Pharmacology & Therapeutics 217 (2021) 107667

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Pharmacological treatment of eating disorders, comorbid mental health

problems, malnutrition and physical health consequences
Hubertus Himmerich a,b,⁎, Carol Kan a,b, Katie Au b, Janet Treasure a,b
a
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK
b
South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK

a r t i c l e i n f o a b s t r a c t

Available online 25 August 2020 The pharmacological treatment of patients with an eating disorder (ED) often includes medications to treat their
ED, comorbid mental health problems, malnutrition and the physical health problems resulting from it. The cur-
Keywords: rently approved pharmacological treatment options for EDs are limited to fluoxetine for bulimia nervosa (BN)
Anorexia nervosa and – in some countries – lisdexamfetamine for binge eating disorder (BED). Thus, there are no approved phar-
Bulimia nervosa macological options for anorexia nervosa (AN), even though study results for olanzapine and dronabinol are
Binge eating disorder
promising. Topiramate might be an additional future option for the treatment of BN and BED. Selective serotonin
Fluoxetine
Lisdexamfetamine
reuptake inhibitors (SSRI), mirtazapine and bupropion could be considered for the treatment of comorbid unipo-
Depression lar depression. However, AN and BN are contraindications for bupropion. For ED patients with a manic episode,
Bipolar disorder we recommend olanzapine in AN and risperidone in BN and BED; whereas for bipolar depression, olanzapine
Anxiety (plus fluoxetine) seems appropriate in AN and lamotrigine in BN and BED. Acute anxiety or suicidality may war-
suicidality rant benzodiazepine treatment with lorazepam. Proton-pump inhibitors, gastroprokinetic drugs, laxatives and
Sleep problems hormones can alleviate certain physical health problems caused by EDs. Therapeutic drug monitoring,
Obesity pharmacogenomic testing, a more restrictive use of “pro re nata” (PRN) medication, an interdisciplinary treat-
Osteoporosis
ment approach, shared decision making (SDM) and the formulation of common treatment goals by the patients,
Reflux
their family or carers and clinicians could improve treatment success and safety. Novel genetic, immunological,
Electrolytes vitamins
Antidepressants microbiome and brain imaging research as well as new pharmacological developments like the use of psyche-
Benzodiazepines delics, stimulants, novel monoaminergic drugs, hormone analogues and drugs which enhance the effects of psy-
Zopiclone chotherapy may extend our therapeutic options in the near future.
Promethazine © 2020 Elsevier Inc. All rights reserved.
proton-pump inhibitors
Gastroprokinetic drugs
Laxatives
insulin, and paracetamol

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Pharmacological treatment of eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Pharmacological treatment of comorbid mental health problems . . . . . . . . . . . . . . . . . . . . . . . . 4
5. Treatment of malnutrition resulting from eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. Treatment of the physical health consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
7. Specific aspects of the pharmacological treatment in eating disorders . . . . . . . . . . . . . . . . . . . . . 10
8. Discussion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

⁎ Corresponding author at: Department of Psychological Medicine, King's College London, 103 Denmark Hill, London, SE5 8AF, UK.
E-mail address: hubertus.himmerich@kcl.ac.uk (H. Himmerich).

https://doi.org/10.1016/j.pharmthera.2020.107667
0163-7258/© 2020 Elsevier Inc. All rights reserved.
2 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
1. Introduction
The prevalence of eating disorders (EDs) is increasing, and more
and more affected people are seeking professional help (Schmidt
et al., 2016). Whereas in other areas of psychiatry the discovery of
antipsychotics and antidepressants in the 1950s led to a massive
breakthrough (López-Muñoz et al., 2005; Steinberg & Himmerich,
2012), people with EDs did not benefit from this psychopharmacolog-
ical progress. There is no single medication approved for anorexia
nervosa (AN) which is the deadliest EDs with a standardized mortality
ratio of more than 5 compared to the general population (Himmerich
et al., 2019). However, people with AN often take a plethora of supple-
ments and medications to alleviate the health consequences of their
disorder such as promethazine, paracetamol and lactulose to tackle
anxiety, sleep disturbances, pain and constipation (Tyrrell-Bunge
et al., 2018). The only psychopharmacological treatment options for
EDs with approval in some countries include fluoxetine for bulimia
nervosa (BN) and lisdexamfetamine for binge eating disorder (BED)
(Himmerich & Treasure, 2018).
The aim of this review is to summarise the pathophysiological, psy-
chological, psychiatric, pharmacodynamic and pharmacokinetic aspects
of the pharmacological treatment of EDs, of the mental health problems
often associated with EDs, of the malnutrition and the physical health
consequences resulting from it. Fig. 1 provides an overview of these
conditions that may potentially need pharmacological treatment.
2. Eating disorders
2.1. Diagnoses
The main EDs according to the Fifth Edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-5) are AN, BN and BED
(American Psychiatric Association, 2013).
AN is characterized by restriction of energy intake that leads to a
body weight less than minimally normal in adults or less than that min-
imally expected in children and adolescents. The extremely low body
weight is associated with an intense fear of gaining weight or of becom-
ing fat; or associated with persistent behaviours which counteract
weight gain; and with a disturbance in the evaluation of one's own
body weight or shape. DSM-5 differentiates between a restricting type
in which weight loss is accomplished primarily through dieting, fasting
or excessive exercise; and a binge eating/purging type, where the
Fig. 1. Connections between eating disorders (EDs), co-morbid mental health problems, malnutrition and physical health consequences. Eating disorders, comorbid mental health
problems and malnutrition maintain and perpetuate each other in a vicious circle. Over- and undernutrition can lead to physical health consequences. As a result, the EDs, the co-
morbid mental health problems, the malnutrition and the physical health consequences may all need specific pharmacological approaches. Abbreviation: Gastrointestinal (GI).
individual engages in binge eating or purging behaviour such as
self-induced vomiting or the misuse of laxatives (American Psychiatric
Association, 2013).
BED is defined by recurrent episodes of binge eating characterized
by eating an excessive amount of food in a discrete period and a lack
of control overeating during this episode. These episodes include eating
much more rapidly than normal, eating until feeling uncomfortably full,
eating even when not feeling hungry, eating alone because of embar-
rassment, and a feeling of disgust or guilt with oneself. Binge eating in
the context of the associated features of AN or BN excludes the diagnosis
of BED (American Psychiatric Association, 2013).
The diagnostic criteria for BN disorder include recurrent episodes of
binge eating, recurrent compensatory behaviours to prevent weight
gain such as self-induced vomiting and the misuse of laxatives,
and a self-evaluation that is unduly influenced by body shape and
weight without the diagnostic features of AN (American Psychiatric
Association, 2013).
Further feeding and EDs included in DSM-5 are pica which is the per-
sistent eating of non-nutritive, non-food substances; rumination disor-
der which is defined by the repeated regurgitation of food; and
avoidant/restrictive food intake disorder (ARFID) in which there is dis-
turbance of eating behaviour causing a failure to meet appropriate nu-
tritional needs in the absence of weight or shape concerns (American
Psychiatric Association, 2013). DSM-5 has further introduced the diag-
nostic category of other specified feeding or EDs (OSFED) to enable cli-
nicians to describe a clinical presentation that does not meet the full
criteria of any of the feeding and EDs. This category includes atypical an-
orexia, BN and BED of low frequency and/or limited duration, purging
disorder and night eating syndrome (American Psychiatric Association,
2013).
EDs are serious mental conditions with a high mortality caused by
suicide as well as physical health consequences (Ahn, Lee, & Jung,
2019; Huas et al., 2013; Pompili, Girardi, Tatarelli, Ruberto, & Tatarelli,
2006; Preti, Rocchi, Sisti, Camboni, & Miotto, 2011).
2.2. Pathophysiology
The pathophysiology of EDs is not completely understood. However,
scientific evidence suggests a multicausal pathogenesis including envi-
ronmental, nutritional and biological factors. Additionally, secondary
aspects of the resulting EDs phenotype such as undernutrition may
 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
serve to maintain the disorder (Himmerich, Bentley, Kan, & Treasure,
2019).
A wide variety of psychological and social environmental factors
have been implicated including socioeconomic status, culture, lifestyle,
the ideal of beauty, stress and problematic relationships as well as co-
morbid psychiatric disorders. The built environment and pollution are
also relevant (Himmerich, Bentley, Kan, & Treasure, 2019).
A core feature of all EDs is the disruption of the core appetite and nu-
tritional regulatory systems (Himmerich & Treasure, 2018). There are
associated reverberations in allied metabolic, endocrine system, im-
mune and gut microbiota systems (Chami, Monteleone, Treasure, &
Monteleone, 2019; Dalton et al., 2018; Dalton et al., 2019; Seitz, Trinh,
& Herpertz-Dahlmann, 2019). Genetic anomalies in the metabolism of
glucose and lipids may contribute to the risk (Hübel et al., 2019;
Watson, Yilmaz, Thornton, & Hübel, 2019). Cytokine signalling and a
set of genes that is assembled in the major histocompatibility complex
(MHC) have also been implicated (Dalton et al., 2018; Dalton et al.,
2020; Himmerich, Bentley, Kan, & Treasure, 2019).
Within the brain, the self-regulatory, the hedonic and the homeo-
static system, play a crucial role in the pathophysiology of EDs
(Himmerich & Treasure, 2018). The prefrontal self-regulatory system
uses serotonin (5-HT) as a key neurotransmitter. The hedonic system
includes prefrontal, basal ganglia and thalamic structures and uses do-
pamine, cannabinoids and endogenous peptides like enkephalins,
dynorphins and endorphin for neurotransmission. The homeostatic sys-
tem is located in the hypothalamus and releases hypothalamic hor-
mones involved in appetite regulation.
Over- or undernutrition often result from, but also maintain EDs
(Himmerich, Bentley, Kan, & Treasure, 2019) and lead to further physi-
cal health consequences like anaemia, osteoporosis, obesity or diabetes
which warrant additional treatment (Himmerich, Bentley, Lichtblau,
Brennan, & Au, 2019). There is a self-perpetuating vicious cycle
consisting of EDs, co-morbid mental health problems and malnutrition
leading to physical consequences. Fig. 1 exemplifies these connections.
2.3. Clinical management
The diversity in clinical presentation means that care pathways are
complex. This can consist of self-help, general practitioner (GP) care,
psychological counselling, or high intensity of care including intensive
outpatient/ day-care, inpatient (medical, psychiatric), and residential/
rehabilitation treatments. Inpatient treatment should be reserved
mainly for medically compromised patients with AN. It usually includes
medical consultation, supervised meals, medication management, and
occasionally restrictive measures such as the use of the Mental Health
Act, one-to-one monitoring and nasogastric (NG) tube feeding
(Anderson et al., 2017; NICE, 2017).
In general, treatment for EDs should include psychological therapy
and dietary advice, but it may also warrant pharmacological treatment.
Treatment for EDs needs to be in contact with, or provided by, multidis-
ciplinary specialist services, and involve, when possible, the person's
family members or carers (NICE, 2017).
The clinical management must include the mental and physical
health consequences. Mental health consequences and comorbidities
include anxiety, depression, bipolar disorder, suicidality and sleep prob-
lems (Ahn et al., 2019; Cinosi et al., 2011; Pompili et al., 2006;
Ulfvebrand, Birgegård, Norring, Högdahl, & von Hausswolff-Juhlin,
2015). Physical health consequences result from over- or under nutri-
tion which may lead to overweight and obesity or to deficiencies of cer-
tain nutrients, electrolytes or vitamins. Further physical health
consequences are problems of the gastrointestinal (GI) tract, the endo-
crine and metabolic disorders, cardiovascular diseases, impaired bone
health, and problems of the skin (Birmingham & Treasure, 2019;
Hanachi et al., 2019; Misra, 2008; Sabel, Gaudiani, Statland, & Mehler,
2013; Sachs, Harnke, Mehler, & Krantz, 2016; Westmoreland, Krantz,
& Mehler, 2016).
3
3. Pharmacological treatment of eating disorders
3.1. Anorexia nervosa
There is growing evidence for the possible benefit from olanzapine
in the treatment of AN (Attia et al., 2019), to a lesser degree aripiprazole
(Frank et al., 2017) and other atypical antipsychotics, and for the canna-
binoid receptor agonist dronabinol (Andries et al., 2014). For a recent
review of pharmacological treatment approaches in AN see (Blanchet
et al., 2019).
Looking at the evidence in more detail, the atypical antipsychotic
drug olanzapine showed superiority with regard to weight gain in 5 ran-
domized controlled trials (RCT) (Attia et al., 2019; Dold, Aigner,
Klabunde, Treasure, & Kasper, 2015). The largest RCT included 302 AN
patients and showed a significant increase in weight, but no significant
influence on AN-typical psychopathology and behaviour (Attia et al.,
2019). Nevertheless, olanzapine may have positive effects on anxiety
and sleep. Thus, olanzapine may be used to augment weight gain
starting with small doses such as 2.5–5 mg/d in adults and 1,25 mg/d
in adolescents increasing to 20 mg/d maximum if necessary
(Himmerich & Benkert, 2019). Case reports and chart reviews suggest
that aripiprazole (5–15 mg/d) has beneficial effects on over-valued
ideas and food rituals (Frank et al., 2017).
The NMDA receptor agonist D-cycloserine appears to improve the
effects of exposure therapy in AN (Levinson et al., 2015). Dronabinol
(tetrahydrocannabinol) showed an increase in weight gain compared
to placebo in an RCT in AN (Andries, Frystyk, Flyvbjerg, & Støving,
2014). Extensive experience with dronabinol exists for the treatment
of cachexia in cancer and in people with an infection by the human im-
munodeficiency virus (HIV).
3.2. Bulimia nervosa
In BN, selective serotonin reuptake inhibitors (SSRI) such as fluoxe-
tine (60 mg/d) have been evaluated most. The positive effect on the
number of binge-purge episodes is seen with higher doses than usually
used in depression and different mechanisms may be involved. Treat-
ment for 2-years has been recommended (Himmerich & Benkert,
2019). Topiramate (75–200 mg/d) has also been shown to be effective
in BN and well tolerated (off label) and has been found in trials to
have beneficial effects on binge eating, self-induced vomiting, dissatis-
faction with one's own body, and the pursuit of thinness (McElroy,
Guerdjikova, Mori, & Romo-Nava, 2019; Nickel et al., 2005). Currently,
topiramate is being evaluated by the U.S. Food and Drug Administration
(FDA) for approval in binge-purge episodes and in BED in a fixed com-
bination with the stimulant phentermine. Positive effects have been re-
ported in individual trials of amitriptyline, imipramine, fluvoxamine
and trazodone particularly with higher than usual doses (Himmerich
& Benkert, 2019). Bupropion is relatively contraindicated despite posi-
tive results due to the increased epileptic seizure risk. Although
ondansetron (5-HT3 antagonist) has been shown to be beneficial in
one RCT (Faris et al., 2000) and two uncontrolled open studies (Faris
et al., 1998; Hartman et al., 1997), it is not recommended due to the
risk of a dose-dependent prolongation of the QTc interval. The opioid re-
ceptor antagonist naltrexone has shown inconsistent results in studies
in patients with BN. In two smaller open studies a reduction of the bu-
limic symptoms was described. Other substances currently being stud-
ied in RCT include the intranasally-applied opioid antagonist
naloxone, lisdexamfetamine, the combination of phentermine and
topiramate, the antiandrogenic oral contraceptive ethinylestradiol in
combination with the progestin drospirenone and the α-adrenoceptor
antagonist prazosin (Himmerich & Benkert, 2019). For a recent review
of pharmacological treatment approaches in BN see (McElroy et al.,
2019).
4 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667

