Update on the treatment of anorexia nervosa: Review of clinical trials, practice guidelines and emerging interventions

Abstract

Background:
Anorexia nervosa is a potentially deadly psychiatric illness that develops predominantly in females around puberty but is increasingly being recognized as also affecting boys and men and women across the lifespan. The aim of this environmental scan is to provide an overview of best practices in anorexia nervosa treatment across the age spectrum.

Method:
A triangulation approach was used. First, a detailed review of randomized controlled trials (RCTs) for anorexia nervosa published between 1980 and 2011 was conducted; second, clinical practice guidelines were consulted and reviewed; third, information about RCTs currently underway was sourced. This approach facilitated a comprehensive overview, which addressed the extant evidence base, recent advances in evidence and improvements in treatment, and future directions.

Results:
The evidence base for the treatment of anorexia nervosa is advancing, albeit unevenly. Evidence points to the benefit of family-based treatment for youth. For adults no specific approach has shown superiority and, presently, a combination of renourishment and psychotherapy such as specialist supportive clinical management, cognitive behavioral therapy, or interpersonal psychotherapy is recommended. RCTs have neither sufficiently addressed the more complex treatment approaches seen in routine practice settings, such as multidisciplinary treatment or level of care, nor specifically investigated treatment in ethnically diverse populations. Methodological challenges that hinder progress in controlled research for anorexia nervosa are explained.

Conclusions:
The review highlights evidence-based and promising treatment modalities for anorexia nervosa and presents a triangulated analysis including controlled research, practice guidelines, and emerging treatments to inform and support clinical decision making.

Full text

Update on the treatment of anorexia nervosa:
review of clinical trials, practice guidelines
and emerging interventions
H. J. Watson
1
,
2
,
3
and C. M. Bulik
4
,
5
*
1
Centre for Clinical Interventions, Department of Health in Western Australia, Perth, WA, Australia
2
Eating Disorders Program, Princess Margaret Hospital for Children, Perth, WA, Australia
3
School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia
4
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Background. Anorexia nervosa is a potentially deadly psychiatric illness that develops predominantly in females
around puberty but is increasingly being recognized as also affecting boys and men and women across the lifespan.
The aim of this environmental scan is to provide an overview of best practices in anorexia nervosa treatment across
the age spectrum.
Method. A triangulation approach was used. First, a detailed review of randomized controlled trials (RCTs) for
anorexia nervosa published between 1980 and 2011 was conducted ; second, clinical practice guidelines were
consulted and reviewed ; third, information about RCTs currently underway was sourced. This approach facilitated a
comprehensive overview, which addressed the extant evidence base, recent advances in evidence and improvements
in treatment, and future directions.
Results. The evidence base for the treatment of anorexia nervosa is advancing, albeit unevenly. Evidence points to
the benefit of family-based treatment for youth. For adults no specific approach has shown superiority and, presently,
a combination of renourishment and psychotherapy such as specialist supportive clinical management, cognitive
behavioral therapy, or interpersonal psychotherapy is recommended. RCTs have neither sufficiently addressed the
more complex treatment approaches seen in routine practice settings, such as multidisciplinary treatment or level of
care, nor specifically investigated treatment in ethnically diverse populations. Methodological challenges that hinder
progress in controlled research for anorexia nervosa are explained.
Conclusions. The review highlights evidence-based and promising treatment modalities for anorexia nervosa and
presents a triangulated analysis including controlled research, practice guidelines, and emerging treatments to inform
and support clinical decision making.
Received 23 January 2012 ; Revised 28 September 2012 ; Accepted 11 October 2012 ; First published online 10 December 2012
Key words : Anorexia nervosa, antidepressants, antipsychotics, clinical trials, cognitive behavioral therapy, eating
disorders, family therapy, family-based treatment, reviews, systematic reviews, treatment.
Introduction
In this invited review, we reflect on the oeuvre of
clinical and academic scholarship that is the bedrock
of present-day anorexia nervosa treatment and draw
attention to emerging developments.
Systematic evidence reviews are the cornerstone of
appraising the status of a field and guiding treatment
delivery. Yet, for anorexia nervosa, they only capture
a fraction of treatments delivered in the community.
Severe anorexia nervosa is typically treated in an in-
patient or residential environment using multimodal
treatment delivered by multidisciplinary teams. The
complexity, cost and logistics of this approach do not
lend readily to examination by randomized controlled
trial (RCT). For example, non-oral feeding approaches,
occasionally used as a life-preserving intervention
for severely malnourished anorexia nervosa patients
(APA, 2006), have not been evaluated in RCTs, with
one exception (Rigaud et al. 2007). Best practices for
the critically ill emaciated patient, for the long-term
chronic patient, and for patients requiring alternative
feeding approaches to oral refeeding (nasogastric
* Address for correspondence : C. M. Bulik, Ph.D., Department of
Psychiatry, University of North Carolina at Chapel Hill, 101 Manning
Drive, CB #7160, Chapel Hill, NC 27599-7160, USA.
(Email : cbulik@med.unc.edu)
Psychological Medicine (2013), 43, 2477–2500. fCambridge University Press 2012
doi:10.1017/S0033291712002620
INVITED REVIEW

tube, nasojejunal tube, gastrostomy–jejunostomy, total
parenteral nutrition) remain the province of clinical
opinion and expert consensus with little guidance
from empirical studies. The conduct and interpret-
ation of RCTs are inhibited by the severity of the
physical and psychiatric aspects of illness, which pre-
clude ethical randomization of participants to waiting
list, non-specific, or placebo control groups. Because
of these limitations and constraints, what we can
glean from RCTs and systematic reviews of anorexia
nervosa represents only a partial picture of the treat-
ment provided for this pernicious and potentially life-
threatening eating disorder.
In this environmental scan, we broadened our per-
spective and ‘ways of knowing ’ beyond the tra-
ditional systematic review to combine three sources of
knowledge. We begin with the ‘ gold standard ’ evi-
dence-based approach. We then review advances
in practice guidelines, which although informed
by science, also incorporate expert consensus on
treatment. Finally, we review treatments that are cur-
rently under investigation by teams endeavoring
to advance the evidence base. Via this triangulated
approach, we provide a scan of best practices in
the treatment of anorexia nervosa across the age
spectrum.
Background on anorexia nervosa : diagnosis and
epidemiology
Anorexia nervosa is an eating disorder characterized
by low body weight (<85% of expected for age and
height), body image disturbance, fear of weight
gain, and amenorrhea (absence of menstruation for
o3 months when otherwise expected) (Diagnostic and
Statistical Manual of Mental Disorders, fourth edition ;
DSM-IV; APA, 2000). The restricting subtype involves
energy restriction, increased energy expenditure, fast-
ing and other non-purging compensatory behaviors
in the absence of binge eating; and the binge-eating/
purging type includes the presence of binge eating or
purging behaviors (or both). The fifth edition of DSM
(DSM-5) will eliminate the amenorrhea criterion.
Anorexia nervosa affects 0.9–2.2 % of women over the
lifetime but subthreshold conditions are more com-
mon. The prevalence is lower in men (about 0.3 %)
(Hudson et al. 2007). Onset typically occurs during
adolescence and naturalistic follow-ups suggest
that less than half of patients fully recover, with the
remainder chronically ill or partially improved
(Berkman et al. 2007). Anorexia nervosa has the high-
est mortality rate of any psychiatric illness (Harris &
Barraclough, 1997; Birmingham et al. 2005 ; Berkman
et al. 2007, Arcelus et al. 2011) and the standardized
mortality ratio is dramatically elevated for mortality
secondary to suicide (56.9, 95% confidence interval
15.3–145.7) (Keel et al. 2003).
Physical corollaries can involve every major organ
of the body, including the cardiovascular, gastroin-
testinal, reproductive, hematological, endocrine and
integumentary systems, and impaired growth in chil-
dren. Many people require hospitalization during the
course of illness for reasons commonly including
extreme low weight, cardiac abnormalities, electrolyte
disturbance, hypotension and bradycardia. An esti-
mated 50% of children with new-onset threshold or
subthreshold anorexia nervosa have life-threatening
medical complications (Madden et al. 2009). Psy-
chiatric co-morbidity is prevalent, in particular, anxi-
ety disorders (>50%) (Bulik, 2002 ; O’Brien & Vincent,
2003), depressive disorders (20–80 %) (Bulik, 2002 ;
O’Brien & Vincent, 2003) and cluster C personality
disorders (O’Brien & Vincent, 2003).
Evidence-based practice
Evidence reviews rely heavily on RCTs, the uncon-
tested ‘gold standard ’ for establishing plausible
causality between an intervention and outcome.
Systematic evidence reviews of treatments for anor-
exia nervosa have rarely been encouraging ; ‘ weak
evidence’ (Bulik et al. 2007), ‘no specific approach can
be recommended’ (Hay et al. 2003), ‘ uniformly dis-
couraging’ (Attia & Schroeder, 2005) have typified
their conclusions leading one practitioner researcher
to ask, ‘Is evidence based treatment of anorexia
nervosa possible? ’ and to respond with, ‘ Barely ’
(Fairburn, 2005).
RCTs for anorexia nervosa are notoriously chal-
lenging to conduct. First, the relative rarity of anorexia
nervosa makes recruitment challenging and multiple
sites are often necessary. Second, drop-out in adult
trials is unacceptably high : about 40 % in medication
trials and about 25% in behavioral trials (Berkman
et al. 2006). Clinical trials for adolescents report lower
drop-out (10–20%), which may be attributable to par-
ents’ ability to compel a child’s treatment (Halmi,
2008). Drop-out can undo the effects of randomization
and make groups no longer comparable. Although
intent-to-treat analysis can be used, drop-out may still
introduce bias, as assumptions about participants’
endpoint outcomes are made to impute missing data.
A treatment effect may be obscured if participants in
the control group worsen and attrite to seek alterna-
tive treatment, as this could bias the control group
toward better outcomes. Similarly, if the intervention
worsened outcome in some patients in the treatment
group, and they dropped out, the overall treatment
effect would be erroneously biased toward better out-
comes. Halmi et al. (2005) opined that no further large
2478 H. J. Watson and C. M. Bulik

