The Role of Psychotropic Medications in The Management

CNS Drugs
DOI 10.1007/s40263-016-0335-6
REVIEW ARTICLE
The Role of Psychotropic Medications in the Management

of Anorexia Nervosa: Rationale, Evidence and Future Prospects
Guido K. W. Frank1,2 • Megan E. Shott1
Ó Springer International Publishing Switzerland 2016
Abstract Anorexia nervosa (AN) is a severe psychiatric

disorder without approved medication intervention. Every Key Points
class of psychoactive medication has been tried to improve
treatment outcome; however, randomized controlled trials Anorexia nervosa (AN) is a severe psychiatric illness
have been ambiguous at best and across studies have not with a complex interplay of bio-psycho-social
shown robust improvements in weight gain and recovery. factors.
Here we review the available literature on pharmacological A multitude of psychoactive drugs have been tried in
interventions since AN came to greater public recognition AN but without robust effects.
in the 1960s, including a critical review of why those trials
Neuroscience-based models of behavior will help in
may not have been successful. We further provide a neu-
the development of effective psychopharmacological
robiological background for the disorder and discuss how
treatments for AN.
cognition, learning, and emotion-regulating circuits could
become treatment targets in the future. Making every effort
to develop effective pharmacological treatment options for
AN is imperative as it continues to be a complex psychi-
atric disorder with high disease burden and mortality. 1 Introduction
Anorexia nervosa (AN) is a severe mental illness with the

highest mortality rate among the psychiatric disorders [1].
AN usually begins during adolescence and occurs most
commonly in females [2]. It is the third most common
chronic illness among adolescent females [3], with a
mortality rate 12-fold higher than the expected death rate
for 15- to 24-year-old females [4]. According to the Di-
agnostic and Statistical Manual for Mental Disorders 5th
edition (DSM-5) [2], the diagnostic criteria for AN include
restriction of energy intake relative to requirements leading
& Guido K. W. Frank
[email protected] to a significantly low body weight in the context of age,
sex, developmental trajectory, and physical health; an
1
Departments of Psychiatry and Neuroscience, and intense fear of gaining weight or becoming fat, even
Developmental Brain Research Program, University of
though underweight; a disturbance in the way in which
Colorado Anschutz Medical Campus, Children’s Hospital
Colorado, Gary Pavilion A036/B-130, 13123 East 16th one’s body weight or shape is experienced and undue
Avenue, Aurora, CO 80045, USA influence of body weight or shape on self-evaluation; or
2
School of Medicine, University of Colorado Denver, denial of the seriousness of the current low body weight.
Anschutz Medical Campus, Aurora, CO, USA Previous editions of the DSM indicated the requirement for
G. K. W. Frank, M. E. Shott
body weight to be below 85 % of that expected and the loss studies are presented in historical chronological order.
of regular menses. In the latest edition (DSM-5), the weight Placebo-controlled and open-label studies are described in
criterion is now less strict, and the latter was dropped Table 1.
altogether. A restricting type (AN-R), marked by food
restriction and commonly overexercising, has been distin- 2.1 Cyproheptadine
guished from a binge-eating/purging type (AN-B/P), where
afflicted individuals eat large amounts of food in a rela- Cyproheptadine is a first-generation antihistamine with
tively short period of time (‘binge eating’) yet remain anticholinergic and antiserotonergic properties. In 1962, it
underweight or engage in behaviors to counteract weight was reported that cyproheptadine could stimulate appetite
gain, such as self-induced vomiting or use of laxatives or and weight gain in children [13], thereby making its use in
diuretics (‘purging’). AN is a chronic disorder character- AN appealing. The first double-blind, controlled study
ized by frequent relapse, high treatment cost and disease published in 1970 suggested weight gain in AN from the
burden. However, we know little about its underlying medication compared with placebo [14]. In 1979, a study
neurobiology, and developing pharmacological treatments using this drug with and without behavior therapy found
for AN has been difficult [5]. Depression and anxiety are that it was helpful for weight gain in patients with AN who
common in AN [6] and are related to eating disorder had a history of complications during delivery, had lost
severity and clinical outcome, which may have implica- between 40 and 50 % weight from expected body weight,
tions for the effectiveness of treatment interventions [7, 8]. or had previous outpatient treatment failure [15]. A follow-
In general, treatment effectiveness for AN is limited [9] up report from the same group indicated that the medica-
and, in particular, no medication has been approved for this tion could reduce negative attitudes toward body weight
disorder [10]. On the other hand, a large proportion of and shape [16]. However, a later double-blind, controlled
individuals with AN are treated with psychotropic medi- study found that cyproheptadine had a ‘marginal effect’ on
cations [11], which raises the question of what place decreasing the number of days necessary to achieve normal
medication interventions may have in its treatment. weight compared with placebo [17]. Interestingly, cypro-
We will review the medication trials that have been heptadine increased treatment efficiency for the restricting
conducted in AN over the past 50 years. The purpose of type of AN but not for the binge/purge subtype in that
this review is to determine whether there is a justified place study.
for psychotropic medications in the management of AN.
We will use a neuroscience-informed approach to discuss 2.2 Tricyclic Antidepressants and Monoamine
how we may be able to improve medication use in AN, and Oxidase Inhibitors
will use basic and clinical brain research to support pos-
sible new psychopharmacological directions. Tricyclic antidepressants, first developed in the 1950s,
were used for anxiety and obsessive-compulsive disorder
aside from depressive disorders, but the side effect profile,
2 Medication Studies in Anorexia Nervosa (AN) including sedation and cardiac arrhythmia, makes these
medications less well tolerated. These medications are only
Our original goal was to review the use of psychotropic rarely used now since selective serotonin reuptake inhibi-
medications in AN using the Preferred Reporting Items for tors (SSRIs) have become available.
Systematic Reviews and Meta-Analyses (PRISMA) A rationale for the use of these medications was based
guidelines [12]. However, there are too few trials in each on the hypothesis that AN is a form of depression as it is
medication category to discuss separately. We will discuss associated with dysphoric mood and anxiety. A 5-week,
case series as well as open and controlled trials to provide double-blind, controlled study using amitriptyline did not
an exhaustive summary of current literature relevant to support benefits of this treatment for AN [18]. A double-
medication use in the treatment of AN. We searched the blind, controlled study that administered clomipramine
National Center for Biotechnology Information database found that the drug stimulated hunger, appetite, and energy
using the search terms anorexia, nervosa, drug, treatments intake; however, the medication was paradoxically also
(1160 hits), as well as anorexia, nervosa, medication (237 associated with lower weight gain compared with placebo,
hits). The relevant articles for this review consisted of 25 perhaps due to more physical activity [19]. Clomipramine
double-blind, placebo-controlled studies; seven double- has direct hypothalamic effects and it has been suggested
blind, placebo-controlled, crossover studies; five single- that this could be the mechanism of action of this medi-
blind, placebo-controlled studies; 23 open-label studies; cation in terms of its appetite-stimulating effects. In
and six retrospective chart reviews. Single case reports another report, the medication was associated with higher
were excluded due to their lack of generalizability. The appetite and calorie consumption at the beginning of
Table 1 Placebo-controlled and open-label studies in anorexia nervosa in historical chronological order
Study, year Study type Treatment conditions Daily medication dose Length of N Mean Anorexia Results
treatment age ± SD type
(years)
Cyproheptadine
Goldberg et al., Double-blind, 1. Cyproheptadine and Cyproheptadine start NA 81 NA NA Promoted weight gain in a subgroup
1979 [15] placebo- behavior therapy 12 mg; max. 32 mg that had a history of birth
controlled 2. Cyproheptadine and no complications, had lost 41–52 %
behavior therapy weight from normal, or who had a
history of prior outpatient treatment
3. Placebo and behavior
failure
therapy
4. Placebo and no behavior
therapy
Halmi et al., Double-blind, 1. Cyproheptadine Max. 32 mg Until within 5 % 72 21 ± 5 Restricting/ Cyproheptadine had a ‘‘marginal
1986 [17] placebo- 2. Amitriptyline Max. 160 mg of target weight binge- effect on decreasing the number of
controlled purge days necessary to achieve a normal
3. Placebo
weight’’ compared with placebo or
amitriptyline; cyproheptadine
showed some beneficial effect for
restricting-type AN but worsened
Psychotropic Medications in the Management of Anorexia Nervosa
outcome for the binge/purge-type

