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Tyrosine supplementation as an adjuncttreatment in anorexia nervosa – anoradrenergic repletion hypothesisMelissa Hart a b , Bridget Wilcken c , Lauren T. Williams a d , DavidSibbritt a & Kenneth Patrick Nunn ca University of Newcastle, Australiab Hunter New England Child and Adolescent Mental HealthService, New South Wales, Australiac University of Sydney, Australiad Faculty of Health, University of Canberra, AustraliaVersion of record first published: 21 Mar 2013.

To cite this article: Melissa Hart , Bridget Wilcken , Lauren T. Williams , David Sibbritt & KennethPatrick Nunn (2013): Tyrosine supplementation as an adjunct treatment in anorexia nervosa – anoradrenergic repletion hypothesis, Advances in Eating Disorders: Theory, Research and Practice,DOI:10.1080/21662630.2013.742978

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Tyrosine supplementation as an adjunct treatment in anorexianervosa – a noradrenergic repletion hypothesis

Melissa Harta,b, Bridget Wilckenc, Lauren T. Williamsa,d, David Sibbritta andKenneth Patrick Nunnc*

aUniversity of Newcastle, Australia; bHunter New England Child and Adolescent Mental Health Service,New South Wales, Australia; cUniversity of Sydney, Australia; dFaculty of Health, University of Canberra,

Australia

(Received 22 August 2012; final version received 7 September 2012)

Anorexia nervosa (AN) is accompanied by an increased frequency of pre-morbid anxiety.Anxiety disorders are associated with increased brain activity of catecholamines, especiallynoradrenaline. It has been hypothesized that noradrenergic dysregulation may be a majorfactor in the causation of AN. In this article, we explore this hypothesis and how it mightaccount for the reduction of anxiety found in starvation, the increase in anxiety found withre-feeding, and thus the reinforcement of anxiety by re-feeding. We propose that alleviationof this dysregulation through the noradrenaline precursor (tyrosine) supplementation, leadingto saturation of supply, may alleviate some of the pathological changes found in AN. Weconsider how the hypothesis might be investigated. The success of tyrosine supplementationwould have important implications from theoretical, research and clinical perspectives.

Keywords: Tyrosine; repletion; noradrenergic hypothesis; etiology; re-feeding related anxiety;primary depletion; secondary depletion.

Background

Anorexia nervosa (AN) has one of the highest levels of morbidity and mortality of any psychiatriccondition and a lack of effective treatments (Sullivan, 1995; Treasure, Claudino, & Zucker, 2010).Key features include body image distortion, excessive fear of fatness and restricted dietary intake,despite emaciation (Kaye, 2008). Notwithstanding the seriousness of the condition, the etiologyof AN is still not completely understood. Nunn et al. (2012) have proposed an explanation of thepathogenesis of specific and unique features of AN, based upon a specific genetic profile,mediated by epigenetic factors, causing noradrenergic dysregulation, the subsequent over-activityof the sympathetic nervous system, impaired neuroplasticity (the ability of the brain and nervoussystem to change as a result of input from the environment) and reduction of cerebral blood flow(Nunn et al., 2011). In this model of AN, dieting is thought to set off the cascade of noradrenergicdysregulation and insula dysfunction, which in turn leads to inaccurate homuncular somatosen-sory representation and, therefore, distorted body image, the key diagnostic characteristicfeature of AN (Nunn, Frampton, & Lask, 2011; Nunn, Lask, & Frampton, 2011).

© 2013 Taylor & Francis

*Corresponding author. Email: kpnunn@gmail.com

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Central to this formulation of AN is the role of anxiety. There is an increased frequency of pre-morbid anxiety in those with AN (Keel, Klump, Miller, McGue, & Iacono, 1995) and anxiety dis-orders are associated with increased brain activity of the catecholamines, especially noradrenaline(Charney & Drevets, 2002). A specific genetic profile of vulnerability to increased noradrenergicactivity in people with AN has been suggested in several studies (Urwin et al., 2002, 2003; Urwin& Nunn, 2005) with particular reference to three gene variants or polymorphisms.