clinical trials for anorexia nervosa should be con-
ducted until drop-out and treatment refusal are ad-
dressed. Third, a no-treatment or placebo comparison
is unethical given the severity and medical complica-
tions of the disorder. Accordingly, in RCTs for anor-
exia nervosa, treatments are generally compared with
other treatments, or with a control group that does not
receive the trialed intervention but rather some other
background treatment such as treatment as usual
in the community. In these instances, non-specific
therapy factors, time, and background interventions
cannot be ruled out as possible explanations for over-
all improvement. Fourth, as noted previously, RCTs
do not lend themselves well to the study of complex
treatment settings and modalities. RCTs are better
suited to the evaluation of single-modality treatments ;
comparison of levels of care can be unethical and may
lose clinical meaning given that admission to level of
care in community clinical settings is typically deter-
mined by clinical severity indices.
Section 1: review of clinical trials
This evidence review provides a resource to activate
existing knowledge, to infill knowledge gaps, and
enhance awareness of recent developments.
Method
Inclusion and exclusion criteria
A priori inclusion and exclusion criteria are noted in
Table 1.
Literature search and retrieval process
We included studies identified in two previous sear-
ches for systematic reviews. Each of the authors was
directly involved with and updated the systematic
searches in these former reviews
1
#
. The methodology
for these two former reviews is described briefly.
Berkman et al. (2006); Bulik et al. (2007): Agency for
Healthcare Research and Quality Evidence Report (USA)
A total of six databases were searched : Medline ;
PsycINFO; the Cumulative Index to Nursing and
Applied Health; Educational Resources Information
Center (ERIC); the National AGRIcultural OnLine
Access; and Cochrane Collaboration libraries. A list of
medical subject heading (MeSH) search terms was
developed for Medline and comparable terms for
other databases. MeSH terms included ‘ anorexia ’ and
‘AN ’, and searches were limited by type of study,
including RCT, single-blind method, double-blind and
crossover designs. Articles were solicited from experts
in the field, and studies published from 1980 to
September 2005 were sought.
Watson et al. (2010): National Eating Disorders
Collaboration Review (Australia)
A total of five databases were searched : Medline (1985
to July 2009); PsycINFO (1985 to July 2009) ; EMBASE
(1980 to July 2009); SCOPUS (1960 to June 2009) ; and
the Cochrane Collaboration libraries. In addition, the
Table 1. Inclusion and exclusion criteria
Category Criteria
Population Humans
All races, ethnicities and cultural groups
Aged 10 years or older
Study settings and geography All nations
Time period Published from 1980 to October 2011
Publication criteria Included :
English language
In print
Excluded :
Articles in gray literature or non-peer-reviewed journals
Study design Original research studies reporting adequate detail of method, results, and data to enable use
Patients of any age or gender with a primary diagnosis of anorexia nervosa according to
DSM-III, DSM-III-R, DSM-IV, ICD-9, ICD-10, Feighner or Russell criteria
Randomized controlled trial study design
Relevant standardized outcomes : e.g. weight, eating pathology
Treatment may be monotherapy or adjunctive
DSM, Diagnostic and Statistical Manual of Mental Disorders ; ICD, International Classification of Diseases.
#The notes appear after the main text.
Treatment of anorexia nervosa 2479

table of contents of the International Journal of Eating
Disorders was hand searched between January 2004
and July 2009. All searches used eating disorders and
anorexia nervosa with truncated terms where rel-
evant. Retrieval was limited to RCTs published from
2004 to July 2009 and to systematic reviews with
search dates between 2004 and July 2009 to identify
earlier RCTs. Medline and EMBASE were searched
with search filters developed by the British Medical
Journal, and PsycINFO was searched based on a search
filter developed for the Wales Health Evidence
Bulletins. Search filters are fully reported in Watson
et al. (2010).
Systematic search updating
The systematic searches were updated to October 2011
using the electronic database search methodology re-
ported in Watson et al. (2010). Abstracts were system-
atically reviewed against a priori criteria to determine
inclusion. Disagreements regarding inclusion were
resolved by discussion between authors.
Reporting of studies and treatment outcomes
All RCTs are summarized in Table 2 according to
study characteristics (year of publication, country,
setting, percentage female, race/ethnicity, number of
subjects (n), study arms, treatment duration and
dosage). Studies are grouped by phase of treatment
(acute or maintenance) and study population (mixed
adults and youth, or youth only). Effect sizes for
weight-related and eating pathology outcomes were
calculated from data reported in RCTs, i.e. means and
standard deviations, t,For x
2
values, significance le-
vels, gain scores, ordinal categories, and frequencies,
following procedures described by Hedges & Olkin
(1985), Cohen (1962), Lipsey & Wilson (2001) and
Rosenthal (1991). In studies with crossover designs,
first period data were considered only. Hedges’ g
(Hedges, 1981) was reported because it is a readily
interpretable variant of the Cohen’s dfamily and cor-
rects for biases associated with small sample sizes.
Tables of treatment outcomes (Tables 3–6) are orga-
nized by timing of outcome measurement (endpoint
or follow-up) and comparator type (control/placebo
or active treatment).
For treatments compared with control/placebo, ef-
ficacious treatments ideally demonstrate large effect
sizes (i.e. standardized difference), which by conven-
tion indicate practical importance
2
, and, conversely
the absence of difference or a nil effect indicates the
lack of a specific treatment effect. For treatments
compared with another active treatment, we interpret
a large effect size as favoring the treatment with the
more positive outcome ; a lack of difference does not
indicate that one or the other treatment is ineffective
(or effective), only that there is no difference in out-
come between the two treatments. A limitation of
these interpretive stances is that they are presumptive
of a lack of bias, which is often not the case in real-
world research.
Results and discussion
Characteristics of studies
A total of 48 RCTs (see Table 2) met inclusion criteria,
including 19% (9/48) unreported in the previous re-
views (Berkman et al. 2006; Bulik et al. 2007 ; Watson
et al. 2010). The majority (90 %, 43/48) evaluated
treatment in the acute phase of illness and the re-
mainder (10%, 5/48) randomized to treatment after
weight restoration and were classified as maintenance
trials. Of the acute trials, 79 % (34/43) had mixed
samples comprising adults and youth (i.e. we define
‘youth ’ according to the National Institutes of Health
guidelines as 21 years) and the rest (9/43) focused
exclusively on youth from 11 to 20 years.
Treatment outcomes
In this section, we summarize RCT study results, em-
phasizing the most impactful treatment findings, de-
fined as the most well-studied interventions, studies
for which results have been highly anticipated, and
studies considerably making an impact on practice
guidelines, and cover psychotherapy and pharma-
cotherapy approaches. Effect sizes for trials are shown
in Tables 3–6.
Mixed samples of adults and youth
Acute treatment. Commensurate with previous reviews
(Hay et al. 2003; Attia & Schroeder, 2005 ; Bulik et al.
2007), and despite an influx of new studies, few treat-
ment studies for anorexia nervosa have identified a
large treatment effect relative to control, placebo, or
active treatment at endpoint or follow-up (Tables 3–6).
Behavioral interventions investigated include cog-
nitive–behavioral therapy (CBT), behavioral therapy
(BT), interpersonal psychotherapy (IPT), specialist
supportive clinical management (SSCM; originally
referred to as non-specific supportive clinical man-
agement), family therapy, focal psychodynamic
psychotherapy, cognitive analytic therapy (CAT),
graded exercise, warming, and nutritional/dietary
treatment. No clear primacy of any approach has been
demonstrated; as seen in Tables 3–6, outcome differ-
ences are generally nil to small.
McIntosh et al.’s (2005) psychotherapy trial rando-
mized 56 women (17–40 years) to CBT, IPT and SSCM
2480 H. J. Watson and C. M. Bulik

(control group; combined aspects of clinical manage-
ment with supportive therapy and education) and was
highly anticipated given that the study compared two
highly plausible treatment approaches with proven
efficacy for depression, namely CBT and IPT. Study
findings were unexpected – overall the control group
had superior outcomes – SSCM was superior to IPT,
and CBT fell somewhere in between. At about 7-year
follow-up, the three groups were equivalent on all
physical, cognitive and behavioral measures of eating
disorders (Carter et al. 2011). There was a good out-
come overall in 49%, although the control group had a
significantly faster rate of recovery than the IPT group
(Carter et al. 2011).
Considerable enthusiasm remains for CBT, which
has been spurred by strong, replicable outcomes for
other eating disorders, plausible and testable theory,
and scholarly backing by treatment experts. The lim-
ited evidence base has not indicated superiority of
CBT over other psychotherapies for anorexia nervosa ;
for example, in addition to the aforementioned
trial, Channon et al. (1989) found that patients im-
proved, but CBT, BT and control did not differ in ef-
fectiveness. Ball & Mitchell (2004) reported that 79 %
of completers achieved a good outcome with CBT,
although it did not differ significantly from family
therapy. This is only one small study out of a larger
group, which generally concluded no effect, and the
sample was small (n=25). Tables 4 and 6 confirm the
minimal effect size differences.
The first RCT to examine nasogastric refeeding
(Rigaud et al. 2007) compared a combination of naso-
gastric feeding plus meals and snacks versus meals
and snacks only in 81 patients with anorexia nervosa
(mean age=23 years). The intervention group had
significantly faster and greater weight gain to the
2-month endpoint (1.36 v. 0.88 kg/week) and a
longer relapse-free period at 1-year follow-up, but
there was no difference in the proportion relapsing
at 1 year. Table 3 shows that at endpoint, the effect
size for weight was large and favored nasogastric
feeding.
For pharmacotherapy interventions, among com-
bined samples of adults and youth, atypical anti-
psychotics and selective serotonin reuptake inhibitors
(SSRIs) have been the most extensively evaluated (see
Table 3). As shown in Tables 3–5, medication treat-
ments have not yielded large effects on weight-related
outcomes or eating pathology. Clinically, atypical
antipsychotics are prescribed to reduce anxiety as-
sociated with co-morbid disorders, reduce obsessional
thinking and anorexic cognitions, and relieve agitation
associated with weight gain and treatment challenges
(i.e. refeeding). In normal-weight and other psy-
chiatric populations, atypical antipsychotics show
an undesired side effect of extreme weight gain, ex-
perienced by up to 80% of individuals with psychotic
illnesses (A
´lvarez-Jime
´nez et al. 2008). Inconsistent
small to moderate overall benefits have been reported
from antipsychotic treatment for anorexia nervosa,
with olanzapine being the most commonly studied
in 55% (5/9) of trials. The majority of these studies
reported no differences between olanzapine and
placebo on psychological outcomes such as eating
pathology, body image, general psychiatric symp-
toms, obsessionality and compulsivity (Mondraty et al.
2005; Bissada et al. 2008 ; Attia et al. 2011 ; Kafantaris
et al. 2011), although one favored olanzapine for re-
ducing depressive symptoms (Brambilla et al. 2007).
Olanzapine was associated with small but statistically
significant weight gain in three trials (Brambilla et al.
2007; Bissada et al. 2008 ; Attia et al. 2011), only in the
binge–purge subtype in one (Brambilla et al. 2007), and
no reported effect beyond control in the other two
trials (Mondraty et al. 2005; Kafantaris et al. 2011).
Compliance was assessed in three of these trials:
Attia et al. (2011) reported detectable medication in
the serum of seven out of eight patients; Bissada et al.
(2008) reported 100% compliance from weekly urine
samples; and Brambilla et al. (2007) reported com-
pliance through pill counts. Four other antipsychotic
trials (Vandereycken, 1984 ; Ruggiero et al. 2001 ; Court
et al. 2010; Hagman et al. 2011) produced inconsistent
findings on weight and psychological outcomes. In
sum, atypical antipsychotics have had a considerable
degree of evaluation, but evidence for a specific treat-
ment effect on anorexia nervosa is inconsistent and
underwhelming.
It remains unclear whether and under what con-
ditions SSRIs are beneficial in the treatment of anor-
exia nervosa. Two trials compared SSRI with placebo
or treatment as usual (Attia et al. 1998 ; Fassino et al.
2002) and found no effect on eating pathology or
weight outcomes. Three trials compared SSRIs with
second-generation antidepressants (Brambilla et al.
1995a,b; Ruggiero et al. 2001). Intervention groups
showed improvement on psychological outcomes (i.e.
eating pathology, depression, anxiety), and there were
generally no statistically significant group differences.
Neurochemical and secondary disturbances, for ex-
ample tryptophan deficiency, may render medication
ineffective in malnourished individuals, and SSRIs
may be more valuable after weight restoration and/or
in conjunction with nutritional supplement augmen-
tation (Attia & Schroeder, 2005). Barbarich et al. (2004)
randomized patients to fluoxetine with or without
nutritional supplementation designed to regulate sero-
tonin function or placebo and found no differences on
weight gain, anxiety, or obsessive–compulsive symp-
toms, suggesting that nutritional supplementation did
Treatment of anorexia nervosa 2481