Table 1
Selected pharmacological treatments that were found efficacious in eating disorders. The listed doses merely provide a rough orientation guide in young and middle-aged adults without
metabolization or elimination problems and refer to oral administration. Abbreviations: Anorexia nervosa (AN), binge eating disorder (BED), bulimia nervosa (BN), cannabinoid receptor
(CB), dopamine (D), eating disorders (EDs), Food and Drug Administration (FDA), gamma-aminobutyric acid (GABA), histamine (H), human immune-deficiency virus (HIV), obsessive-
compulsive disorder (OCD), serotonin (5-HT), serotonin reuptake inhibitor (SSRI), trace amine-associated receptor (TAAR). For further details and references see text.

Eating Medication Mechanism of Action Dose Clinical Effect Comments

disorder

AN Olanzapine 5-HT2a, D2 and H1 antagonist 2.5–10 mg/d Weight gain, beneficial effects Not approved for AN
on sleep and anxiety
Dronabinol Non-selective CB1 and CB2 5–15 mg/d Appetite stimulation Used for patients with HIV- and cancer-associated
agonist cachexia; not approved for AN
BN Fluoxetine SSRI 20–60 mg/d, high Antidepressant, reduction of Approved for BN, depression, anxiety disorders
doses effective for BN binge-purge episodes and OCD; long half-life of up to 3 days
Topiramate Modulator of sodium channels, 12.5–200 mg/d, start at Antiepileptic, reduction of binge Not approved for BN; side effect: cognitive
calcium channels and GABAA low dose, slow eating, vomiting and body problems
receptors up-titration dissatisfaction
BED Lisdexamfetamine Prodrug that is converted to 30–70 mg/d Reduction in binge-eating FDA-approved for BED
the TAAR1 agonist episodes, weight loss
dextroamphetamine
Topiramate Modulator of sodium channels, 12.5–200 mg/d, start at Reduction in binge-eating Efficacious, but not approved for BED
calcium channels and GABAA low dose, slow symptoms, weight loss
receptors up-titration
Topiramate plus See above plus Phentermine: Reduction of binge-eating Not approved for BED; study by Safer et al. (Safer
phentermine sympathomimetic 3.75–7 mg/d; et al., 2020) too small (N = 22) to make firm
amphetamine-like analogue topiramate: recommendations
23–46 mg/d