MAOA – long variant – the longer, more transcriptionally active form of the MAOA-uVNTR(MAOA-L) in the promoter region for MAOA on the X chromosome.

The NETpPR – L – a polymorphic region located in the promoter of the solute carrier family 6(neurotransmitter transporter and noradrenalin) member 2 (SLC6A2) gene with a 4-bp insertion(L4) in AAGG4 resulting in gain of function. Hu et al. (2007) did not replicate the selective trans-mission of this gene in isolation in AN although it has been shown to be functional in humans byZhang, Smith, Liu, and Holden (2010).

5-H TTPR – although independent activity with this gene in AN was not found, an interactionwith 1. and 2. and the SERT gene promoter which contains a functional polymorphism known as the5-HTTLPR due to a 44-bp insertion (5-HTTLPR-L) or deletion (5-HTTLPR-S) was found (Urwin& Nunn, 2005). The transcriptional activity of 5-HTTLPR-S is less than half that of 5-HTTLPR-L.

However, as in oncogenetics, in any given individual, all or none of these particular genes arenecessarily implicated. What is critical is that genetic variation, when interrogated across thewhole noradrenergic system, renders the system more active in relation to substrate utilizationand functional activity. This study has yet to be done, but is possible using next generationsequencing when whole genome studies will be available over the next 12–18 months(Metzker, 2010). For a relatively low cost, it will now be possible to identify the number ofgenetic ‘hits’ and, thence, the number of functional polymorphisms and the cumulative impacton the noradrenergic system.

Various epigenetic factors that may influence the development of both the sympathetic nervoussystem and the noradrenergic systems (Davis & Lowell, 2006; Nunn, Lask, et al., 2011), includingmaternal starvation (Gheorghe, Goyal, Holweger, & Longo, 2009; Harshaw, 2008).

Noradrenergic dysregulation has recently been discussed as a major factor in the causation ofAN (Nunn, Frampton, et al., 2011). Given the role of noradrenaline in regulating sympatheticarousal (Nestler et al., 2009), increased noradrenaline activity may contribute to higher sensitivitystates and anxiety symptomatology (Bremner, Krystal, Southwick, & Charney, 1996). The litera-ture has focused on the role of serotonin depletion (Brewerton, 2012 for an excellent recentreview) and emphasized obsessive-compulsive comorbidity rather than noradrenaline andanxiety symptoms. So far, competing claims and hypotheses viz. the noradrenergic, the serotoner-gic and the dopaminergic hypotheses have not been explored.

Tyrosine is an amino acid comprising around 3% of dietary proteins and is a key precursor tothe synthesis of catecholamines (Fernstrom & Fernstrom, 2007). Tyrosine restriction throughdieting and resultant starvation causes nutritional depletion of noradrenergic precursors(Avraham, Bonne, & Berry, 1996). This may bring temporary relief from anxiety, althoughwith time and neuro-adaptation of the noradrenergic brain systems, there may be compensatoryup-regulation and oversensitivity of the catecholaminergic system (Nunn, Lask, et al., 2011). Thismay also result in an increase in anxiety when food (and with it tyrosine) is re-introduced into achronically up-regulated system, escalating reinforcement of the disorder. The present articleextends the recently published hypothesis by proposing a substrate-repletion intervention hypoth-esis for AN, namely that chronic supplementation of tyrosine with saturation of supply may alle-viate some of the pathological changes found in AN. Tyrosine presented as medication in additionto conventional re-feeding has two advantages over simple re-feeding: it would increase theplasma tyrosine/large neutral amino acid (LNAA) ratio and thus tend to facilitate an increase

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in tyrosine available to the brain. Additionally, it could be quite separated from re-feeding, and thepatient’s reluctance to engage in increased food intake. First, in presenting our hypothesis, weexamine how continual tyrosine administration may alleviate key features of AN in line withthe broader noradrenergic hypothesis, then we discuss strategies for testing the hypothesis andits potential clinical significance.

