new directions in treatment research of anorexia and...

REVIEW

New Directions in Treatment Research of Anorexia andBulimia Nervosa

Walter Kaye, Michael Strober, Daniel Stein, and Kelly Gendall

Although considerable progress has been made in theunderstanding and treatment of anorexia and bulimianervosa, a substantial proportion of people with thesedisorders have a limited response to treatment. Treatmentstrategies used in eating disorders have tended to beadopted from therapies that were devised to treat otherpsychiatric illnesses. Recent studies suggest that eatingdisorders are independently transmitted familial liabilitieswith a unique pathophysiology. These new findings raisethe possibility that an improved understanding of thepathogenesis of eating disorders will generate more spe-cific and effective psychotherapies and pharmacologicinterventions. Biol Psychiatry 1999;45:1285–1292© 1999 Society of Biological Psychiatry

Key Words: Anorexia, bulimia nervosa, pharmacother-apy, psychotherapy

Introduction

Anorexia nervosa (AN) and bulimia nervosa (BN) arecomplex, multiply determined disorders of unknown

etiology that occur preponderantly in young women(American Psychiatric Association 1994). An unusual,morbid preoccupation with weight and shape bridges thetwo syndromes, yet distinctive patterns of weight regula-tion and feeding behavior supports the validity of theirclinical differentiation. In AN, a seemingly purposeful,ego syntonic restriction of food intake culminating inprofound emaciation is pathognomonic. Two AN patientsubgroups have been identified by consummatory behav-ior: a restricting type, in whom a relatively enduringpattern of dietary restriction is characteristic, and a bingeeating type, in whom episodes of binge eating or purgingcoincide with dietary restriction and subnormal bodyweight. In BN, average body weight is maintained al-though the illness may, nevertheless, be precipitated by

dieting and weight loss, and further weight loss may bedesired. Individuals with BN suffer recurring disinhibitionof restraint resulting in cycles of binge eating and com-pensatory actions including self induced vomiting, abuseof laxatives/diuretics, and pathologically extreme exerciseand restricting (Kaye and Strober, in press).

The past decade bears witness to substantial advances inour knowledge of the pathogenesis of eating disorders andthe efficacy of certain types of structured psychotherapiesand antidepressant pharmacotherapies in their treatment(Table 1). In the area of treatment research, AN stands insharp contrast to BN in the dearth of large-scale, random-ized controlled clinical trials of therapeutic modalities(Agras 1991; Mitchell et al 1993; Wilson and Fairburn1993). In this article, we highlight these studies as a pointof departure for considering potentially promising newavenues of treatment research.

It is to be noted that recent treatment studies in eatingdisorders tend, by and large, to be based on interventionparadigms and strategies previously tested on psychiatricdisorders that co-occur frequently with AN and BN, suchas depression, anxiety, and substance use. Although somerisk factors in eating disorders may be shared with moodand anxiety disorders (e.g., Fairburn et al 1997), a numberof recent family and twin studies (see Lilenfeld et al 1997)suggest that eating disorders and the conditions that arecomorbid with them tend to sort independently in familiesor have unique genetic liability factors. Thus, the searchfor unique treatment modalities, targeting underlying vul-nerabilities that contribute specifically to the pathogenesisof eating disorders, remains a theoretically and clinicallyjustifiable endeavor.

Anorexia Nervosa (AN)

AN was first described more than a century ago, althoughits notation in archival medical literature is far older(Habermas 1989). Its early treatment derived largely frompsychoanalytic, family systems, or behavioral paradigms,until the pioneering work of Bruch (1973) broadened ourunderstanding of its psychological underpinnings in im-paired self-concept, body image, and interoceptive pro-cesses. Still, the first generation of controlled treatmentstudies were narrowly focused on testing the value ofbehavior modification in increasing the rate of weight gainin hospitalized, emaciated patients, or the efficacy of

From the Eating Disorders Module, Western Psychiatric Institute and Clinic,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (WK,DS, KG); Eating Disorders Program, Neuropsychiatric Institute & Hospital,University of California at Los Angeles School of Medicine, Los Angeles,California (MS); and Sackler School of Medicine, University of Tel Aviv,Ramat Aviv, Israel and Adolescent Inpatient Department, Abarbanel MentalHealth Center, Bat Yam, Israel (DS)

Address reprint requests to Walter H. Kaye, Western Psychiatric Institute andClinic, 3811 O’Hara Street E-724, Pittsburgh, PA 15213.

Received September 11, 1998; revised February 15, 1999; accepted February 19,1999.

© 1999 Society of Biological Psychiatry 0006-3223/99/$20.00PII S0006-3223(99)00048-7

adjunctive pharmacologic treatment with either neurolep-tic or antidepressant drugs. This work showed that weightgain could be achieved in many patients through a com-bination of supportive nursing care and behavioral tech-niques, whereas pharmacotherapy proved to have littleincremental advantage in the treatment of severely illpatients (Jimerson et al 1996).

