They initially attributed this to the “onset of adolescence” but when her weight loss became more obvious, she was evaluated by her pediatrician, and was referred to an outpatient eating disorder clinic, where she ate 3 dinners/week. She also had weekly individual supportive therapy, and weekly meetings with a nutritionist. Her parents also saw a therapist separately. Her weights are summarized on Table 1; prior to illness she weighed 61.1 kg (136 lbs); height 1.62 meters (5’4”) with a Body Mass Index (BMI) of 23.3.

Twelve months into the course of her illness, she had a grand mal seizure. At the time, her weight was 43.5 kg (96 lbs) with BMI of 16.5, and her treatment was changed to incorporate Maudsley treatment in which the parents are actively taught to re-fed the child (15). She was resistant, and meals were rarely successful; after 6 months of out patient treatment she was hospitalized for 15 days followed by 30 days of “partial hospitalization.” On admission to the inpatient unit, her weight was 50.8 kg (112 lbs.) with a BMI of 19.2. Her pulse was 80 sitting, rising to 103 standing, and her blood pressure was 94/60 sitting; and 110/82 standing. The remainder of the exam was normal as were her electrolytes, and kidney and renal function tests, and complete blood count, MRI, EEG, and EKG. A bone density exam showed mild osteopenia of the hip and spine. She had had a normal menarche age 13, but had been amenorrheic for 7 months. She denied binging, purging, laxative, or diuretic abuse and was given the diagnosis of anorexia nervosa restricting type. She was discharged to home after attaining a weight of 54.4 kg (120 lbs.) with a BMI of 20.6.

She returned to high school, yet she never regained friendships she had prior to the hospitalization, and remained dismissive of her parents’ efforts to supervise her eating. Her weight generally hovered near 54.5 kg (120 lbs.). She started college several times, and dropped out several times, but eventually graduated from an excellent university. Over the next 8 years, she had three month-long admissions to alcohol & drug rehabilitation programs. She worked as a recovery coach in several wilderness rehabilitation programs, and began graduate school.

The only medications she was prescribed were lamotrigine for six months following the seizure, and lisexamfetamine dimesylate (Vyvanse).

At age 29, on physical exam, she appeared fit and well. Her BP was 120/72 and pulse 50, without orthostatic changes, and her weight was 56.7 kg. (125 lbs). Her physical exam was normal, as was her complete blood count, electrolytes, liver and kidney function tests. She was coached by an experienced KG nutritionist on ways to prepare high fat, low carbohydrate meals and smoothies, and encouraged to eliminate non-nutritive sweeteners. The goal was to induce a stable degree of ketosis, following a liberal KG diet with a 2:1 to 1:1 ratio of fats: carbohydrates + protein in grams. While we anticipated it might be difficult for her to eat fatty foods, as it is known that individuals with AN avoid high calorie foods (16), she found it relatively easy.

● “The whole time I was anorexic, I ate my safe foods, and there were not many: Lots of Splenda®, frozen yogurt, zucchini, eggplant and coffee. I only ate such a ridiculously limited amount of food, that the logistics of switching to keto were not that hard – when you think you want x, have y instead. If you have three x’s and that’s it, then have three y’s, and for me the ketos were bacon, eggs, cheese avocado, Medium Chain Triglyceride (MCT) oil”

Initially, she varied between strictly following the KG diet and being lax, but gradually found she was gaining insights into the anorexic “voice”, and it became easier to follow the diet and remain in ketosis.

● “Until now (KG), I ate sweetener with everything. I used to put Splenda on broccoli.”

● “I now consider myself to have a sugar allergy. When I eat avocados or bacon and eggs, the “voice” is softer, if I eat sugar I feel euphoric, but the euphoria has feelings of panic.”

She measured breath acetone levels with a portable breath monitor, 2–3 times/week. Breath acetone levels are scored qualitatively from 0 to 6, and she was at 2 or 3 (mild-medium range) when she was on the KG diet.

