Pharmacotherapeutic strategies for the treatment of anorexia nervosa – too much for one drug?

Abstract

Introduction:

Anorexia nervosa is a severe psychiatric illness and no medication has been approved for its treatment. This lack of biological treatments requires the development of new directions for pharmacological research.

Areas covered:

There is modest but emerging evidence that dopamine D2 and serotonin 1A and 2A receptor agonistic and antagonist medication might be beneficial for weight gain, although the underlying mechanisms are uncertain. Improving quality of life including treating comorbid conditions is an additional important outcome measure, but this has not been well researched.

Biological and psychological risk factors together with neurobiological alterations during the illness maintain the disorder ‘s pathophysiology. Neuroscience research can be used to understand those interactions and advance the research agenda. The authors discuss the above as well as give perspectives on future research.

Expert opinion:

If a multidisciplinary approach that includes evidence-based psychotherapy shows unsatisfactory success in weight normalization and cognitive-emotional recovery, then more experimental treatments that are safe and have indicated treatment effectiveness should be tried to augment treatment. Identification and treatment of comorbid conditions to improve quality of life of the patient should also be part of the treatment regimen, even if the effect on weight gain is uncertain.

1. Introduction

Anorexia nervosa is the third most common chronic illness among adolescent females [1]. Anorexia nervosa has the highest mortality rate among the psychiatric disorders and most deaths occur between 16 and 29 years of age [2]. The illness is associated with severe emaciation from self-driven food refusal, a perception of being overweight despite severe underweight, and there is a complex interplay between neurobiological, psychological and environmental factors [3]. The lack of insight can in some go to the extent of losing touch with reality and take on a psychotic quality [4]. It is a chronic disorder with frequent relapse, high treatment costs and severe disease burden [5]. Treatment effectiveness is limited for anorexia nervosa [6], no medication has been approved, and little is known about the pathophysiology or biomarkers that characterize anorexia nervosa brain function [7]. In addition, anorexia nervosa shows a high level of psychiatric comorbidity, in particular anxiety and mood disorders [3].

For most psychiatric illnesses there is at least one category of medications that has shown efficacy and effectiveness including for affective, psychotic, anxiety, and substance use disorders [8]. For eating disorders in general, there are few available options. What sets anorexia nervosa and eating disorders in general apart from other psychiatric disorders is its “egosyntonic” nature as it is often referred to, the pursuit of weight loss despite its detrimental effects and while already being underweight [9]. The “eating disorder voice” that often drives the illness can be so powerful that the person with anorexia nervosa often does not feel strong enough to withstand this drive [10]. On the other hand, recovery can only be accomplished with a high level of motivation of the person with anorexia nervosa [11]. This dynamic creates a high level of ambivalence about treatment and recovery.

Medication intervention trials typically use one medication and look for specific treatment effects. This approach aims to identify and target a specific brain system that codes for illness behavior. However, what if such an ideal one illness – one treatment approach is not effective in an illness such as anorexia nervosa? The lack of successful medication trials suggests that the field needs to develop innovative methods and directions to improve outcome in anorexia nervosa treatment.

This article has three main aims. The first section is to provide a narrative review that summarizes research that has been published on medication interventions in anorexia nervosa. The goal is to identify the most promising medication approaches to aid in anorexia nervosa treatment based on the available literature. The second section discusses a research agenda to consider for understanding and eventually pharmacologically targeting core symptoms of anorexia nervosa, associated bodily changes and comorbidity that may need an approach of combination of treatments. The last section of the manuscript describes a practical approach for current medication treatment of anorexia nervosa.

2. Methods

The review portion of this article provides a narrative review of pharmacological treatments in anorexia nervosa. The narrative review was chosen to integrate a broad range of issues in anorexia nervosa treatment relating to pharmacological intervention and because of the relative lack of randomized controlled studies [12]. For this review we adhered to the scale for the quality assessment of narrative review articles (SANRA)[13]. The US National Library of Medicine National Institutes of Health database PubMed was searched separately for “anorexia nervosa”, and the search terms “medication” and ”treatment” were subsequently entered in the search engine. This search identified 37 double blind placebo controlled studies, which were included in this review. In addition, four other controlled studies and seven retrospective studies are discussed as well as two naturalistic follow up studies as this type of research is rare but longitudinal studies are needed. Open label studies were not included as they have a higher bias propensity [14] (Table 1.). Studies before the year 2000 are mentioned in the main text but described in detail in the supplemental file, to emphasize newer studies. The results are grouped in the text by targeted behaviors or pathophysiology.

Table 1.

Summary of pharmacological studies reviewed.