A more recent series of randomized controlled studieshas examined the efficacy of various types of psycholog-ical therapies in promoting weight gain in acutely illpatients (Channon et al 1989; Crisp et al 1991; Treasure etal 1995), or in preventing relapse after restoration ofnormal body weight (Russell et al 1987). Overall, theresults indicate that substantial improvement in body massand general psychosocial adjustment can be achieved insome anorectic subjects using cognitive behavioral, psy-choeducational, and family therapy techniques (in somestudies coupled with dietary counseling), although treat-ment gains are not as robust in patients with more chronic,longstanding disability. In addition, several studies haveshowed that fluoxetine reduced relapse and obsessionalitywhen administered after weight restoration in women withanorexia nervosa (Kaye et al 1991b; Kaye et al 1997).Unambiguous interpretation of these data is, however,hampered by a variety of methodological shortcomingsacross the studies, including small sample sizes, signifi-cant drop-out rates, initial use of inpatient treatment formedically compromised patients, and importantly, absenceof longer-term follow-up assessment of the durability ofthese gains in preventing relapse. In summary, improve-ments in the treatment of AN remains an issue of immenseclinical and public health importance considering that ANis a chronic, relapsing illness (Herzog et al 1992) withsubstantial and costly medical morbidity (McKenzie andJoyce 1992) for a sizable minority of patients. Hence, it isencouraging that the efficacy of psychological therapiesand serotonergic antidepressants in reducing risk of re-lapse in weight restored patients with AN is now beingtested by several investigative groups.

Bulimia Nervosa (BN)

BN has been the focus of clinical study for only twodecades, yet a considerable number of controlled clinicaltrials have demonstrated the efficacy of both antidepres-sant medications (Walsh 1991a; Mitchell et al 1993) andpsychological therapies (cognitive behavior therapy(CBT) in particular) (Fairburn et al 1993) in reducing thefrequency of binge eating and purging. In addition, thereare improvements with these psychological interventionsin certain core features of the illness such as bodydissatisfaction, pursuit of thinness, and perfectionism(Fairburn et al 1993; Garner et al 1993). Even so, these

Table 1. Landmark Studies in Eating Disorders

Author and Year Event

Hobbes 1908 First description of a possible case ofanorexia nervosa in 1668 in England.

Gull 1874 First case series of restricting anorexianervosa published.

Wulf 1932 First description of what is thought to bebulimia nervosa.

Stunkard et al 1955 First description of a night time bingeeating syndrome.

Stunkard 1959 First formal description of what is thoughtto be binge eating disorder.

Bruch 1973 Bruch described impaired self-concept,body image, and interoceptive processesin anorexia nervosa.

Russell 1979; Garnerand Garfinkel 1979

First acknowledged description of bulimianervosa in the literature. Eating AttitudesTest developed to measure the intensityof symptoms in anorexia nervosa.

Casper et al 1980;Garfinkel et al 1980

Recognition of distinct purging andrestriction subtypes of anorexia nervosa.

Fairburn 1981Gross et al 1981

First cognitive behavior therapy study forthe treatment of bulimia nervosa.

The first of a range of psychopharmaco-therapy trials in anorexia nervosashowing unimpressive results.

Pope and Hudson 1982;Walsh et al 1982

Report that tricyclic antidepressants decreasebinge eating in bulimia nervosa.

Rosen and Leitenberg1982

Monoamine oxidase inhibitors found todecrease binge eating in bulimia nervosa.

Exposure and response prevention therapydescribed for bulimia nervosa.

Garner et al 1983 Eating Disorder Inventory developed tomeasure eating disorder severity, subtypesand treatment outcome.

Russell et al 1987 Family therapy found to be superior toindividual supportive therapy in young,nonchronic anorexia nervosa patients.

Henderson and Freeman1987

The Bulimic Investigatory Test, Edinburghdeveloped to measure symptoms andseverity of bulimia nervosa.

Cooper et al 1989 Eating Disorder Examination, a structuredinterview for eating disorder diagnosisdeveloped.

Agras et al 1992;Mitchell et al 1990

First investigations of the comparativeefficacy of psychotherapy andpharmacotherapy in bulimia nervosa:Psychotherapy and cognitive behaviortherapy superior to pharmacotherapy alone.

Gwirtsman et al 1990;Kaye et al 1991b

Uncontrolled trials suggest fluoxetine ishelpful during weight maintenance phaseof anorexia nervosa.

Kendler et al 1991 Modest evidence for genetic influences inbulimia nervosa reported.

Spitzer et al 1991 Binge eating disorder defined as a distinctdisorder.

Fairburn et al 1993 Interpersonal psychotherapy shown to beequivalent to cognitive behavior therapy intreatment of bulimia nervosa.

Collier et al 1997;Enoch et al 1998;Sorbi et al 1998

Evidence for an association of apolymorphism for the2A serotonin receptorin anorexia nervosa.