After 3 months on the diet, she reported she was “30-40% better, but was still troubled by anorexic compulsions.” She was referred for ketamine infusions. She underwent comprehensive evaluation, and met DSM-V criteria for anorexia nervosa, restricting type, and major depressive disorder, recurrent, moderately severe, with Patient Health Questionnaire-9 (PHQ-9) of 13 (17). She began treatment with racemic IV ketamine at dose of 0.75 mg/kg (42.68 mg), in 30 cc 0.9% normal saline infused over 45 min in a private room with dimmed lights, sound machine, using an eye mask. Pulse, blood pressure, respiration, O2 saturation, and cardiac waveform were monitored continuously throughout her infusion and showed expected variations in pulse and blood pressure which did not require intervention. Dissociation was present, as evidenced by patient report of feeling “out of my body” and “seeing things in layers,” and clinical observations. She displayed decreased verbal fluency and mild 1-2 beat end-gaze nystagmus during treatment, which resolved completely. She developed mild nausea following her first infusion. There were no other reported or observed side effects during treatment. All treatment-emergent side effects dissipated within 20 min. Within one hour of her first infusion, she felt the anorexic voice was weakening, and she had more ability to “be herself.” PHQ-9 dropped to 6. She then had three more IV ketamine infusions over the next fourteen days, at doses titrated to 1.0 mg/kg, 1.1 mg/kg, and 1.2 mg/kg to achieve and maintain dissociation during infusion. Each infusion was preceded by ondansetron 4 g sublingual and she denied nausea during or after these infusions. Her response was dramatic and occurred after the 4^th infusion.

● “I know this sounds ridiculous, but I am no longer anorexic. I had so many rules I didn’t even know them. But they are gone. I can exercise because it feels good. It isn’t that I have to. I can stop when I want to.”

Notably, her PHQ-9 dropped to 6 after her first treatment, and to 2 following her third infusion.

Follow Up

She has continued to feel free from the intrusive AN obsessive thoughts, rigid AN rules, and compulsive behaviors, and to explore a fuller life, and is now over 6 months post ketamine infusion. She continues to eat a KG diet and her weight has inched up to 61.3 kilograms (136 pounds), the weight when the disease took hold at age 14.5. When she weighs herself now she notes:

● “I really didn’t know how I would feel getting on a scale and looking at my weight. Now, I am so relieved. I think I do not CARE about the number because I can SEE myself now in the mirror, so the number on the scale is ‘like’ ONE source of information, but not the ONLY one. I think 136 pounds is fine and I LOVE the way I look”,

Following treatment, she sees a therapist weekly for supportive psychotherapy, although during the COVID-19 pandemic visits have occurred by telemedicine. She checks her own weight every few weeks when she visits her cousin’s apartment where there is a scale, and it has been stable at her premorbid weight of 61.8 kg (136 lbs).

Patient Perspective

“All these years, I was still in there watching, waiting, and hoping to escape. Every single interaction now is a new freedom.”

She is very supportive of this publication and hopes this treatment will be studied to determine if it is effective for other patients who suffer, as she did.

Discussion

This is a striking case report of an unusual combination of a ketogenic diet and a short series of titrated ketamine infusions in a patient with severe chronic AN of 15 years – modalities that have a rational medical justification, but have never been used clinically for this disorder, or in this patient population. This resulted in a surprising and long lasting complete remission which has continued despite the stressors of living in New York City in the midst of the COVID-19 pandemic. The strength of this case report is that it offers an innovative approach to chronic AN, a disorder which is exceedingly resistant to treatment and associated with an increased risk of death.

KG diets for AN have been roundly dismissed by eating disorder experts, and with the exception of an early study in 1998, ketamine has not been reported as effective in AN. Thus, it is critical to consider the context of how this treatment sequence evolved for this patient.

The impetus for this treatment arose when the patient was presented with an etiological theory of AN, known as Adaptation to Flee Famine Hypothesis, which frames the genesis of AN as metabolic rather than psychological (18). This resonated deeply with the patient, as she often had felt she was battling invisible forces. Seeing her symptoms as the result of distorted physiological signals and offering a metabolic solution was powerfully motivating. Explaining that there was an animal model for AN that replicated many of its symptoms, was also empowering, as it countered the narrative that she was somehow “choosing” this disorder in order to exert “control” over her life. These psycho-social constructs, which she had heard many times in rehabilitation centers, had never rung true for her, and had also burdened her with guilt for “causing her own illness.”