Table 2. Characteristics of randomized controlled trials of anorexia nervosa treatment
Study, first author (year)
Country, setting, female
%, race/ethnicity (n)nStudy arms Treatment duration (and dosage if applicable)
Acute trials – mixed adults
and youth
Pillay (1981) UK, in-patient, 100 %, NR 33 Social skills/social anxiety training v. non-specific control 12 sessions
Vandereycken (1984) Belgium, in-patient, 100%, NR 18 Sulpiride v. pill placebo 3 weeks (300–400 mg/day)
Biederman (1985) USA, in-patient/out-patient, NR, NR 25 Amitriptyline v. pill placebo 5 weeks (115 mg/day
a
)
Halmi (1986) USA, in-patient, 100 %, NR 72 Amitriptyline v. cyproheptadine v. pill placebo Until within 5% of ideal body weight ; up to 90 days of
treatment
Hall (1987) UK, out-patient, 100 %, NR 30 Individual and family psychotherapy v. dietary
advice group
12 sessions
Channon (1989) UK, out-patient, 100 %, NR 24 CBT v.BTv. TAU 12 months
Crisp (1991) UK, in-patient/out-patient, 100 %,
NR
90 In-patient then out-patient v. out-patient individual
psychodynamic and family therapy v. out-patient
group psychotherapy v. no further treatment
Several months to 1 year
Stacher (1993) Austria, out-patient, 100%, NR 12 Cisapride v. pill placebo 6 weeks (10 mg/3rday)
Birmingham (1994) Canada, in-patient, 100 %, NR 54 Zinc v. placebo Until 10 % increase in BMI achieved
Brambilla (1995a) Italy, out-patient, 100 %, NR 22 Nortiptyline v. fluoxetine 16 weeks (nortiptyline 75 mg/day ; fluoxetine 60 mg/day)
Brambilla (1995b) Italy, out-patient, 100 %, NR 13 Amineptine v. fluoxetine 16 weeks (amineptine 300 mg/day; fluoxetine 60 mg/day)
Klibanski (1995) USA, out-patient, 100%, NR 48 Estrogen/progestin v. control (calcium carbonate) 1.5 years
b
Szmukler (1995) Australia, in-patient, NR, NR 34 Cisapride v. pill placebo 8 weeks (10 mg/3rday)
Treasure (1995) UK, out-patient, 97 %, NR 30 BT v. CAT 20 weeks
Attia (1998) USA, in-patient, 100%, NR 33 Fluoxetine v. pill placebo 7 weeks (56 mg/day
a
)
Thien (2000) Canada, out-patient, 94 %, NR 16 Graded exercise v. control 12 weeks
Dare (2001) UK, out-patient, 98 %, NR 84 Focal psychodynamic psychotherapy v. family therapy
v. CAT v. low contact routine care
12 months. Focal psychodynamic psychotherapy : 25 sessions
b
.
Family therapy : 13 sessions
b
. CAT : 13 sessions
b
. Low contact
routine care: 10 sessions
b
Ruggiero (2001) Italy, in-patient, NR, NR 35 Amisulpride v. fluoxetine v. clomipramine 12 weeks (amisulpride 50 mg/day
a
; fluoxetine 28 mg/day
a
;
clomipramine 58 mg/day
a
)
Fassino (2002) Italy, out-patient, 100 %, NR 52 Citalopram v. waiting-list control 12 weeks (20 mg/day)
Barbarich (2004) USA, unspecified, NR, NR 26 Nutritional supplements (adjunct to fluoxetine) v.
placebo (adjunct to fluoxetine)
6 months (fluoxetine 20–60 mg/day
c
)
Birmingham (2004) Canada, in-patient, 100 %, NR 21 Warming v. placebo 21 days
Ball (2004) Australia, out-patient, 100 %, NR 25 CBT v. family therapy 12 months, 21–25 sessions
Mondraty (2005) Australia, in-patient, NR, NR 15 Olanzapine v. chlorpromazine (control) 1.5 months
b
(olanzapine 10 mg/day
a
; chlorpromazine 50 mg/day
a
)
McIntosh (2005) NZ, out-patient, 100%, NR 56 CBT v.IPTv. SSCM 20 weeks, 20 sessions
Brambilla (2007) Italy, out-patient, 100 %, NR 30 Olanzapine v. pill placebo 12 weeks (2.5 mg/day for 1 month, 6 mg/day for 2 months)
Rigaud (2007) France, in-patient, 97 %, NR 81 Refeeding v. TAU 8 weeks
Bissada (2008) Canada, partial, 100 %, NR 34 Olanzapine v. pill placebo 10 weeks (6 mg/day
d
)
Court (2010) Australia, out-patient, 96 %, NR 33 Quetiapine v. control 12 weeks (322 mg/day
a
)
Fazeli (2010) USA, unspecified, 100%, NR 21 rhGH v. injection placebo 12 weeks
2482 H. J. Watson and C. M. Bulik

Janas-Kozik (2011) Poland, in-patient, 100 %, NR 24 Bright light therapy v. control 6 weeks
Kafantaris (2011) USA, in-patient/partial/out-patient,
100 % ; Caucasian (n=16), Asian
(n=2), Hispanic (n=1), black (n=1)
20 Olanzapine v. pill placebo 10 weeks (8.5 mg/day
a
)
Miller (2011) USA, out-patient, 100 %, NR 77 Testosterone v. risedronate v.
combination v. double placebo
12 months (testosterone 150–300 mg/day
d
; risedronate
35 mg/week
d
)
Hagman (2011) USA, in-patient/partial, 100 %, NR 40 Risperidone v. pill placebo 9 weeks
b
(2.5 mg/d
d
)
Attia (2011) USA/Canada, out-patient, 96%, NR 23 Olanzapine v. pill placebo 8 weeks (8 mg/day
a
)
Acute trials – youth only
le Grange (1992) UK, out-patient, 89%, NR 18 Conjoint family therapy v. separated
family therapy
6 months, nine sessions
b
Robin (1999) UK, out-patient, 100 % ; white
(n=35), middle eastern (n=2)
37 Family therapy v. EOIT 16 months
b
Wallin (2000) Sweden, out-patient, 100 %, NR 26 BAT (adjunct to family therapy) v. family therapy BAT : 22 sessions
b
. Family therapy : 25 sessions
b
Geist (2000) Canada, in-patient, 100 %, NR 25 Family therapy v. family group psychoeducation 16 weeks
Hill (2000) USA, in-patient, 93 %, NR 15 rhGH v. placebo 28 days
Eisler (2000) UK, out-patient, 97%, NR 40 Conjoint family therapy v. separated
family therapy
16 sessions
b
Lock (2005) USA, out-patient, 89 % ; white
(n=64), Hispanic (n=10), Asian
(n=8), native American (n=1),
other (n=3)
86 Short-term FBT v. long-term FBT Short : 6 months, 10 sessions. Long : 12 months, 20 sessions
Gowers (2007) UK, in-patient/out-patient, 92 %, NR 170 In-patient v. specialized out-patient v. TAU In-patient : 4 weeks. Out-patient and TAU : limit of 6 months
Lock (2010) USA, out-patient, 91 % ; white
(n=54), Asian (n=1), black (n=0),
other (n=2), Hispanic (n=4)
121 FBT v. EOIT 12 months, 24 sessions
Maintenance trials – mixed
adults and youth
Russell (1987) UK, out-patient, NR, NR 57 Family therapy v. individual supportive psychotherapy 12 months. Family therapy : 10 sessions
b
. Individual supportive
psychotherapy : 15 sessions
b
Kaye (2001) USA, in-patient/out-patient, 100 %,
NR
39 Fluoxetine v. pill placebo 12 months (40 mg/day
a
)
Pike (2003) USA, out-patient, 100 %, NR 33 CBT v. nutritional counseling 12 months
Walsh (2006) USA/Canada, out-patient, 100 %, NR 93 Fluoxetine v. pill placebo Up to 12 months (63 mg/day
a
)
Maintenance trials – youth
only
Rhodes (2008) Australia, out-patient, 100 %, NR 20 FBT v. FBT with parent-to-parent consultation FBT : 20 sessions. FBT with parent-to-parent consultation :
21 sessions
NR, Not reported ; CBT, cognitive–behavioral therapy ; BT, behavioral therapy; TAU, treatment as usual ; BMI, body mass index; CAT, cognitive analytic therapy ; NZ, New Zealand; IPT, interpersonal
psychotherapy ; SSCM, specialist supportive clinical management (formerly non-specific supportive clinical management) ; rhGH, recombinant human growth hormone ; EOIT, ego-oriented individual therapy/
adolescent-focused individual therapy ; BAT, body awareness therapy; FBT, family-based treatment/family therapy.
a
Average at end of study.
b
Average number for sample.
c
Range at end of study.
d
Average over study period.
Treatment of anorexia nervosa 2483

