AN IDEA WORTH RESEARCHING

Restless Activation and Drive for Activity in Nervosa May Reflect a Disorder of Energy

Regina C. Casper, MD* VC 2016 The Authors. International (Int J Eat Disord 2016; 49:750–752) Journal of Eating Disorders Published by Wiley Periodicals, Inc.

Introduction avenues for exploring and understanding the pathology of the disorder. (AN), an uncommon disorder of voluntary food restriction emerging during adoles- cence, is a condition known in Western Europe for The Long Reported Symptoms of “A at least 500 years, if not longer. Although AN is cur- Relatively Extraordinary Degree of rently categorized as an eating disorder, “anorexia” Physical and Mental Activity” in AN or “loss of appetite” are infrequent. AN is also an intensely personal disorder in that the person with A century ago, physicians, whose main diagnostic AN concentrates most of his/her thoughts, emo- tool was clinical observation, identified some hall- tions, and actions on food avoidance and weight mark features of AN. Gull wrote in 1873 “the loss. patient complained of no pain, but was restless The etiology of AN remains obscure. There is and active. This was in fact a striking expression of good agreement that AN constitutes a clinical the nervous state, for it seemed hardly possible, entityandthatitdoesnotdevelopinthecon- that a body so wasted could undergo the text of another psychiatric disorder. Neverthe- which seemed agreeable” (for most references in less, co-morbid psychiatric disorders are the text, please see Ref. 2. frequently associated with AN and they have an A “remarkable strikingly disproportionate impact on the severity and duration of AN. abundance of physical and mental energy” Importantly, twin and family studies point to a remained a distinct ingredient of the phenome- significant genetic component in AN with twin- nology of AN in the early 20th century. Numer- based heritability estimates ranging from 50 to ous studies in recent decades have focused on 1 80%. So far, neither genome-wide linkage stud- the frequency of behavior, termed variously ies or candidate gene studies, nor genome-wide “hyperactivity” or “excessive exercise” by inter- association studies (GWAS) have reported incon- 1 viewing patients, through self-rating scales and trovertible findings. through retrospective reviews of medical The occurrence of AN in other cultures has records. Differences in methodologies and renewed the interest in taking a fresh look at the patient populations which have resulted in clinical phenomenology of AN. Indeed, research inconsistent findings of excessive exercise in AN aimed at identifying and refining new phenotypes with prevalence rates ranging from 30 to 80% might provide a link to genetic studies and open were recently critically reviewed.3 From a devel- opmental perspective, a reported predisposition This is an open access article under the terms of the Creative to greater than average activity levels in child- Commons Attribution-NonCommercial-NoDerivs License, which hood in nearly half of adolescents with AN is permits use and distribution in any medium, provided the origi- nal work is properly cited, the use is non-commercial and no relevant. modifications or adaptations are made. Equally, if not more, remarkable than excessive Accepted 26 May 2016 exercise is the fact that persons with AN appear to *Correspondence to: R. Casper. E-mail: [email protected] Department of Psychiatry, Stanford University School of display a normal, sometimes a slightly higher than Medicine, Stanford, California, 94305 normal, baseline physical activity level. Clinical Published online 17 June 2016 in Wiley Online Library descriptions mention a “persistent wish to be on (wileyonlinelibrary.com). DOI: 10.1002/eat.22575 VC 2016 The Authors. International Journal of Eating Disor- the move” and an “internal urge toward increased ders Published by Wiley Periodicals, Inc. activity.”