The Adaptation to Flee Famine Hypothesis posits that it would have been evolutionarily advantageous to a nomadic tribe if some members acted uniquely when presented with a state of food scarcity or famine. If these individuals could deny hunger, dismiss their obvious body inanition, act as if they were just fine, and engage in hyperactive running long distances, they might lead the tribe to better hunting grounds. These are precisely the behaviors seen in adolescents with AN.

The activity-based-anorexia rodent model involves housing a rodent in a cage with a running wheel, and decreasing the food supply slightly (19). Some animals, often female and adolescent, will increase running and reduce eating drastically, thus replicating aspects of human AN. The model requires both stimuli of decreased food supply plus unlimited access to a running wheel.

Advising the patient to adopt a KG diet was prompted by two factors. First, two studies employing an activity-based-anorexia model demonstrated that a KG diet rescued the animals from self-starvation (20); and a high-fat diet (although not ketogenic) prevented the animals’ self starvation (21). Secondly, the KG diet has an impressive record of safety and efficacy for treating seizure disorders in children, and has been used continuously since the 1920s (22). It is an emerging therapy for treatment of other neurological and psychiatric disorders such as Parkinson’s, early Alzheimer’s, and bipolar disorder (23). Thus, since it is generally safe and effective for other neurological disorders, it might also prove effective for AN, especially since AN has been shown to be genetically linked with abnormalities in fat metabolism (6).

There are known side effects of the KG diet which are occasionally observed in patients treated for seizures. These include weight loss, constipation, nephrolithiasis, and hypoglycemia. These effects are seen most often in children who are on multiple anti-seizure medications and are often physically compromised. Fortunately, this patient did not experience any of these symptoms and her weight increased as she ate with more freedom. The patient was at a stable weight and the only medication was lisexamfetamine dimesylate (Vyvanse). Furthermore, a more rigid ketogenic diet of 4:1 fat: protein plus carbohydrate diet is often employed for patients with seizures, while the diet employed in this case was a more liberal diet of 2:1 or 1:1 which may have mitigated some of the possible side effects of the KG diet.

It is unknown whether the positive results from the KG diet arm of the treatment were due to adopting a KG diet, or if simply adopting a high fat diet without the carbohydrate restriction required for ketosis would have been effective. We believe it was the ketogenic nature of the diet because the biochemical changes seen with ketosis are different from those seen with increased fat. A recent article testing a ketogenic diet in humans, and also transplanting the microbiome into mice, noted that the microbiome responds differently to a moderate fat diet, a high fat diet that is not ketogenic, and a high fat/low carbohydrate that is ketogenic (24). This is an area of active research.

If the patient had been pleased with the results of the KG diet alone, the treatment would have stopped at that point. She reported the symptoms of AN were “30-40% improved but she was still troubled with anorexic compulsions. Thus the second “arm” of the treatment began—ketamine infusions. The addition of ketamine treatment in this case was also based on studies on the activity-based-anorexia model, plus one very interesting, and overlooked case series report from 1998.

Experiments with the activity-based-anorexia model found that individual rodents vulnerability to self-starvation correlated with levels of N-methyl-D-aspartate (NMDA) glutamine receptors in the dorsal hippocampus (19). Since ketamine is a well known antagonist to NMDA glutamine receptors, an elegant experiment examined whether injection of ketamine on day 2 when the animal had started to self-starve and hyper-exercise could alter the behavior (25). As predicted, those treated with ketamine ate more, exercised less, and were resilient to the self-starvation when they were re-exposed to the paradigm, compared to those treated with placebo.

Very similar reasoning was described for the rationale of a study from Cambridge, England, published in 1998 in which Mills et al. treated 15 patients with chronic severe AN with a series of ketamine infusions (14). Significant prolonged improvement was reported in 9 patients. Some of the responses resembled the dramatic changes noted in this case report.

It is difficult to determine the doses of ketamine administered in this report because the authors describe that infusions were delivered at 20 mg/h for 10 h using doses “similar to that used to produce analgesia” but exact doses were not stated. Furthermore all patients in this series were prescribed an opiod blocker to “ensure they remained conscious”.