anorexia subgroup
Tricyclic antidepressants/monoamine oxidase inhibitors
Lacey and Double-blind, 1. Clomipramine 50 mg 76 days 8 21 Restricting/ Clomipramine was associated with
Crisp, 1980 placebo- clomipramine binge- increased hunger, appetite and
[19] controlled 2. Placebo 72 days placebo 8 purge energy intake but reduced weight
gain
Biederman Double-blind, 1. Amitriptyline Amitriptyline 5 weeks 11 18 ± 5 NA All three groups showed little
et al., 1985 placebo- 2. Placebo 2.8 ± 0.3 mg/kg 14 17 ± 4 improvement; no differences
[18] controlled favoring amitriptyline were found in
3. No Intervention 18 16 ± 2
any outcome variables
Kennedy et al., Open-label 1. Isocarboxazid Mean 34 mg 6 weeks 6 24.5 Restricting No weight change during the study;
1985 [23] however, AN patients gained weight
in the 6 months following the study;
mood and anxiety ratings improved
by week 4
Ruggiero et al., Open-label 1. Clomipramine Mean 57.7 ± 25.8 mg 3 months 10 23.7 ± 4.6 Restricting Patients taking amisulpride gained
2001 [21] 2. Fluoxetine Mean 26.0 ± 10.3 mg 13 4.5 ± 5.1 significantly more weight than
patients taking fluoxetine
3. Amisulpride Mean 50.0 ± 0.0 mg 12 24.3 ± 5.8
Table 1 continued
(years)
Strobel et al., Retrospective 1. Paroxetine ? intensive Mean 18.4 ± 4.7 mg 39 ± 26 days 39 No mean Restricting/ Paroxetine and clomipramine had the
2004 [22] psychotherapy paroxetine given, binge- same BMI increase, but in
range purge significantly less time for
2. Clomipramine ? Mean 75.3 ± 16.6 mg 58 ± 30 days 57 10.9–18.1 All with an paroxetine—72 days for paroxetine
intensive psychotherapy clomipramine additional versus 97 days for clomipramine
depressive
episode
Typical antipsychotic medications
Vandereycken Double-blind, 1. Pimozide Range 4–6 mg 6 weeks 18 NA NA Pimozide did not significantly
and Pierloot, placebo- 2. Placebo improve weight gain
1982 [25] controlled,
crossover
Vandereycken, Double-blind, 1. Sulpiride—placebo 300 or 400 mg 2–3 weeks 9 23.2 ± 6.5 Restricting/ Sulpiride initially promoted weight
1984 [64] placebo- sequence binge- gain over placebo but this was not
controlled, 2. Placebo—sulpiride 9 23.7 ± 9.6 purge sustained throughout the study
crossover sequence
Weizman et al., Open-label 1. Pimozide 3 mg 20 weeks 5 15.8 ± 0.8 NA Pimozide did not aid in weight gain
1985 [26] 2. Behavior therapy 5 16.2 ± 1.3
program
Cassano et al., Open-label 1. Haloperidol Months 1 to 3, mean 6 months 13 22.8 ± 4.2 Restricting A significant increase in BMI was
2003 [27] 1.2 ± 0.4 mg; reported in a chronic and treatment
months 4 to 6, refractory group
mean 1.1 ± 0.1 mg
Mood stabilizers
Gross et al., Double-blind, 1. Lithium carbonate ? Start 300 mg, with 4 weeks 8 20.6 ± 1.8 NA Lithium was associated with greater
1981 [29] placebo- behavior modification 300 mg increases until weight gain at weeks 3 and 4 only
controlled, therapy mean plasma lithium
crossover 2. Placebo ? behavior level was 1.0 ± 0.1 8 18.8 ± 2.6
modification therapy
Zinc
Safai-Kutti, Open-label 1. Zinc Range 45–90 mg Range 8–56 20 Range NA 17 patients increased their weight by
1990 [33] months 14–26 over 15 % and no patient lost
weight
Lask et al., Double-blind, 1. Zinc 50 mg 6 weeks 26 Children NA Zinc deficiency is common in AN,
1993 [35] placebo- 2. Placebo levels normalize after introducing
controlled, normal diet without
crossover supplementation, and zinc levels are
not related to weight gain
Table 1 continued
(years)
Birmingham Double-blind, 1. Zinc 100 mg 24.6 ± 10.0 days 16 20.6 ± 3.8 NA The rate of increase in BMI of the
et al., 1994 placebo- 2. Placebo 31.5 ± 18.5 days 19 23.8 ± 6.1 zinc supplemented group was twice
[34] controlled that of the placebo group; this
difference was statistically
significant (p \ 0.03)
Opiates and cannabinoids
Moore et al., Open-label 1. Naloxone Range 3.2–6.4 mg 5 weeks (range 12 22.5 NA Naloxone infusion was associated
1981 [38] 1–11 weeks) with significantly greater weight
gain compared with the periods
before and after
Gross et al., Double-blind, 1. 9-tetrahydrocannabinol Range 7.5–30 mg 4 weeks 11 24 ± 2 NA No significant differences in weight
1983 [40] placebo- 2. Active placebo, Range 1–15 mg or daily calorie intake were noted
controlled, diazepam between 9-tetrahydrocannbinol and
crossover placebo
Marrazzi et al., Double-blind, 1. Naltrexone 100 mg 12 weeks 19 27.3 ± 6.7 AN binge- Reduction in binge-purge behaviors
1995 [39] placebo- 2. Placebo purge type but no effect on weight reported
controlled, or bulimia
crossover nervosa
Andries et al., Double-blind, 1. Dronabinol – placebo 5 mg 4 weeks 24 33.3 Restricting/ During dronabinol treatment,
2014 [41] placebo- dronabinol, binge- participants gained a small amount
controlled, 4 weeks purge (0.73 kg) compared with placebo;
crossover washout, no significant adverse events were
4 weeks reported
placebo
2. Placebo – dronabinol 4 weeks placebo,
4 weeks
washout,
4 weeks
dronabinol
Benzodiazepines and a2-adrenergic agonists
Casper et al., Double-blind, 1. Clonidine Range 500–700 lg 4 weeks on 4 Range Restricting/ Clonidine did not influence the rate of
1987 [44] placebo- 2. Placebo placebo, 19–28 binge- weight gain, or hunger or satiety
controlled, alternating with purge sensations
crossover 4 weeks on
clonidine
Steinglass Double-blind, 1. Alprazolam 0.75 mg 2 test meals, 20 25.6 ± 7.8 Restricting/ Alprazolam was not superior to
et al., 2014 placebo- 2. Placebo 1 week apart binge- placebo
[42] controlled, purge
crossover
Table 1 continued
(years)
Selective serotonin reuptake inhibitors (SSRIs)