1286 W.H. Kaye et alBIOL PSYCHIATRY1999;45:1285–1292

findings are counterbalanced by the more sobering realitythat medication alone produces full remission in only aminority of patients, many patients require multiple trialsof medication before they achieve clinically significantimprovement, drop-out rates in controlled clinical trialsdue to adverse events are not inconsequential, and relapseduring continuation therapy is high.

With regard to psychological treatment, the evidenceseems to suggest that CBT alone produces higher rates offull remission than does antidepressant monotherapy(Agras et al 1992; Walsh et al 1997). Even so, some40%–60% of patients who have participated in studies ofCBT remain symptomatic to some degree upon comple-tion of acute treatment (Agras et al 1992; Garner et al1993; Wilson and Fairburn 1993). Psychological therapiesmay vary in overall spectrum of efficacy. For example,direct comparisons of CBT with other psychologicaltreatments suggest this modality is more effective thanpsychodynamically oriented supportive expressive psy-chotherapy in reducing core symptoms of BN (Garner et al1993; Walsh et al 1997), and is more effective than astrictly behavioral treatment in preventing early relapseinto dietary restriction, binge eating, and purging (Fair-burn et al 1993). The mechanisms through which thesetreatments actually achieve their effects are not wellunderstood, but are assumed to be more complex thanoriginally thought. Thus, Fairburn et al (1993), in a studycomparing the effects of CBT, interpersonal therapy (IPT),and pure behavior therapy, showed that IPT, that studi-ously avoided any direct reference to abnormal eatingattitudes or dietary behaviors, achieved long-term benefitsin controlling binge eating and purging equal to thoseobtained with CBT.

How long to continue treatment once binge eatingabates to maximally protect against risk of relapse orrecurrence is a question that remains unanswered.Indeed, with respect to antidepressant therapy, relapserisk during continuation therapy in BN (Walsh et al1991b) may be higher than that typically observed instudies of continuation therapy in unipolar depression(Keller and Boland 1998). Moreover, factors that dif-ferentially predict longer-term outcome within andacross treatment modalities remain largely unstudied(Jimerson et al 1996), just as the question of whether ornot combination therapy with CBT and antidepressantdrugs truly has additive or synergistic effects remainsunsettled. Two recent studies (Agras et al 1992; Walshet al 1997) have suggested that combined treatment mayhave an advantage over CBT alone in reducing bingeeating and purging, but the incremental benefit wasmodest at best. In this same regard, Agras et al (1992)showed that CBT combined with desipramine adminis-tered for 24 weeks was more effective than both CBT

alone and CBT plus 16 weeks of desipramine inreducing dietary preoccupation and emotional eating.

In summary, a truly optimal therapeutic strategy for BNhas yet to be identified within a range of possible treat-ment algorithms. Critically important questions remainunstudied, including the optimal duration of either psy-chosocial or antidepressant therapies needed to sustaineffects achieved during acute phase treatment, mecha-nisms underpinning possible synergistic effects of com-bined treatment, predictors of differential treatment out-comes, reasons for a more rapid decay of acute antidepressanttreatment effects in BN compared to depression, and theanticipated effects of crossing over to alternative modalitiesof treatment when initial treatment fails.

Pathophysiology

It is hard to dismiss outright the relevance of culturalpressures toward thinness in the pathogenesis of eatingdisorders (Strober 1995), but even if the disorders areinfluenced pathoplastically by culturally reinforced atti-tudes regarding ideal shape and weight, these are not likelyto be preeminent causal determinants. As common asdieting behavior and the pursuit of thinness is in industri-alized countries throughout the world, AN and BN affectonly an estimated 0.3%–0.7% and 1.5%–2.5%, respec-tively, of females in the general population (Hoek 1995).This disparity, combined with clear evidence of thesyndromes’ existence dating back several centuries, theirstereotypic presentation, predominance in females, anddevelopmentally specific age-of-onset distribution under-score the role played by more complex interactive biolog-ical and environmental risk and vulnerability factors(Kaye and Strober in press).

Adding further impetus to this renaissance of interest incomplex biopsychosocial models of etiopathogenesis ismounting evidence that both AN and BN are familial andheritable disorders (see Lilenfeld et al 1997; Strober 1995;Kendler et al 1991; Bulik et al 1998). Moreover, there isevidence of transmission of a more broadly definedsubthreshold phenotype of extreme weight and shaperelated anxiety (Lilenfeld et al 1998), as well as person-ality traits common to individuals with eating disorders,including behavioral constraint, perfectionism, and rigid-ity (Lilenfeld et al 1997). Recent studies have shown thatafter recovery from AN and BN there is a persistence ofoverconcern with body image and thinness, elevated harmavoidance, dysphoric/negative affect, and obsessionalsymmetry, exactness, and perfectionism (Casper 1990;Kaye et al 1998, Srinivasagam et al 1995). Recent obser-vations have also shown an elevation of CSF 5-HIAA, themajor metabolite of serotonin in the brain, after long-term