We approached the ketamine arm of the treatment cautiously because the patient had struggled with alcohol dependence, substance abuse is common in patients with AN, and ketamine is a drug that is recreationally abused. A recent study, pooling data from 5 clinical trials found no evidence of serious side effects from a single infusion of ketamine for clinical depression, and ketamine was not associated with increased abuse (26). Many patients reported feeling “loopy” or “dissociative” during the infusion, but this passed rapidly. While this study is promising, racemic ketamine infusions for psychiatric disorders remains off-label, and issues of optimal dose, duration, titration, and number of infusions needs further research. In AN, these questions deserve further investigation and warrant controlled trials. This patient did indeed experience dissociation during her infusions, which she found was part of its therapeutic effect.

Although the efficacy of KG diet for seizure disorders, and ketamine infusion for severe treatment resistant depression has been clearly demonstrated, the mechanisms of actions of both agents are not well understood. It is notable that both ketamine and KG diet have been shown to intimately affect brain-derived neurotrophic factor (BDNF), gamma-Aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA) glutamate receptors which are the same molecules affected in the activity- based-anorexia model (27, 28). It is possible that the KG diet and IV ketamine act synergistically, with the KG diet “priming” the response to ketamine. This requires further study.

There are several important limitations to this report and to the generalizability of the findings. Most importantly, this is a single case report and further study is needed. Secondly, standardized eating disorder rating scales were not used to monitor progress. This is because this is a report about a clinical experience with a patient used to monitoring her own eating and activity levels by journaling; it was not organized as a clinical trial. There are no eating disorder scales that have been validated for used with ketamine treatment. Third, this treatment paradigm essentially involved three modalities, and not just two treatment arms: first the patients adoption and reconsideration of AN as a disorder whose symptoms are predominately metabolically driven, which was an enormous paradigm shift for her; secondly adopting the KG diet and contextualizing ketosis as helpful for her brain rather than as a weight loss or weight control method for her body; and third IV ketamine infusions at a dose and titration schedule not previously reported. The fact that this sequential treatment resulted in complete and sustained remission of this patient’s severe AN thoughts and behaviors was unexpected. Furthermore, her remission has persisted despite extreme stressors, social isolation, work restrictions, and treatment disruptions during the COVID-19 pandemic in NYC. At his point it is not possible to state which modality was essential, or which had the most important therapeutic benefit, if both ketogenesis and ketamine are necessary and synergistic, or if the treatment would have been as effective if the KG diet were initiated with ketamine when ketamine infusions began instead of preceding them by several months. It is possible that ketamine infusions alone would have been effective. Future studies are necessary to address these questions, and to address optimal KG diet ratios and optimization of ketamine dose, duration, and frequency.

Conclusions

There remain many unanswered questions about the generalizability of these findings to other patients with AN. Yet, the medical plausibility of this treatment and the dire prognosis of chronic anorexia nervosa, suggest that both the KG diet and ketamine treatment warrant further study in this patient population towards the goals of restoring weight, normalizing cognitive and emotional functioning, and improving quality of life. It is hoped that this report will stimulate this research.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.

Ethics Statement

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided her written informed consent to participate in this study. Written informed consent was obtained from the individual, for the publication of any potentially identifiable images or data included in this article.

Author Contributions

All authors contributed to the article and approved the submitted version. BS orchestrated the treatment and wrote the first draft of paper. BK coached the patient on the ketogenic die and edited the paper. LC performed a comprehensive evaluation of the patient, treated the patient with ketamine infusions, and edited the paper. CA performed the studies on activity-based-anorexia, kept the authors informed of her studies, and edited the paper. TH was the primary medical provider 15 years ago when the patient first became ill, continued to consult regarding her care over the years, and edited the paper.

Conflict of Interest

Author BZ-K was employed by the company Ketogenic Diet Therapy LLC.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Murray SB, Loeb KL, LeGrange K. Treatment outcome reporting in anorexia nervosa: time for a paradigm shift? J Eating Disord (2018) 6:10 . doi: 10.1186/s40337-018-00195-1

CrossRef Full Text | Google Scholar

2. Eddy KT, Tabri TN, Thomas JJ, Murray HB, Keshaviah A, Hastings E, et al. Recovery from anorexia nervosa and bulimia nervosa at 22-year follow up. J Clin Psychiatry (2017) 78(2):184–9. doi: 10.4088/JCP.15m10393