Table 3. Randomized controlled trials identified through systematic review : anorexia nervosa treatment outcomes at treatment endpoint for active intervention versus control
Trial
c
Treatment outcomes
a
Group comparison
b
Weight-related effect size : Hedges’ gEating disorder pathology effect size : Hedges’ g
(+)(x) Nil Small Medium Large Nil Small Medium Large
Intent-to-treat
Acute trials – mixed adults and youth
Vandereycken (1984) Sulpiride Placebo – – – 0.80
d
–––x1.00
e,f
Halmi (1986) Amitriptyline Placebo – 0.25
g
––– – – –
Cyproheptadine Placebo – – 0.56
g
–– – – –
Stacher (1993) Cisapride Placebo – – – 0.94
h
– 0.24
i
–x2.94
f,j
Szmukler (1995) Cisapride Placebo x0.09
k
–– –– – – –
Attia (1998) Fluoxetine Placebo x0.08
l
–– –x0.17
e
–––
Brambilla (2007) Olanzapine Placebo 0.18
o
–– –x0.18
m
x0.47
n
,x0.43
i
,
x0.36
j
––
Rigaud (2007) Refeeding Control – – 0.63
k
1.13
g
––––
Bissada (2008) Olanzapine Placebo – – 0.54
o
–– – – –
Hagman (2011) Risperidone Placebo 0.00
h,p
– – – 0.00
i
0.42
j
––
Attia (2011) Olanzapine Placebo 0.10
o
–– –x0.13
q
x0.31
n
––
Janas-Kozik (2011) Bright light Control 0.00
p
–– –– – – –
Acute trials – youth only
Hill (2000) rhGH Placebo – – 0.63
d
–– – – –
Maintenance trials – mixed adults and youth
Kaye (2001) Fluoxetine Placebo – 0.21
h
– – – 0.20
s
––
Walsh (2006) Fluoxetine Placebo – 0.38
o
– – 0.05
q
,x0.05
n
, 0.11
m
,
0.19
i
,x0.16
j
–––
Completer
Acute trials – mixed adults and youth
Biederman (1985) Amitryptyline Placebo x0.19
d
– – – – – 0.53
t
–
Birmingham (1994) Zinc Placebo – 0.41
d
0.60
o
–– – – –
Klibanski (1995) Estrogen Control – x0.35
g
––– – – –
Thien (2000) Graded exercise Control 0.05
o
–– –– – – –
Fassino (2002) Citalopram Placebo – 0.49
k
0.72
o
– – 0.26
m
––
Barbarich (2004) Nutritional
supplementation
Placebo – – 0.54
d
–– – – –
Birmingham (2004) Warming Placebo – x0.25
o
––– – – –
Court (2010) Quetiapine Control 0.13
d
0.26
o
––– x0.21
m
– 1.39
i
, 1.41
j
Kafantaris (2011) Olanzapine Placebo – 0.20
o
––– – – –
2484 H. J. Watson and C. M. Bulik

not enhance fluoxetine efficacy. The effect size differ-
ence between groups (Table 3) on body mass index
(BMI) was medium.
It is necessary to note that in Table 3, sulpiride
appeared to have a large impact on weight gain at
endpoint in an early study; however, inspection of the
primary study data revealed that the effect is an arti-
fact of failed randomization, with large group differ-
ences at pretreatment carrying over to endpoint. The
earliest study of cisapride showed a similar phenom-
enon, leading to marked variation in endpoint out-
comes; cisapride also has been voluntarily withdrawn
in many countries because of cardiac risks.
Maintenance treatment for weight-restored anorexia
nervosa. A total of four maintenance trials were ident-
ified – two on fluoxetine (Kaye et al. 2001 ; Walsh et al.
2006), one on family therapy (Russell et al. 1987) and
one on CBT versus nutritional counseling (Pike et al.
2003). Walsh et al. (2006) found no differences between
fluoxetine and placebo in time to relapse, or changes
during treatment on BMI, core eating disorder path-
ology, depression, and other psychiatric symptoma-
tology, except for anxiety, which was reduced more in
the intervention group. Kaye et al. (2001) found that
only those who remained on fluoxetine for 1 year had
significant improvement on weight and psychological
outcomes; however, effect sizes did not reflect this
(Table 5) and the numbers of subjects were small.
Family therapy showed superior benefit to individ-
ual supportive psychotherapy at 1 year in the group
whose illness was not chronic and had begun before
the age of 19 years (Russell et al. 1987); and, at 5-year
follow-up, more patients in family therapy (90%) ex-
perienced a good outcome (i.e. normal body weight
and regular menses) compared with individual sup-
portive psychotherapy (36%) (Eisler et al. 1997) ; how-
ever, as shown in Table 4 the effect size difference on
weight was small.
Compared with nutritional counseling, CBT for
1 year was associated with a significantly higher
proportion of participants attaining a good outcome
(i.e. normal body weight and regular menses). The
CBT group had lower relapse (22 v. 53%) at 1 year,
although this difference was not statistically signifi-
cant (Pike et al. 2003).
Youth
Acute treatment. Family therapy was evaluated in
six trials, five with out-patients (le Grange et al. 1992;
Robin et al. 1999; Eisler et al. 2000 ; Lock et al. 2005,
2010) and one with in-patients (Geist et al. 2000).
Family therapy for anorexia focuses primarily on
weight gain by empowering the family to take control
Maintenance trials – mixed adults and youth
Kaye (2001) Fluoxetine Placebo – – x0.67
h
–– – x0.54
s
–
Unclear
Acute trials – mixed adults and youth
Fazeli (2010) rhGH Placebo x0.19
l
–x0.59
k
–– – – –
Miller (2011) Risedronate+
testosterone
Placebo 0.00
o,k,l
–– –– – – –
Risedronate Placebo 0.00
o,k,l
–– –– – – –
Testosterone Placebo 0.00
o,k,l
–– –– – – –
rcGH, Recombinant human growth hormone ; EAT/ChEAT, Eating Attitudes Test/Children’s Eating Attitudes Test ; EDI, Eating Disorders Inventory ; BMI, body mass index ;
YBC-EDS, Yale-Brown-Cornell Eating Disorder Scale ; EAT-Bulimia, Eating Attitudes Test bulimia subscale.
a
Effect size conventions : nil, <0.2 ; small, 0.2–<0.5 ; medium, 0.5–<0.8 ; large, >0.8. Effect sizes were calculated from data reported in the primary study with effect sizes calculated
from means and standard deviations, t,For x
2
values, significance levels, gain scores, ordinal categories, and frequencies and followed procedures described by Hedges & Olkin (1985),
Cohen (1962), Lipsey & Wilson (2001) and Rosenthal (1991). Studies with crossover designs had first-period data considered only.
b
A positive effect size favors the group in the (+)
column ; a negative effect size favors the group in the (x) column.
c
For further details of treatment groups, see Table 2.
d
Weight gain.
e
EAT/ChEAT total.
f
Randomization clearly failed :
the groups had large baseline differences on the outcome measure. Using average gain scores instead, the effect size was nil.
g
Achieved target weight.
h
Change in percentage ideal body
weight.
i
EDI-body dissatisfaction.
j
EDI-drive for thinness.
k
Weight.
l
Percentage ideal body weight.
m
EDI-bulimia.
n
EDI-total.
o
BMI.
p
Change in BMI.
q
YBC-EDS.
r
BMI percentile.
s
Change in YBC-EDS.
t
EAT-Bulimia.
Treatment of anorexia nervosa 2485

Table 4. Randomized controlled trials identified through systematic review : anorexia nervosa treatment outcomes at treatment endpoint for active intervention versus active intervention
Trial
c
Treatment outcomes
a
Group comparison
b
Weight-related effect size: Hedges’ gEating disorder pathology effect size : Hedges’ g
(+)(x) Nil Small Medium Large Nil Small Medium Large
Intent-to-treat
Acute trials – mixed adults
and youth
Halmi (1986) Cyproheptadine Amitriptyline – 0.31
d
––– – – –
Hall (1987) Psychotherapy Dietary 0.00
e
–––– – ––
Channon (1989) CBT BT 0.00
f
– – – 0.00
g,h,i
–––
CBT or BT TAU 0.00
f
– – – 0.00
g,h,i
–––
Brambilla (1995a) Nortriptyline Fluoxetine – – – x0.81
f
x0.07
j
–––
Brambilla (1995b) Fluoxetine Amineptine – – 0.64
f
–– – – x1.73
j
Dare (2001) FT TAU – – 0.62
k
–– – – –
Focal TAU – – 0.75
k
–– – – –
CAT TAU 0.00
k
–––– – ––
Ruggiero (2001) Fluoxetine Clomipramine – 0.45
k
––– – – –
Fluoxetine Amisulpride 0.00
k
–––– – ––
Amisulpride Clomipramine – 0.39
k
––– – – –
Mondraty (2005) Olanzapine Chlorpromazine – – 0.56
f
– – 0.23
g
0.72
i
, 0.66
h
–
McIntosh (2005) CBT IPT 0.00
f
,x0.05
k
– – – – 0.24
l
, 0.30
g
, 0.20
h
,
0.26
i
,x0.39
o
0.74
m
, 0.54
n
–
SSCM IPT 0.17
k
0.25
f
– – 0.00
o
,x0.05
h
0.49
n
, 0.27
g,l
, 0.41
i
– 1.17
m
SSCM CBT – x0.34
f
,x0.28
k
– – 0.06
n
, 0.09
g
,x0.15
i
,x0.06
l
x0.40
m
,x0.39
o
, 0.23
h
––
Acute trials – youth only
Geist (2000) FGP FBT 0.00
e
– 0.62
p
–x0.13
i
x0.20
h
x0.54
g
–
Eisler (2000) Conjoint FT Separated FT – x0.48
f
,x0.42
p
x0.52
k
– 0.10
r
x0.39
j
, 0.29
q
––
Lock (2005)
s
FBT long FBT short 0.00
f
, 0.10
k
– – – 0.11
m,n
, 0.18
l
0.26
o
, 0.25
t
––
Lock (2005)
u
FBT long FBT short 0.00
f
, 0.15
k
– – – 0.12
m
, 0.19
l
0.21
n
, 0.38
o
, 0.34
t
––
Lock (2010) FBT EOIT – – – 1.05
w
– 0.35
x
––
Maintenance trials – mixed
adults and youth
Pike (2003) CBT Nutritional – – – – – – – –
Russell (1987) FT Individual therapy – 0.39
y
––– – – –
Maintenance trials – youth only
2486 H. J. Watson and C. M. Bulik