Treatment of Eating Disorders 1287BIOL PSYCHIATRY1999;45:1285–1292

clinical recovery from AN and BN (Kaye et al 1991a;Kaye et al 1998). Importantly, behaviors in people recov-ered from AN and BN tend to be opposite in character tothe impulsive and aggressive behaviors displayed bypeople with low 5-HIAA levels (Stein et al 1993). To-gether, these data support the hypothesis that increasedCSF 5-HIAA concentrations may be associated withexaggerated anticipatory overconcern with negative con-sequences (Cloninger 1987), although the lack of suchconcerns may explain impulsive, aggressive acts that areassociated with low CSF 5-HIAA. Moreover, increasedCSF 5-HIAA might reflect an overactive serotonin systemthat could contribute to behavioral constraint, obsession-ality, and inhibition of appetite (Soubrie 1986; Spoont1992). Increased serotonin activity could make peoplespecifically vulnerable to developing an eating disorder aswell as certain core phenotypic aspects of these disorders,including anxious dysphoria, obsessional thinking, perse-veration, and cognitive distortions of the aversive conse-quences of eating and weight gain (Kaye and Strober inpress). These processes could be further enhanced bymalnutrition triggered changes in hypothalamic neuropep-tides that modulate aversively conditioned learning(Demitrack et al 1990). Extreme dieting, by its effects onplasma tryptophan, the precursor of serotonin, could be ameans of reducing brain serotonin functional activity(Kaye et al 1988) and thus briefly reverse dysphoricaffects (Steinberg et al 1990).

Implications for Future Treatment Research

Molecular Pharmacology

Antidepressants do not have actions specific to eatingdisorders. Moreover, the early hypothesis that antidepres-sants would have a particular value in the treatment of BNbecause the disorder had causative mechanisms shared incommon with primary mood disorders has been called intoquestion (Jimerson et al 1996). With research advancesholding out the very real promise for enhancing efforts tocharacterize brain function and process at the molecularlevel, the not too distant may yield precise reformulationsof models of how neurobiological perturbations related tomalnutrition act in concert with risk factors of primarypathophysiological relevance to initiate, and then sustain,in more or less autonomous fashion, the core behavioralmanifestations of AN and BN.

Molecular Genetics and Heritability

Recent family and twin data, that implicate heritablefactors in eating disorders (Lilenfeld et al 1997), havegiven impetus to the search for disease susceptibility geneslinked to AN and BN (Collier et al 1997; Enoch et al 1998;

Sorbi et al 1998; Kaye and Strober in press) with the goalof delimiting proximal biological events in the etiopatho-genesis of these disorders. In short, a convergence of newresearch paradigms may give fresh impetus to morehypothesis guided applications of novel pharmacologiccompounds whose function and mechanisms of actionsuggest the potential for specific therapeutic action andsuperior efficacy in suppressing binge eating or persevera-tive, obsessionally-driven weight and shape-related cogni-tions.

Treatment Efficacy, Outcome, and RelapsePrevention

A particularly critical practical question is what types andintensities of interventions across sequential phases oftreatment are truly optimal and cost effective for longerterm management of eating disorders. It is distressinglyclear that treatment interventions that may have value inthe acute management of AN and BN do not guaranteelonger-term maintenance of gains, and may not be opti-mally effective in prophylaxis. This is reflected in thedifficulty of achieving complete remission of illness in BNpatients with either psychosocial (Garner et al 1993) orpharmacologic therapies (Walsh et al 1991b), the frequentrelapse of BN patients during continuation therapy withantidepressants (Walsh et al 1991b), and the frequencywith which AN patients lose weight after hospital dis-charge, coupled with the protracted course of their fullrecovery (Strober et al 1997). These issues are of substan-tial concerns because the treatment of these disorders canbe prolonged and costly (McKenzie and Joyce 1992).

Several questions can be extrapolated from these obser-vations. For example, what factors (historical, clinical, andbiological) actually differentiate AN and BN patients whoachieve full remission during acute treatment from thosewho remain partially or fully symptomatic? It is notknown at present whether or not being fully asymptomaticupon completion of acute therapy in BN patients, or beingat a normal body weight for some period of time for ANpatients, is facilitative of fuller and more enduringrecovery.