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Fichter MM, Quadflieg N, Crosby RD, Koch S. Long-term outcome of anorexia nervosa: results from a large clinical longitudinal study. Int J Eat Disord (2017) 50:1018–30. doi: 10.1002/eat.22736

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Touyz S, Hay P. Severe and enduring anorexia nervosa in search of a new paradigm. J Eat Disord (2015) 3:26. doi: 10.1186/s400337-015-00650-z

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Shih PB, Yang J, Morisseau C, German JB, Zeeland AA, Armando AM, et al. Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa. Mol Psychiatry (2016) 21(4):537–46. doi: 10.1038/mp.2015.26

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Watson HJ, Yilmaz Z, Thornton LM, Hubel C, Coleman JR II, Gaspar HA, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet (2019) 51(8):1207–14. doi: 10.1038/s41588-019-0439-2

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Holman RT, Adams CE, Nelson RA, Grater SJ, Jaskiewicz JA, Johnson SB, et al. Patients with Anorexia Nervosa Demonstrate deficiencies of selected essential fatty acids, compensatory changes in nonessential fatty acids and decreased fluidity of plasma lipids. J Nutr (1995) 125(4):901–7.

PubMed Abstract | Google Scholar

8. Scolnick B. Hypothesis: Clues from mammalian hibernation for treating patients with anorexia nervosa. Front Psychol (2018) 9:2159. doi: 10.3389/fpsyg.2018.02159

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Kraeuter AK, Phillips R, Sarnyai Z. Ketogenic therapy in neurodegenerative and psychiatric disorders: From mice to men. Prog. Neuropsychopharmacol Biol Psychiatry (2020) 101:109913. doi: 10.1016/j.pnpbp.2020.109913

CrossRef Full Text | Google Scholar

10. Giordano C, Marchio M, Timofeeva E, Biagnin G. Neuroactive peptides as putative mediators of antiepileptic ketogenic dies. Front Neurol Rev (2014) 29(5):63. doi: 10.3389/fneuro.2014.00063

CrossRef Full Text | Google Scholar

11. Marucci S, Ragione LD, De Iaco G, Mococci T, Vicini M, Guastamacchia E, et al. Anorexia Nervosa and Comorbid Psychopathology. Endocr Metab Immune Disord Drug Targets (2018) 18(4):316–24. doi: 10.2174/1871530318666180213111637

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Fond G, Loundou A, Rabu C, Macgregor A, Lancon C, Brittner M, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacol (Berl) (2014) 231(18):3663–76. doi: 10.1007/s00213-014-3664-5

CrossRef Full Text | Google Scholar

13. Calabrese L. Titrated serial ketamine infusions stop outpatient suicidality and avert ER visits and hospitalizations. Int J Psychiatr Res (2019) 2(6):1–12.

Google Scholar

14. Mills IH, Park GR, Manara AR, Merriman RJ. Treatment of compulsive behavior in eating disorders with intermittent ketamine infusions. QJM (1998) 91(7):493–503. doi: 10.1093/qjmed/91.7.493

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Le Grange D. The Maudsley family-based treatment for adolescent anorexia nervosa. World Psychiatry (2005) 4(3):1142–146.

Google Scholar

16. Schebendach JE, Mayer LE, Devlin MJ, Atia E, Contento IR, Wolf RL, et al. Food choice and diet variety in weight-restored patients with anorexia nervosa. J Am Diet Assoc (2011) 111(5):732–6. doi: 10.1016/j.jada.2011.02.002

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Beard C, Hsu KH, Rifkin LS, Busch AB, Bjorgvinsson T. Validation of the PHQ-9 in a psychiatric sample. J Affect Disord (2016) 193:267–73. doi: 10.1016/j.jad.2015.12.075

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Guisinger S. Adapted to flee famine: adding an evolutionary perspective on anorexia nervosa. Psychol Rev (2003) 110(4):745–61. doi: 10.1037/0033-295X.110.4.745

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Aoki C. Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa. Brain Res (2017) 1654(PtB):102–15. doi: 10.1016/j.brainres.2016.01.019

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Barboriak JJ, Wilson AS. Effect of diet on self-starvation in the rat. J Nut (1972) 102(11):1543–6. doi: 10.1093/jn/102.11.1543