Gwirtsman Open-label 1. Fluoxetine Mean 43 ± 15 mg; Range 6 27 ± 9 Restricting Fluoxetine was associated with
et al., 1990 range 20–60 mg 2–5 months reduced depressive symptoms and
[45] weight gain
Kaye et al., Open-label 1. Fluoxetine after weight Mean 38 ± 18 mg Mean 31 20 ± 7 Restricting/ 29 patients had maintained weight at
1991 [46] restoration 11 ± 6 months binge- or above 85 % average body weight
purge
Strober et al., Retrospective 1. Fluoxetine ? eating Mean 33.9 ± 18 mg Follow-up at 33 17.6 NA Fluoxetine showed no benefit for
1997 [53] disorder treatment 6-month weight gain or prevention of relapse
program intervals after
2. Controls ? eating inpatient 33
disorder treatment treatment for
program 24 months
Pallanti et al., Open-label 1. Citalopram Start 20 mg 6 months 32 Restricting Citalopram may have aided in weight
1997 [59] improvement but this was uncertain
without a control group
Attia et al., Double-blind, 1. Fluoxetine Mean 56 mg 7 weeks 15 Range Restricting/ Fluoxetine showed no benefit over
1998 [49] placebo- 2. Placebo Mean 58.7 mg 16 16–45 binge- placebo
controlled purge
Calandra et al., Open-label 1. Citalopram 20 mg 8 weeks 6 20.5 ± 4.7 Restricting/ Citalopram was associated with
1999 [57] binge- reduced body dissatisfaction, but no
purge weight change reported
Ferguson et al., Retrospective 1. Clomipramine Range 25–75 mg Naturalistic 3 Mean Restricting/ SSRI treatment did not improve
1999 [62] 2. Fluvoxamine 100 mg follow-up 1 23 ± 10 binge- treatment outcome
(SSRI); purge
3. Paroxetine Range 10–40 mg 4
mean
4. Fluoxetine Range 10–40 mg 10 21 ± 8
5. Sertraline Range 25–150 mg 6 (non-
SSRI)
Ricca et al., Open-label 1. Venlafaxine ? cognitive 75 mg 6 months 12 18.9 ± 3.8 Atypical AN Venlafaxine and fluoxetine showed no
1999 [55] behavior therapy differences in weight change or
2. Fluoxetine ? cognitive 40 mg 12 19.1 ± 3.6 behavior outcomes
behavior therapy
Kaye et al., Double-blind, 1. Fluoxetine after weight Start range 20–60 mg 52 weeks 16 23 ± 9 Restricting/ Patients receiving fluoxetine had
2001 [51] placebo- restoration binge- reduced relapse and higher weight
controlled 2. Placebo after weight 19 22 ± 6 purge gain
restoration
Table 1 continued
(years)
Santonastaso Open-label 1. Sertraline Range 50–100 mg 64 weeks 11 19 ± 3 Restricting Sertraline was not superior to placebo
et al., 2001 2. Control group 20 ± 6 in weight recovery; however it was
[60] associated with greater
improvement of depressive
symptoms, self-perceived
ineffectiveness, lack of
interoceptive awareness, and
perfectionism
Fassino et al., Open-label 1. Citalopram 20 mg 12 weeks 19 24.3 ± 5.4 Restricting Citalopram did not improve weight
2002 [58] 2. Waitlist control group 20 25.2 ± 8.6 gain over the control group but was
associated with reduced depression
scores
Barbarich Double-blind, 1. Nutritional supplement Nutritional supplement 6 months 15 23.0 ± 6.3 Restricting/ Fluoxetine plus supplement showed
et al., 2004 placebo- ? fluoxetine (2.3 g of tryptophan; binge- no benefit over placebo
[56] controlled 600 mg purge
docosahexaenoic acid;
180 mg arachadonic
acid); 20–60 mg
(fluoxetine)
2. Fluoxetine Range 20–60 mg 11
(fluoxetine)
Ruggiero et al., Single-blind, 1. Nutritional management Mean 30 ± 9.4 mg 1 year 21 23.4 ± 4.0 Restricting/ Fluoxetine was not superior to support
2003 [52] placebo- ? fluoxetine binge- weight gain
controlled 2. Nutritional management 74 purge
Holtkamp Retrospective 1. Fluoxetine 35 mg 6-month follow- 7 14.5 ± 1.4 Restricting/ SSRI treatment did not improve
et al., 2004 2. Fluvoxamine 20 mg up 8 binge- treatment outcome
[61] purge
3. Sertraline 100 mg 4
Walsh et al., Double-blind, 1. Fluoxetine Mean 63.5 ± 15.8 mg 52 weeks 49 22.4 ± 4.5 Restricting/ Fluoxetine showed no benefit over
2006 [54] placebo- 2. Placebo Mean 71.4 ± 15.2 mg 44 24.2 ± 4.5 binge- placebo
controlled purge
Yu et al., 2011 Naturalistic 1. Fluoxetine Max 60 mg 1 year 14 25.6 ± 6.4 Restricting/ Fluoxetine was not superior to support
[48] follow-up 2. Cognitive behavior 17 binge- weight gain
therapy purge
3. Fluoxetine ? cognitive 22
behavior therapy
Table 1 continued
(years)
Atypical antipsychotic medications