3.3. Binge eating disorder 4. Pharmacological treatment of comorbid mental health problems

In recent years, a total of three positive RCTs for acute treatment of
BED and its relapse prevention with effect of lisdexamfetamine have
been reported (Appolinario, Nardi, & McElroy, 2019; Himmerich &
Treasure, 2018) using a dose of 50-70 mg/d. Lisdexamfetamine led to
a significant reduction in binge eating episodes compared to placebo
(off label). Patients lost approximately 5 kg within 11 weeks (McElroy
et al., 2015). In a relapse prevention RCT, the proportion of relapsed pa-
tients was ~4% in the lisdexamfetamine group compared to ~32% in the
placebo group (Hudson, McElroy, Ferreira-Cornwell, Radewonuk, &
Gasior, 2017). Therefore, it is the only drug shown to be efficacious in
an RCT for the maintenance treatment of individuals with BED.
Lisdexamfetamine has been approved in the US, Canada, Brazil, Puerto
Rico, Mexico and Israel for the treatment of BED. For the treatment of
ADHD, lisdexamfetamine is approved in the US, Canada, Brazil,
Australia, Europe, and Japan.
For SSRIs (citalopram, fluvoxamine, fluoxetine and especially sertra-
line) there are good indications of efficacy, with special emphasis on the
positive effect on impulse control and the treatment of comorbid anxi-
ety and depression. The dose is in the upper range, as is often used in
the treatment of obsessive-compulsive disorder. Among the SSRIs, ser-
traline has particularly good evidence in the treatment of BED (off
label).
Among the anticonvulsants, topiramate has also been found effica-
cious in the treatment of BED in terms of weight loss and reduction of
BED symptoms. Four RCTs are available (Appolinario et al., 2019, off
label). The combination of phentermine and topiramate was also
shown to be effective in reducing binge-eating (Himmerich & Benkert,
2019; Safer et al., 2020). In one RCT, atomoxetine (40–120 mg/d)
showed significant superiority over placebo in terms of frequency de-
crease in binge eating episode and reduction in body weight. For a cur-
rent overviews of pharmacological treatment approaches for BED see
(Appolinario et al., 2019; McElroy, 2017). Table 1 summarizes the
most promising medications tested for the treatment of EDs as
discussed.
For the newly established diagnosis of ARFID, pica and rumination
disorder, no pharmacological RCTs have been published. However,
cases of positive effects of olanzapine, cyproheptadine and fluoxetine
in adolescent patients with ARFID have been reported (Brewerton &
D'Agostino, 2017; Spettigue, Norris, Santos, & Obeid, 2018).
4.1. Affective disorders and anxiety disorders
Social anxiety and depression have been found to be the most com-
mon psychiatric comorbidities in patients with EDs. In AN, for example,
recent studies found comorbidity rates of >50% for social anxiety disor-
der, ~40% for depression and 20–30% for generalised anxiety disorder
(Catone et al., 2019; Ulfvebrand et al., 2015). About 45% of patients
with BN or BED suffer from a comorbid unipolar depression, and more
than 50% of patients with BN or BED suffer from a comorbid anxiety dis-
order (Ulfvebrand et al., 2015). The direction of causality is not fully un-
derstood. An ED may be a risk factor for the development of a depressive
or anxiety disorder (Razzak, Harbi, & Ahli, 2019), but anxiety disorders
are also frequently observed prior to emergence of an ED (Beesdo-Baum
& Knappe, 2012; Kaye, Bulik, Thornton, Barbarich, & Masters, 2004;
Wittchen, Kessler, Pfister, Höfler, & Lieb, 2000). Anxiety, affective and
EDs seem to share common genetic and environmental risk factors
(Fairweather-Schmidt & Wade, 2020). Transdiagnostically, the seroto-
nergic system is considered to be most relevant for most cases of de-
pression (Dell'Osso, Carmassi, Mucci, & Marazziti, 2016; Graeff &
Zangrossi Jr., 2010; Haleem, 2012; Kaye, 2008; Majuri et al., 2017).
However, it is possible that other mechanisms are relevant for treat-
ment resistant depression (the usual presentation of comorbid depres-
sion in anorexia nervosa) (see below).
In depression, it is recommended to use second-generation antide-
pressants as first-line treatment such as selective serotonin reuptake in-
hibitors (SSRI), selective serotonin and norepinephrine reuptake
inhibitors (SNRI), noradrenaline and dopamine reuptake inhibitors
(NDRI) or noradrenergic and specific serotonergic antidepressant
(NaSSA). They have been found to be better tolerated than the first-
generation tri- (TCA) or tetracyclic antidepressants and monoamine ox-
idase inhibitors (MAO-I). Second-generation antidepressants cause
fewer anticholinergic and cardiovascular side effects (Bauer, Severus,
Möller, & Young, 2017). For the treatment of depression in patients
with EDs, however, there are specific efficacy and safety aspects to con-
sider during treatment with SSRIs, SNRIs and NDRIs. The NDRI
bupropion is contraindicated in AN and BN, because further weight
loss can be a side effect (Benkert & Hippius, 2019).
In AN, the clinical challenge lies in the differentiation of depressive
symptoms that are a consequence of self-starvation, transitory and
 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
likely to improve without antidepressant medication during the recov-
ery from AN from those that signal the presence of an additional depres-
sive episode. Criteria that are indicative of a depression process
independent from self-starvation are a familial history of a mood disor-
der, the time course of the trajectory of symptoms and features such as
morning insomnia, daily variation, suicidal ideation/attempts and rumi-
nations related to guilt, unworthiness (Leblé, Radon, Rabot, & Godart,
2017).
SSRIs have not been found to have much benefit targeting depres-
sive symptoms in the acute phase of AN (Marvanova and Gramith,
2018). A potential explanation may be that people with AN have a def-
icit in amino acids such as tryptophan which is needed for the
production of the neurotransmitter serotonin. Thus, tryptophan supple-
mentation has been suggested as a means to augment antidepressants
in AN patients (Haleem, 2017). But a trial that sought to determine
whether nutritional supplements could potentiate the effects of fluoxe-
tine in underweight AN subjects found that supplement strategies like
the supplementation of tryptophan are not a substitute for adequate nu-
trition and are ineffective in increasing the efficacy of fluoxetine in un-
derweight AN subjects (Barbarich et al., 2004). However, SSRIs and
the tetracyclic NaSSA mirtazapine may help with depressive or anxious
symptoms in weight-restored patients with AN (Marvanova & Gramith,
2018).
As discussed above the SSRI fluoxetine is approved for the treatment
of BN symptoms. (Lutter, 2017). Less is known about how to treat co-
morbidity with depression. Interestingly, a study performed by
Leombruni et al. (Leombruni et al., 2006) compared two SSRIs, fluoxe-
tine and citalopram, showed different efficacy profiles. Citalopram
seemed to better address depressive symptoms in patients with BN,
whereas fluoxetine was more beneficial for bulimic symptoms and clin-
ical features associated with BN such as introjected anger. Overall, there
is no placebo-controlled RCT available with a focus on the use of antide-
pressants to treat depressive symptoms in patients with BN and a co-
morbid depressive disorder. Therefore, the recommendation to treat
depressive syndromes in BN with an SSRI should be given with caution.
For the treatment of patients with both, depression and BED, a retro-
spective cohort study, compared the NDRI bupropion and the SSRI ser-
traline. It was found that both drugs reduced anxious and depressive
symptoms and the binge frequency. However, bupropion showed supe-
rior effectiveness in reducing weight and improving sexual problems
(Calandra, Russo, & Luca, 2012). Bupropion is available as a sole medica-
tion but also as a fixed combination of naltrexone plus bupropion. This
combination is approved as an adjunct to diet and physical activity for
chronic weight management. In a prospective open study in 25
women with depression and overweight or obesity, in which many pa-
tients showed high levels of BED symptomatology, naltrexone plus
bupropion reduced weight and depressive symptoms. Thus, there is a
suggestion that bupropion can alleviate depression in patients
with BED.
Studies in people with bipolar disorder (BD) have found an in-
creased prevalence of BN and BED, and studies in BN and BED have
found an increase in BD compared to the general population (McElroy,
Kotwal, Keck Jr., & Akiskal, 2005). When considering a broader bipolar
definition and including the whole spectrum of bipolar symptoms,
~70% of patients with eating disorders show a clinically significant de-
gree of bipolarity (Campos, Dos Santos, Cordás, Angst, & Moreno,
2013). This comorbidity is clinically relevant. Bipolar disorder in itself
is a serious mental illness that confers significant functional impairment
plus the financial, social and emotional sequelae of illness episodes
(McAulay, Hay, Mond, & Touyz, 2019). However, the combination of
BD with BN or BED it is associated with even more problems such as
an earlier age of onset and a more severe course of the bipolar illness
(McElroy et al., 2011). For people with EDs, the co-occurrence of BD is
associated with an increased risk for suicide attempts requiring hospi-
talization (***Cliffe et al., 2020). However, to our knowledge, there are
no studies available on the specific treatment of BD in people with
5
EDs. Thus, the judgment needs to be based on theoretical consider-
ations, BD guidelines, contraindications for people with EDs and clinical
experience. The British Association for Psychopharmacology guidelines
(Goodwin et al., 2016) recommend dopamine antagonists for short-
term treatment of acute mania. Valproate, lithium and carbamazepine
can be alternatives. As people with EDs are often young women of
child bearing potential, valproate is not recommendable as it can lead
to malformations (Goodwin et al., 2016). Furthermore, people with
EDs have an elevated risk for QTc prolongation, electrolyte disturbances
and leukopenia (Franke, Halfter, & Himmerich, 2010; Himmerich,
Schönknecht, Heitmann, & Sheldrick, 2010). Thus, one should exercise
caution with haloperidol and quetiapine which are both known to
lead to QTc prolongation, whereas olanzapine and risperidone have a
lower risk (Dietle, 2015; Himmerich & Hamilton, 2020). Lithium treat-
ment requires stable salt intake and electrolyte levels (Haussmann,
Lewitzka, Severus, & Bauer, 2017). This prerequisite cannot be met in
patients who binge, vomit or abuse laxatives. Therefore, lithium should
only be considered in patients with EDs, if no alternative as available.
Additionally, lithium as well as carbamazepine can lead to pathological
blood count alterations, specifically to leukopenia (Himmerich &
Hamilton, 2020). Olanzapine has been shown to have therapeutic ben-
efits in AN (Attia et al., 2019; Dold et al., 2015). Therefore, it seems sen-