Presentation of the noradrenergic repletion hypothesis

This hypothesis has not previously been proposed in detail, or tested, though limited available evi-dence suggests that ongoing administration of tyrosine may be a beneficial component of treatmentin AN (Avraham et al., 1996; Keel et al., 1995; Nunn, Frampton, et al., 2011; Nunn, Lask, et al.,2011). The fundamental basis of our hypothesis is that a deficient substrate (tyrosine) supply tothe catecholaminesmay be contributory to key features ofAN.Continuous and ongoing tyrosine sup-plementation may be beneficial by facilitating catecholamine repletion and progressive down-regu-lation of the catecholamine system (Apparsundaram, 2007). This in turn may alleviate some illnesseffects and assist in improving treatment outcomes for people with AN. The proposed sequence ofevents and potential effects on the key features of AN are presented in Figure 1, specifically.

Predisposing developmental up-regulation (pre-morbid anxiety) (a). Polymorphisms (normalvariations in DNA sequences) mediate a genetically up-regulated noradrenergic system and pre-dispose people to pre-morbid sensitivity and anxiety (Urwin et al., 2002). These polymorphismscould occur anywhere in the synthesis and catalytic pathways with a net result in increasing tyro-sine turnover and catecholaminergic activity.

Figure 1. The proposed sequence of physiological events for the repletion intervention hypothesis.

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Acute down-regulation (dieting-related anxiety reduction) (c). Dieting or illness (b), bothcommon in young people, may lead to food restriction and substrate depletion, providing aninitial reduction in the activity of the sympathetic system and, therefore a reduction in anxietyin the short term.

Chronic up-regulation and behavioral reinforcement (illness re-emergent anxiety) (e). Theusual response to substrate depletion is up-regulation of receptor numbers and key enzymeactivity (Stahl, 2008) which, in AN, may result in the re-emergence of anxiety. Positive reinforce-ment for dietary restriction may continue, as intermittent substrate restriction may lead to tempor-ary anxiety reduction (g), while negative reinforcement may be a parallel punishment or aversiveoperant conditioning regimen in which re-feeding and repletion of noradrenaline may lead to overwhelming anxiety (f). Chronic depletion-related changes (h) may occur if the system continues tofunction in a depleted state, including comorbid depression and effects on other systems includingcardiovascular, renal and thermoregulatory systems (Morilak, 2007).

Acute up-regulation of a chronically up-regulated system (overwhelming re-feeding relatedanxiety) (k). The influx of dietary tyrosine (i) in an environment of increased receptor andenzyme numbers characteristic of chronic up-regulation (Stahl, 2008) may cause profoundover-stimulation of the sympathetic system, and increased anxiety, even panic.

Down-regulation of a chronically up-regulated system (repletion-based recovery of normal, orat least pre-morbid, levels of noradrenergic activity) (l). Steady repletion of tyrosine may returnthe system to normal function, allowing successful re-introduction of food provided epigeneticeffects have not supervened to change gene expression. There is very little published researchon epigenesis and the noradrenergic system in AN as yet. It is predicted that body-related distresswill reduce with sustained tyrosine repletion (Halmi & Yum, 2007; Nelson, 2007) through redu-cing rigidity of neuroplasticity and that cognitive function will improve by enhancing problem-solving, reducing behavioral rigidity and attentional processes (Arnsten, 2007; Aston-Jones,Iba, Clayton, & Rajkowski, 2007; Reimherr, Schwartz, Marchant, & Higgens, 2007; Roozendaal,2007), and reducing the negative impact of anxiety and depression on cognitive effort and effi-ciency (Avraham et al., 1996; Nunn, Lask, et al., 2011).