Powers et al., Open-label 1. Olanzapine 10 mg 10 weeks 14 26.8 ± 12.3 Restricting/ Of the 14 patients who completed the
2002 [65] binge- study, 10 gained an average of
purge 8.75 lb, 3 of whom attained their
ideal body weight. The remaining 4
patients who completed the study
lost a mean of 2.25 lb
Malina et al., Retrospective 1. Olanzapine Mean 4.7 ± 2.4 mg Mean 18 22 ± 7 NA Subjects reported a significant
2003 [67] 17 ± 20 weeks reduction in anxiety and difficulty
eating
Barbarich Open-label 1. Olanzapine Mean 4.7 ± 1.6 mg 6 weeks 17 20.5 ± 5.1 Restricting/ Olanzapine was associated with
et al., 2004 binge- weight increase and decrease in
[66] purge anxiety and depression
Mondraty et al., Double-blind, 1. Olanzapine 10 mg Mean 8 25.3 ± 7.4 NA No significant difference in weight
2005 [68] placebo- 46 ± 31 days gain was noted between groups
controlled 2. Chlorpromazine 50 mg Mean 7 25.3 ± 7.3
53 ± 26 days
Brambilla Double-blind, 1. Olanzapine ? cognitive 2.5 mg for 1 month; 3 months 10 23 ± 4.8 NA Olanzapine was not superior to
et al., 2007 placebo- behavior therapy ? 5 mg for 2 months placebo to support weight gain
[75] controlled nutritional rehabilitation
2. Placebo ? cognitive 10
behavior therapy ?
nutritional rehabilitation
Brambilla Double-blind, 1. Olanzapine ? cognitive 2.5 mg for 1 month; 3 months 15 23.7 ± 4.8 Restricting/ No difference for weight gain
et al., 2007 placebo- behavior therapy 5 mg for 2 months binge- between groups but olanzapine was
[69] controlled 2. Placebo ? cognitive 15 26.3 ± 8.5 purge associated with greater
behavior therapy improvement of eating disorder
inventory ineffectiveness and
maturity fear scores
Bosanac et al., Open-label 1. Quetiapine Range 50–800 mg 8 weeks 8 33.3 ± 7.7 Restricting/ Quetiapine was not associated with
2007 [77] binge- significant weight gain
purge
Powers et al., Open-label 1. Quetiapine Range 150–300 mg 10 weeks 19 26.8 ± 11.2 Restricting/ Patients gained 1.6 lbs over the study
2007 [78] binge- duration
purge
Bissada et al., Double-blind, 1. Olanzapine Start 2.5 mg; max. 10 weeks 16 23.6 ± 6.5 Restricting/ Olanzapine was associated with
2008 [70] placebo- 2. Placebo 10 mg—flexible dose 18 29.7 ± 11.6 binge- greater weight increase and faster
controlled regimen purge achievement of weight goals
Leggero et al., Open-label 1. Olanzapine ? 4.1 ± 2.9 mg 6 months 13 13.7 ± 2.3 Restricting Patients gained weight but the effect
2010 [71] psychotherapy of olanzapine was not certain
Table 1 continued
(years)
Court et al., Open-label 1. Quetiapine Start 50 mg; max. 12 weeks 10 23.8 ± 9.4 Restricting/ No significant difference in outcome
2010 [80] 2. Treatment as usual 400 mg 11 21.0 ± 3.3 binge- measures between the quetiapine
purge and control groups
Attia et al., Double-blind, 1. Olanzapine Start 2.5 mg; last 8 weeks 11 27.7 ± 9.1 NA Olanzapine was associated with a
2011 [72] placebo- 2. Placebo 4 weeks 10 mg 12 small but significant increase in
controlled BMI over placebo
Kafantaris Double-blind, 1. Olanzapine ? Start 2.5 mg; week 4 10 weeks 10 16.4 ± 2.2 Restricting Olanzapine was not superior to
et al., 2011 placebo- psychotherapy target 10 mg placebo to support weight gain
[73] controlled 2. 10 18.1 ± 2.0
Placebo ? psychotherapy
Norris et al., Retrospective 1. Olanzapine Median 5 mg 1038 ± 585 days 43 14.4 ± 1.9 Restricting/ No firm conclusions could be drawn
2011 [74] 2. Comparison group were 540 ± 441 days 43 14.8 ± 1.6 binge- due to methodological problems of
patients matched for age, purge the study
diagnosis and level of
care
Hagman et al., Double-blind, 1. Risperidone Mean 2.5 ± 1.2 mg 17 weeks 18 16.2 ± 2.5 NA No significant difference in weight
2011 [83] placebo- 2. Placebo Mean 3.0 ± 1.0 mg 22 15.8 ± 2.3 gain between groups; the
controlled risperidone group showed greater
reduction in drive for thinness over
the first half of the study but this
was not sustained
Powers et al., Double-blind, 1. Quetiapine Mean 177.7 ± 90.8 mg 8 weeks 4 34 ± 14.5 Restricting/ No difference in any outcome
2012 [79] placebo- 2. Placebo 6 binge- measure between quetiapine and
controlled purge placebo
Other
Hotta et al., Open-label 1. Ghrelin 3 lg/kg body weight for 26-day 5 26 ± 8 Restricting Daily energy intake during ghrelin
2009 [92] 5 min 29/day before hospitalization infusion increased by 12–36 %
lunch and dinner compared with the pretreatment
period
Lechin et al., Open-label 1. Amantadine 100 mg 3 months 22 22 ± 6.4 Restricting/ Amantadine reduced AN symptoms
2011 [90] binge- when given 45 min prior to meal;
purge all subjects showed significant and
sustained BMI increases
Bloch et al., Double-blind, 1. DHEA 100 mg 6 months 13 26.9 ± 8.2 NA BMI increase in the DHEA group was
2012 [91] placebo- 2. Placebo 8 significantly higher than the placebo
controlled group at 4 months
Levinson et al., Double-blind, 1. D-cycloserine 250 mg 1 h before 4 exposure 20 25.4 Restricting/ D-Cycloserine group showed a
2015 [89] placebo- 2. Placebo exposure therapy therapy 16 binge- significantly greater increase in BMI
controlled session sessions purge than those in the placebo group
Table 1 continued
(years)
Misra et al., Single-blind, 1. Estrogen 100 lg twice weekly 18 months 38 16.9 ± 0.2 NA At 18 months follow-up (n = 20,
2013 [94] placebo- with 2.5 mg of (SE) estrogen group; n = 17, placebo
controlled 2. Placebo medroxyprogesterone 34 16.2 ± 0.2 group), the estrogen group showed a
acetate administered (SE) significant decrease in STAIC-trait
daily for the first scores. No differences in BMI
10 days of every month changes were noted between groups
Kibanski et al., Randomized 1. Estrogen plus progestin 0.625 mg Premarin (days 1.57 ± 0.89 22 23.7 ± 7.2 NA No differences in bone density
1995 [95] controlled 1–25) and 5 mg years between the estrogen-treated and
2. Unmedicated control Provera (days 16–25) 1.41 ± 0.69 26 25.8 ± 6.6 control groups
group or 35 lg years
ethinylestradiol
Miller et al., Single-blind, 1. Testosterone Range 150–300 lg 3 weeks 6 23.7 ± 3.5 NA Brain glucose hypometabolism in AN
2004 [96] placebo- 2. Placebo 6 changed toward normal in the
controlled posterior cingulate cortex with
testosterone treatment
Hill et al., 2000 Double-blind, 1. rhGH 0.05 mg/kg 28 days 8 15 NA Patients treated with rhGH reached
[97] placebo- 2. Placebo 7 14.5 medical/cardiovascular stability
controlled more rapidly than those treated with
placebo
AN anorexia nervosa, SD standard deviation, SE standard error, max. maximum, NA not available, BMI body mass index, DHEA dehydroepiandrosterone, SE standard error, rhGH recombinant
human growth hormone, STAIC State-Trait Anxiety Inventory for Children
treatment, but did not improve weight gain in the long run Neuroscience and, in particular, reward-system research
during inpatient hospitalization. However, that study implicated dopamine circuits in AN, but the typical dopa-
seemed to only reanalyze data from the previous reference mine receptor blockers have shown little promise to con-
[20]. A single-blind study that compared the dopamine D2 sistently improve food reward in AN.
antagonist amisulpride, the SSRI fluoxetine, and clomi-
pramine in restricting AN found that clomipramine was not 2.4 Mood Stabilizers
effective [21]. A study that directly compared clomipra-
mine with the SSRI paroxetine while patients were in an Lithium, probably the most effective mood stabilizer for
eating disorder program found no differences in weight both manic and depressed episodes, is prescribed as a salt,
gain between medications. Paroxetine shortened the treat- most frequently as lithium carbonate. Its specific mecha-
ment duration for achieving a similar weight gain [22]. nism of action is not well understood but it reduces nora-
The antidepressants of the monoamine oxidase inhibitor drenaline and increases serotonin activity in the brain. A
type are also not widely used anymore due to their side small, double-blind, controlled study of adults with AN
effect profile; however, before the advent of SSRIs, these who were also enrolled in a behavior therapy program,
medications were commonly prescribed and also tried in showed at weeks 3 and 4 (end of study) a small benefit with
AN. An open-label trial using isocarboxazid in AN indi- respect to weight in the lithium-treated group [29]. How-
cated improved mood and anxiety, but no significant ever, the benefit did not seem to outweigh the risks,
weight gain, during this 6-week trial [23]. especially as lithium treatment is sensitive to fluid shifts, a
Collectively, tricyclics and monoamine oxidase inhibi- problem in AN, where patients frequently restrict fluid
tors showed little consistent promise as effective treatments intake, which could lead to lithium intoxication.
for AN. In addition, their unfavorable side effect profile
and potential for use in committing suicide make this class 2.5 Zinc
of medications a less-used category in psychiatry in
general. Zinc is a mineral with key functions in human metabolism.
It has long been hypothesized that zinc deficiency could
2.3 Typical Antipsychotic Medications contribute to the pathophysiology of AN [30, 31]. Reduced
zinc levels in AN respond to supplementation [32], and an
The older, first-generation, so-called typical antipsychotics open-label study of youth and adults with AN suggested
have been used in the past but are now only rarely used in promotion of weight gain in AN [33]. One double-blind,
new-onset psychosis. These medications can have severe controlled study of adult AN suggested more rapid weight
side effects, such as drug-induced parkinsonism or tardive gain when receiving zinc supplementation [34], but another
dyskinesia. In general, they share strong dopamine D2 study of youth with AN found that zinc deficiency nor-
receptor antagonism. In 1976, Barry and Klawans specu- malized quickly with weight restoration, and zinc levels
lated that dopamine receptors could be hypersensitive in were not related to rate of weight gain [35]. In summary,
AN and contribute to body image distortion in the disorder the role of zinc in the treatment of AN is still controversial.