sible to recommend olanzapine for acute and long term-treatment for
mania in people with AN. However, olanzapine is known to induce
binge eating, food craving and weight gain (Himmerich, Minkwitz, &
Kirkby, 2015; Kluge et al., 2014). Therefore, it does not seem advisable
to prescribe olanzapine in BN and BED. Instead, risperidone may be
used in the acute phase and long-term treatment of BD in patients
with BN and BED. Risperidone might also be considered in binge-
purge type AN. For the short and long-term treatment of bipolar depres-
sion, olanzapine with or without fluoxetine, quetiapine, lamotrigine or
aripiprazole are recommended across various guidelines (Goodwin
et al., 2016; Grunze et al., 2013; NICE, 2014). Due to the above-
mentioned potential effects and side effects of olanzapine, it seems rea-
sonable to use olanzapine with or without fluoxetine only in people
with AN and lamotrigine in people with BN and BED to treat bipolar de-
pression. Aripiprazole can be an alternative for long-term treatment of
BD in people with AN, BN and BED. Again, these recommendations for
the treatment of BD in people with EDs are an expert opinion and not
based on trials in patients with EDs.
Regarding the psychopharmacological treatment of anxiety
disorders such as post-traumatic stress disorder (PTSD) and obsessive-
compulsive disorder (OCD), the British Association for Psychopharma-
cology guidelines (Baldwin et al., 2014) recommend SSRIs as first-line
treatment. However, before prescribing an SSRI for generalised anxiety
disorder, panic disorder, PTSD or OCD clinicians need to consider
whether the severity or course of the disorder justifies psychopharma-
cological treatment (Baldwin et al., 2014). As yet there has been no
pharmacological study in EDs designed with anxiety as the primary out-
come. Therefore, it seems sensible to use SSRIs to treat patients with
both, an ED and an anxiety disorder, if psychopharmacological treat-
ment is necessary.
Some benzodiazepines like lorazepam have proven efficacy in the
acute treatment of patients with panic disorder, generalised anxiety dis-
order and social anxiety disorder (Baldwin, Waldman, & Allgulander,
2011; Batelaan, Van Balkom, & Stein, 2012). However, benzodiazepines
can cause troublesome sedation and cognitive impairment in both
short-term and long-term treatment, and tolerance and dependence
can occur with prolonged use (Dell'Osso & Lader, 2012). Therefore, the
use of these medications should be time-limited, if it is necessary at all.
Pregabalin has also been reported to be effective in generalised anx-
iety disorder and social anxiety disorder (Baldwin et al., 2011; Baldwin
et al., 2014). Common adverse effects include drowsiness and dizziness;
weight gain appears in approximately 20% of patients (Montgomery,
Emir, & Haswell, 2013). It is not subject to hepatic metabolism and is ex-
creted unchanged in the urine, which is a potential advantage in
6 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
patients with hepatic impairment and in patients taking other drugs
metabolized by the liver, but potentially disadvantageous in patients
with renal disease. There is no known untoward interaction with lith-
ium. Discontinuation symptoms after abrupt withdrawal of pregabalin
have been reported, and individuals with a history of substance abuse
may also abuse pregabalin. Thus, there appears to be the potential for
addiction (Baldwin et al., 2014). RCTs on the use of pregabalin as an an-
xiolytic drug in people with EDs are not available.
4.2. Suicidality
EDs are associated with high rates of suicide (Ahn et al., 2019;
Pompili et al., 2006). Moreover, patients and their families note that
symptoms such as social disconnection and hopelessness are of rele-
vance for recovery and suicidality may not be given as much priority
as the physical symptoms (De Vos et al., 2017; Duncan, Sebar, & Lee,
2015).
The strongest association between suicide attempts and ED symp-
toms pertains to purging behaviour (Lipson & Sonneville, 2020). There
are neither published clinical trials nor recommendations available for
the specific pharmacological treatment of suicidality in EDs. However,
it seems clinically reasonable to combine psychotherapeutic and psy-
chopharmacological strategies and make the therapeutic decision de-
pendent on the underlying cause and comorbidities. As it is
recommended to treat suicidality in depressive, anxiety and personality
disorders with benzodiazepines such as lorazepam 0.5–4 mg/24 h
(Benkert & Hippius, 2019), we would propose this approach in EDs as
well. However, the risk for misuse, tolerance and the development of
addiction when using benzodiazepines long-term should be considered.
4.3. Sleep problems
Sleep problems in EDs include problems falling asleep, middle of the
night insomnia or early awakening in AN and BN as well as night eating
syndrome and sleep-related ED in BED or OSFED which can all lead to
tiredness during the day, concentration difficulties or daytime sleepi-
ness (Cinosi et al., 2011). Benzodiazepine hypnotics carry the risk for
hangover, fatigue, lack of concentration and limited attention and re-
duced responsiveness especially patients with liver and kidney prob-
lems (Benkert & Hippius, 2019). Therefore, non-benzodiazepine
hypnotic agents with a short half-life such as zopiclone 7.5 mg at
night may be recommended, if sleep hygiene measures and behavioural
approaches fail. Antihistamines like promethazine 25 mg at night (up to
100 mg/d) might also be considered. Promethazine maybe beneficial for
symptoms of anxiety. It was found to be the most-prescribed PRN med-
ication during a chart review on a specialised ward for EDs (Tyrrell-
Bunge et al., 2018). Table 2 summarizes the pharmacological treatment
of comorbid mental health problems.
5. Treatment of malnutrition resulting from eating disorders
5.1. Deficiency of vitamins and trace elements
Patients with AN are at risk for vitamin and trace element deficiency.
In a study with 374 AN patients, deficiencies in zinc were most common
(~60%), followed by vitamin D, copper, selenium, vitamin B1, B12, and
B9 (Hanachi et al., 2019). Thus, broad and mineral vitamin supplements
should be used to augment nutritional support. Individual patients may
require additional supplements or smaller amounts of certain
micronutrients, depending on their clinical condition (Berger &
Shenkin, 2006; Franques, Chiche, & Mathis, 2017).
A randomized controlled trial of zinc supplementation in AN pa-
tients reported a two-fold increase of BMI in the zinc group
(Birmingham, Goldner, & Bakan, 1994), and a meta-analysis of zinc
studies supported the evidence for the need of zinc supplementation
in AN patients (Su & Birmingham, 2002). Zinc has been suggested to
be an appetite stimulator and may thus have some additional therapeu-
tic potential in AN or cachexia associated with other diseases (Suzuki
et al., 2011).
Vitamin D deficiency (Franques et al., 2017; Gatti et al., 2015) may
be related to low bone mineral density (Giollo et al., 2017), immune def-
icits, and depressive symptoms (Tasegian et al., 2016).
The relevance of copper deficiency and its consequences in AN pa-
tients is unclear. Theoretically, the lack of copper could contribute to ar-
rhythmias, anaemia (Matak et al., 2013), neutropenia (Khera, Sharma, &
Singh, 2016), and bone demineralization (Medeiros, 2016) in patients
with AN (Hanachi et al., 2019).
In the literature, vitamin B9 deficiency varies between 20% and 45%
(Achamrah et al., 2017; Hanachi et al., 2019), whereas vitamin B12 de-
ficiency seems to be less frequent (Hanachi et al., 2019). However, in a
case report vitamin B12 deficiency led to sensory neuropathy in a pa-
tient with AN (Franques et al., 2017).
Clinical investigation and judgment are needed to decide whether
specific nutritional replacements should be used over and above broad
balanced replacements. The MARSIPAN guidelines (The Royal Colleges
of Psychiatrists, Physicians and Pathologists, 2014) recommend the ad-
dition of thiamine replacement at the start of refeeding and phosphate
may also be needed at this phase to prevent refeeding syndrome.
As there is a huge symptomatic overlap between deficiency syn-
dromes, and as a proportion of patients with AN may be deficient in sev-
eral vitamins such as thiamine, riboflavin, vitamin C and vitamin D, a
generous provision of balanced multi-vitamins and minerals rather
than the supplementation of specific vitamins or minerals is recom-
mended as part of acute treatment and refeeding in AN (NICE, 2017).
There are evidence and guidelines in place for refeeding, prevention
of refeeding syndrome and treatment of malnutrition with vitamins and
trace elements. For example, in the UK there are the NICE Guidelines
(NICE, 2017), the “MARSIPAN” (The Royal Colleges of Psychiatrists,
Physicians and Pathologists, 2014) and the “Junior MARSIPAN” (The
Royal College of Psychiatrists, 2012) reports.
5.2. Fluid and electrolyte deficiencies
Malnutrition and purging behaviours cause disturbances of the fluid
and electrolyte balance in people with restrictive AN (such as
hyponatremia, hypomagnesemia and hypophosphatemia) as well as
in the binge-purge type of AN and BN (mainly hypokalaemia,
hypocalcaemia, hypomagnesaemia). In general, chronic restriction and
purging behaviours lead to fluid and electrolytes depletion, extra-
cellular volume reduction and activation of the renin-angiotensin sys-
tem with increased aldosterone, increased renal reabsorption of sodium
and bicarbonate and further potassium excretion (Gravina, Milano,
Nebbiai, Piccione, & Capasso, 2018). The abuse of diuretics also causes
hypochloremic metabolic alkalosis; the abuse of laxative, with acute di-
arrhoea, may cause hyperchloremic metabolic acidosis as a result of the
bicarbonates loss from the intestine (Mehler, 2003; Olson, 2005). Acute
renal injury can result from the dehydration secondary to excessive
vomiting or laxative purging. These abrupt fluid variations consequent
to excessive purging behaviour may be associated with oedema
(Bihun, McSherry, & Marciano, 1993).
A severe hypokalemic metabolic alkalosis is almost always due to
vomiting or diuretic abuse. Hypokalaemia may also result also from ex-
cessive water intake (water intoxication). It can cause seizures and, in
rare cases, coma, respiratory arrest and death (Gravina et al., 2018;
Olson, 2005). Hypokalaemia can lead to QTc elongation, arrhythmias,
torsade de pointes, and sudden cardiac death (Westmoreland et al.,
2016). Chronic potassium depletion causes characteristic lesions in the
epithelial cells of the proximal and distal tubule leading to interstitial fi-
brosis, tubular atrophy, the formation of cysts, glomerulosclerosis which
is responsible for the reduction in glomerular filtration and progressive
loss of renal function (Arimura et al., 1999; Stheneur, Bergeron, &
Lapeyraque, 2014). Hypokalaemia can also occur as a symptom of
 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667 7