Testing the hypothesis

Increasing dietary intake of tyrosine-containing foods poses significant therapeutic adherence chal-lenges in the context of fear of fatness and restrictive eating. An alternative to food-based treatmentalone is the administration of daily tyrosine supplementation, in capsule or similar form, in excess ofnormal dietary intake. Testing the pharmacological response to, and side effects of, tyrosine admin-istration in a small sample of adolescents with AN in comparison to healthy peers would be the firstpart of hypothesis testing. Subsequently, a double-blind randomized controlled trial would berequired to test whether a continuous supply of tyrosine improves cognitive performance andeating disorders or other psychopathology in people with AN. Finally, dosage studies wouldneed to be conducted to determine appropriate parameters for tyrosine administration, along withstudies to address acceptable modes of administration and treatment compliance.

Implications of the hypothesis for research and practice

(1) Nutrition and psychological well-beingEvidence of noradrenergic dysfunction in AN may alter theories about causal mechanisms in

AN and have implications for other psychiatric disorders, including depression, anxiety, bulimianervosa and obsessive compulsive disorder.

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(2) Brain-based, not just symptom-based, diagnosisThe hypothesis proposes an intervention that affects AN at multiple causal explanatory levels

simultaneously (Apparsundaram, 2007; Arnsten, 2007; Aston-Jones et al., 2007; Avraham et al.,1996; Insel & Quirion, 2012). The gradual move from approximate clusters of symptoms andsigns to an understanding of the underlying mechanisms of gene–brain dysfunction together withtheir environmental interactions, are analogous to similar changes in general medicine. The shiftfrom treating chest pain as a symptom irrespective of its cause to a differential diagnosis of the poss-ible causes based upon a detailed understanding of the mechanisms that give rise to chest pain, suchas cardiac, musculoskeletal and respiratory disease, is a simple example of the same trend. Disco-vering these mechanisms and translating them into meaningful interventions for individual patientswill be the task of the coming decade in line with the general timetable set out by the National Insti-tute for Mental Health in the United States for addressing mental illness as a whole (Figure 2).

(3) The shift from serotonin and dopamine to noradrenalineTo date the focus has been on the serotonergic (pain, sleep, vomiting, obsessive and negative

affect systems) and dopaminergic systems (reward and reinforcement systems) with only a smallnumber of clinical interventions conducted. Our hypothesis shifts the focus of investigation tonoradrenergic pathways.

(4) Medications must be tested with regard to mediating biological mechanismsMost medication studies using re-uptake inhibitors have ignored the possibility that substrate

depletion may render the SSRI’s or other re-uptake inhibitors ineffective since there is little to

Figure 2. Pathophysiologic descriptions of mental disorders will permit diagnoses validated by biologicalmeasures and treatments aimed at core pathology. Care will become personalized via an understanding ofindividual risk, allowing for strategic approaches to prevention and treatment. These ambitious goalsrequire application of genomics and proteomics to mental disorders. From Insel and Collins (2003) andInsel and Quirion (2012).

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‘re-uptake’ from the synapse (Nelson, 2007). Many of these studies will need to be re-examined inthe medium to the long-term repleted state to give a meaningful answer about efficacy.

(5) Cause and consequenceMany studies have not distinguished between primary (i.e. metabolically related) and second-

ary depletion (i.e. starvation-related) and, therefore, have potentially confounded cause and effect.We have been focusing on causal depletion and not consequential depletion as the basis for inter-vention, even though it is likely that, for treatment, both will need to be considered. Evidence ofnoradrenergic dysfunction and the effects of tyrosine administration on psychopathology willprovide further directions for research, including longitudinal testing to assess different stagesof activity, repletion and time course of AN. It is also possible that repletion of starvation-related neurotransmitter precursors will be necessary in subsequent studies, for example, 5 OHtryptophan is a precursor of serotonin which does not compete for tyrosine at the blood brainbarrier and, therefore, can be repleted without interfering with the tyrosine /LNAA ratio.

(6) PreventionFrom a primary preventive perspective, dieters and others at risk of restrictive eating disorders

could be encouraged to consume tyrosine supplements to prevent progression to AN.