[24]. This would make the prescription of dopamine In support of zinc as a treatment agent is animal research
antagonists a logical choice. A double-blind, controlled that showed that zinc deficiency is associated with weight
study of the diphenylbutylpiperidine pimozide or placebo loss and that zinc supplementation can stimulate food
combined with behavior therapy showed active drug-en- intake [36]. Research suggests that zinc may act mecha-
hanced weight gain in the beginning phase of the treatment nistically via neuropeptide Y and that zinc deficiency may
[25]. In a small study that compared pimozide with inhibit neuropeptide Y release and interfere via that path-
behavior therapy, both groups gained weight over a way with normal regulation of food intake [37].
20-week period [26]. In one study, haloperidol, a buty-
rophenone and the most commonly prescribed typical 2.6 Opiates and Cannabinoids
neuroleptic, administered as an adjunct to psychotherapy
over 6 months, was associated with weight gain [27]. In a Opiates and opiate antagonists are associated with hedonic
more recent case series identified by chart review, it was aspects of food and drug use, and opiates are used with the
found that low-dose haloperidol was well-tolerated in hope of stimulating eating in AN or interrupting the sus-
treatment-resistant AN inpatients and that it reduced body pected auto-addictive properties of food restriction. Con-
image distortion and drive for thinness [28]. Chlorpro- tinuous infusion of the opiate antagonist naloxone in one
mazine, a phenothiazine, was suggested to be helpful in study was associated with weight gain in AN [38]. During
weight recovery in an open study, but no follow-up studies that treatment, serum fatty acid levels were reduced, sug-
were conducted [28]. gesting that the drug affected lipid metabolism. To
interrupt the AN behavior spiral, naltrexone, an opioid double-blind, controlled study using fluoxetine in AN in an
antagonist, was administered to patients with AN of the inpatient setting did not show beneficial effects [49], nor
binge/purging type [39]. In that study, naltrexone was did an open-label study in inpatients with AN [50]. A later
associated with reduced binge/purge frequency. Cannabi- double-blind, controlled study tested whether fluoxetine
noids have long been indicated to stimulate appetite, but a was beneficial for relapse prevention in the treatment of
double-blind, controlled study of adults with AN who were AN, and indeed suggested that AN patients, after short-
also in a behavior management program showed no benefit term recovery and on active fluoxetine, had reduced relapse
from the application of 9-tetrahydrocannabinol [40]. In in the 1-year follow-up period [51]. This was in line with
fact, the medication caused dysphoria and sleep distur- an open-label study [52] but not with a naturalistic follow-
bance in AN. In contrast, a very recent 4-week, randomized up after specialized eating disorder treatment over a 2-year
controlled trial in which the tetrahydrocannabinol dron- period [53]. Nonetheless, another study of a larger sample
abinol was administered to women with severe relapsing that prospectively used the randomized control design and
AN found that the medication was associated with weight tested time to relapse with fluoxetine versus placebo could
gain, although weight increase was small (approximately not show that fluoxetine was superior to placebo [54]. A
1.5 pounds) [41]. New cannabis strains have recently been comparison between fluoxetine and the serotonin–nora-
developed that may either stimulate (indica) or suppress drenaline reuptake inhibitor venlafaxine could not distin-
appetite (sativa), but these have not been researched in AN. guish the two drugs [55]. As AN is associated with poor
In summary, opiates and cannabinoids profoundly affect nutritional intake, and thus with a lack of dietary trypto-
eating behavior, but how they relate to AN and how ago- phan, the precursor of the neurotransmitter serotonin, it
nists or antagonists may be used to facilitate recovery seemed logical to test whether tryptophan supplementation
requires further study. would improve fluoxetine effectiveness; however, a dou-
ble-blind, controlled study using fluoxetine with supple-
2.7 Benzodiazepines and a2-Adrenergic Agonists ment or placebo did not show benefits from the added
tryptophan [56].
In the clinical environment, benzodiazepines are some- A small, open-label study using citalopram together
times used in the treatment of AN with the hope of with individual psychotherapy gave some indication of
reducing eating-related anxiety. Studies that systematically reduction in body dissatisfaction but no effect on weight
investigated benzodiazepines in AN in animal models or gain [57]. Compared with a waitlist control group, follow-
humans are scarce. One recent study using a randomized up open-label citalopram studies found improvement in
and controlled design in humans investigated the benzo- anxiety and depression but no benefit in weight gain [58,
diazepine alprazolam in an inpatient setting and did not 59]. Paroxetine, another SSRI, was investigated in a ret-
find this drug beneficial in the treatment of AN [42]. Basic rospective chart review and compared with clomipramine
research has shown that the a2-adrenergic agonist cloni- [22]. Weight gain achieved was similar between medica-
dine may increase feeding behavior, making a case to try tions but the rate of weight gain with paroxetine took only
this medication in AN [43]. However, administered in a three-quarters of the time needed on clomipramine. A
placebo-controlled, crossover design, this medication had small, open-label study that compared sertraline with pla-
no beneficial effect in AN but was associated with hemo- cebo over 14 weeks in an outpatient setting [60] found that
dynamic side effects such as hypotension [44]. sertraline improved depressive symptoms, perception of
ineffectiveness, lack of interoceptive awareness, and per-
2.8 Selective Serotonin Reuptake Inhibitors fectionism compared with placebo, but not weight gain.
Two retrospective studies in AN tested whether medication
The introduction of the SSRI fluoxetine brought an effec- with any SSRI improved treatment outcome but did not
tive and relatively well-tolerated antidepressant to the show benefits [61, 62]. A retrospective case review on the
market. In an open trial of six women with chronic AN, serotonergic/noradrenergic medication mirtazapine did not
fluoxetine was associated with reduced depression and support that mirtazapine was superior to other medications
weight gain [45]. In a mixed group of AN individuals at or no medication in AN [63].
low weight or already weight recovered, restricting-type
AN improved or maintained weight better when receiving 2.9 Atypical Antipsychotic Medications
fluoxetine [46]. On the other hand, one report advised
caution because fluoxetine could affect appetite to the Compared with the first-generation ‘typical’ antipsychotics
degree of inducing AN [47]. A study that contrasted flu- such as haloperidol, atypical neuroleptics have less
oxetine, cognitive behavior therapy, or a combination did extrapyramidal side effects. Some block dopamine D2
not find a benefit from fluoxetine [48]. Furthermore, a receptors as the first-generation drugs do, while others have
more serotonergic and less or no significant dopamine serotonin 1A and 2A, receptor sites, and also shows strong
receptor affinity. The benzamide and dopamine D2 antago- histamine H1 receptor antagonism. Aside from its
nist amisulpride was studied in a double-blind design [64], antipsychotic effects, it is known to reduce anxiety and is
and the authors found that the active drug was superior to often associated with weight gain. One open-label study in
placebo with respect to weight gain, but only in the beginning AN suggested improved weight gain related to the medi-
phase of therapy and not in the crossover phase. Another cation [77], and another suggested that quetiapine was
single-blind study that compared amisulpride with clomi- helpful in reducing anxiety and depression but the effects
pramine and fluoxetine found this medication superior with on weight gain were minimal [78]. A double-blind, con-
respect to weight gain over a 3-month period, but no group trolled study in an outpatient setting from the same group
differences with respect to fear of weight gain, body image did not find benefits from quetiapine on treatment outcome
distortion, or amenorrhea [21]. The atypical neuroleptic most for AN core symptoms [79]. A more recent, small, open-
frequently studied in AN is the thienobenzodiazepine olan- label study using quetiapine in young adults suggested that
zapine. It is a dopamine D2 antagonist and an inverse agonist the medication might improve anxiety and depression but
at the serotonin 2A and histamine H1 receptor. The particular not weight [80].
appeal of olanzapine is that it is associated with substantial The atypical antipsychotic risperidone has potent
weight gain in populations with psychosis or mania, pre- dopamine D2 antagonism, especially at higher doses, but
sumably mediated by the histamine receptor. Open-label also has serotonin 1A, 2A, and histamine H1 receptor
studies suggested improved weight gain in AN [65, 66] in antagonistic action. Case reports suggested that risperidone
both inpatient and outpatient settings. A retrospective study could benefit weight gain in AN [81, 82]. The only double-
of previously ill AN individuals suggested that olanzapine blind, controlled study of this medication in adolescent AN
reduced fear of eating and weight gain [67]. The first ran- did not show benefits from the drug over placebo [83].
domized controlled study of olanzapine in AN that compared The atypical antipsychotic aripiprazole is different
this medication with chlorpromazine in a small sample found compared with the other atypical antipsychotics as it is a