Table 2
Pharmacological treatment options for comorbid mental health problems in people with eating disorders. The listed doses merely provide a rough orientation guide in young and middle-
aged adults without metabolization or elimination problems and refer to oral administration. Abbreviations: Noradrenergic α2 (α2), anorexia nervosa (AN), bipolar disorder (BD), binge
eating disorder (BED), bulimia nervosa (BN), dopamine (D), eating disorders (EDs), gamma-aminobutyric acid (GABA), histamine (H), noradrenaline and dopamine reuptake inhibitor
(NDRI), noradrenergic and specific serotonergic antidepressant (NaSSA), obsessive-compulsive disorder (OCD), serotonin (5-HT), selective serotonin reuptake inhibitor (SSRI). For further
details and references see text.

Mental Health Associated Medication Mechanism of Action Dose Clinical Effect Comments
Problem ED

Depression AN, BN, Citalopram; SSRI Citalopram: 10–40 mg/d; Antidepressant and No benefit in the acute phase of
and Anxiety BED Escitalopram; Escitalopram: 5–20 mg/d; anxiolytic effects AN, but in weight-restored
Fluoxetine; Fluoxetine: 20–60 mg/d; patients; citalopram more
Fluvoxamine; Fluvoxamine 50–300; effective than fluoxetine for
Paroxetine; Paroxetine: 20–60 mg/d; depressive symptoms in BN
Sertraline Sertraline: 50–200 mg/d patients.
Mirtazapine NaSSA 15–45 mg/d Antidepressant and May help with depressive or
anxiolytic effects anxious symptoms in
weight-restored AN patients;
side effect: weight gain
Bupropion NDRI 150–300 mg/d Antidepressant, reduction Contraindication: AN, BN; side
of anxious and depressive effects: weight loss, epileptic
symptoms and binge seizures
frequency in BED
BD/Manic AN Olanzapine 5-HT2a, D2 and H1 antagonist 5–20 mg/d (higher dose in Antimanic and Alternatives: risperidone for
episode BD than for treatment of mood-stabilizing effect acute and aripiprazole for
AN) long-term treatment
BN, BED Risperidone D2, 5-HT2, α2 antagonist 1–16 mg/d (older patients: Antimanic and Alternative: aripiprazole for
up to 4 mg/d) mood-stabilizing effect long-term treatment
BD/Depressive AN Olanzapine 5-HT2a, D2 and H1 antagonist Olanzapine: 5–20 mg/d; Antidepressant and Alternatives: aripiprazole or
episode (plus (plus SSRI) fluoxetine: 20–60 mg/d mood-stabilizing effect lamotrigine
fluoxetine)
BN, BED Lamotrigine Interaction with voltage-gated Start dose: 12.5 mg, slow Antidepressant and Slow up-titration to avoid
sodium channels dose increase up to mood-stabilizing effect allergic skin reaction;
100–200 mg/d alternative: aripiprazole
Acute anxiety AN, BN, Lorazepam Benzodiazepine, enhances the 0.5–4 mg/d Acute anxiolytic, hypnotic Long-term use: risk of tolerance,
and BED effects of GABA at GABAA and anti-suicidal effects dependence and addiction; cave:
suicidality receptors fatigue and reduced
responsiveness
Sleep AN, BN, Zaleplon; Nonbenzodiazepines, enhance Zaleplon: 5–10 mg/d; Hypnotic and anxiolytic Long-term use: risk of tolerance,
problems BED Zolpidem; the effects of GABA at GABAA Zolpidem 5–10 mg/d; effects dependence and addiction
Zopiclone receptors Zopiclone: 7.5 mg/d smaller than with
benzodiazepines
Promethazine H1 receptor antagonist 25–100 mg/d Sedative and anxiolytic Also used as anti-allergic
effects medication and to treat sea
sickness

refeeding syndrome (Stheneur et al., 2014). The early stage of
hypokalaemia nephropathy is usually reversible with potassium re-
placement, but persistent hypokalaemia leading to tubulointerstitial ne-
phritis and associated renal failure may be irreversible (Sim et al., 2010).
Generally, these fluid and electrolyte imbalances are resolved with
the cessation of the purging behaviours and with the improvement of
the nutritional status (Gravina et al., 2018). If necessary, potassium
should be replaced orally. Only in case of emergency or in cases of gas-
trointestinal absorption problems, should intravenous (i.v.) medication
be considered (Himmerich, Bentley, Lichtblau, et al., 2019; Trent,
Moreira, Colwell, & Mehler, 2013). Treatment options for persistent
hypokalaemia are proton-pump inhibitors such as omeprazole or mag-
nesium replacement. The latter is also indicated for hypomagnesaemia,
usually given oral or i.v. as emergency treatment. Dehydration may re-
quire fluid replacement with water and electrolytes which should pref-
erably be given orally. In cases of severe hypochloraemia, sodium
chloride oral or i.v. may be considered.
More than 80% of patients with AN have been reported to show vita-
min D deficiency leading to a lack of calcium uptake from the GI tract,
hypocalcaemia and a loss in bone mineral density. Thus, hypocalcaemia
is an indication for calcium and vitamin D supplementation (Hotta,
2018). For further information see the section on impaired bone health
and osteoporosis below.
Severe hypophosphatemia can make the oral supplementation of
phosphate necessary. Hypophosphatemia should not be seen as a
mere electrolyte disturbance, but rather as a potential symptom of
refeeding syndrome which is characterized by electrolyte disturbances,
especially hypophosphatemia, fluid retention and impaired carbohy-
drate metabolism (Kohn, Madden, & Clarke, 2011; Malczyk &
Oświęcimska, 2017). Systemic phosphorous resources decrease during
starvation in order to maintain its normal serum concentration. Sudden
return to normal feeding after a long period of malnutrition, especially
increased intake of carbohydrates, leads to a rise in insulin secretion
and enhanced penetration of phosphorus from the extracellular to in-
tracellular space, where it is used to produce high-energy phosphates
such as adenosine triphosphate (ATP). Phosphorus deficiency during
refeeding can lead to serious, life-threatening consequences such as ar-
rhythmias and sudden cardiac arrest. In order to avoid refeeding syn-
drome in patients with AN, it is necessary to gradually increase the
number of introduced calories starting refeeding from 5 to 20 kcal/kg
body weight according to European or from 30 to 40 kcal/kg according
to US guidelines (Malczyk & Oświęcimska, 2017).
5.3. Iron deficiency and resulting anaemia
Recent studies (De Filippo et al., 2016; Sabel et al., 2013) have looked
into the prevalence of haematological abnormalities such as anaemia,
leukopenia and thrombocytopenia in people with AN of different sever-
ity and found that 17% of patients with AN had anaemia, 8% neutropenia
and ~ 9% thrombocytopenia (De Filippo et al., 2016), whereas in severe
cases (BMI ~ 12.5 kg/m2), the prevalence of these haematological abnor-
malities was even higher with 83% of patients suffering from anaemia,
8 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
79% leukopenia, 29% neutropenia and 25% thrombocytopenia. There-
fore, marked hematologic deficiencies are often present in patients
with severe AN; and they are interpreted as the result of starvation-
mediated gelatinous marrow transformation which resolves with
proper nutritional rehabilitation (Sabel et al., 2013). The reduced
granulopoiesis in AN patients may additionally be mediated by a de-
creased production of bone marrow growth factors such as
granulocyte-macrophage colony-stimulating factor (GM-CSF) or
insulin-like growth factor-1 (IGF-1) (Polli et al., 2008; Vaisman et al.,
1996). Anaemia tends to be normocytic and normochromic. Haemato-
logical changes usually disappear with weight restoration (Cleary,
Gaudiani, & Mehler, 2010). Therefore, specific treatment with growth
factors does not seem to be necessary. However, about 6% of patients
with AN have been found to show iron deficiency (Sabel et al., 2013).
In these cases, iron may be substituted. Table 3 summarizes the treat-
ment of malnutrition and specific deficiencies resulting from EDs
through supplementation of fluids, vitamins, trace elements and
electrolytes.
6. Treatment of the physical health consequences
6.1. Gastrointestinal tract problems
Patients with EDs present with various GI disturbances such as post-
prandial fullness, abdominal distention, abdominal pain, gastric disten-
sion, early satiety, and altered oesophageal motility (Sato & Fukudo,
2015). Other common conditions noted in patients with EDs are post-
prandial distress syndrome, superior mesenteric artery syndrome, irri-
table bowel syndrome, and functional constipation. Binge eating may
cause acute gastric dilatation and gastric perforation, while self-
induced vomiting can lead to dental caries, salivary gland enlargement,
gastroesophageal reflux disease, and electrolyte imbalance.
Frequently, patients with AN suffer from lower oesophageal sphinc-
ter failure, delayed gastric emptying and gastroesophageal reflux dis-
ease (GERD) (Eraslan, Ozturk, & Bor, 2009; Hadley & Walsh, 2003).
The cardinal symptoms of GERD are heartburn and regurgitation
(Serra Pueyo, 2014). Heartburn is defined as a burning sensation in
the retrosternal area, and regurgitation as the perception of flow of
refluxed gastric content into the mouth or hypopharynx (Vakil, Van
Zanten, Kahrilas, Dent, Jones, and The Global Consensus Group, 2006).
Even though the evidence for drug treatment of GERD in people with
EDs is low, in clinical practice, patients with EDs are treated with sodium
alginate, sodium bicarbonate or calcium carbonate or proton-pump in-
hibitors like omeprazole or lansoprazole which have been recom-
mended for GERD in general (Himmerich, Bentley, Lichtblau, et al.,
2019; Serra Pueyo, 2014).
Patients with AN have significantly slowed gastric emptying accom-
panied by early satiety, nausea, and bloating, when they are severely
underweight (Benini et al., 2004). This gastroparesis which could lead
to acute gastric dilatation or even gastric perforation usually resolves
with weight gain, but symptoms may respond early on to low-dose,
short-term use of the dopamine antagonist metoclopramide before
meals (Westmoreland et al., 2016). Domperidone, a dopamine D2-
receptor antagonist that is also used as a prokinetic agent has been dem-
onstrated to improve delayed gastric emptying in AN patients (Stacher
et al., 1986). Another prokinetic agent, cisapride, a serotonin 5-HT4 ag-
onist, effectively enhanced gastric emptying in AN patients in several
studies. However, cisapride is not available in most countries because
of the critical cardiac adverse effects of QT prolongation and ventricular
tachycardia (Sato & Fukudo, 2015).
Motility disorders in the course of AN may also affect the distal part
of the GI tract and may be responsible for constipation occurring in ap-
proximately 60% of patients with AN (Weterle-Smolińska et al., 2015).
Further lower GI problems in people with AN are a prolonged bowel
transit time, rectal and anal motor weakness, as well as abnormal sensa-
tion of rectal filling (Chiarioni et al., 2000). As remedies to help with
constipation, non-absorbable osmotic laxatives like lactulose and glyc-
erine can help. Lactulose is given orally, whereas glycerine is a rectal os-
motic laxative which is usually applied as suppository. However, people
with EDs are at risk for developing laxative abuse or dependence, and
the laxatives themselves have further medical consequences such as di-
arrhoea, hypokalaemia, metabolic alkalosis, or renal tubular damage
(Müller-Lissner, 1993; Turner, Batik, Palmer, Forbes, & McDermott,
2000).
6.2. Endocrine and metabolic disorders
Genome-wide association studies (GWAS) have demonstrated close
links between EDs and metabolic traits (Himmerich, Bentley, Kan, &
Treasure, 2019; Hübel et al., 2019; Watson et al., 2019) such as a signif-
icant negative genetic correlation of AN with BMI and correlations of AN
with key indicators of glucose and lipid metabolism (Bulik-Sullivan
et al., 2015; Watson et al., 2019). Thus, metabolic features in patients
with EDs may not merely be a consequence of disturbed eating. Instead,
the psychological and behavioural symptoms as well as the metabolic
disturbances may be the result of a common genetic predisposition.
However, this speculation must be handled with caution, because data
from BN and BED GWAS are not yet available to prove this theory.
Up to 50% of those individuals with obesity (BMI ≥ 30 kg/m2) who
attend a weight loss program suffer from BED (Palavras, Kaio, Mari, &
Claudino, 2011) and that almost half of the individuals with BED will de-
velop obesity (Hudson, Hiripi, Pope Jr., & Kessler, 2007). Thus, obesity
frequently follows BED, and individuals with obesity are at high risk of
several further physical diseases, such as certain cancers, diabetes, hy-
pertension, heart disease, stroke, as well as being at increased risk of
mortality (Da Luz, Hay, Touyz, & Sainsbury, 2018; Weschenfelder,
Bentley, & Himmerich, 2018).
As BED and obesity are closely related, using anti-obesity agents to
treat BED would seem like a logical treatment strategy. Orlistat is such
an approved weight loss medication which promotes weight loss by
inhibiting dietary fat absorption. Orlistat has been tested in placebo-
controlled RCTs as an adjunct to a restricted-calorie diet (Golay et al.,
2005) or as an add-on to cognitive behaviour therapy (Grilo, Masheb,
& Salant, 2005). In these studies, the groups receiving orlistat achieved
a significantly greater weight loss than the placebo group. Thus, al-
though orlistat may not be an effective monotherapy for BED, it may
be a useful adjunct for patients who have managed to reduce binge fre-
quency with CBT but have been unable to lose weight. However, if pa-
tients begin to use orlistat as a means of compensating for bingeing,
then the BED diagnosis would evolve into BN (Malhotra & McElroy,
2002).
As already mentioned above, the combination of topiramate and
phentermine led to a significant reduction in binge-eating in people
with BED (Safer et al., 2020). This combination has also been tested in
obesity. Three RCTs tested topiramate and phentermine versus placebo
(Allison et al., 2012; Gadde et al., 2011; Garvey et al., 2014), and one RCT
compared the combination of topiramate and phentermine with the
single substances of topiramate and phentermine alone (Aronne et al.,
2013). These RCTs found that the fixed combination of topiramate and
phentermine leads to significantly more weight loss and improvement
of several metabolic parameters than placebo or the single substances
of topiramate or phentermine alone. Accordingly, this combination be-
came approved by the approved extended-release phentermine plus
topiramate as an addition to a reduced-calorie diet and exercise for
chronic weight management in overweight or obese adults.
In BED or BED plus obesity associated with hypercholesterolaemia,
statins like atorvastatin or simvastatin could also be considered
(Himmerich, Bentley, Lichtblau, et al., 2019).
A recent meta-analysis of cross-sectional studies and recent cohort
studies (Nieto-Martínez, González-Rivas, Medina-Inojosa, & Florez,
2017) showed that both BED and BN might be associated with an in-
creased risk of type 2 diabetes (T2D). Medications to treat T2D include
 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667 9