(7) The centrality of anxietyThis repletion hypothesis moves anxiety to center stage in the clinical treatment program and

posits reduction in anxiety as the key to uncoupling the contingency schedule of the intermittentpartial reinforcement schedule. We fully appreciate that not all patients with AN have intenseanxiety and, therefore, there will be some patients for whom this hypothesis will be insufficient,incomplete or inadequate.

(8) Reducing cognitive work but enhancing cognitive functionCognitive processes may be improved by tyrosine supplementation to allow people with AN

to work through complex aspects of treatment more successfully (Aston-Jones et al., 2007). Inparticular, the specific improvement of processing speed, cognitive and behavioral flexibilitywill be measurable outcomes, and therefore test the efficacy of this treatment.

(9) Modifying the key diagnostic criterion of body image disorderImproving cerebral blood flow, increasing somatosensory neuroplasticity and reducing the

demand on the insula to be controlling amygdala activity during overwhelming anxiety, allfavor the possibility of affecting one of the most unmodifiable characteristics of AN – the distor-tion in bodily experience and perceived image.

Conclusions

This hypothesis, if proven, has the potential to improve the efficacy of the treatment of AN, a chronicdisease with a substantial mortality rate. Alleviating anxiety, promoting neuroplasticity and increas-ing cerebral blood flow addresses the pathology of AN directly. Tyrosine supplementation has thepotential to reduce a key barrier to re-feeding and to offer a preventive dietary treatment of AN.

AcknowledgementsKenneth Patrick Nunn and Melissa Hart developed the repletion hypothesis. Melissa Hart conducted anin-depth literature search and prepared the initial draft of the manuscript. All authors have contributed exten-sively to writing the manuscript and have read and approved the final manuscript. Development of thishypothesis was in part supported by seed funding from the Hunter Medical Research Institute, Newcastle,NSW, Australia and the specific funding of Dr Peter Vaughan and his wife Karen.

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Notes on contributorsMelissa Hart is a Local Health District Eating Disorders Coordinator (Hunter New England) and ConjointLecturer and current PhD candidate at the University of Newcastle, Australia. More recently Melissa hasworked as a Statewide Coordinator for Eating Disorders and Dietetics (child and adolescent), statewide nutri-tion consultant, senior mental health dietitian and Area Coordinator for eating Disorders. Melissa has manyyears experience as a clinical dietitian both in Australia and overseas, and has a special interest in nutrition inmental health and research.

Professor Bridget Wilcken graduated in medicine from Edinburgh University, and obtained a doctoratefrom Sydney University. She is a metabolic physician, and until recently was clinical director of the NewSouthWales Biochemical Genetics and Newborn Screening Services at the Children’s Hospital at Westmead,Sydney. She is a former President of the International Society for Neonatal Screening, and of the HumanGenetics Society of Australasia. She was awarded the Order of Australia in 2002 and the Guthrie Medalof the International Society for Neonatal Screening in 2004. Recent research has been related mainly tonewborn screening, but homocystinuria and disorders of fatty acid oxidation were early strong interests.

Professor Lauren T. Williams has been Head of the Discipline of Nutrition and Dietetics at the Universityof Canberra since August 2011. She has over 20 years experience as an academic delivering education inNutrition and Dietetics, and holds honorary appointments at the University of Newcastle, and InternationalMedical University in Kuala Lumpur. She has made high level contributions to the Dietitians Association ofAustralia, including two terms as Vice President, and three terms as Associate Editor of the journal Nutritionand Dietetics. Professor Williams maintains her clinical practice as an Advanced Accredited Practising Die-titian, specializing in weight management.

David Sibbritt is Professor of Epidemiology at the University of Technology Sydney. He has been involvedin health services research for over 20 years; with a particular interest in nutrition research, having conductednumerous studies on the topic within Australia and internationally.