of re-nutrition. Three RCTs compared alternative
content/delivery formats of family therapy (le Grange
et al. 1992; Eisler et al. 2000 ; Lock et al. 2005) and as
such effect size differences of nil to medium (Table 4)
imply no differences between the alternative delivery
formats. One trial (le Grange et al. 1992) showed
large effect sizes, favoring ‘family-based treatment ’
(FBT) on weight and eating pathology compared
with a similar approach whereby parents and child
were seen separately. Three RCTs compared family
therapy with treatment as usual or an active com-
parator (Robin et al. 1999; Geist et al. 2000, Lock et al.
2010). Lock et al. (2010) randomized 121 youth aged
12–18 years to FBT or adolescent-focused individual
therapy for 12 months. There was a large end-
of-treatment effect size difference on weight, favoring
FBT (Table 4). Remission, defined as achieving o95 %
of expected weight and eating pathology scores within
1S.D. of community norms, did not differ statistically
between groups at end of treatment (42 v. 23 %), but
was significantly higher in FBT at 6 months (40 v.18%)
and 12 months (49 v. 23%). An in-patient RCT (Geist
et al. 2000) comparing family therapy with family
group psychoeducation reported equivalent effects
but found family group psychoeducation more econ-
omical. Findings from this trial have been labeled
difficult to interpret because both treatments occurred
in the context of in-patient weight restoration and
most weight gain (76%) was attained prior to hospital
discharge (le Grange, 2005). As seen in Table 4, there
were no large effect size differences on weight and
eating outcomes between groups.
Gowers et al. (2007) randomized 170 youth aged
12–18 years to: specialized in-patient treatment
(multimodal intervention with a focus on weight
restoration), specialized out-patient (primarily CBT-
oriented), or Child and Adolescent Mental Health
Service community treatment as usual. Overall, parti-
cipants improved over the 2-year follow-up with no
group differences, consistent with effect sizes in
Table 6.
Maintenance treatment for weight-restored anorexia ner-
vosa. Rhodes et al. (2008) randomized 20 families of
girls aged 12–16 years to family therapy with or with-
out one parent-to-parent consultation early in treat-
ment. Immediately after the consultation, there was a
significant increase in weight in the consultation
group; however, at the end of the treatment program,
there were no statistically significant between-group
differences in weight or recovery status and effect size
estimates indicated no difference (Table 4).
Since the last published systematic reviews, the
evidence base has expanded most in the area of FBT
for youth. Although not yet definitive, findings do
Rhodes (2008) FBT FBT+PPC 0.00
p
–––– – ––
Completer
Acute trials – mixed adults and youth
Ball (2004) CBT BFT x0.13
f
–––x0.10
h
, 0.12
z
, 0.02
q
x0.31
x
––
Acute trials – youth only
Robin (1999) BFST EOIT – – 0.51
f
–– x0.27
r
––
CBT, Cognitive–behavioral therapy ; BT, behavioral therapy; TAU, treatment as usual ; FT, family therapy ; CAT, cognitive analytic therapy; IPT, interpersonal psychotherapy ; SSCM, specialist supportive c linical
management (formerly non-specific supportive clinical management) ; FBT, family-based treatment/family therapy; FGP, family group psychoeducation ; EOIT, ego-oriented individual therapy/adolescent-
focused individual therapy ; PPC, parent-to-parent consultation; BFT, behavioral family therapy ; BFST, behavioral family systems therapy ; BMI, body mass index; EDI, Eating Disorders Inventory ; EDE-SC, Eating
Disorder Examination shape concern subscale ; EDE-R, Eating Disorder Examination restraint subscale ; EDE-EC, Eating Disorder Examination eating concern subscale ; EDE-WC, Eating Disorder Examination
weight concern subscale ; EAT/ChEAT, Eating Attitudes Test/Children’s Eating Attitudes Test ; YBC-EDS, Yale-Brown-Cornell Eating Disorder Scale ; ABOS, Anorectic Behavior Observation Scale.
a
Effect size conventions : nil, <0.2 ; small, 0.2–<0.5; medium, 0.5–<0.8 ; large, >0.8. Effect sizes were calculated from data reported in the primary study with effect sizes calculated from means and standard
deviations, t,For x
2
values, significance levels, gain scores, ordinal categories, and frequencies and followed procedures described by Hedges & Olkin (1985), Cohen (1962), Lipsey & Wilson (2001) and Rosenthal
(1991). Studies with crossover designs had first-period data considered only.
b
A positive effect size favors the group in the (+) column ; a negative effect size favors the group in the (x) column.
c
For further details
of treatment groups, see Table 2.
d
Achieved target weight.
e
Weight gain.
f
BMI.
g
EDI-bulimia.
h
EDI-body dissatisfaction.
i
EDI-drive for thinness.
j
EDI-total.
k
Weight.
l
EDE-SC.
m
EDE-R.
n
EDE-EC.
o
EDE-WC.
p
Percentage ideal body weight.
q
Morgan–Russell total score.
r
EAT/ChEAT total.
s
At FBT short endpoint.
t
YBC-EDS.
u
At FBT long endpoint.
v
Weight for height.
w
BMI percentile.
x
EDE global.
y
Maintained
target weight.
z
ABOS.
Treatment of anorexia nervosa 2487

Table 5. Randomized controlled trials identified through systematic review : anorexia nervosa treatment outcomes at treatment follow-up for active intervention versus control
Trial
c
Follow-up
Treatment outcomes
a
Group comparison
b
Weight-related effect size :
Hedges’ g
Eating disorder pathology effect size :
Hedges’ g
(+)(x) Nil Small Medium Large Nil Small Medium Large
Intent-to-treat
Acute trials – mixed adults
and youth
Crisp (1991) In-patient then out-patient Control 1 year from baseline – – – – x0.03
d
–– –
Individual out-patient+FT Control 1 year from baseline – – – – – 0.28
d
––
Group out-patient Control 1 year from baseline – – – – 0.19
d
–– –
Rigaud (2007) Refeeding Control 1 year from baseline –
–
– – 0.15
e
–– –
Acute trials – youth only
Wallin (2000) BAT Control 2 years after baseline – – – – – – – –
Completer
Acute trials – mixed adults
and youth
Pillay (1981) Social skills Placebo 1 year after treatment 0.08
f
, 0.13
g
,
0.10
i
–– –– – – –
Crisp (1991) In-patient then out-patient Control 1 year from baseline – – – – x0.09
d
–– –
Individual out-patient+FT Control 1 year from baseline – – – – – 0.42
d
––
Group out-patient Control 1 year from baseline – – – – 0.19
d
–– –
Court (2010) Quetiapine Control 1 year from baseline – – – 0.99
i
–x0.28
j
– 1.42
k
, 2.48
l
FT, Family therapy; BAT, body awareness therapy ; EDI, Eating Disorders Inventory ; BMI, body mass index.
a
Effect size conventions : nil, <0.2 ; small, 0.2–<0.5 ; medium, 0.5–<0.8; large, >0.8. Effect sizes were calculated from data reported in the primary study with effect sizes calculated
from means and standard deviations, t,For x
2
values, significance levels, gain scores, ordinal categories, frequencies, and narrative descriptions of no effect if no other useable data were
reported, and followed procedures described by Hedges & Olkin (1985), Cohen (1962), Lipsey & Wilson (2001) and Rosenthal (1991). Studies with crossover designs had first-period data
considered only.
b
A positive effect size favors the group in the (+) column; a negative effect size favors the group in the (x) column.
c
For further details of treatment groups, see Table 2.
d
Morgan–Russell global score.
e
EDI-total.
f
Weight.
g
Percentage ideal body weight.
h
Achieved target weight.
i
BMI.
j
EDI-bulimia.
k
EDI-body dissatisfaction.
l
EDI-drive for thinness.
2488 H. J. Watson and C. M. Bulik

converge toward the value of including family mem-
bers in systematically delivered family-based inter-
vention. Worldwide, the practice milieu for acute child
and adolescent eating disorders has been indelibly
influenced by controlled research on family therapy,
particularly FBT, which RCT evidence supports to
date and is commonly used clinically. Unfortunately,
in both pharmacological and psychotherapeutic inter-
ventions for adults, no clear superior treatments have
emerged. Further, the evidence base has yet to develop
novel and feasible designs that allow testing of the
entire spectrum of interventions for anorexia nervosa
(i.e. from in-patient weight restoration to maintenance
and relapse prevention).
Section 2: practice guidelines
We purposely target this section to an eating disorder
non-specialist readership and focus on two widely
used sets of guidelines : the National Institute for
Health and Clinical Excellence (NICE, 2004) and the
American Psychiatric Association (APA, 2006). We
acknowledge that many countries and specialties have
developed practice guidelines for the treatment of
anorexia nervosa, but the broad influence of these two
guidelines stems from the high standard of develop-
ment, which in each case involved a detailed system-
atic review of evidence and literature, expert opinion
and consensus, and wide circulation and review.
The objectives of this section are : to share the main
areas addressed in the practice guidelines that are not
addressed by the extant RCT literature (i.e. treatment
setting and team, renourishment, and family in-
volvement); to share recommendations essential for
clinicians; and to highlight important evidence-based
developments that may inform guideline revision. We
integrate this section with the previous section by
highlighting whether recommendations are consistent
with the evidence base.
Treatment setting and team
Services available for people with eating disorders
range from out-patient to partial hospitalization,
in-patient, and residential care. Most people with
anorexia nervosa should be managed in an out-patient
setting (NICE, 2004; APA, 2006). In-patient treatment
is warranted for specific medical, psychiatric and so-
cial reasons, such as acute medical stabilization relat-
ing to the complications of malnutrition, suicidality,
severe family environment or social problems, and
a decline in weight despite maximally intensive
community-based care (NICE, 2004; APA, 2006).
The decision to admit patients on a medical versus
psychiatric unit should be informed by the patient’s
general medical and mental health status and the
skills, availability and suitability of staff and inter-
ventions on respective units (APA, 2006). Continuity
of care across levels is essential, which can be assisted
with a designated care coordinator (APA, 2006).
Treatment is optimally delivered by a multi-
disciplinary team, given the variety of physical and
psychiatric aspects of the illness (APA, 2006).
Appropriate professionals include a psychiatrist,
other physician, clinical psychologist, dietitian, nurse,
social worker and occupational therapist (APA, 2006).
Renourishment
The first treatment priority of anorexia nervosa is to
restore healthy weight and treat physical complica-
tions (APA, 2006). Management necessarily involves
restoration of nutritional status (i.e. healthy weight,
normal perceptions of hunger and satiety, normalized
eating patterns, and correction of malnutrition)
through a renourishment program (NICE, 2004 ;
APA, 2006). Oral-based nutrition is the most common
refeeding approach; enteral or parenteral nutrition
support may be warranted in extreme cases of mal-
nutrition and patient refusal to eat, at which time
nasogastric feeding is preferable to intravenous feed-
ing (APA, 2006). Total parenteral nutrition should not
be used, unless the patient has severe gastrointestinal
dysfunction (NICE, 2004). Feeding against patient
will is an absolute last resort (APA, 2006). Critics of
the guidelines claim that the conservative, ‘ defensive ’
refeeding approach that is recommended to protect
against refeeding syndrome is outdated, and may
obstruct timely improvement and cause harm.
Alternatively, renourishment can afford to be more
aggressively implemented, while being more efficient
and safe (Kohn et al. 2011; Garber et al. 2012).
Family involvement
For youth, guidelines suggest that family members
including siblings should be involved in the wider
treatment, and, for adults, family and spousal involve-
ment should be considered on a case-by-case basis
(NICE, 2004; APA, 2006). RCT evidence has supported
family involvement in youth treatment (see Section 1).
Treatment modality
The recommended treatment for youth is family ther-
apy that directly addresses the eating disorder (NICE,
2004; APA, 2006). This therapy was assigned a Grade
B in the NICE guidelines (indicating that a treatment
has evidence of effectiveness in well-conducted clini-
cal studies), the highest grade of all the treatment ap-
proaches for anorexia nervosa. This recommendation
Treatment of anorexia nervosa 2489