Table 3
Supplementation of fluids, vitamins, trace elements and electrolytes to treat malnutrition and specific deficiencies resulting from eating disorders. For dosing recommendations see na-
tional and hospital guidelines. Abbreviations in alphabetical order: Anorexia nervosa (AN), binge eating disorder (BED), bulimia nervosa (BN), eating disorders (EDs), gastroesophageal
reflux disease (GERD), haemoglobin (Hb), intravenous (i.v.), For further details and references see text.

Clinical Indication Associated Medication Mechanism of Action Clinical Effect Comments

EDs

Systemic undernutrition with deficiency AN Multivitamins Multivitamin and Treatment of deficiency Generous provision of balanced
of vitamins and minerals and minerals multi-mineral syndromes multi-vitamins and minerals
supplementation recommended as part of acute
treatment and refeeding in AN
Dehydration AN, BN Water and Increase in fluid and Treatment of fluid deficit, i.v. fluid replacement only if oral
electrolytes electrolyte supply improvement of hypotension replacement insufficient
Hyponatremia AN, BN Sodium Sodium replacement Normalisation of sodium levels i.v. only in case of emergency
Hypokalaemia AN, BN Potassium Potassium replacement Normalisation of potassium i.v. only in case of emergency
levels
Magnesium Magnesium replacement Normalisation of potassium Magnesium also indicated in
levels persistent hypomagnesaemia
Hypomagnesaemia AN, BN Magnesium Magnesium replacement Normalisation of magnesium Magnesium also indicated in
levels persistent hypokalaemia
Hypophosphatemia AN Phosphate Phosphate replacement Normalisation of phosphate Low phosphate levels indicate
levels refeeding syndrome; i.v. only in
case of emergency
Hypochloraemia AN, BN Sodium chloride Chloride replacement Normalisation of chloride levels Additional measure: Preventions
of fluid loss through vomiting
Iron deficiency and anaemia AN Iron Increase in iron supply Normalisation of Hb and Haematological changes usually
erythrocyte count disappear with weight
restoration
Vitamin D deficiency and reduced bone AN Calcium and Supplementation of calcium Prevention of osteoporosis Calcium and vitamin D by
mineral density vitamin D and vitamin D themselves do not restore bone
density