that olanzapine, but not chlorpromazine, reduced eating dopamine D2 and serotonin 1A and 2C receptor partial
disorder ruminations [68]. Another open-label study found agonist, as well as a serotonin 2A receptor antagonist. No
that the effects of olanzapine on weight gain and mood were controlled studies exist but case series on adults and youth
significant in the binge/purge subtype of AN but not in the similarly suggest that this medication may reduce fear of
restricting subtype [69]. Eventually, a double-blind, con- eating in AN and facilitate recovery, and it was suggested
trolled trial was conducted over a period of 10 weeks [70], that aripiprazole might downregulate dopamine receptor
and olanzapine was credited with faster and greater weight sensitivity [84–86].
gain compared with placebo [70]. One small, open-label
study found that olanzapine reduced hyperactivity and 2.10 Other Agents
improved weight gain in youth with AN [71]. A 2011 study
randomized (double-blind) individuals with AN to medica- A variety of investigations have been undertaken to expand
tion management with olanzapine or placebo and found that medication trials beyond the traditional psychoactive
the active drug was associated with significantly greater drugs. The most promise may come from the glutaminergic
weight gain compared with placebo [72]. Several studies NMDA agonist d-cycloserine, which has shown promising
tested whether olanzapine was beneficial to enhance psy- results in the treatment of anxiety disorders with respect to
chotherapy. One study of adolescents who received olanza- fear extinction [87]. In a laboratory design, one study tested
pine or placebo in addition to a behavior modification this substance in AN in order to facilitate eating and found
program did not show benefits from the drug [73]. A retro- that d-cycloserine was associated with greater caloric
spective chart review on olanzapine, in addition to psy- intake compared with no medication [88]. In a randomized
chotherapy, in adolescents was not able to draw firm controlled study that used food exposure and d-cycloserine
conclusions in favor of olanzapine due to methodological or placebo, the active treatment group showed greater
problems of the study [74]. In addition, in a study in which weight gain after four exposure sessions and at the 1-month
AN patients received more than 3 months of cognitive-be- follow-up [89]. The opposite approach was taken in a study
havioral and specific weight gain support paired with olan- in which individuals with AN were administered the
zapine or placebo, olanzapine was not superior to placebo NMDA antagonist amantadine, and reported rapid
with respect to weight gain [75]. Of note here is that olan- improvement, including weight gain, over 3 months of
zapine in AN, as in other conditions, can lead to hyper- treatment [90]. A study in which dehydroepiandrosterone
glycemia [76]. (DHEA) was administered in a double-blind design to
The atypical antipsychotic quetiapine is a relatively patients with AN in order to improve bone mineral density
weak antagonist at the dopamine D1 and D2, as well as did not find the expected effect over placebo, but at the
4-month follow-up, BMI was higher in the DHEA group, the reward system, while the orbitofrontal cortex con-
as was improved reported mood [91]. Ghrelin is a gut tributes to the mechanisms that determine when to stop
hormone produced in the stomach and pancreas that stim- eating [103]. Thus, altered brain volume in those structures
ulates food intake, making it a potential treatment agent for could affect function and thus the normal biological food
AN. A study that provided infusion of ghrelin over 14 days reward circuitry. Neurotransmitter receptor studies using
in five individuals with AN reported quickly improved positron emission tomography (PET) to study receptor
gastrointestinal discomfort and improved nutritional intake distribution showed that serotonin 1A receptor availability
and weight gain [92]. In one case report, the serotonin 1A in AN was higher compared with controls, while the
agonist tandospirone was tried in two female patients with serotonin 2A receptor tended to be reduced across the
AN, one of the restricting type and the other of the binge/ cortex compared with controls [1]. The function of the
purge type [93]. There the authors suggested that the serotonin system is multifold and is frequently associated
medication led to weight gain and relapse prevention. with high anxiety and low mood, behaviors that have long
Onset of AN is common during adolescence, and hormonal been associated with AN [1]. The dopamine D2 receptor
surge during puberty, as well as the low gonadal hormone was found to be higher in AN after recovery in the antero-
state in AN, led to speculations that sex hormones might be ventral striatum [104], and the cannabinoid 1 receptor was
involved in the pathophysiology of AN. In one report, the higher in AN in the insular, infero-frontal, and infero-
prescription of estrogen replacement in a randomized temporal pole [105] compared with healthy controls. Both
controlled trial reduced trait anxiety but had no eating dopamine and opioid circuits code neural reward process-
disorder-specific effects [94]. Another study that used ing. Dopamine neurons code motivation (‘wanting’) and
estrogen replacement for bone restoration in AN did not reward approach and learning, and the opioid system codes
find this treatment effective for improving bone mass or pleasurable experience from rewards (‘liking’). Thus,
body weight [95]. One study used testosterone in order to altered receptor availability could interfere with this feed-
improve bone loss, cognitive deficits, and mood in AN, and back circuitry in AN [106, 107]. Functional magnetic res-
this hormone was associated with improved spatial cogni- onance brain imaging (fMRI) tests brain activation across
tion and mood [96]. Another hormone, human growth brain regions and circuits, such as reward or anxiety
hormone, was hypothesized to be beneficial for weight pathways. These studies do not usually test brain neuro-
recovery in AN but was not superior to placebo [97]. In transmitters directly, but the response during tasks that test
summary, the majority of these pharmacological agents did specific behaviors might help in understanding neuro-
not show significant benefits in AN treatment, but it is also transmitters involved in the brain response [108]. In such
not certain whether their potential is fully explored. Also studies during fMRI, individuals with AN showed greater
not well understood and not well studied in human AN are brain activation compared with controls when viewing
neuropeptides and whether they can improve recovery [98]. anxiety-provoking food pictures; during taste or monetary
reward tasks, individuals with AN tended to show
increased activation to unexpected stimulus presentation,
3 Neurobiology of AN while brain response tended to be lower when the specific
stimulus was expected [109]. Importantly, a paradigm that
3.1 Human Studies specifically targets dopamine-related pathways (prediction
error model [110]) suggested increased brain responsive-
The role of neurobiological mechanisms, including devel- ness in AN, implying high dopamine receptor sensitivity,
opmental and environmental factors that contribute to the which is consistent with basic science research. The field of
beginning and perpetuation of AN, is not well understood, genetic research also continues to investigate the neurobi-
although over the past 2 decades we have started to better ological underpinnings of AN, including genes for neuro-
understand brain neurobiology that is involved in AN. transmitters and neuropeptides [111], as well as genome-
Studies on brain volume have been inconsistent but with wide association studies [112, 113]. However, the aggre-
the general notion that brain volumes are reduced in AN gate of research has not yet led to breakthroughs in the field
[99]; however, more recent studies contradict this percep- with respect to eating disorder etiology or psychopathol-
tion. Acute food and fluid restriction reduces brain volume ogy. This may be due in part to the large sample sizes
and this normalizes quickly with nutritional rehabilitation needed, and much further effort will be required [114]. A
[100]. Moreover, AN individuals who were studied under potentially promising approach that might help in this
short-term nutritionally controlled conditions showed in- effort is a new correlation analysis that uses data from
creased orbitofrontal and insula cortical volumes across different genome-wide studies and which could identify
age groups and stages of illness [101, 102]. The insula overlap between disorders such as AN, obesity, and
contains the primary taste cortex and provides signals to schizophrenia [115].
3.2 Animal Models [131]. Brain reward learning is altered in AN, behavior that
has been associated with brain dopamine function, sug-
The predominant animal model for AN is the rodent gesting that dopaminergic agents could ameliorate this
activity-based AN (ABA) model, where, after food dysfunction [132]. One study that tested serotonin 2A/2C,
restriction and access to a running wheel, the animal serotonin 3, dopamine D1-like, D2, D3 and D2/3 receptor
increasingly uses the wheel, which seems to further reduce antagonists indicated that the dopamine D2 and D3
food intake, and, if not stopped, the animal exerts itself to receptor antagonists increased survival, while the other
death [116]. That model replicates the vicious cycle of food agents did not [133]. This is an interesting result as the
restriction and excessive exercise, continuous weight loss, clinical studies using antipsychotics with dopamine D2/D3
and death. One study applied olanzapine to rats, which antagonism have not shown benefits (see above).
reduced hyperactivity on the running wheel, suggesting In summary, a number of biological factors are involved
that this drug could reduce excessive exercise drive in AN in AN pathophysiology, including monoamine neuro-