750 International Journal of Eating Disorders 49:8 750–752 2016 RESTLESS ACTIVATION IN ANOREXIA NERVOSA

This tendency of AN patients to be active con- energy balance. The strongest experimental evi- trasts sharply with the slowing of movements dence supporting normal or higher than expected observed in prolonged starvation. daily energy levels in AN comes from measure- Keyes et al.4 were the first investigators to study ments of total energy expenditure (TEE) using the systematically the cascade of physiological and doubly labeled water method, the most reliable physical changes in response to caloric under- and valid method currently available that provides nutrition under controlled conditions in the Min- estimates of habitual energy expenditure over a nesota Experiments. A 25% of original time period of 14 days. body weight induced a significant reduction in the Total energy expenditure (TEE) is composed of metabolic rate, led to bradycardia, hypotension, the resting metabolic rate (RMR), the energy hypothermia, loss of sexual interest, increasing expended in activity, and the dietary-induced ther- muscular weakness, reduced motivation, and mogenesis. Four studies (see Pirke et al. 1991, Cas- energy as well as a decrease in spontaneous and per et al. 1991 in Refs. 2,5,6) concur in finding TEE self initiated activity. A few men reported a short- in anorexia nervosa not to be different from normal lived of quickening; with progressive semi- weight healthy age-matched controls, whereas two starvation all men reported “general slowing down, studies of older and chronically ill AN patients7,8 tiredness, and lack of energy.” The experiments observed lower than normal TEE. demonstrated that the body’s physiological and These observations need to be replicated. They molecular adaptations to caloric under-nutrition ought to be supplemented by data from other serve one purpose, to cope with decreased energy objective, less labor-intensive, methods using availability by conserving energy. devices that measure motion and actual physical activity levels, preferably before hospital admission when movements are not restricted. “Restless Activation” and “Drive for A third source of information would be the expe- Activity” in AN Seem to be the riences of persons with AN. Self-ratings and Expression of a Specific Trait Related observer-ratings can measure “restless activation” to a Disturbance in the Mechanisms through items such as being fidgety, feeling rest- Regulating Energy Balance less, feeling active, strong, alert, motivated, a sense In light of these observations, normal activity and of liveliness, feelings of elation, and through ratings energy levels and continued alertness in persons of fatigue, weakness, and loss of energy. The “drive with AN, whose weight loss frequently exceeds 25% for activity” can be assessed as the desire to move of normal weight, appear inexplicable. The first and an inability to sit still. Concomitantly, body idea worth researching then would be that such weight, nutritional intake, degree of , eating “physical and mental energy preserved in the pres- disorder symptoms, including intense fear of/ ence of physical and physiological signs of desire for and the full profile of psy- starvation” might constitute a fundamental charac- chological symptoms, especially anxiety and teristic, a phenotype, determined by both genetic depression, as well as co-morbid psychiatric disor- and environmental influences. Its clinical expres- ders need to be recorded. A self-rating instrument sion seems to be that persons with AN feel restless with acceptable reliability and validity would be 9 and active. The terms “restless activation” and the International Physical Activity Questionnaire. “drive for activity” describe these sensations. The preserved physical and mental energy appears to allow the person to exercise. Possible Factors and Genetic Components in the Postulated Within this conceptual framework, a second Up-Regulation of Energy Levels hypothesis worth investigating can be generated, Under Catabolic Conditions in AN specifically that a pattern of continued normal, sometimes higher than normal, activity levels with- Priority ought to be given to research exploring sys- out signs of fatigue on muscle exertion in AN tems mobilized during the body’s adaptation to points to a disturbance in energy homeostasis. caloric restriction in AN. Studies on , an Energy homeostasis is maintained by neurons adipocyte-secreted hormone involved in energy throughout the CNS that sense hormonal and met- homeostasis which acts as a signal from the abolic signals of systemic energy status and relay periphery to the brain conveying information this information to secondary neurons that regu- about the amount of energy available, have shown late physiological processes so as to maintain an inverse relationship between plasma leptin