oral hypoglycemics, e.g. biguanides such as metformin or, if oral antidi-
abetic treatments fail, rapid-, short- or long-acting insulins and
glucagon-like peptide-1 (GLP-1) analogues like liraglutide which are
also known as incretin mimetics. Liraglutide combined with diet and ex-
ercise counselling was found to be significantly superior to diet and ex-
ercise counselling alone for reducing binge eating symptoms and
obesity in a pilot study (Robert et al., 2015). In a randomized, open-
label, parallel-group trial, the combination of liraglutide with an oral an-
tidiabetic (e.g. metformin) was found to be more efficacious than the
oral antidiabetic alone (Kiyosue, Seino, Nishijima, Bosch-Traberg, &
Kaku, 2018). Liraglutide itself has been found to be effective in weight
loss and lead to improvement of glycemic control in several RCTs and
a recent meta-analysis (Singh & Singh, 2020), and it has been approved
by the FDA and the European Medicines Agency (EMA) for the treat-
ment of obesity. In summary, the meta-analysis of Singh and Singh
(2020) revealed that all five drugs approved by the FDA for the as
anti-obesity drugs, orlistat, phentermine plus topiramate, lorcaserin,
naltrexone plus bupropion and liraglutide lead to significantly greater
body weight reduction in obesity compared to placebo. However, we
did not find any evidence for a clinical effect of orlistat or lorcaserin
on obesity in people with BED.
From a clinical perspective, the combinations of type 1 diabetes
(T1D) with AN and BN are clinical challenges, because this combination
conveys a five times greater mortality rate than anorexia alone (Nielson,
Emborg, & Molbak, 2002). It has been suggested that the increased mor-
tality is driven by minimising insulin replacement in order to produce
weight loss from ketotic states and hyperglycemia, a technique which
also increases the risk of renal disease and retinopathy (Masters,
2014; Takii et al., 2002). This purging strategy is unique to people
with AN & BN and diabetes and needs the special attention of clinicians.
Many patients with AN present with a condition called “low T3 syn-
drome,” which is characterized by low triiodothyronine (T3) and nor-
mal or low thyroxine (T4) levels. At the time of diagnosis, T3 levels
are reduced, but they normalize again with weight gain. The extremely
reduced T3 levels in these patients are due to altered peripheral
deiodination that preferentially transforms T4 into the inactive metabo-
lite, reverse T3. These thyroid alterations normalize with weight resto-
ration without pharmacological intervention (Himmerich et al., 2010;
Kiyohara, Tamai, Takaichi, Nakagawa, & Kumagai, 1989; Leslie, Isaacs,
Gomez, Raggatt, & Bayliss, 1978).
6.3. Cardiovascular diseases
Several cardiovascular abnormalities associated with AN have been
described in the literature, including pericardial and valvular pathology,
changes in left ventricular mass and function, conduction abnormalities,
bradycardia, hypotension, and dysregulation in peripheral vascular con-
tractility (Sachs et al., 2016). Epidemiologic data suggest that BED is not
only associated with obesity and including diabetes, but also hyperten-
sion (Olguin et al., 2017) which warrants treatment with appropriate
lifestyle measures and anti-hypertensive therapy with the goal to re-
duce the excess of cardiovascular mortality and morbidity related to
chronically elevated blood pressure (Cuspidi, Tadic, Grassi, & Mancia,
2018). In general, high blood pressure may be treated with diuretics,
beta-blockers, calcium antagonists, angiotensin converting enzyme
(ACE) inhibitors and angiotensin receptor blockers, either as monother-
apy or in some combinations. However, from a theoretical EDs perspec-
tive, the use of diuretics such as furosemide or bendroflumethiazide
might facilitate the transition to BN, and beta-blockers might influence
the central monoaminergic neurotransmission. Therefore, an ACE inhib-
itor like ramipril or a calcium channel blocker like amlodipine may be
most appropriate.
6.4. Impaired bone health and osteoporosis
Osteoporosis is a major physical health consequence of AN (Misra,
2008). However, there are currently no treatments specifically ap-
proved for the osteoporosis of patients AN available. Weight gain and
resumption of menses are key and associated with significant increases
in spine and hip bone mineral density (Miller et al., 2011). RCTs on the
effect of oestrogen substitution, however, did not have convincing ben-
eficial effects on bone mineral density, e.g. (Strokosch, Friedman, Wu, &
Kamin, 2006). Transdermal oestrogen patches, however, have shown
promising results in adolescents (Misra et al., 2011). Calcium and vita-
min D by themselves do not restore bone density (Mehler &
Mackenzie, 2009). Bisphosphonates such as alendronate have been
10 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
shown to be effective in AN with an increase of 3% to 4% in spine bone
mineral density after 12 months of treatment (Golden et al., 2005).
There is a potential risk of fetal harm if a woman becomes pregnant fol-
lowing bisphosphonate therapy. Thus, bisphosphonates should not be
used in female patients who plan to have a baby (Hotta, 2018).
Recently, teriparatide, a human recombinant parathyroid hormone,
has demonstrated beneficial effects in this population (Fazeli et al.,
2014). However, there is still not enough evidence to recommend
teriparatide treatment in people with AN and decreased bone mineral
density, and it requires daily injections. Testosterone therapy has been
suggested to have some benefits in male patients with AN who also
have low serum testosterone levels (Mehler, Sabel, Watson, &
Andersen, 2008; Westmoreland et al., 2016). However, there is not
enough convincing scientific evidence for such a statement.
6.5. Pain
In EDs, pain can be caused by a plethora of health conditions such as
myopathy and muscle cramps due to low potassium, phosphorus or
magnesium levels, neuropathy due to low vitamin B12 storages or pres-
sure on a peripheral nerve, refeeding syndrome, serotonergic syndrome,
bone pain because of osteoporosis or fracture and migraine
(Birmingham & Treasure, 2019). Therefore, it is important to detect
the reason for the presented pain and treat the patient accordingly. In
clinical practice with people with severe AN, paracetamol is one of the
most often used pain killers. It is indeed the drug of choice in patients
who cannot be treated with non-steroidal anti-inflammatory drugs
(NSAID), such as people with peptic ulcer disease. Even though paracet-
amol is well tolerated drug and produces few side effects from the gas-
trointestinal tract, every year has seen a steadily increasing number of
registered cases of paracetamol-induced liver intoxication all over the
world (Jóźwiak-Bebenista & Nowak, 2015). Liver toxicity is particularly
important in patients with AN, because starvation causes hepatocyte in-
jury (Rosen, Bakshi, Watters, Rosen, & Mehler, 2017).
Acute migraine is often treated with pain relievers such as aspirin or
ibuprofen. However, these have the potential to increase oesophageal
reflux symptoms and even lead to oesophageal ulcers (Xu, Zhu, & Yin,
2016). Preventive medications for migraine include beta blockers such
as propranolol which may worsen the hypotension of patients with
AN or amitriptypine. Amitriptyline could cause problems in patients
with BN treated with fluoxetine due to pharmacokinetic interactions
(Benkert & Hippius, 2019).
6.6. Skin problems
Mild dermatologic symptoms are almost always detectable in patients
with severe AN or BN. Cutaneous manifestations are the expression of the
medical consequences of starvation, vomiting, abuse of drugs like laxa-
tives and diuretics, and of psychiatric morbidity. These manifestations in-
clude xerosis, lanugo-like body hair, telogen effluvium, carotenoderma,
acne, hyperpigmentation, seborrheic dermatitis, acrocyanosis, petechiae,
livedo reticularis, interdigital intertrigo, paronychia, generalised pruritus,
slower wound healing, prurigo pigmentosa, oedema, acral coldness, pel-
lagra, scurvy, and acrodermatitis enteropathica (Glorio et al., 2000;
Strumia, 2005).
The most characteristic cutaneous sign of vomiting in patients with
binge-purge type AN or BN is Russell's sign (knuckle calluses). Even
though skin signs of EDs improve with weight gain, some conditions
may require additional pharmacological treatment (Strumia, 2005).
Xerosis improves with moisturizing ointments. Angular cheilitis, stoma-
titis, and nail fragility appear to respond to topical vitamin E, and
Russell's sign may decrease in size following applications of ointments
that contain urea (Strumia, 2005).
Acne is a risk factor for AN (Lee, Leung, Wing, Chiu, & Chen, 1991),
but it can also appear as a result of self-starvation (Strumia, 2005) or
as a side effect of antidepressants (Benkert & Hippius, 2019). Acne
may be treated with topical benzoyl peroxide, antibacterials or azaleic
acid; these agents may be administered as monotherapy or in combina-
tions. Combination antibacterials, such as erythromycin with zinc, are
also recommended because of the possibility of zinc deficiency in pa-
tients with EDs. The antiandrogen cyproterone acetate combined with
ethinyl estradiol may improve acne in women with AN and should be
given for 2–4 months (Strumia, 2005). Contraindications of this combi-
nation are being on another contraceptive medication, pregnancy,
breast feeding, breast cancer and a history of thrombosis, myocardial in-
farction or stroke, and thrombosis is a serious potential side effect.
Table 4 summarizes the discussed medications for the pharmacological
treatment of important physical health consequences of EDs.
7. Specific aspects of the pharmacological treatment in eating
disorders
7.1. Side effects and pharmacokinetics
For physicians working in EDs, it is important to know about the
pharmacokinetic problems that might appear with drugs such as fluox-
etine and lisdexamfetamine, which are approved for the treatment of
EDs (Himmerich & Treasure, 2018).
Fluoxetine has a long half-life of up to three days. Therefore, it needs
several weeks to reach a steady state. Its active metabolite norfluoxetine
has a half-life of about two weeks. This has to be considered with regard
to potential pharmacokinetic interactions. The main side effects of flu-
oxetine are drowsiness, yawning, fear, nervousness, restlessness, ten-
sion, unusual dreams, dizziness, taste disorders, lethargy, somnolence,
palpitations, tremor, arthralgia, loss of appetite, weight loss, nausea, di-
arrhoea, dry mouth, frequent urination, sweating, itching, rash, urti-
caria, blurred vision and loss of libido. Fluoxetine inhibits cytochrome
P 450 2D6 (CYP2D6) (Benkert & Hippius, 2019; Hiemke et al., 2018).
Severe intoxications because of a combination of amitriptyline with
fluoxetine has been reported because amitriptyline is also metabolized
by CYP2D6 (Benkert & Hippius, 2019). A fluoxetine-free interval of
five weeks is necessary before starting a monoaminoxidase (MAO) in-
hibitor (Benkert & Hippius, 2019).
Fluoxetine itself is metabolized by CYP2D6, CYP2B6, CYP2C19 and
CYP2C9. In depression and obsessive-compulsive disorder, genetic test-
ing of CYP2D6 and CYP2C19 gene variants have been tested to predict
fluoxetine treatment response and the appearance of side effects
(Brandl et al., 2014). As yet this strategy has not been applied to eating
disorders although supra normal doses have been advocated.
Lisdexamfetamine is a prodrug which is metabolized to amphet-
amine in erythrocytes. Amphetamine is metabolized by CYP2D6. The
metabolites norephedrine and 4-hydroxyamphetamine are pharmaco-
logically active. The most frequent side effects of lisdexamfetamine are
decreased appetite, headache, sleep disorders, upper abdominal pain,
weight loss, decreased growth in children and nervousness. In most
countries, a specific narcotic prescription is necessary. Before and during
the prescription of amphetamine, an electrocardiogram (ECG) should
be done. As a psychostimulant this has the potential for abuse and
dependence.
In general, the disturbed metabolism of people with ED and the ex-
tremely low bodyweight of people with AN need to be considered,
when deciding upon the dose. Therapeutic drug monitoring may be of
value; see Hiemke et al. (2018).
7.2. Patients' and carers' perspective
Family member, friends and close others often play an important
role in recognising the early signs of EDs, accessing and implementing
treatment, and helping with the recovery process (Treasure & Nazar,
2016). They can specifically support pharmacological treatment by
prompting the intake of medication, monitoring the appearance of ef-
fects and side effects, and motivate patients for regular therapeutic
Table 4
Pharmacological treatment of the physical health consequences of eating disorders. The listed doses merely provide a rough orientation guide in young and middle-aged adults without metabolization or elimination problems and refer to oral ad-
ministration unless indicated otherwise. Abbreviations in alphabetical order: Angiotensin-converting enzyme (ACE), anorexia nervosa (AN), binge eating disorder (BED), bulimia nervosa (BN), cyclooxygenase (COX), dopamine (D), eating disorders
(EDs), Food and Drug Administration (FDA), gamma-aminobutyric acid (GABA), gastrointestinal (GI), gastroesophageal reflux disease (GERD), glucagon-like peptide-1 (GLP-1), 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA), intravenous
(i.v.), noradrenaline and dopamine reuptake inhibitor (NDRI), μ-opioid receptor (μ), per rectum (p.r.), type 2 diabetes (T2D). For further details and references see text.

Organ system Clinical Associated Medication Mechanism of action Dose Clinical effect Comments
indication ED

GI tract GERD AN Omeprazole; Proton-pump inhibition Omeprazole: Reduction of Proton-pump inhibitors also
Lansoprazole 20–120 mg/d; heartburn used to treat persistent
Lansoprazole: hypokalaemia in EDs
15–30 mg/d
Sodium alginate; Antacids Sodium alginate: Reduction of Cave: Antacids can add to the
Sodium 0.3–1 g/d; Sodium heartburn risk for hypophosphatemia and
bicarbonate; bicarbonate: reduce bone mineral density in
Calcium carbonate 4–20 g/d; people with EDs
Calcium carbonate:
1–4 g/d
Gastroparesis AN Domperidone D2-receptor antagonist, 10–80 mg/d Improves delayed Cisapride, another prokinetic

H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667

prokinetic gastric emptying agent, not recommended
because of critical cardiac
adverse effects
Abdominal AN Mebeverine Not known, may have 135–450 mg/d Antispasmodic, Cave: Can have systemic
Discomfort anaesthetic effects and influence relaxation of gut anticholinergic side effects
calcium channels muscles
Constipation AN Lactulose Oral osmotic laxative 10–30 g/d Softens stool, Risk of laxative abuse or
laxative effect in the dependence, hypokalaemia,
colon metabolic alkalosis, or renal
damage
Glycerol Rectal hyperosmotic laxative 4 g/d p.r. Causes rectal Risk of rectal irritation and
distention, urge to tenesmus
defecate
Endocrine and Obesity BED Bupropion plus NDRI/μ-antagonist Bupropion Weight loss Potential future treatment of
metabolic system naltrexone 90–360 mg/d; BED
naltrexone
8–32 mg/d
Obesity BED Topiramate plus Calcium and sodium channel Topiramate: Weight loss, FDA-approved for weight
phentermine blocker, glutamate and GABA 3.75–15 mg; improvement of management in overweight or
modulator/sympathomimetic phentermine glycaemic control obese adults; potential future
amphetamine-like analogue 23–92 mg and other metabolic treatment of BED
consequences of
obesity
Obesity and T2D BED Liraglutide (plus GLP-1 analogue 0.6–1.8 mg/d Antidiabetic effect, Subcutaneous injections
oral antidiabetic, e.g. (metformin: weight loss
metformin) 0.5–2 g)
T2D BED Rapid-, short- or Activation of glucose 1–300 units/d; Reduction of blood Subcutaneous injections
long-acting insulins transporters specialist sugar levels
responsible for
dosing
High cholesterol BED Atorvastatin; Inhibition of HMG-CoA Atorvastatin: Reduction of Side effects of statins: Headache,
Simvastatin reductase, inhibition of 10–80 mg/d; cholesterol levels muscle ache, abdominal pain
cholesterol synthesis Simvastatin:
10–80 mg/d
Cardiovascular Hypertension BED Ramipril ACE inhibition 1.25–10 mg/d Normalisation of Cave: May cause dizziness or
system blood pressure faintness due to drop of blood
pressure
Amlodipine Blockage of calcium channels 5–10 mg/d Normalisation of Cave: Can cause pedal oedema
blood pressure secondary to arteriolar dilatation

(continued on next page)