CrossRef Full Text | Google Scholar

21. Brown AJ, Avena NM, Hoebel BG. A high fat diet prevents and reverses the development of activity-based anorexia in rats. Int J Eat Disord (2008) 41(5):383–9. doi: 10.1002/eat.20150

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Freeman JM, Kossoff EH. Ketosis and the ketogenic diet.2010: advances in treating epilepsy and other disorders. Adv Pediatr (2010) 57(1):315–29. doi: 10.1016/j.yapd.2010.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Strafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol (2012) 3:59. doi: 10.3389/fpharm.20012.00059

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Ang QY, Aleaxander, Newman JC, Tian Y, Cai J, Turnbaugh PJ. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell (2020) 181:1263–75. doi: 10.1016/j.cell.2020.04.027

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Chen YW, Sherpa AD, Aoki C. Single injection of ketamine during mid-adolescence promotes long-lasting resilience to activity based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety like behavior. Int J Eat Disord (2018) 51:1020 –1025. doi: 10.1002/eat.22937

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Acevedo-Diaz E, Cavanaugh GW, Kraus C, Bashkim K, Zarate CA. Comprehensive assessment of the side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord (2019) 263:568–75. doi: 10.1016/j.jad.2019.11.028

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Hartman AL, Gasior M, Vining E, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediat Neurol (2007) 36(5):281–92. doi: 10.1016/j.pediatrneurol.2007.02.008

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and ketamine metabolite pharmacology- insights into therapeutic mechanisms. Pharmacol Rev (2018) 70(3):621–60. doi: 10.1124/pr.117.015198

PubMed Abstract | CrossRef Full Text | Google Scholar

By Hannah Towfiq 5 February 2021

Anorexia Nervosa is an eating disorder that can affect people of all ages, genders, sexual orientations, races, and ethnicities. It is characterized by extreme weight loss and consequent difficulties maintaining an appropriate body weight for the height and age of the sufferer. It is not a new condition, and many historians believe there is evidence to suggest that individuals have been displaying symptoms of anorexia for hundreds or even thousands of years. Treatment plans are often tailored to the individual patient and can range from cognitive behavioural therapy, a hospital stay, psychotherapy and help from a registered dietitian. However, despite these treatments, recovery is a long process.

In this piece, we have the privilege of taking a look at a new potential treatment option for Chronic Anorexia Nervosa, from the three viewpoints – the author of a compelling research article, the Faculty Member who recommended the work, and the patient involved in the study. Let’s introduce these participants:

Barbara Scolnick is a semi-retired internist who lives in Boston, MA. She graduated from Columbia College of Physicians & Surgeons in 1977. During this time she often worked part-time in outpatient clinics and also raised 3 children.

Caroline Beckwith is Barbara’s niece and the patient in this study. She has a Bachelor’s Degree from the University of Wisconsin Madison and half of a Master’s Degree from Columbia University Teachers College. Her Anorexia and addiction ultimately made finishing this program pretty impossible.

Maria Consolata Miletta is an Associate Faculty Member for Faculty Opinions who works with Tamas Horvath to evaluate the literature relevant to their research interests. She is currently a group leader at the University of Zurich. Her main research interests are the neurobiology of anorexia nervosa and she hopes that one day she can study the condition at a single-cell resolution and begin to lay the foundation of an effective cure.

*This study was conceptualized and implemented by Prof. Tamas Horvath, Faculty Member, principal investigator and last author on the paper, and performed in his lab at the Yale School of Medicine.

What sparked your interest in researching Anorexia Nervosa?

BS: Everything changed 15 years ago when my niece Caroline Beckwith was 14 years old. Since her mother and I are identical twins, our families are very close. Caroline was funny, athletic, easy-going, and in general a pleasure to be around, until she developed anorexia nervosa, and was swallowed up, not to emerge for 15 years. Once she developed anorexia nervosa, I tried to find answers.

MM: My main research interest at the end of my PhD was the physiology of fasting: specifically, what happens to our body when we fast and how long can we? Hence I contacted Prof Tamas Horvath, a worldwide expert in the field and I moved to Yale for a postdoc in his lab. He has been studying for 25 years a family of neurons physiologically active during fasting called AgRP neurons. The hypothesis was that these neurons might be involved in the development of Anorexia Nervosa. There were some supportive data from clinical studies too. Patients suffering from Anorexia have a high level of circulating AgRP protein in the blood for example. These neurons are located in the hypothalamus, a deep region in the brain mainly involved in feeding behavior.