International Journal of Eating Disorders 49:8 750–752 2016 751 CASPER levels and symptoms of motor restlessness and and to explore the phenomenon of “physical and physical activity, indicating a positive association mental energy preserved in the presence of weight between “restless activation” and the caloric deficit loss and under-nutrition in AN.” If validated, this in AN.10 clinical phenotype will prove useful for identifying Determining specific genetic changes or altered the biological pathways and genetic regulation of regulation of gene expression that may be triggered energy homeostasis not only in AN, but also under by any of the numerous adaptations during caloric normal conditions. deprivation and which might contribute to reset- ting energy levels in AN is extraordinarily complex. Concerning possible candidates, exposed during References lipolysis, Yoon et al.11 have recently identified genetic variations in extracellular nicotinamide 1. Yilmas ZHJ, Bulik CM. Genetics and epigenetics of eating disorders. Adv Genom Genet 2015;5:131–150. phosphoribosyltransferase (eNAMPT), the key nic- 2. Casper R. The ‘drive for activity’ and ‘restlessnes’ in anorexia nervosa, poten- otinamide adenine dinucleotide (NAD1) biosyn- tial pathways. J Affect Disord 2006;92:99–107. thetic enzyme, secreted by which is 3. Rizk M, Lalanne C, Berthoz S, Kern L, Godart N. Problematic exercise in ano- an important modulator for maintaining normal rexia nervosa: Testing potential risk factors against different definitions. hypothalamic NAD1 levels, SIRT1 activity, and PloS One 2015;10:e0143352. 4. Keys A, Brozek J, Henschel A, Mickelsen O, Taylor H. The Biology of Human physical activity, particularly in response to fasting. Starvation. Minneapolis: University of Minnesota Press, 1950. Another type of variation may involve missense 5. Zipfel S, Mack I, Baur LA, Hebebrand J, Touyz S, Herzog W, et al. Impact of mutations in the estrogen related receptor a exercise on energy metabolism in anorexia nervosa. J Eat Disord 2013;1:37. (ESRRA) gene and the transcriptional repressor his- Epub 2014/02/07. tone deacetylase 4 gene (HDAC4) identified by Cui 6. Bossu C, Galusca B, Normand S, Germain N, Collet P, Frere D, et al. Energy 12 expenditure adjusted for body composition differentiates constitutional et al. that segregated with AN. ESRRA participates thinness from both normal subjects and anorexia nervosa. Am J Physiol in energy balance and metabolism and is up- Endocrinol Metab 2007;292:E132–E137. Epub 2006/08/17. regulated by exercise and restriction in 7. Platte P, Pirke K, Trimborn P, Pietsch K, Krieg J, Fichter M. Resting metabolic peripheral tissues.12 Furthermore, altered mito- rate and total energy expenditure in acute and weight recovered patients chondrial gene expression of evolutionary con- with anorexia nervosa and in healthy young women. Int J Eat Disord 1994; served genes, in line with the theory of activity- 16:45–52. 8. Van Marken Lichtenbelt W, Heidendahl G, Westerterp K. Energy expenditure anorexia ensuring survival, perhaps by increasing and physical activity in relation to bone mineral density in women with muscle work efficiency through changes in fuel uti- anorexia nervosa. Eur J Clin Nutr 1997;51:826–830. lization, may be involved. Alternatively, a polygenic 9. Hagstromer M, Oja P, Sjostrom M. The International Physical Activity Ques- pattern with genes of small effect might modulate tionnaire (IPAQ): A study of concurrent and construct validity. Pub Health re-setting energy homeostasis in AN. Nutr 2006;9:755–762. Epub 2006/08/24. 10. Holtkamp K, Herpertz-Dahlmann B, Hebebrand K, Mika C, Kratzsch J, In conclusion, we propose as a hypothesis that Hebebrand J. Physical activity and restlessness correlate with leptin levels in an abnormal response of the body’s energy regula- patients with adolescent anorexia nervosa. Biol Psychiatry 2006;60:311–313. tion to severe under-nutrition and weight loss Epub 2005/12/27. manifested in the symptoms of “restless activation” 11.YoonMJ,YoshidaM,JohnsonS,TakikawaA,UsuiI,TobeK,etal.SIRT1-medi- and “drive for activity” are fundamental elements ated eNAMPT secretion from adipose tissue regulates hypothalamic NAD1 and function in mice. Cell Metab 2015;21:706–717. Epub 2015/04/30. of the pathology of AN. Future research will be 12. Cui H, Moore J, Ashimi SS, Mason BL, Drawbridge JN, Han S, et al. Eating dis- required to establish the validity of the concepts of order predisposition is associated with ESRRA and HDAC4 mutations. J Clin “restless activation” and “drive for activity” in AN Invest 2013;123:4706–4713. Epub 2013/11/13.

752 International Journal of Eating Disorders 49:8 750–752 2016