	Study Type	Treatment Conditions	Daily Medication Dose	Length of Treatment	N	Mean Age ± SD (Years)	Anorexia Type	Results
Opiates and Cannabinoids
Andries et al., 2014 (15)	Double-blind placebo controlled crossover	1. Dronabinol - placebo	5 mg	4 weeks dronabinol, 4 weeks washout, 4 weeks placebo	24	33.3	Restricting/binge-purge	During dronabinol treatment, participants gained a small amount 0.73 kg compared to placebo; there were no significant adverse events reported
		2. Placebo - dronabinol		4 weeks placebo, 4 weeks washout, 4 weeks dronabinol
Benzodiazepines
Steinglass et al., 2014 (29)	Double-blind placebo controlled crossover	1. Alprazolam	0.75 mg	2 test meals, 1 week apart	20	25.6 ± 7.8	Restricting/binge-purge	Alprazolam was not superior to placebo
		2. Placebo
Selective Serotonin Reuptake Inhibitors (SSRIs)
Kaye et al., 2001 (22)	Double-blind placebo controlled	1. Fluoxetine after weight restoration	Start Range = 20 – 60 mg	52 weeks	16	23 ± 9	Restricting/binge-purge	Patients on fluoxetine had reduced relapse and higher weight gain
		2. Placebo after weight restoration			19	22 ± 6
Barbarich et al., 2004 (23)	Double-blind placebo controlled	1. Nutritional supplement + fluoxetine	Nutritional supplement (2.3 g of tryptophan; 600 mg docosahexanoic acid; 180 mg arachadonic acid); 20 – 60 mg (fluoxetine)	6 months	15	23.0 ± 6.3	Restricting/binge-purge	Fluoxetine plus supplement showed no benefit over placebo
		2. Fluoxetine	Range = 20 – 60 mg (fluoxetine)		11
Ruggiero et al., 2003 (31)	Single-blind placebo controlled	1. Nutritional management + fluoxetine	Mean = 30 ± 9.4 mg	1 year	21	23.4 ± 4.0	Restricting/binge-purge	Fluoxetine was not superior to support weight gain
		2. Nutritional management			74
Holtkamp et al., 2004 (26)	Retrospective assessment	1. Fluoxetine	35 mg	6 month follow-up	7	14.5 ± 1.4	Restricting/binge-purge	SSRI treatment did not improve treatment outcome
		2. Fluvoxamine	20 mg		8
		3. Sertraline	100 mg		4
Walsh et al., 2006 (24)	Double-blind placebo controlled	1. Fluoxetine	Mean = 63.5 ± 15.8 mg	52 weeks	49	22.4 ± 4.5	Restricting/binge-purge	Fluoxetine showed no benefit over placebo
		2. Placebo	Mean = 71.4 ± 15.2 mg		44	24.2 ± 4.5
Yu et al., 2011 (21)	Naturalistic follow-up	1. Fluoxetine	Max = 60 mg	1 year	14	25.6 ± 6.4	Restricting/binge-purge	Fluoxetine was not superior to support weight gain
		2. Cognitive behavior therapy			17
		3. Fluoxetine + cognitive behavior therapy			22
Atypical Antipsychotic Medication
Ruggiero et al., 2001 (31)	Single-blind, no placebo	1. Amisulpride	50.0 ± 0.0 mg	3 months	13	23.7 ± 4.6	Restricting type	Amisulpride was associated with higher weight gain, but body image disturbance or fear of weight gain were similar across groups
		2. Fluoxetine	28.0 ± 10.3 mg		10	24.5 ± 5.1
		3. Clomipramine	57.7 ± 25.8 mg		12	24.3 ± 5.8
Mondraty et al., 2005 (32)	Double-blind placebo controlled	1. Olanzapine	10 mg	Mean = 46 ± 31 days	8	25.3 ± 7.4	n.av.	There was no significant difference in weight gain between groups
		2. Chlorpromazine	50 mg	Mean = 53 ± 26 days	7	25.3 ± 7.3
Brambilla et al., 2007a (38)	Double-blind placebo controlled	1. Olanzapine + cognitive behavior therapy + nutritional rehabilitation	2.5 mg for 1 month; 5 mg for 2 months	3 months	10	23.0 ± 4.8	n.av.	Olanzapine was not superior to placebo to support weight gain
		2. Placebo + cognitive behavior therapy + nutritional rehabilitation			10
Brambilla et al., 2007b (39)	Double-blind placebo controlled	1. Olanzapine + cognitive behavior therapy	2.5 mg for 1 month; 5 mg for 2 months	3 months	15	23.7 ± 4.8	Restricting/binge-purge	No difference for weight gain between groups, but olanzapine was associated with greater improvement of eating disorder inventory ineffectiveness and maturity fear scores
		2. Placebo + cognitive behavior therapy			15	26.3 ± 8.5