Professor Kenneth Patrick Nunn is a paediatric neuropsychiatrist with special interest in developing causalmodels of mental illness which can be tested. He has put forward with other colleagues a nested modelof causes for anorexia nervosa that involves genetic, neurochemical, anatomical and neurocircuitry levelsof explanation. He works at the Children’s Hospital Westmead where he is the Clinical Director of asmall Molecular Neuropsychiatry Service and is a member of the Neurodevelopmental Team inPsychological Medicine. His academic affiliation is with the University of Sydney

ReferencesApparsundaram, S. (2007). The norepinephrine transporter and regulation of synaptic transmission. In G. A.

Ordway, M. A. Schwartz & A. Frazer (Eds.), Brain norepinephrine, neurobiology and therapeutics(pp. 580–584). Cambridge: Cambridge University Press.

Arnsten, A. F. T. (2007). Norepinephrine and cognitive disorders. In G. A. Ordway, M. A. Schwartz &A. Frazer (Eds.), Brain norepinephrine, neurobiology and therapeutics (pp. 580–584). Cambridge:Cambridge University Press.

Aston-Jones, G., Iba, M., Clayton, E., & Rajkowski, J. (2007). The locus coeruleus and regulation of behav-ioural flexibility and attention: Clinical implications. In G. A. Ordway, M. A. Schwartz & A. Frazer(Eds.), Brain norepinephrine, neurobiology and therapeutics (pp. 580–584). Cambridge: CambridgeUniversity Press.

Avraham, Y., Bonne, O., & Berry, E. M. (1996). Behavioral and neurochemical alterations caused by dietrestriction – the effect of tyrosine administration on mice. Brain Research, 732, 133–144.

Bremner, J., Krystal, J., Southwick, S., & Charney, D. (1996). Noradrenergic mechanisms in stress andanxiety: II – Clinical studies. Synapse, 23, 39–51.

Brewerton, T.D. (2012).Antipsychotic agents in the treatment of anorexia nervosa:Neuropsychopharmacologicrationale and evidence from controlled trials. Current Psychiatry Reports, 14, 398–405. doi: 10.1007/s11920-012-0287-6

Charney, B. S., & Drevets, W. C. (2002). Neurological basis of anxiety disorders. In K. L. Davis, D. Charney,J. T. Coyle & C. Nemeroff (Eds.), Neuropsychopharmacology, the fifth generation of progress.Philadelphia, PA: Lippincott Williams and Wilkins.

Davis, G. E., & Lowell, W. E. (2006). Solar cycles and their relationship to human disease and adaptability.Medical Hypotheses, 67, 447–461.

Advances in Eating Disorders: Theory, Research and Practice 7

Dow

nloa

ded

by [

Uni

vers

ity o

f W

isco

nsin

- M

adis

on]

at 0

7:52

18

Apr

il 20

13

Fernstrom, J. D., & Fernstrom, M. H. (2007). Tyrosine, phenylalanine, and catecholamine synthesis andfunction in the brain. The Journal of Nutrition, 137, 1539S–1547S.

Gheorghe, C. P., Goyal, R., Holweger, J. D., & Longo, L. D. (2009). Placental gene expression responses tomaternal protein restriction in the mouse. Placenta, 30(5), 411–417.

Halmi, K. A., & Yum, S. Y. (2007). Psychopharmacology of norepinephrine and eating disorders. In M. A.Schwartz, A. Frazer & G. A. Ordway (Eds.), Brain norepinephrine, neurobiology and therapeutics(pp. 580–584). Cambridge: Cambridge University Press.

Harshaw, C. (2008). Alimentary epigenetics: A developmental psychobiological systems view of the percep-tion of hunger, thirst and satiety. Developmental Review, 28(4), 541–569.

Hu, X., Karwautz, A., Wagnerd, G., Holliday, J., Li, T., Treasure, J., & Collier, D. A. (2007). No associationbetween a promoter polymorphism in the noradrenaline transporter gene and anorexia nervosa.Psychiatric Genetics, 17(4), 247–248.

Insel, T. R., & Collins, F. S. (2003). Psychiatry in the genomics era. The American Journal of Psychiatry,160(4), 616–620.