The project was risky but we really surprised by the results. We found that AgRP neurons, when activated in an activity-based anorexia model, modulate a complex response that involve both metabolic and behavioral changes to adapt to fasting.

What is your relationship with the study “Remission from Chronic Anorexia Nervosa With Ketogenic Diet and Ketamine: Case Report”?

BS: This entire project was dependent upon my easy access to PubMed, initially at the Harvard medical school library, and then my home computer. I used this tool to read papers of scientists who worked at different decades and disparate fields—lipid research, hibernation, brain histology. Among the influential scientists was Ralph Holman who described the skewed fatty acid profile seen in patients with anorexia nervosa. Shan Guisinger authored “Adaptation to Flee Famine” and noted that patients with anorexia nervosa and migrating mammals both engage in constant motion and minimal eating, and suggested that anorexia nervosa was a manifestation of an ancient adaptation to fleeing famine.

Discovering that an animal model of anorexia had been described since the 1960s was eye-opening. The activity-based anorexia rodent model of anorexia nervosa was based on the observation that some rodents when placed in a cage with a running wheel and subjected to a slight decrease in the food supply, proceed to hyper-exercise and reject all food, and actually starve to death if not removed from the cage. This self-starvation required both stimuli; the running wheel and decreased food supply.

”The most important message is that: Anorexia is not a choice. There is so much stigma in society for people suffering from Anorexia and this might delay getting the most appropriate treatment or even getting appropriate funding for research. Patients do not choose to starve to death.Maria Miletta, Group Leader, Department of Neonatology, University of Zürich.

I wondered if a faulty brain circuit responsible for recognizing the ambient food supply might be the underlying pathology in anorexia nervosa. One could hypothesize, that this “faulty circuit” would be asymptomatic unless the patient experienced an initially minor episode of insufficient nutrition, and then, unfortunately, it would become obvious. Hibernation is an adaptation that requires the mammal to recognize and anticipate changes in ambient food supply so I focused my reading on hibernation.

The ketogenic diet has been shown to be an effective treatment for seizure disorders since it was described in 1921. While the exact mechanism of action remains unknown, the diet causes the brain energy supply to shift from being dependent on glucose to being driven by ketones. This is a fundamental change which alters many pathways. When I found articles from 1970s, that suggested the ketogenic diet was useful in the activity-based anorexia model, I wondered why it was not tried in humans. It seemed to tie the pieces together.

MM: Currently, there is no effective treatment for anorexia. It is worrisome because it is the psychiatric disorder with the highest mortality (almost 10% according to the national institute of mental health). Actual treatment involves the restoration of the normal body weight, addressing the abnormal behaviors that promote and support this eating disorder, often a parallel treatment with antidepressants. 20% of patients will develop chronic anorexia. This study report is interesting because find a long-term strategy that can help in both managing the weight and the psychiatric symptoms (phobia to eat, compulsive behaviors). Certainly, to be considered effective, the treatment should be extended to a greater number of patients.

What were the limitations and challenges of this study?

BS: I was so excited to come up with something that might help Caroline. The disappointment was severe when no one in academia would research these ideas, and few would even entertain them. Ketogenic diets are commonly used for weight loss, so it was thought to be contraindicated. Ketamine was more palatable to the “specialists” I reached out to, but the doses considered by the academics who were treating depression with ketamine were lower than those used in the Mills study.

”It feels absolutely fantastic to be recommended by Faculty Opinions. This recommendation, which is from an excellent basic scientist has given us all a very needed boost. It is wonderful to have basic scientists and clinicians work together.Barbara Scolnick MD, Associate Investigator, Clinical Trial Ketogenic Diet/Ketamine for Anorexia Nervosa

BS: Caroline was nearing 30. She had been ill for 15 years. While her weight was nearly normal, she was consumed with compulsions to exercise and to eat in a ritualistic manner. It was not a life worth living, in her opinion. We could not wait for academics. Caroline and I talked, and walked endlessly through the streets of New York City in the pre-COVID months of 2019. Finally, we simply tried it ourselves, with the help of two great clinicians.