Issues currently debated in the long-term treatment ofchronic, relapsing illnesses like unipolar and bipolar af-fective illness may be informative to eating disorders.Unipolar (Keller and Boland 1998) and bipolar affectivepatients (Coryell et al 1995) who recover and become fullyasymptomatic have a lower risk of recurrence compared topatients who improve, but have continuing residual symp-toms or breakthroughs of subsyndromal symptoms duringprophylaxis treatment. These observations raise the ques-tion of whether or not acute and continuation treatmentsthat bring about a sustained remission of symptoms in


eating disorders patients (i.e., total abstinence from binge-ing and purging, or reduced drive for thinness and defenseof normal body weight) effectively reduce the longer-termcumulative risk of relapse and recurrence, and if so, whatmechanisms initiate and maintain the greater durability ofsymptom control. For example, is there benefit to long-term continuation pharmacotherapy in BN patients whorecover although receiving this treatment? Does exposureof BN patients who recover with CBT to continuing‘booster’ sessions of this modality reduce risk of relapse?If so, what duration and frequency of exposure to boosterCBT is optimal? Do patients who recover on a combina-tion pharmacotherapy and psychosocial treatment regimenrequire continuation of both modalities to suppress theirsymptoms? If so, for what duration, or can one of thesecomponents be discontinued without a sacrifice in prophy-laxis? In light of the difficulty in achieving full remissionduring acute phase therapy in BN, might greater efficacybe achieved through use of combination pharmacotherapy(e.g., SSRI-tricyclic regimens), at least in certain patients?Does this strategy have an advantage over switching topsychosocial treatment in patients whose initial treatmentis exclusively pharmacologic? With AN, does an extendedduration of inpatient care in a specialty treatment program,thus permitting a lengthier period of time at normal bodyweight before discharge, decrease the risk of early relapseinto florid illness by allowing for a more sustainednormalization of disease promoting biological sequelae ofstarvation and by enhancing receptivity to psychothera-peutic interventions?

In short, we can envision a new generation of clinicaltrials in eating disorders that not only compare the acuteefficacy of a wider range of treatment strategies thanheretofore investigated, but investigate, as well, the com-parative efficacy of strategies differing in type and inten-sity in reducing longer-term risk of relapse and recurrence.

Psychophysiologic Vulnerabilities and Illness State

It is possible that many AN and BN patients havedifficulty achieving robust improvements during acutetreatment because of underlying pathophysiological pro-cesses. As noted above, altered serotonergic neurotrans-mission and behavioral symptoms persist after recoveryfrom AN and BN. Whether such persisting phenomenahave etiological relevance, are scars of illness, or arecompensatory, adaptational effects, is unknown. Still, anintriguing question is raised as to the possibility thatbiological phenomena, whether of primary causal signifi-cance, or a secondary consequence of pathologic eatingbehavior, constrain treatment effects or actually promotethe development of treatment tolerance. In addition, littleis known about the consequence of malnutrition on both

somatic and psychological therapies. In this vein, severalauthors (Attia et al 1998; Ferguson et al 1999) have arguedthat SSRIs may have limited utility during acute phasetreatment of AN due to reduced availability of plasmatryptophan or the effects on serotonin gene expression oflow circulating levels of gonadal steroids.

Heuristic and clinical paradigms advanced in the studyof affective illness may be germane. Although speculative,Post and Weiss (1997) have applied models of kindlingand stress sensitization to the study of treatment respon-sivity and illness course. They suggest that early and veryaggressive therapies may be necessary to abort the unfold-ing progressive cascade of neurobiological events thatmay act to promote recurrence and treatment tolerance incyclical disease processes. This raises questions regardingthe possible long-term value of high intensity combinationtreatments sustained over extended periods of continuationtherapy. Admittedly speculative, the arguments advancedby Post and Weiss (1997) are provocative at the very least,and although their relevance to eating disorders is argu-able, these concepts underscore the future importance ofintegrative models of research wherein treatment andbehavioral neurobiology are viewed in a dynamic, tempo-ral framework.

Cost of Treatment and the Cost of Failure to Treat

Managed care has produced a substantial reduction insupport of the treatment of eating disorders. Althoughmanaged care companies seem relatively resistant toarguments that treatments improve quality of life, theymay be more open to arguing the cost effectiveness ofaggressive treatments early in the course of these illnesses.The high morbidity and mortality of AN in particular(Herzog et al 1992; Sullivan 1995) raises the question ofwhether failure to adequately treat in the short run is offsetby the cost of treating severe medical complications orincreased public welfare burden. Moreover, as Koran et al(1995) have noted, it is becoming necessary to considerthe cost of treatment when comparing the efficacy ofdifferent treatment.

Advocacy Movement and Destigmatization ofEating Disorders

Alliances between research, mental health treatment, andaffected people and their families have become increas-ingly important. For example, alliances between NAMIand NARSAD have been successful in using biologicadvances to destigmatize treatment for schizophrenia andargue for parity. The advocacy movement in eating disor-ders has been a strong and active movement for manyyears. Still, contemporary treatment, managed care, andlegislative issues suggest that certain revolutionary direc-


tions might confer benefits to the eating disorder field.This relates, for example, to increased national presence interms of legislative lobbying and improved collaborationsbetween research and families to destigmatize eatingdisorders.