Table 6. Randomized controlled trials identified through systematic review : anorexia nervosa treatment outcomes at treatment follow-up for active intervention versus active intervention
Trial
c
Follow-up
Treatment outcomes
a
Group comparison
b
Weight-related effect size : Hedges’ gEating disorder pathology effect size : Hedges’ g
(+)(x) Nil Small Medium Large Nil Small Medium Large
Intent-to-treat
Acute trials – mixed adults
and youth
Hall (1987) Psychotherapy Dietary 1 year from baseline 0.00
d
–––– – ––
Channon (1989) CBT BT 6 months (12 months)
after treatment
0.00
e
(0.00
e
) – – – 0.00
f,g,h
(0.00
f,g,h
)
–––
CBT or BT TAU 6 months (12 months)
after treatment
0.00
e
(0.00
e
) – – – 0.00
f,g,h
(0.00
f,g,h
)
–––
Crisp (1991) In-patient then
out-patient
Individual out-
patient+FT
1 year from baseline – – – – – x0.30
i
––
In-patient then
out-patient
Group
out-patient
1 year from baseline – – – – – x0.22
i
––
Individual out-
patient+FT
Group
out-patient
1 year from baseline – – – – 0.07
i
–––
Treasure (1995) BT CAT 1 year from baseline x0.04
d,j
x0.41
e
––– x0.32
i
––
McIntosh (2005) CBT IPT 6.7 (¡1.2) years
after treatment
–x0.32
e
,x0.20
j
– – 0.07
k
, 0.00
l
,
x0.06
n
0.24
m
,x0.40
f
,
0.32
g
x0.51
h
–
SSCM IPT 6.7 (¡1.2) years
after treatment
0.14
e
, 0.11
j
– – – 0.11
m
,x0.17
n
,
x0.04
f
,x0.05
g
x0.41
l
x0.73
k
,
x0.72
h
–
SSCM CBT 6.7 (¡1.2) years
after treatment
–x0.39
e
,x0.30
j
– – 0.11
h,m,n
0.38
l
,x0.37
f
,
0.33
g
0.69
k
–
Acute trials – youth only
le Grange (1992) Family
counseling
FBT 8 months from
baseline
–– –x0.91
o
x0.09
p
––x0.81
i
Lock (2005) FBT long FBT short 6 months after short,
0 months after long
0.00
e
, 0.15
j
– – – 0.12
k
, 0.19
m
0.34
q
, 0.21
l
, 0.38
n
––
Gowers (2007) In-patient Specialized
out-patient
1 year (2 years) from
baseline
x0.18
e
,x0.15
r
(0.00
e
, 0.03
r
)
–––x0.06
s
, 0.08
i
(x0.04
i
)
(0.28
s
)––
In-patient TAU 1 year (2 years) from
baseline
–x0.32
e
,x0.36
r
(x0.25
e
,x0.29
r
)
– – 0.16
s
, –0.04
i
(0.00
i
)
(0.46
s
)––
Specialized
out-patient
TAU 1 year (2 years)
from baseline
x0.16
e
x0.22
r
(x0.29
e
,x0.36
r
)
––x0.13
i
(0.17
s
,
0.04
i
)
0.22
s
––
Lock (2010) FBT EOIT 6 months (1 year)
after treatment
– 0.30
t
(0.42
t
) – – 0.16
u
(0.18
u
)– – –
2490 H. J. Watson and C. M. Bulik

Completer
Acute trials – mixed
adults and youth
Crisp (1991) In-patient then
out-patient
Individual out-
patient +FT
1 year from baseline – – – – – x0.30
i
––
In-patient
then out-
patient
Group out-
patient
1 year from baseline – – – – x0.09
i
–––
Individual
out-
patient+FT
Group out-
patient
1 year from baseline – – – – – 0.21
i
––
Treasure (1995) BT CAT 1 year from baseline – x0.35
e
,
x0.28
d
x0.73
j
–– – x0.55
i
–
Ball (2004) CBT BFT 6 months after
treatment
––x0.55
e
– 0.02
v
, 0.06
i
x0.41
s
,
x0.46
g
––
Acute trials – youth only
Robin (1999) BFST EOIT 12 months after
treatment
– 0.27
e
––– x0.40
p
––
CBT, Cognitive–behavioral therapy; BT, behavioral therapy; TAU, treatment-as-usual ; FT, family therapy ; CAT, cognitive analytic therapy; IPT, interpersonal psychotherapy ; SSCM, specialist supportive
clinical management (formerly non-specific supportive clinical management) ; FBT, family-based treatment/family therapy; BFT, behavioral family therapy ; BFST, behavioral family systems therapy ;
EOIT, ego-oriented individual therapy/adolescent-focused individual therapy ; BMI, body mass index; EDI, Eating Disorders Inventory ; EDE-R, Eating Disorder Examination restraint subscale; EDE-EC, Eating
Disorder Examination eating concern subscale ; EDE-SC, Eating Disorder Examination shape concern subscale; EDE-WC, Eating Disorder Examination weight concern subscale ; EAT/ChEAT, Eating Attitudes
Test/Children’s Eating Attitudes Test ; ABOS, Anorectic Behavior Observation Scale.
a
Effect size conventions : nil, <0.2 ; small, 0.2–<0.5; medium, 0.5–<0.8 ; large, >0.8. Effect sizes were calculated from data reported in the primary study with effect sizes calculated from means and standard
deviations, t,For x
2
values, significance levels, gain scores, ordinal categories, frequencies, and narrative descriptions of no effect if no other useable data were reported, and followed procedures described by
Hedges & Olkin (1985), Cohen (1962), Lipsey & Wilson (2001) and Rosenthal (1991). Studies with crossover designs had first-period data considered only. Numbers in parentheses denote a second follow-up.
b
A positive effect size favors the group in the (+) column; a negative effect size favors the group in the (x) column.
c
For further details of treatment groups, see Table 2.
d
Weight gain.
e
BMI.
f
EDI-bulimia.
g
EDI-body dissatisfaction.
h
EDI-drive for thinness.
i
Morgan–Russell global score.
j
Weight.
k
EDE-R.
l
EDE-EC.
m
EDE-SC.
n
EDE-WC.
o
Percentage ideal body weight.
p
EAT/ChEAT.
q
YBC-EDS.
r
Weight for
height.
s
EDI-total.
t
BMI percentile.
u
EDE global.
v
ABOS.
Treatment of anorexia nervosa 2491

for youth is consistent with the evidence base (see
Section 1), with the study by Lock et al. (2010) adding
further strong support.
Among adults, Grade C (indicating expert consen-
sus or opinion) is the highest level of evidence, and
recommends CAT, CBT, IPT and focal psychodynamic
therapy, with no primacy assignable to any particular
approach (NICE, 2004; APA, 2006). Dietary counseling
should not be the sole treatment, nor should pharma-
cological interventions (NICE, 2004). For adults, these
recommendations are consistent with the evidence
base (see Section 1), with no treatments demonstrating
clear superiority.
Pharmacotherapy interventions have a limited
evidence base and should not be used as the primary
or sole treatment (APA, 2006). Caution is advised
when administering pharmacological treatments, as
some clinical features (i.e. depression, obsessive–
compulsiveness) remit with weight regain (NICE,
2004; APA, 2006). In the USA, there are no Food and
Drug Administration-approved medications for the
treatment of anorexia nervosa. These recommenda-
tions hold on the basis of current RCT evidence (see
Section 1). It is our contention that more research is
needed to investigate efficacy, particularly for anti-
psychotics, where inadequate compliance measure-
ment and mixed findings have dominated the control
trial landscape.
Section 3: on the horizon
Controlled trial findings and practice guidelines
have captured many components of clinical practice,
but new empirical forays to develop and advance the
evidence base are underway. The objective of this
section is to overview the hub of activity that will yield
the data to inform the coming decades of clinical
practice. Because of the enormous scope of ongoing
research, we have limited our discussion to RCTs. The
trials underway are motivated by : methodological
shortcomings of previous trials (i.e. drop-out, non-
compliance); new theoretical developments (i.e.
neurocognitive, socio-emotional) ; theoretical exten-
sions [i.e. transdiagnostic theory/’enhanced CBT’
(CBT-E)]; replication (i.e. efficacy of SSCM over theo-
retically based alternatives); adaptations for sub-
populations and contexts (i.e. couple-based therapy,
adult-based family therapy); lack of research on
the efficacy of treatment levels (i.e. in-patient, day, out-
patient); and most significantly, because both the
extant RCT base (see Section 1) and the practice
guidelines (see Section 2) have been unable, for adults,
to identify any first-line treatment options. Our ability
to address critical components such as drop-out and
compliance will have to await the completion of these
trials.
Information about active or completed but un-
published RCTs at the time of this search (October
2011) was sourced from clinical trials registries
[National Institutes of Health Research Portfolio
Online Reporting Tool (RePORTer), clinicaltrials.gov,
Australian New Zealand Clinical Trials Registry
(ANZCTR) and ISRCTN], contact with experts in the
field, and the Eating Disorders Research Society
LISTSERV (see Table 7 for the summary list of
‘ongoing ’ trials).
In 2007 and in response to the leanness of the evi-
dence base, the National Institute of Mental Health
issued a request for proposals entitled ‘ Innovative
Trials for the Treatment of Anorexia Nervosa in Late
Adolescence & Adulthood ’. They sought novel appli-
cations addressing priority areas for anorexia nervosa
as identified in a National Institutes of Health work-
shop (for the report describing proceedings, see
Agras et al. 2004). The initiative funded four studies
which are, respectively: (1) [principal investigator
(PI): Lock] cognitive remediation therapy (Tchanturia
& Hambrook, 2010), which is designed to improve
neurocognitive abilities such as central coherence and
set-shifting skills; (2) (PI : Bulik/Baucom) couple-
based cognitive–behavioral intervention (Bulik et al.
2011), which helps couples work together in the treat-
ment of anorexia nervosa ; (3) (PI : Marcus) emotion
acceptance behavior therapy (Wildes & Marcus, 2011),
which aims to encourage emotional awareness, reduce
emotional avoidance, and support resumption of
valued activities outside the eating disorder ; and (4)
(PI: Steinglass) exposure and response prevention
therapy with motivational interviewing for weight-
restored patients (Steinglass et al. 2011), which ad-
dresses eating-related fear using traditional exposure
techniques and has a motivational enhancement el-
ement. Table 7 provides further information on these
studies.
As shown in Table 7, several pharmacotherapy
placebo-controlled RCTs are underway, examining
olanzapine, aripiprazole and quetiapine.
The majority of RCTs identified are examining
psychotherapeutic interventions. FBT in its standard
form is being compared with systems family therapy
(PI: Agras), and an RCT in Australia (PI : Touyz) is
investigating whether FBT outcomes are significantly
better if preceded by in-patient weight restoration.
FBT adaptations undergoing testing include a
more intensive ‘multi-family group day treatment ’
(PI: Dare; Dare & Eisler, 2000) ; FBT for young adults
(PIs: le Grange and Chen), which broadens family of
origin to include family of ‘ choice ’ (e.g. spouse/
cohabiting partner, aunts/uncles, grandparents, etc.)
2492 H. J. Watson and C. M. Bulik