[117]. A study that compared olanzapine and the SSRI transmitters, such as serotonin and dopamine, neuropep-
fluoxetine found that 1-week treatment with olanzapine tides, and hormones, but environmental factors are also
improved survival, but a 4-week course of fluoxetine did involved. This suggests that we have to start building more
not [118]. Interestingly, olanzapine did not affect feeding complex models that test interactions of those individual
or wheel running. The dopamine D1, 2 and 3 receptor factors to better understand the neurobiology of AN [134,
antagonist cis-flupenthixol was administered to ABA rats, 135]. In fact, it has been suggested that this need for better
and improved feeding behavior and reduced weight loss integration of genetic, environmental, and developmental
[119]. Application of the serotonin agonist fenfluramine factors applies to animal models in relation to psychiatric
resulted in faster weight loss in one study but not in another disorders in general [136]. What animal models do not
[120, 121]. In contrast, the serotonin 1A receptor agonist represent well are the cognitive–emotional aspects of AN
8-OH-DPAT reduced hyperactivity and associated weight and its ego-syntonic nature of food restriction [137].
loss [122]. Another group found that in the ABA model, Another caveat to keep in mind when considering sub-
the application of the cannabinoid receptor agonist delta-9- stance use disorder treatment research is that drug devel-
tetrahydrocannabinol in conjunction with a high-fat diet led opment can show much promise in animals, but not all of
to reduced use of the running wheel as well as increased these results can be directly translated to humans [138].
body weight [123]. One study investigated the cannabinoid
system and applied either delta-9-tetrahydrocannabinol or
the endocannabinoid uptake inhibitor, OMDM-2, to ABA 4 Why Do No Medications Show Robust Benefits
mice that had lost weight and shown excessive wheel in the Treatment of AN?
running [124]. In that study, both agents increased food
intake but did not improve survival; in fact delta-9-te- The reasons why hypothesis-driven drug development in
trahydrocannabinol decreased survival rates. Leptin is a psychiatry in general has been challenging is the com-
hormone produced by fat cells to downregulate feeding plexity of the human brain [139]. The hope and expectation
drive, presumably via brain dopamine receptors, and was is that with increasing capability of novel research methods
found to reduce running-wheel activity, suggesting that to study the human brain we will eventually understand
dopamine circuits in the context of food restriction drive mechanisms, which will then allow us to develop targeted
hyperactivity [125, 126]. The ABA model also allows pharmacological interventions. There are various aspects of
studying specific dietary manipulations, and both high-fat the progression of AN that may have particular relevance
and high-carbohydrate diets promoted fast weight recovery when developing a medication. First, AN typically devel-
but may also be associated with fatty liver development ops during childhood and adolescence, and there is an
[127, 128]. Dietary supplementation is another strategy interplay between normal brain development and AN start
and, recently, a small study tested the effects of agmatine, a and progression. This interaction is associated with brain
metabolite of L-arginine, on ABA. That study indicated neurotransmitter receptor changes, and medication may
that 20 and 40 mg/kg of agmatine ameliorated ABA weight only be effective for a discrete time. This is a problem in
loss and plasma corticosterone increase, suggesting a pro- child psychiatry in general. Second, there may be pre-
tective effect, possibly mediated via blockade of dopamine morbid conditions, such as anxiety or depression, that
D2 and activation of 5-HT1A receptors [129]. A recent could respond to medication and impact AN development
ABA study suggested that progesterone interacts with a4- and course, but as soon as AN, with all its associated
GABA receptors and worsens wheel-running behavior behaviors, has started, the changing biological conditions
[130], supporting the notion that the increased hormone due to malnutrition may require ongoing adaptation of the
release during puberty is a vulnerability for developing AN most effective treatment regimen. For instance, it is well-
known that weight loss is associated with a sensitization of 5 New Approaches to Medication Intervention
dopamine neuronal function, while overweight and weight in AN
gain show decreased dopamine receptor activity [140–
142], and any psychopharmacological approach has to take The first question we have to ask in this effort is, what
such changes into consideration. However, the past aspect of AN do we want to treat, and what mechanisms do
approach to medication treatment in AN has not always we target? Drug research in psychiatry in general has not
been built on a systematic, neuroscience-based empirical always been guided by systematically targeting a particular
approach. Historically, in the field of psychiatry, new mechanism [143]. We still do not know well what mech-
medications have been typically found by serendipity anisms drive mental illness or, one may better say, psy-
[143]. The problem is that (i) we have limited knowledge chiatric brain disorders. Neuroscience and psychology have
about disorder-specific pathophysiology, and (ii) our now provided us with a much better understanding of brain
medication arsenal is limited and we try any medication we function, and we should take advantage of that. It is
have with the hope that it will improve the condition. This probably unlikely that we will identify a medication that
approach is likely to lead to both type I and type II errors. will cure AN but we may be able to identify medications
Another potential source of errors and unsuccessful medi- that can improve outcome based on behavioral concepts
cation intervention trials is the dose of a medication. and diagnostic subgroups. Importantly, new hypothesis-
Typically, medications have been prescribed based on driven drug research is necessary but often challenging,
knowledge from mood disorder or schizophrenia literature; especially in psychiatry; however, clinicians can inform
however, there is no reason to believe that those dose researchers on new applications and dose regimens of
regimens apply to AN. Those ‘typical’ doses may lead to existing agents to expand the available therapeutics [144].
side effects without benefit, while a different approach to Furthermore, specific AN-associated behaviors that are
dosage could be more effective. Ideally, research would encountered in clinical care need to become research and
pair animal models of starvation with the clinical trial and treatment targets.
determine what medication dose is most adequate. As
much as extremes of food restriction or intake alter neu- 5.1 Learning and Fear Extinction
rotransmitters, so do medication doses need to be adjusted.
Another potential confounder is comorbidity. Medication AN is driven by fear of weight gain, and psychotherapy is
trials are often assessed for reductions in depression or designed to overcome this anxiety. The above-described
anxiety scores; however, not every person with AN has a studies used d-cycloserine-targeted fear extinction, but
current anxiety or depressive disorder, and this variability further studies are needed to determine whether this type
could confound outcome. It is possible that only patients of medication approach can be helpful. Animal studies
with a current comorbid major depressive disorder would have found that there is an interaction between hormonal
truly benefit from an antidepressant medication, which, in state and fear extinction, and, in particular, females in a
turn, could improve AN treatment outcome and prognosis. low-estrogen state may benefit from dopamine receptor
Most medication trials are small, and a stratification that stimulation when trying to suppress previous fears after
includes comorbidity is hard to accomplish, but if we do extinction training (‘extinction retrieval’) [145]. Thus,
not do that we cannot truly assess the effects from the dopamine D1 receptor stimulation could support anxiety
medication. In support of this argument is that controlling reduction specifically in females with AN as the disorder
for comorbid conditions in biological studies typically is typically associated with low gonadal hormone levels.
improves the signal-to-noise ratio. Another limitation of The dopamine D2 receptor could also be a target for
medication trials in eating disorders is that they typically reducing conditioned fear as quinpirole reduced expres-
focus on the acute phase of the illness and not whether a sion of conditioned fear response in rodents, and it was
medication may prevent relapse long after weight recovery. hypothesized that this was mediated by presynaptic
In most cases, studies had a duration of between 1 and 6 dopamine release modulation via the dopamine D2
months and very rarely went to 12 months or beyond. In receptor [146]. In another study, the D2 receptor agonist
summary, it may be that AN is not that different compared quinpirole reduced amygdala dopamine levels and asso-
with other psychiatric disorders with respect to biological ciated fear response [147]. An additional effect of the
underpinnings. However, the complex interactions between dopamine D2 agonist quinpirole was to block conditioned
intrinsic brain abnormalities and changes that occur during fear memories that affected both fear conditioning and
the illness and during food restriction will need extra effort extinction [148]. Taken together, the dopamine D1 and
to better understand and create biological models of the D2 receptors appear to be potential targets for the treat-
disorder. ment of anxiety and modulation of conditioned fear.
Receptor stimulation could therefore be promising, 5.3 Social Cognition