Conclusions

The difficulties faced by clinicians in the treatment ofAN and BN will continue, and may even magnify, astrends in health care delivery reduce access to extendedcare and treatment in specialty inpatient facilities.These external forces may compromise efforts, at leastwith respect to more severely ill patients, to suppressbehavioral and biological sequelae of illness whosecontrol is fundamental to the longer-term effectivenessof available therapies. Ultimately, the complexitiesinvolved in treatment research conducted withinbroader integrative research paradigms will likely re-quire multi-site collaborations between specialty treat-ment centers so that talents from a broad array ofdisciplines can be applied with the greatest possibleeffectiveness and efficiency.

ReferencesAgras WS (1991): Nonpharmacologic treatments of bulimia

nervosa.J Clin Psychiatry52 Suppl:29–33.

Agras WS, Rossiter EM, Arnow B, Schneider JA, Telch CF,Raeburn SD, et al (1992): Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled com-parison.Am J Psychiatry149:82–87.

American Psychiatric Association (1994):Diagnostic and Sta-tistical Manual of Mental Disorders,4th ed. Washington, DC:American Psychiatric Press.

Attia E, Haiman C, Walsh BT, Flater SR (1998): Does fluoxetineaugment the inpatient treatment of anorexia nervosa?Am JPsychiatry155:548–551.

Bruch H (1973):Eating Disorders. Obesity, Anorexia Nervosaand the Person Within.New York: Basic Books.

Bulik C, Sullivan PF, Kendler KS (1998): Heritability of binge-eating and broadly defined bulimia nervosa.Biol Psychiatry44:1210–1218.

Casper RC (1990): Personality features of women with goodoutcome from restricting anorexia nervosa.Psychosom Med52:156–170.

Casper RC, Eckert ED, Halmi KA, Goldberg S, Davis JM(1980): Bulimia. Its incidence and clinical implications inpatients with anorexia nervosa.Arch Gen Psychiatry37:1031–1035.

Channon S, de Silva P, Hemsley D, Perkins R (1989): Acontrolled trial of cognitive-behavioral and behavioral treat-ment of anorexia nervosa.Behav Res Ther27:529–535.

Cloninger CR (1987): A systematic method for clinical descrip-tion and classification of personality variants.Arch GenPsychiatry44:573–588.

Collier DA, Arranz MJ, Li T, Mupita D, Brown N, Treasure J(1997):Association between 5-HT2A gene promoter polymor-phism and anorexia nervosa.Lancet350(9075):412.

Cooper Z, Cooper P, Fairburn CG (1989): The validity of theeating disorder examination and its subscales.Brit J Psychi-atry 154:807–812.

Coryell W, Endicott J, Maser JD, Mueller T, Lavori P, Keller M(1995): The likelihood of recurrence in bipolar affectivedisorder: the importance of episode recency.J Affect Disord33:201–206.

Crisp AH, Norton K, Gowers S, Halek C, Bowyer C, YeldhamD, et al (1991): A controlled study of the effect of therapiesaimed at adolescent and family psychopathology in anorexianervosa.Br J Psychiatry159:325–33.

Demitrack MA, Lesem MD, Listwak SJ, Brandt HA, JimersonDC, Gold PW (1990): CSF oxytocin in anorexia nervosa andbulimia nervosa: clinical and pathophysiologic consider-ations.Am J Psychiatry147:882–886.

Enoch MA, Kaye WH, Rotondo A, Greenberg BD, Murphy DL,Goldman D (1998): 5-HT2A promoter polymorphism:1438G/A, anorexia nervosa, and obsessive-compulsive disor-der.Lancet351:1785.

Fairburn CG (1981): A cognitive behavioral approach to thetreatment of bulimia.Psychological Med11:707–711.

Fairburn CG, Jones R, Peveler RC, Hope RA, O’Connor M (1993):Psychotherapy and bulimia nervosa: the longer-term effects ofinterpersonal psychotherapy, behavior therapy and cognitive-behavior therapy.Arch Gen Psychiatry50:419–428.

Fairburn CG, Welch SL, Doll HA, Davies BA, O’Connor ME(1997): Risk factors for bulimia nervosa: a community-basedcase-control study.Arch Gen Psychiatry54:509–517.

Ferguson CP, La Via MC, Crossan PJ, Kaye, WH (1999): AreSSRI’s effective in underweight anorexia nervosa?Int JEating Disorders25:11–17.

Garfinkel PE, Moldofsky H, Garner D (1980): The heterogeneityof anorexia nervosa. Bulimia as a distinct subgroup.Arch GenPsychiatry37:1036–1040.

Garner DM, Garfinkel PE (1979): The Eating Attitudes Test: anindex of the symptoms of anorexia nervosa.PsychologicalMed 9:273–279.

Garner DM, Olmstead MA, Polivy J (1983): The Eating Disor-ders Inventory: a measure of cognitive-behavioral dimensionsof anorexia nervosa and bulimia. In: Darbey PL, GarfinkelPE, Garner DM, Coscina DV, editors.Anorexia Nervosa:Recent Developments in Research. New York: Alan R. Liss,pp 173–184.