Beth Zupic-Kania is a nutritionist who has been treating children with seizure disorders with the ketogenic diet for a decade and graciously agreed to help us. Lori Calabrese is a psychiatrist who has used ketamine infusions to treat suicidal depression. We simply gave it a try and hoped for the best. Caroline’s response was so amazing, we were all stunned. After 4 weeks on the ketogenic diet, and 3 ketamine infusions, the anorexia nervosa related thoughts, behaviors, compulsions dissolved, and she remains in complete remission now over 12 months since the intervention.

CB: The largest, most obvious challenge, was convincing the anorexic voice in my head to allow me to eat fat. Anorexia has so many rules, but the strictest for me was to avoid high-fat food. If it was not avoidable, then I had to exercise the calories away. This voice in my head was with me every second of every day, so as I learned about the keto diet, anorexia did as well. The voice wakes up in the morning with you and starts to tell you your day. “First we’ll make coffee then we’ll do squats then we’ll do push-ups then we will go for a walk etc” ALL day. I found by eating a high fat “keto” breakfast first thing in the morning, before anything else, made anorexia quieter throughout the day. Getting myself to do this was hard, but not impossible.

There was a time in the beginning when I stopped eating keto and went back to eating what anorexia wanted me to eat (lots of walking down the streets of NYC while eating m&m’s and frozen yogurt) and this made it very clear that the high-fat diet was truly helping. I think I had to “go back” to be fully convinced that going forward with keto was the way out of anorexia. After that, eating this way became much easier.

I felt empowered every morning when I would wake up and eat bacon, eggs, avocado, and get to say “you can’t scream at me right now,” to anorexia. By the time I got the ketamine infusions, I had whole chunks of time in the day that were quiet from anorexia. It was not gone, but I could feel how much weaker it was from the diet.

MM: There is currently a growing body of evidence which shows that there is an area of the brain involved in the aetiology of anorexia, but isn’t necessarily under the conscious control of the brain. The combination of ketogenic diet and ketamine might surprisingly work in synergy with behavioral therapy because it targets these deep areas of the brain.

”The largest, most obvious challenge, was convincing the anorexic voice in my head to allow me to eat fat. Eventually, I felt empowered every morning when I would wake up and eat bacon, eggs,avocado, and get to say “you can’t scream at me right now,” to anorexia. By the time I got the ketamine infusions, I had whole chunks of time in the day that were quiet from anorexia. It was not gone, but I could feel how much weaker it was from the diet.Caroline Beckwith, Research Assistant, Clinical Trial Ketogenic Diet/Ketamine for Anorexia Nervosa

What is one thing you would like the average person to know about Anorexia Nervosa?

CB: I think people do not realize how much of a person’s life is stolen from anorexia. Looking back, I cannot believe I was allowed to go to college, live alone, feed myself, and have any chance of success.

I think the “average person” imagines someone with anorexia as a rail-thin ballerina or model. I think the easiest way to identify if someone has it is if they are clearly “following rules” that are punishing and isolating and do not appear to be in their best interest. Of course, I didn’t want to wake up at 4am and go on the elliptical machine for three hours! I just didn’t have a choice, and anorexia would not allow me to tell anyone this.

Anorexia is not a choice, or a “control issue”, or the result of some family trauma. It is completely out of control to anyone who has it, and they do not want it, but the voice tells you to keep that all a secret.

MM: The most important message is that: Anorexia is not a choice. There is so much stigma in society for people suffering from Anorexia and this might delay getting the most appropriate treatment or even getting appropriate funding for research. Patients do not choose to starve to death.

How does it feel to have your work recommended by Faculty Opinions?

BS: Absolutely fantastic. Most of the eating disorder community is absolutely shunning this idea, and I have gotten some very nasty emails, claiming it is absurd to use a diet to treat anorexia nervosa. This recommendation, which is from an excellent basic scientist has given us all a very needed boost. It is wonderful to have basic scientists and clinicians work together. As far as our pilot clinical trial, we will persist, and we will do it safely, and we will get answers.

If you’re interested in learning about research in this area, then you can read more in our Eating Disorder and Clinical Nutrition Sections. You can also follow our Associate Faculty Member, Maria Miletta.