11
12 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667

appointments. However, quite often carers have a different perspective

If necessary; most skin signs of

reason for pain is known, treat

EDs improve with weight gain

2–4 months; serious potential

on the treatment goals, the usefulness and the side effects of pharmaco-

have children or are pregnant

female patients who wish to
Should not be prescribed for

important in AN; if specific

Severe cases, females only;

Scientific evidence in AN is
logical therapy.

paracetamol particularly

side effect: thrombosis

In a recent survey in 36 patients and 37 carers, most patients with

Cave: Liver toxicity of

treatment duration:
AN did not believe that medication could help with AN, but they stated
that medication for AN should help with anxiety, concentration, sleep
problems and anorexic thoughts; and the patients had concerns about

accordingly
Comments

potential weight gain, increased appetite, changes in body shape and

scarce

metabolism during psychopharmacological treatment. In contrast,

most carers had less concerns about some of these side effects which
may be overemphasised because of AN. However, their desire for help
with anxiety and anorexic thoughts, which is shared by their carers,
oxidative stress and

Rehydration of the
should be taken seriously by clinicians when choosing a medication or
Inhibition of bone

Increase in bone

processes (acne,
skin, keratolytic
Protection from
mineral density

planning psychopharmacological studies (Dessain, Bentley, Treasure,

excessive hair
UVB radiation
Clinical effect

Treatment of
androgen--
Schmidt, & Himmerich, 2019).

dependent
resorption

Pain relief

growth)
7.3. Shared decision making

Clinicians, patients and their carers should make treatment decisions

together in a shared decision making (SDM) process. Regarding drug
Application of urea
over affected area

treatment in EDs, such decisions may include the psychopharmacologi-

affected area 1–3

acetate: 2 mg/d;
vitamin E cream

ethinylestradiol
ointment over

cal treatment for the ED itself, or medications for potential co-morbid

Application of

Cyproterone
1–3 times/d

0.035 mg/d

psychiatric disorders or the mental or physical health consequences of

0.5–4 g/d
20 μg/d

times/d
5 mg/d

the ED, and PRN medication given in conjunction with acute intensive
Dose

care. Decisions regarding drug treatment in EDs should be specific in

terms of the active pharmacological substance, its dose, its route of ad-
ministration, and the duration of treatment; and they should take alter-
native measures, additional therapies, and specific combinations of
Blockage of androgen receptors,
hydrogen bonds between water
Protein denaturant, modulates
Bisphosphonate; inhibition of

Inhibition of COX in the brain

therapies into account (Himmerich, Bentley, Lichtblau, et al., 2019).

The differences in the expectations of patients, carers, and clinicians to-
Recombinant parathyroid

stimulation of oestrogen
Free-radical scavenger

wards drug treatment (Dessain et al., 2019), the lack of specific sugges-
Mechanism of action

tions for drug treatment in EDs in clinical practice guidelines, and the
osteoclast activity

lack of approved psychopharmacological treatment options make

SDM necessary, but also a challenge (Himmerich, Bentley, Lichtblau,
molecules

receptors
hormone

et al., 2019).

8. Discussion and future perspectives

8.1. Summary
plus ethinylestradiol
Cyproterone acetate
Topical vitamin E

Urea ointment

Taken together, the only worldwide approved medication for EDs is

Paracetamol
Teriparatide
Risedronate
Medication

fluoxetine for BN. In the United States of America (USA), the FDA has
also approved lisdexamfetamine for BED. There is no approved medica-
tion for people with AN, ARFID, pica or rumination disorder. However,
there is preliminary evidence for the benefit of olanzapine, other atypi-
cal antipsychotics and the cannabinoid receptor agonist dronabinol in
AN, BN, BED

people with AN (Attia et al., 2019; Frank et al., 2017; Andries et al.,
Associated

2019). In BN and BED, there is also evidence for the effectiveness of

AN, BN

topiramate (Himmerich & Treasure, 2018; McElroy et al., 2019). Phar-

AN

AN

AN
ED

macodynamic and pharmacokinetic considerations must be considered

when combining these medications.
associated with EDs

8.2. Limitations
health conditions

Angular cheilitis;
Pain caused by

Russell's sign;
Osteoporosis

Nail fragility

Patients might suffer from complicating mental or physical disorders

Stomatitis;
indication

such as mood disorders, anxiety disorders, obsessive-compulsive disor-

Clinical

Xerosis

Acne

ders, developmental disorders like autistic spectrum and attention-

deficit hyperactivity disorder, personality disorders, substance abuse
(Marucci et al., 2018), epilepsy (Kolstad et al., 2017) or type 1 diabetes
(Zaremba et al., 2019) which are all prevalent in EDs and play a signifi-
cant role for treatment decisions. However, due to space limitations we
Table 4 (continued)

were not able to cover all the potential co-morbidities or combinations

Organ system

of possible co-morbidities in one article. Due to the lack of specific stud-

ies of the pharmacological treatment of health consequences of EDs, we
Bones

Pain

Skin

were not able to perform a systematic review or a meta-analysis. We did

not cover the area of NG tube feeding and restraint, even though this
 H. Himmerich et al. / Pharmacology & Therapeutics 217 (2021) 107667
does also play a significant role in clinical practice when treating se-
verely ill patients with EDs.
8.3. Future perspectives
Given the amount of novel genetic, immunological, microbiome,
neuroimaging and neurocognitive research (Himmerich, Bentley, Kan,
& Treasure, 2019; Seitz et al., 2019; Steinglass, Berner, & Attia, 2019),
one can assume that further insights into the pathophysiology of EDs
will lead to pharmacological innovations to help these patients. For ex-
ample, pro-inflammatory cytokines such as tumor necrosis factor
(TNF)-α have been found to be over-expressed in patients with AN
and hypothesized to contribute to the etiology of this ED (Dalton
et al., 2019; Dalton et al., 2020; Dalton, Bartholdy, et al., 2018; Dalton,
Campbell, et al., 2018). Meanwhile, TNF-α blockers are available, and
meta-analytic research has demonstrated that these drugs increase
weight (Patsalos, Dalton, Leppanen, Ibrahim, & Himmerich, 2020).
Treatment with TNF-α blockers may therefore be a future
pharmacotherapeutic approach in AN.
It is notable that much of the qualitative feedback about treatment
from patients and carers relates to the need to consider treatment of
the psychological symptoms of EDs and not merely the normalisation
of body weight. Indeed, as highlighted in this review (Dessain et al.,
2019), this aspect of care has been somewhat neglected. Often it is as-
sumed that these symptoms are merely secondary to the illness. How-
ever, many precede the illness or take on a life of their own in the
severe enduring phase of the illness.
Given the limited evidence-based treatment available for patients
with EDs, novel therapeutic approaches are urgently needed. A range
of different medications has been or is currently being trialled. For ex-
ample, there is currently a pilot study on the effects of ketamine on
mood and ED cognitions in people with enduring severe AN which is
registered on the Australia New Zealand Clinical Trial Registry
(ANZCTR, 2019). Ketamine has been demonstrated rapid antidepres-
sant effects and reduction of suicidal ideation in patients with
treatment-resistant depression (Murrough et al., 2013; Murrough
et al., 2015; Price et al., 2014; Wan et al., 2015). It has also resulted in
greater reductions in obsessive thoughts and compulsions in people
with obsessive-compulsive disorder compared to placebo (Rodriguez
et al., 2013). Given the common comorbidities of depression and
obsessive-compulsive disorder in people with EDs, there may be room
to consider in incorporating psychedelics as an augmentation treatment
in the future. Thus, scientists from the Johns Hopkins Psychedelic Re-
search Unit are currently exploring the effects of psilocybin, a psychoac-
tive substance found in certain species of mushrooms, in people with
chronic AN (Johns Hopkins University, 2019).
With regard to monoaminergic substances, two randomized con-
trolled trials have been conducted with dasotraline, a novel dopamine
and norepinephrine reuptake inhibitor, in people with binge EDs
(Citrome et al., 2019; Navia et al., 2018). Both demonstrated highly sig-
nificant and clinically meaningful reductions with dasotraline compared
to placebo in the frequency of binge eating. The FDA is currently consid-
ering whether to approve dasotraline for the treatment of patients with
moderate-to-severe BED.
Another important current and future area of research is the combi-
nation of pharmacological and psychological treatment, specifically the
amplification of psychotherapy by pharmacological interventions such
as the application of D-cycloserine to boost the effects of exposure ther-
apy (Levinson et al., 2015) and the use of oxytocin as an adjunct to psy-
chotherapy which might strengthen the psychotherapeutic relationship
(Patin, Scheele, & Hurlemann, 2018). Despite some first steps in this di-
rection, this is a largely unexplored area.
A closer look at the physical health consequences might help de-
velop new pharmacological strategies. With regard to obesity, for exam-
ple, the combination of naltrexone and bupropion is approved for
weight loss. In a pilot study by McElroy and colleagues in women with
13
major depressive disorder who were also obese or overweight received
treatment with the combination of naltrexone and bupropion plus die-
tary and behavioural counselling. The treatment was associated with re-
ductions in binge eating symptoms, weight, food craving and appetite,
and depressive symptoms. Thus, this combination could also be benefi-
cial in obese people with BED (McElroy et al., 2013). As already men-
tioned, the injectable GLP-1 receptor agonist liraglutide has also been
found to reduce binge eating symptoms and obesity (Robert et al.,
2015).
We have mentioned the progress pharmacogenetic testing has made
for the prediction of treatment response and side effects in people with
depression (Brandl et al., 2014). In people with bipolar disorder, pharma-
cogenetic testing has been demonstrated to reduce costs, the necessity of
emergency treatment and hospitalization (Callegari, Isella, Caselli, Poloni,
& Ielmini, 2019). However, even though pharmacogenomics and thera-
peutic drug monitoring are among the most promising approaches for
applying individualized medicine to psychiatry (Müller, Kennedy, &
Himmerich, 2013), there is a lack of pharmacogenomics studies in EDs.
However, such information could make prescribing of pharmacological
agents in patients EDs more targeted, more individualized and eventually
safer.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgment
Janet Treasure and Hubertus Himmerich receive salary support from
the NIHR Mental Health Biomedical Research Centre at South London
and Maudsley NHS Foundation Trust and KCL. The views expressed
are those of the authors and not those of the NHS, the NIHR or the De-
partment of Health.
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