Garner DM, Rockert W, Davis R, Garner MV, Olmsted MP,Eagle M (1993): Comparison between cognitive-behavioraland supportive-expressive therapy for bulimia nervosa.Am JPsychiatry150:37–46.

Gross HA, Ebert MH, Faden VB (1981): A double-blind con-trolled study of lithium carbonate in primary anorexia ner-vosa.J Clin Psychopharmacol1:376–381.

Gull W (1874): Anorexia nervosa (apepsia hysterica, anorexiahysterica).Trans Clin Soc London7:22–31.

Gwirtsman HE, Guze BH, Yager J, Gainsley B (1990): Fluox-etine treatment of anorexia nervosa: an open trial.J ClinPsychology51:378–382.

Habermas T (1989): The psychiatric history of anorexia nervosa


and bulimia nervosa: weight concerns and bulimic symptomsin early case reports.Int J Eating Disord8:259–273.

Henderson M, Freeman CPL (1987): A self-rating scale forbulimia. The ‘BITE.’ Brit J Psychiatry150:18–24.

Herzog DB, Keller M, Strober M, Yeh CJ, Pai SY (1992): Thecurrent status of treatment for anorexia nervosa and bulimianervosa.Int J Eating Disord12:215–220.

Hobbes T (1908): Letter 1668. In: Gee SJ, editor.Medical Lecturesand Clinical Aphorisms. London: Oxford University Press.

Hoek HW (1995): The distribution of eating disorders. In:Brownell KE, Fairburn CG, editors.Eating Disorders andObesity—A Comprehensive Handbook.New York: The Guil-ford Press, pp 207–211.

Jimerson DC, Wolfe BE, Brothman AW, Metzger ED (1996):Medications in the treatment of eating disorders.PsychiatryClin North Am19:739–754.

Kaye WH, Gwirtsman HE, Brewerton TD, George DT, WurtmanRJ (1988): Bingeing behavior and plasma amino acids: apossible involvement of brain serotonin in bulimia nervosa.Psychiatry Res23:31–43.

Kaye WH, Gwirtsman HE, George DT, Ebert MH (1991a):Altered serotonin activity in anorexia nervosa after long-term weight restoration: does elevated cerebrospinal 5-hy-droxyindoleacetic acid level correlate with rigid and ob-sessive behavior?Arch Gen Psychiatry48:556 –562.

Kaye WH, Greeno CG, Moss H, Fernstrom J, Fernstrom M,Lilenfeld LR, et al (1998): Alterations in serotonin activityand psychiatric symptomatology after recovery from bulimianervosa.Arch Gen Psychiatry55:927–935.

Kaye WH (1997): Relapse Prevention with Fluoxetine in An-orexia Nervosa: A Double-Blind Placebo-Controlled Study.Program and Abstracts on New Research,150th AnnualMeeting of the American Psychiatric Association, San Diego,CA, May 17–22, 1997.

Kaye WH, Strober M (in press): Neurobiology of eating disor-ders. In: Charney D, Nestler E, Bunney W, editors.Neurobi-ological Foundations of Mental Illness.Oxford: OxfordUniversity Press.

Kaye WH, Weltzin T, Hsu LKG, Bulik CM (1991b): An opentrial of fluoxetine in patients with anorexia nervosa.J ClinPsychiatry52:464–471.

Kendler KS, MacLean C, Neals M, Kessler R, Heath A, Eaves L(1991): The genetic epidemiology of bulimia nervosa.Am JPsychiatry148:1627–1637.

Keller MB & Boland RJ (1998): The implications of failure toachieve successful long-term maintenance treatment of recur-rent unipolar depression.Biol Psychiatry44(5):348–360.

Koran LM, Agras WS, Rossiter EM, Arnow B, Schneider JA,Telch CF, et al (1995): Comparing the cost effective treat-ment of psychiatric treatments: bulimia nervosa.PsychiatryRes58:13–21.

Lilenfeld LR, Kaye WH, Strober M (1997): Genetics andfamily studies of anorexia nervosa and bulimia nervosa. In:Jimerson DC, Kaye WH, editors.Bailliere’s ClinicalPsychiatry, Vol. 3: Eating Disorders.London: BailliereTindall, pp 177–197.

Lilenfeld LR, Kaye WH, Greeno CG, Merikangas KR, PlotnicovKH, Pollice C, et al (1998): A controlled family study of

anorexia nervosa and bulimia nervosa: psychiatric disordersin first-degree relatives and effects of proband comorbidity.Arch Gen Psychiatry55:603–610.

McKenzie JM, Joyce PR (1992): Hospitalization for anorexianervosa.Int J Eating Disord11: 235–241.