although systemic application of dopamine D2 blockade
facilitated fear extinction [149]. However, most studies Social cognition has long been suspected of involvement in
generally used acute, short-term designs. Chronic dopa- the psychopathology of AN, and the disorder has been
mine D2 receptor antagonist application enhances this compared with autism spectrum disorder [163, 164].
receptor system over time, while chronic agonists Whether such deficits exist is still under investigation but
decrease dopamine receptor activity [150, 151]. Thus, the various studies have applied pharmacological interventions
effects of dopamine D1 and D2 agonists and antagonists in an attempt to improve social functioning in AN. Oxy-
have to be studied over longer periods and in relation to tocin is a neuromodulatory prosocial hormone that is
weight state. The dopamine D2 receptor partial agonist released by the hypothalamus and stored in the pituitary
aripiprazole showed anxiolytic effects during a fear-con- gland. The literature is discrepant whether this hormone is
ditioning paradigm in animals [152], and reduced distress increased, decreased, or normal in AN [165, 166], and one
around eating in individuals with AN [84]. Therefore, it is study found that plasma oxytocin levels predicted anxiety
possible that dopamine receptor activation is beneficial in and depression ratings after a meal [167]. A series of
the treatment of AN. double-blind studies from the same group indicated that
oxytocin reduced attention bias to disgust in both AN and
5.2 Reward System Responsiveness control groups, suggesting that, in AN, oxytocin reduced
attention bias to food- and body-related stimuli but had no
Dopamine circuits within the brain reward system drive effect on emotion recognition or food intake [168–170]. In
food approach and the motivation to eat [153]. It is particular, the latter report does not support the usefulness
therefore conceivable that in AN the poor motivation to of oxytocin as a therapeutic agent in AN; however, a long-
recover is, in part, related to dopamine system alterations term application might have produced different results.
[154, 155]. Animal studies have shown that extremes of
food intake change brain dopamine chemistry, regardless 5.4 Novel Therapeutics
of whether there was an alteration before developing AN.
Specifically, dopamine response becomes sensitized with The development of novel therapeutic agents in psychiatry
food restriction and weight loss and does not quickly has been very slow and may, in part, be due to the phar-
normalize with normalization of food intake [140, 142]. maceutical industry’s ‘withdrawal’ from this area [171].
Using fMRI and a task that is specifically designed to test On the other hand, neuroscience continues to make pro-
dopamine neuronal activation (‘prediction error model’ gress in identifying mechanisms that underlie disorder
[156]), we found that AN was associated with greater processes with the study of neuroplasticity, neurogenetics,
brain response in insula and ventral striatum, suggesting and neural circuitry [172]. This holds promise in identi-
abnormally heightened dopamine receptor sensitivity fying disease mechanisms and new molecules to treat
compared with controls [132]. If in fact there is a psychiatric disorders. In depression treatment research,
hypersensitivity of dopamine D1 and D2 receptors in AN, various compounds have been identified that are currently
then long-term application of dopamine receptor antago- under investigation (see review by Papakostas and Ionescu
nists could further increase receptor availability and sys- [173]), including glutamatergic N-methyl-D-aspartate
tem activity [150, 151, 157]. On the other hand, cautious (NMDA) receptor antagonists, such as ketamine or lan-
application of dopamine receptor agonists could be ben- icemine, which rapidly reduce depressive feelings with few
eficial as it would result in a net decrease in dopamine side effects. Previously, a hypercholinergic state has been
binding sites and desensitization over time, and possibly postulated as a mechanism that contributes to depression,
reduced response sensitivity [150, 158–161]. Such dopa- and the antimuscarinic agent scopolamine has shown fast
mine receptor downregulation might then attenuate antidepressant response. Vortioxetine, a novel medication
reward system responsiveness. One case report in a that modulates serotonin receptors, has recently been
sample of six patients with AN showed that a low dose of approved for major depressive disorder and has not been
the dopamine agonist levodopa was helpful for weight tested in eating disorders. This drug has also been con-
gain in four patients, while the two non-responders sidered as a potential treatment for generalized anxiety
maintained their weight [162]. Other evidence for dopa- disorder [174]. Glutamatergic agents, corticotrophin-re-
mine agonists comes from case reports that suggest that leasing factor 1 antagonists, and angiotensin II receptor
the dopamine receptor partial agonist aripiprazole at a antagonists may also have anti-anxiety effects but may not
relatively low dose can reduce fear of weight gain and be available for clinical use for some time [175]. Never-
support AN treatment outcome [84, 85]. theless, these agents could be investigated in animal
models of AN. From relevant research in the addiction shown beneficial effects in treating depression [185].
literature, we learned that potential therapeutic target for Basic research has suggested that these agents could
the eating disorders field are gastrointestinal peptides, increase survival in animal studies [186], and small case
which are active in the brain [176]. These peptides include reports from one group indicated potentially beneficial
substance P, neurotensin, ghrelin, neuropeptide Y, and effects in AN [187, 188]. Some have made a compelling
glucagon-like peptide 1. They have been shown to increase theoretical argument that this class of nutritional supple-
or decrease alcohol consumption in animal models and ments could support brain health in disordered eating
could have implications for food intake in AN. Their [189] but rigorous studies supporting this hypothesis are
activity is related to the body’s immune system as well as still outstanding.
monoaminergic neurotransmitters such as serotonin or
dopamine [98]. Those peptides are often altered during the 5.6 Comorbidity
ill state of an eating disorder, and normalize with recovery,
but is it largely unknown whether they contribute mecha- Depression and anxiety are very common in AN [6] and
nistically to AN [177]. A new area of research is the one would expect that comorbidity affects treatment out-
intestinal microbiome, and one small study suggested that come. A recent meta-analysis indicated that depression and
the bacterial composition in the intestine is altered in AN general psychopathology unfavorably affected treatment
and that weight recovery is associated with changes in the outcome; however, the studies typically assess depression
microbiome [178]. Future research may identify pharma- or anxiety with continuous measures such as the Beck
cological interventions that could be beneficial for the Depression Inventory or State Anxiety Questionnaire
recovery from AN. score, and do not necessarily stratify by diagnosis [190].
New techniques have been developed to manipulate and This is a potential problem as one would, for instance, in a
better understand brain neurocircuitry. One such technique clinical setting, prescribe an anti-anxiety or antidepressant
is optogenetics, which allows the use of light to switch on medication based on a diagnostic assessment. One retro-
or off certain brain circuits, but at this point is only spective chart review studied adolescent patients with AN,
applicable in the animal model [179]. There are several who also had a depressive episode at the time of treatment,
new nonpharmacological interventions in psychiatry that and compared the effectiveness of paroxetine with clomi-
effect brain activity, including repetitive transcranial pramine [22]. In that study, BMI increase was similar
magnetic stimulation (rTMS) [180], transcranial direct between groups (2.6 and 2.8 BMI points) but the parox-
current stimulation (tDCS) [181], or deep brain stimulation etine group took significantly less time (72 days) to reach
[182]. Those approaches have been associated with mod- ideal body weight compared with the clomipramine group
ulation of dopamine, serotonin, and other neurotransmitter (97 days). Tricyclic medications have shown little benefit
systems [183, 184]. While their effectiveness is still under in the treatment of adolescent depression, while SSRIs
investigation, it is possible that the combination of brain have shown efficacy, although the specific effectiveness of
stimulation and pharmacological agents might be beneficial paroxetine has recently been questioned [191]. At our
in improving outcome in psychiatric disorders, including treatment facility, we carefully assess comorbid conditions
eating disorders. and if, for instance, a major depressive disorder or anxiety
disorder is diagnosed that cannot be attributed to the eating
5.5 General Neural Protection disorder, then we typically treat those conditions. This is
with the rationale that the eating disorder treatment work is
Nutritional supplements constitute a large segment in the already intense, and our impression is that treating anxiety
personal health improvement market. In the US, these and depressive disorder facilitates AN treatment and, at the
products are not regulated by the FDA but other countries least, improves quality of life. One school of thought was
may have more stringent rules. The true effectiveness of that SSRIs could not be effective because of poor nutrition
many agents is still unclear, but omega-3 fatty acids, and low tryptophan intake, which contributes to low brain
which are part of neuronal cell structures and support serotonin. This has never been proven and specific sup-
human metabolism, have been well studied. The omega-3 plementation with tryptophan did not make the medication
fatty acids (a-linolenic acid [ALA], eicosapentaenoic acid more effective [56]. It may be more likely that the SSRI is
[EPA], and docosahexaenoic acid [DHA]) are naturally just not specific enough for AN treatment, and it might
occurring in foods such as fish or flax seeds and can be only be helpful in individuals who have a full major
administered as a nutritional supplement. The available depressive episode. Thus, we suggest that specific research
studies on the effects of omega-3 fatty acids in psychiatry be undertaken that stratifies AN individuals by comorbid
are typically small and not well-controlled but have diagnoses, and tests whether SSRIs are beneficial or not.
5.7 Dosage Funding None.
Dosage in medication trials is guided by dose ranges estab-

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The Role of Psychotropic Medications in The Management

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CNS Drugs

The Role of Psychotropic Medications in the Management

Ó Springer International Publishing Switzerland 2016

Abstract Anorexia nervosa (AN) is a severe psychiatric

Anorexia nervosa (AN) is a severe mental illness with the

outcome for the binge/purge-type

Selective serotonin reuptake inhibitors (SSRIs)

Atypical antipsychotic medications

Receptor stimulation could therefore be promising, 5.3 Social Cognition

5.7 Dosage Funding None.

Dosage in medication trials is guided by dose ranges estab-

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