Table 7. Characteristics of ongoing randomized controlled trials for anorexia nervosa
PI(s), projected
completion date
Study and sample characteristics : country, setting,
number of sites, sample age in years, sample gender,
special characteristics, if applicable nStudy arms
Treatment duration
(and dosage if applicable) Status
Agras, 2012 USA/Canada, out-patient, 7, 12–18, m/f 164 FBT v. systems family therapy 9 months, 14 sessions Recruitment closed
Attia, 2015 USA/Canada, out-patient, 5, 18–55, m/f 160 Olanzapine v. placebo 16 weeks (10 mg/day) Recruiting
Attia, 2009 USA, out-patient, 1, 16+, m/f 22 Olanzapine v. aripiprazole 12 weeks (olanzapine 10 mg/day ; aripiprazole
15 mg/day)
Completed
Attia, 2009 USA/Canada, out-patient, 2, 16+, m/f 23 Olanzapine v. placebo 12 weeks (10 mg/day) Completed
Attia, 2008 USA, in-patient, 1, 16+, m/f 39 In-patient v. stepped care (in-patient
then day-patient)
To normal weight Completed
Bulik/Baucom, 2011 USA, out-patient, 1, 18+, m/f, living with partner 32 Couple-based CBT v. family
supportive therapy
20 weeks, 20 sessions Recruitment closed
Bulik/Baucom, 2012 USA, out-patient, 1, 18+, m/f, living with partner 50 Couple-based CBT v. individual CBT 23 weeks Recruiting
Byrne, 2014 Australia, out-patient, 3, 18+, m/f 200 CBT-E v. SSCM v. MANTRA 10 months, 25–40 sessions Recruiting
Dingemans/
Danner, 2011
Netherlands, in-patient/day-patient, 2, 17–53, f only 82 CRT+TAU v. TAU 10 sessions Completed
Eisler, 2011 UK, in-patient, 5, 13–20, m/f 400 Multi-family day treatment v.in-
patient treatment+follow-up TAU v.
out-patient family therapy
12 months Completed
Fichter, 2011 Germany, out-patient, 8, 16+, f only, after discharge
from in-patient treatment
258 Internet-based relapse prevention v.
TAU
8 months, nine sessions Completed
Godart, 2004 France, in-patient, 1, 13–21, m/f, onset <19 years and
duration f3 years
60 Family therapy+TAU v. TAU Family therapy+TAU : 33.7¡24.6 sessions.
TAU : 27.2¡12.7 sessions
Completed
Hay, 2015 Australia/UK, out-patient, 3, 18+, m/f 90 CBT v. CBT with adjunct LEAP 8–10 months, 34 sessions Recruiting
Herpertz-Dahlmann,
2011
Germany, in-patient/day-patient, 6, 11–18, f only 180 In-patient v. day-patient To BMI 15–20th percentile Completed
Kaye/Powers, 2011 USA, out-patients, 2, 18–65, m/f 15 Quetiapine v. placebo 8 weeks (mean 178 mg/day) Completed
Klibanski/Herzog,
2014
USA, out-patient, 1, 18–45, f only 90 Testosterone v. placebo 8 months, seven visits (300 mg/day) Recruiting
Klibanski, 2016 USA, out-patient, 1, 18–45, f only, on oral
contraceptives
100 rhIGF-1+placebo tablet then
risedronate tablet v. placebo
injection+risedronate tablet then
risedronate tablet v. placebo
tablet+placebo injection then
placebo tablet
rhIGF-1 30 mcg/kg twice daily for 6 months
then risedronate 35 mg once weekly
Recruiting
Klibanski, 2016 USA/Canada, in-patient/out-patient, 2, 14–21, f only 100 rhIGF-1+estradiol+progesterone v.
placebo+estradiol
replacement+progesterone
12 months, nine visits (rhIGF-1 30 mcg/kg
twice daily; estradiol 100 mcg patch twice
weekly; progesterone, 100 mg/day/10 days/
month)
Recruiting
le Grange/Lock, 2014 USA, out-patient, 2, 12–18, m/f 60 FBT v. adaptive FBT 6 months, 18 sessions Recruiting
le Grange/Sawyer, 2015 Australia, out-patient, 1, 12–18, m/f 100 FBT v. parent-focused therapy 6 months, 18 sessions Recruiting
Treatment of anorexia nervosa 2493

Table 7. (cont.)
PI(s), projected
completion date
Study and sample characteristics : country, setting,
number of sites, sample age in years, sample gender,
special characteristics, if applicable nStudy arms
Treatment duration
(and dosage if applicable) Status
Lock/le Grange, 2015 USA, out-patient, 2, 12–18, m/f, non-responders early
in FBT
90 Intensive family-focused treatment v.
FBT
6 months Recruiting
Lock, 2011 USA, out-patient, 1, 18+, m/f 46 CBT v. CRT 6 months Recruitment closed
Loeb, 2011 USA, out-patient, 1, 10–17, m/f, prodromal anorexia
nervosa
60 FBT v. individual supportive
psychotherapy
14 sessions Recruitment closed
Madden/Touyz/
le Grange, 2011
Australia, in-patient at commencement, 2, 12–18, m/f 84 In-patient weight restoration+out-
patient FBT v. brief in-patient weight
restoration+out-patient FBT
17 days in-patient weight restoration plus
12 months FBT v. 50 days in-patient weight
restoration plus 12 months FBT
Completed
Moya
´, 2012 Spain, in-patient/day-patient, 1, 12–18, f only 60 Aripiprazole v. placebo 26 weeks (10 mg/day) Recruiting
Russell, 2012 Australia, in-patient/day-patient, 2, 16+, f only 80 Oxytocin v. placebo 6 weeks (36 international units twice daily) Recruiting
Schmidt, 2010 UK, out-patient, 1, 18–60, m/f 71 MANTRA v. SSCM 6 months, 20–30 weekly sessions Completed
Schmidt, 2011 UK, out-patient, 1, 13+, m/f, relapse prevention 98 Internet-based relapse prevention v.
TAU
6 months Completed
Schmidt, 2013 UK, out-patient, 4, 18–60, m/f 223 MANTRA v. SSCM 6 months, 20–30 weekly sessions Recruiting
Smith, 2011 Australia, in-patient/out-patient, 1, 15+, m/f 20 Acupuncture v. light massage v. TAU 6 weeks, 10 sessions Recruitment closed
Steinglass, 2011 USA, in-patient, 1, 16–45, m/f, partially weight-
restored patients
30 AN-EX/RP v. CRT 4 weeks, 12 sessions Completed
Touyz/le Grange/
Lacey, 2011
Australia/UK, two sites, out-patient, 18–45, f only,
chronic (o7 years)
63 CBT v. SSCM 6 months, 30 sessions Completed
Treasure, 2013 UK, out-patient, 40, 13–21, m/f, living with carer 350 (175
patients,
175
carers)
ECHO+TAU v. ECHOc+TAU v.
TAU
ECHO : self-help only so no defined duration,
ECHOc : 10 telephone coaching sessions per
family to be completed within 5-month
period
Recruiting
Treasure, 2012 UK, in-patient/day-patient, 15, 13+, m/f 444 (178
patients,
266
carers)
ECHOc+TAU v. TAU ECHOc : 10 telephone coaching sessions per
family to be completed within 5-month
period
Recruitment closed
Waller, 2015 UK, out-patient, 1, 18+, m/f 132 CBT v. CAT 12 months, 40 sessions Recruiting
Zipfel/Herzog, 2009 Germany, out-patient, 10, 18+, f only 243 CBT-E v. FPT v. TAU 10 months, 40 sessions Completed
Zucker, 2010 USA, out-patient, 1 11–18, m/f 36 Group parent training/adolescent
skills training v. FBT
20 sessions Recruitment closed
PI, Principal investigator ; m, male ; f, female; FBT, family-based treatment ; CBT, cognitive–behavioral therapy; CBT-E, cognitive–behavioral therapy – enhanced ; SSCM, specialist supportive clinical manage-
ment ; MANTRA, cognitive–interpersonal treatment (Maudsley model of anorexia nervosa treatment for adults) ; CRT, cognitive remediation therapy; TAU, treatment as usual ; LEAP, Loughborough Eating
disorders Activity therapy ; BMI, body mass index ; rhIGF-1, recombinant human insulin-like growth factor-1; AN-EX/RP, exposure and response prevention for anorexia nervosa ; ECHO, Experienced Carers
Helping Others self-help intervention ; ECHOc, Experienced Carers Helping Others guided self-help intervention ; CAT, cognitive analytic therapy; FPT, focal psychodynamic therapy.
2494 H. J. Watson and C. M. Bulik