Mitchell JE, Pyle RL, Eckert ED, Hatsukami D, Pomeroy C,Zimmerman R (1990): A comparison study of antidepres-sants and structured intensive group psychotherapy in thetreatment of bulimia nervosa.Arch Gen Psychiatry47:149 –157.

Mitchell JE, Raymond N, Specker S (1993): A review of thecontrolled trials of pharmacotherapy and psychotherapy inthe treatment of bulimia nervosa.Int J Eating Disord14:229 –247.

Pope HG, Hudson JI (1982): Treatment of bulimia nervosa withantidepressants.Psychopharmacology78:176–179.

Post RM, Weiss SR (1997): Emergent properties of neuralsystems: how focal molecular neurological alterations canaffect behavior.Develop Psychopathol9:907–929.

Rosen JC, Leitenberg H (1982): Bulimia nervosa: treatment withexposure and response prevention.Behav Ther13:177–124.

Russell GFM (1979): Bulimia nervosa: an ominous variant ofanorexia nervosa.Psychol Med9:429–448.

Russell GF, Szmukler GI, Dare C, Eisler I (1987): An evaluationof family therapy in anorexia nervosa and bulimia nervosa.Arch Gen Psychiatry44(12):1047–1056.

Sorbi S, Nacmias B, Tedde A, Ricca V, Mezzani B, Rotella CM(1998): 5-HT2A promoter polymorphism in anorexia nervosa.Lancet351:1785.

Soubrie P (1986): Reconciling the role of central serotoninneurosis in human and animal behavior.Behav Brain Sci9:319–363.

Spitzer RL, Devlin MJ, Walsh BT, et al (1991): Binge eatingdisorder: to be or not to be in DSM-IV.Int J Eat Dis10:627-629.

Spoont MR (1992): Modulatory role of serotonin in neuralinformation processing: implications for human psychopa-thology.Psychol Bull112:330–350.

Srinivasagam NM, Kaye WH, Plotnicov KH, Greeno C, WeltzinTE, Rao R (1995): Persistent perfectionism, symmetry andexactness after long-term recovery from anorexia nervosa.Am J Psychiatry152:1630–1634.

Stein DJ, Hollander E, Liebowitz MR (1993): Neurobiology ofimpulsivity and impulse control disorders.J NeuropsychiatrClin Neurosci5:9–17.

Steinberg S, Tobin D, Johnson C (1990): The role of bulimicbehaviors in affect regulation: different functions for differentpatient subgroups?Int J Eating Disord9:51–55.

Strober M (1995): Family-genetic perspectives on anorexianervosa and bulimia nervosa. In: Brownell KE, FairburnCG, editors.Eating Disorders and Obesity—A Comprehen-sive Handbook.New York: The Guilford Press, pp 212–218.

Strober M, Lampert C, Morrell W, Burroughs J, Jacobs C(1990): A controlled family study of anorexia nervosa:evidence of familial aggregation and lack of shared trans-mission with affective disorders.Int J Eating Disord9:239 –253.


Strober M, Freeman R, Morrell W (1997): The long-termcourse of severe anorexia nervosa in adolescents: Survivalanalysis of recovery, relapse, and outcome predictors over10 –15 years in a prospective study.Int J Eating Disord22:339 –360.

Stunkard AJ (1959): Eating patterns and obesity.PsychiatricQuarterly 33:284–292.

Stunkard AJ, Grace WJ, Wolf HG (1955): Night eating syn-drome: a pattern of food intake among certain obese patients.Am J Med19:78–86.

Sullivan PF (1995): Mortality in anorexia nervosa.Am J Psychi-atry 152:1073–1074.

Treasure J, Todd G, Brolly M, Tiller J, Nehmed A, Denman F(1995): A pilot study of a randomized trial of cognitiveanalytical therapy vs. educational behavioral therapy for adultanorexia nervosa.Behav Res Ther33:363–367.

Walsh BT (1991a): Psychopharmacologic treatment of bulimianervosa.J Clin Psychiatry52:34–38.

Walsh BT, Hadigan CM, Devlin MJ, Gladis M, Roose SP(1991b): Long-term outcome of anti-depressant treatment forbulimia nervosa.Am J Psychiatry148:1206–1212.

Walsh BT, Stewart WJ, Wright L, Harrison W, Roose SP,Glassman AH (1982): Treatment of bulimia with monoamineoxidase inhibitors.Am J Psychiatry139:1629–1630.

Walsh BT, Wilson GT, Loeb KL, Devlin MJ, Pike KM, Fleiss J,et al (1997): Medication and psychotherapy in the treatmentof bulimia nervosa.Am J Psychiatry154:523–531.

Wilson GT, Fairburn CG (1993): Cognitive treatments for eatingdisorders.J Consult Clin Psychol61:261–269.

Wulf M (1932): Uber einen interassanten oralen Symptoomen-komplex und seine Beziehung zur Sucht.InternationaleZeitschrift fur Psychoanalyse18:281–258.


new directions in treatment research of anorexia and...

Documents