Insel, T. R., & Quirion, R. (2012). NIMH website.Kaye, W. (2008). Neurobiology of anorexia and bulimia nervosa. Physiology & Behavior, 94, 121–135.Keel, P. K., Klump, K. L., Miller, K. B., McGue, M., & Iacono, W. G. (1995). Shared transmission of eating

disorders and anxiety disorders. International Journal of Eating Disorders, 38, 99–105.Metzker, M. L. (2010). Sequencing technologies – the next generation. Nature Genetics, 11, 31–45.Morilak, D. (2007). Norepinephrine and stress. In G. A. Ordway, M. A. Schwartz & A. Frazer (Eds.), Brain

norepinephrine, neurobiology and therapeutics (pp. 580–584). Cambridge: Cambridge UniversityPress.

Nelson, J. C. (2007). The clinical role of norepinephrine in depression and anxiety disorders. In G. A.Ordway, M. A. Schwartz & A. Frazer (Eds.), Brain norepinephrine, neurobiology and therapeutics(pp. 580–584). Cambridge: Cambridge University Press.

Nestler, E. J., Hyman, S. E., & Malenka, R. G. (2009). Molecular neuropharmacology – a foundation forclinical neuroscience (pp. 227–245). New York, NY: McGraw Hill.

Nunn, K., Frampton, I., & Lask, B. (2012). Anorexia nervosa – a noradrenergic dysregulation hypothesis.Medical Hypotheses, 78, 580–584.

Nunn, K., Lask, B., & Frampton, I. (2011). Toward a comprehensive, causal and explanatory neurosciencemodel of anorexia nervosa. In B. Lask & I. Frampton (Eds.), Eating disorders and the brain(pp. 580–584). London: Wiley International Publications.

Reimherr, F. W., Schwartz, M. A., Marchant, B. K., & Higgens, E. (2007). Norepinephrine in attentiondeficit/hyperactivity disorder. In G. A. Ordway, M. A. Schwartz & A. Frazer (Eds.), Brain norepi-nephrine, neurobiology and therapeutics (pp. 580–584). Cambridge: Cambridge University Press.

Roozendaal, B. (2007). Norepinephrine and long-term memory function. In G. A. Ordway, M. A. Schwartz& A. Frazer (Eds.), Brain norepinephrine, neurobiology and therapeutics (pp. 580–584). Cambridge:Cambridge University Press.

Stahl, S. M. (2008). Signal transduction and the chemically addressed nervous system. In Stahl’s essentialpsychopharmacology, neuroscientific basis and practical applications (pp. 51–90). New York, NY:Cambridge University Press.

Sullivan, P. (1995). Mortality in anorexia nervosa. American Journal of Psychiatry, 152(7), 1073–1074.Treasure, J., Claudino, A. M., & Zucker, N. (2010). Eating Disorders. The Lancet, 375, 583–593.Urwin, R. E., Bennetts, B., Wilcken, B., Lampropoulos, B., Beumont, P., Clarke, S., & Nunn, K. P. (2002).

Anorexia nervosa (restrictive subtype) is associated with a polymorphism in the novel norepinephrinetransporter gene promoter polymorphic region. Molecular Psychiatry, 7, 652–657.

Urwin, R. E., Bennetts, B. H., Wilcken, B., Beumont, P. J. V., Russell, J. D., & Nunn, K. P. (2003).Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anor-exia nervosa. Neuropsychopharmacology, 28(7), 1351–1355.

Urwin, R. E., & Nunn, K. P. (2005). Epistatic interaction between the monoamine oxidase a and serotonintransporter genes in anorexia nervosa. European Journal of Human Genetics, 13, 370–375.

Zhang, H., Smith, G. N., Liu, X., & Holden, J. J. A. (2010). Association of MAOA, 5-HTT, and NETPromoter polymorphisms with gene expression and protein activity in human placentas.Physiological Genomics, 42, 85–92.

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