and FBT for children and adolescents with prodromal
presentations (PI: Loeb) (Loeb et al. 2011).
SSCM is based on theoretical models of
clinical management and supportive psychotherapy
(McIntosh et al. 2005). The unexpected superior effect
of SSCM spurred interest in whether the approach has
a ‘specific ’ active ingredient beyond non-specific or
placebo factors, or whether the small sample size and
high attrition rate in the initial trial influenced find-
ings. Until now, there have been no further RCT data
to inform this discussion. SSCM is a comparator in
four active RCTs (PIs: Byrne ; Schmidt ; Schmidt ;
Touyz). Notably, one of these trials (PI : Touyz) is
evaluating the efficacy of SSCM and CBT in a chronic
anorexia nervosa population. The goals of treatment of
chronic anorexia have been adapted to improve qual-
ity of life, reduce the impact of the eating disorder,
achieve some weight gain, and reduce the use of
medical services; a key question of this study is whe-
ther psychological symptom change can occur despite
the chronicity and previous failures of treatment.
A novel cognitive–interpersonal treatment which
addresses perfectionism, obsessive–compulsive per-
sonality traits, avoidance, pro-anorectic beliefs, and
responses of close others (Schmidt & Treasure, 2006) is
being evaluated in two trials (PIs: Byrne; Schmidt).
Based on preliminary open trial data (Wade et al.
2011), this approach offers promise. A large 10-site
German study (Wild et al. 2009) is comparing CBT-E
with focal psychodynamic therapy and treatment as
usual-enhanced. This study promises to have one of
the largest sample sizes of any clinical trial for anor-
exia ever conducted and important public health im-
plications for service planning in Germany.
There is growing interest in caregiver and parent
skill-building interventions to improve skills in caring
for a loved one with an eating disorder, reduce carer
distress, and remediate eating disorder symptoms and
maintaining factors. An RCT comparing group parent
training with FBT among adolescents is underway
(PI: Zucker). The program draws from traditional and
contemporary therapy approaches (Zucker et al. 2006).
In addition, the Maudsley team has developed skill-
building workshops for carers and parents of adults
with eating disorders, based on motivational inter-
viewing and CBT (Treasure et al. 2008). Compassion,
emotional intelligence, resilience and stress manage-
ment, expressed emotion (i.e. overprotective, hostile,
or critical responses), and communication are tar-
geted, and the program is supplemented by a carer
skills-based manual (Treasure et al. 2007). Open pilot
studies have demonstrated acceptability and impact
on carer knowledge and skills ; however, evaluation of
the impact on clinical outcomes in an anorexia-only
population is needed.
Excessive exercise has had no focused attention in
treatment evaluations. Meyer et al. (2011) view ex-
cessive exercise as a maintaining factor of illness, as
one of the last symptoms to recede, and as a behavior
that heightens risk of relapse. A CBT intervention to
address excessive exercise, developed from a cogni-
tive–behavioral theoretical model (Meyer et al. 2011), is
being trialed in an RCT among adult out-patients (PI :
Hay).
It is anticipated that this plethora of research will
yield new and helpful treatment models that can be
readily disseminated, and will resolve perplexing
clinical questions that currently pervade the field.
Concluding remarks
In psychiatry and psychology, the standing of a
field rests considerably on the evidence base for treat-
ment. Treatment trials with anorexia nervosa patients
are challenging. Recruitment is trying; prevalence
is low, and ambivalence and reluctance to engage
in treatment are common. The medical compromise
associated with the illness precludes allocation to a
control group without proper treatment (i.e. waiting
list, placebo); hence all treatment trials for anorexia
nervosa begin methodologically penalized. As a re-
sult, treatment trials for anorexia nervosa are unable
to determine whether treatment produces improve-
ment beyond what the passage of time alone would
produce. Nor are they able to determine whether im-
provement extends beyond the impact of non-specific
factors, such as the care provider–patient relationship,
treatment expectations, or medically necessary back-
ground treatments (e.g. hospitalization), which
are typically uncontrolled and possibly unbalanced
across comparison arms. Drop-out rates are inordi-
nately high compared with many psychological con-
ditions and even other eating disorders (Halmi et al.
2005; Berkman et al. 2006 ; Halmi, 2008), posing prob-
lems for cost, attainment of sufficiently powered
samples, and interpretation of findings. Possibly the
biggest challenge facing treatment research is that
treatment as usual in clinical practice often involves
multidisciplinary management and choices about le-
vel of care, raising the question, what proportion of
variance in our treatments are actually captured
by RCTs?
In endeavoring to understand and advance best
practice in anorexia nervosa treatment, clinicians
and researchers may be best served by adopting an
approach that incorporates knowledge of : the treat-
ment evidence base; clinical practice guidelines, par-
ticularly recommendations for practice areas that
RCT evidence cannot or has not brought to light ; and
ongoing treatment research. Together, these three lines
Treatment of anorexia nervosa 2495

of knowledge will support safe, effective and relevant
clinical practice.
The evidence base for the treatment of anorexia
nervosa is advancing, albeit unevenly. In three
decades of research, family therapy (also termed FBT)
is the treatment of choice for young people.
Notwithstanding, the methodological issues that
challenge interpretation of RCTs in anorexia nervosa
generally apply to this body of research, as discussed
elsewhere (e.g. Downs & Blow, in press) and ad-
ditional advances for this evidence base are needed,
such as comparison of FBT with other plausible ap-
proaches, such as CBT. At a broader level, where
possible, the family including siblings should be
involved in treatment, and community-based care is
preferable, with in-patient care generally reserved
primarily for medical stabilization or necessary weight
restoration as noted in practice guidelines.
For adults, the research and practice guidelines
are less instructive; psychotherapy is the treatment
of choice, but there is limited evidence as to which
psychotherapy with SSCM, CBT, IPT, CBT, focal
psychodynamic therapy, and family therapy as re-
commended options (NICE, 2004 ; APA, 2006). In
terms of pharmacotherapy, SSRIs have not shown
benefit in malnourished individuals even with nu-
tritional supplementation to modulate neurochemical
deficits. Atypical antipsychotics have been evaluated
to a moderate degree but findings are inconsistent.
Although weight gain is a common side effect of
atypical antipsychotics in normal-weight populations,
clear efficacy in malnourished patients with anorexia
nervosa has not yet been established, and long-term
metabolic effects have not yet been documented.
Given the medical and cognitive compromise
secondary to malnourishment, it is also meaningful
to evaluate psychotherapy from the point of weight
restoration. Few studies have done this. Among youth,
only family therapy has been evaluated and shown
promise; among adults, CBT and family therapy have
(very limited) evidence of specific effectiveness.
Despite limited evidence of treatment efficacy, par-
ticularly for adults, and challenges in interpreting
findings, a lack of evidence is not commensurate with
‘lack of effectiveness ’ or a ‘ do nothing ’ approach
(Carney et al. 2006). There is a clinical imperative to
treat individuals with anorexia nervosa despite un-
certainty over the comparative effectiveness of inter-
ventions. Proper management can be both life
extending and life saving.
To assist the conduct of future RCTs, drop-out,
retention and barriers to pharmacological uptake need
to be addressed and collaborative investigator net-
works fostered. Pharmacotherapy and psychotherapy
trials ought to report compliance data to establish
whether null effects are attributable to the intervention
or non-compliance. Dosage has a positive relationship
with antipsychotic-induced weight gain (Nemeroff,
1997) and it is noteworthy that the patients in the
anorexia nervosa trials received lower average do-
sages compared with psychotic patients (A
´lvarez-
Jime
´nez et al. 2008).
Serious concerns remain with the evidence base
even when projecting outcomes of the many and
varied trials on the horizon. First, it is conceivable that
over the next 5 years as these trials come to fruition,
we will accumulate more partial knowledge based on
small underpowered clinical trials – either secondary
to single-site designs or to the impact of treatment
drop-out on statistical power. Second, few trials are
designed specifically to address the applicability of
treatments to males or minority participants – includ-
ing racial, ethnic and sexual minorities. Third, even
including the treatments on the horizon, completed
and emerging RCTs do not focus on optimal in-patient
hospitalization and renourishment approaches, there-
by omitting a critically important aspect of treatment
for severe anorexia nervosa. Fourth, even with the
most promising treatment for youth, FBT, it is critical
to know how best to treat those individuals for whom
FBT does not succeed. Fifth, will the extant research
literature generalize to the diagnostic groups that will
be identified under the new DSM-5 schema ?
The treatment of anorexia nervosa is neither simple
nor cheap. Ultimately the goal should be to develop
a rich and developmentally tailored pharmacopeia
and theracopeia (i.e. palette or collection of psy-
chotherapies) to meet the needs of the full range
of individuals who present for anorexia nervosa
treatment – from prepubertal youth to late-life adults,
from acute to chronic, from individuals with families
and/or partners to individuals with less social sup-
port, and from individuals with close access to spe-
cialized care to those remotely located.
We look for advances in treatment that emerge
from expanding bodies of literature on neurocog-
nition, biomarkers, and genetics of eating disorders.
Enhanced understanding of cognitive function may
assist with understanding barriers to engaging in
treatment and challenges in penetrating the recalci-
trant core symptoms of the illness. Biomarker in-
vestigations that successfully parse biomarkers of
starvation from biomarkers of illness may point to-
ward new drug targets that focus on the core features
of the disease rather than the historical approach of
adopting medications that have been successful in
other related conditions. Finally, further advances in
genetics may provide insight into biological pathways
that influence anorexia nervosa that can guide treat-
ment development. Together, these advances could
2496 H. J. Watson and C. M. Bulik

allow us to develop medications that specifically
and effectively target the core features of the illness
and advance us to the stage of other areas of neuro-
psychiatry in which pharmacogenomic approaches
are beginning to pave the way toward individualized
medicine approaches (McMahon & Insel, 2012).
In addition to treatment research, there is a critical
need for improved detection and early referral, both at
first presentation and relapse, to reduce duration of
exposure to the most severe stages of anorexia nervosa
illness.
Finally, our interventions must not abandon in-
dividuals with anorexia nervosa after initial successful
treatment. Individuals with histories of anorexia ner-
vosa face ongoing challenges even post-recovery with
developmental milestones such as pregnancy, child
rearing, adult stressful life events, and the perimeno-
pausal transition. We must continue to refine inter-
ventions to assist with these challenges to enable our
patients to thrive throughout their lives and interrupt
the cycle of risk that perpetuates eating disorders
across generations.
Declaration of Interest
None.
Notes
1
In contrast to Watson et al. (2010), studies that reported
mixed-age samples (i.e. adults and youth combined)
across the inclusion time period were included from the
original and updated systematic searches.
2
Although this convention is somewhat arbitrary and will
depend on whether the field deems the size of the stan-
dardized difference to be clinically meaningful.
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