Bissada et al., 2008 (33)	Double-blind placebo controlled	1. Olanzapine	Start = 2.5 mg; Max = 10 mg - flexible dose regimen	10 weeks	16	23.6 ± 6.5	Restricting/binge-purge	Olanzapine was associated with greater weight increase and faster achievement of weight goals
		2. Placebo			18	29.7 ± 11.6
Attia et al., 2011 (34)	Double-blind placebo controlled	1. Olanzapine	Start = 2.5 mg; Last 4 Weeks = 10 mg	8 weeks	11	27.7 ± 9.1	n.av.	Olanzapine was associated with a small but significant increase in BMI over placebo
		2. Placebo			12
Kafantaris et al., 2011 (36)	Double-blind placebo controlled	1. Olanzapine + psychotherapy	Start = 2.5 mg; week 4 target = 10 mg	10 weeks	10	16.4 ± 2.2	Restricting	Olanzapine was not superior to placebo to support weight gain
		2. Placebo + psychotherapy			10	18.1 ± 2.0
Norris et al., 2011 (37)	Retrospective chart review	1. Olanzapine	Median = 5 mg	1038 ± 585 days	43	14.4 ± 1.9	Restricting/binge-purge	No firm conclusions could be drawn due to methodological problems of the study
		2. Comparison		540 ± 441 days	43	14.8 ± 1.6
Hagman et al., 2011 (41)	Double-blind placebo controlled	1. Risperidone	Mean = 2.5 ± 1.2 mg	17 weeks	18 `	16.2 ± 2.5	n.av.	No significant difference in weight gain between groups; the risperidone group showed greater reduction in drive for thinness over the first half of the study, but this was not sustained
		2. Placebo			22	15.8 ± 2.3
Powers et al., 2012 (40)	Double-blind placebo controlled	1. Quetiapine	Mean = 177.7 ± 90.8 mg	8 weeks	4	34 ± 14.5	Restricting/binge-purge	No difference in any outcome measure between quetiapine and placebo
		2. Placebo			6
Frank et al., 2017 (42)	Retrospective chart review	1. Aripiprazole	Mean = 3.6 ± 1.9 mg	19 ± 13 days IP 40 ± 17 days PHP	22	15.0 ± 2.2	n.av.	Aripiprazole treatment was associated with higher weight gain compared to the treatment as usual group
		2. Treatment as usual		16 ± 10 days IP 34 ± 13 days PHP	84	14.4 ± 2.5
Attia et al., 2019 (35)	Double-blind placebo controlled	1. Olanzapine	Mean = 7.77 ± 2.7 mg	16 weeks	75	28.0 ± 10.9	Restricting/binge-purge	Small but significantly higher BMI increase in the olanzapine group (0.7 units higher BMI increase)
		2. Placebo			77	30.0 ± 11.0
Hormones
Hill et al., 2000 (53)	Double-blind placebo controlled	1. Recombinant human growth hormone (rhGH)	0.05 mg/kg	28 days	8	15	n.av.	Patients treated with rhGH reached medical/cardiovascular stability more rapidly than those treated with placebo without change in weight gain.
		2. Placebo			7	14.5
Gordon et al., 2002 (49)	Double-blind, no placebo control	1. Micronized DHEA	50 mg/d orally	12 Months	30	17.8 ± 2.9	n.av.	DHEA and HRT had similar effects on bone mass density but there was no significant increase after accounting for weight gain. The DHEA group
		2. Ethinyl estradiol and levonorgestrel	20 μg 0.1 mg		31
Miller et al., 2005 (51)	Single-blind placebo controlled	1. Testosterone	Range = 150 – 300 micogram	3 weeks	6	23.7 ± 3.5	n.av.	Brain glucose hypometabolism in AN changed toward normal in the the posterior cingulate cortex with testosterone treatment.
		2. Placebo			6
Bloch et al., 2012 (48)	Double-blind placebo controlled	1. DHEA	100 mg	6 months	13	26.9 ± 8.2	n.av.	BMI increase in DHEA group was significantly higher than placebo group at 4 months
		2. Placebo			8
Kim et al., 2014 (57)	Double-blind placebo controlled crossover	1. Oxytocin	40 IU	Single dose, intranasal	31	23.1 ± 9.4	n.av.	Reductions in attentional biases toward eating-related and shape stimuli
		2. Placebo
Kim et al., 2015 (56)	Double-blind placebo controlled crossover	1. Oxytocin	40 IU	Single dose, intranasal	35		n.av.	No beneficial effect on emotion recognition sensitivity or on consummatory behaviour.
		2. Placebo
Misra et al., 2013 (47)	Single-blind placebo controlled	1. Estrogen	100 micrograms twice weekly with 2.5 mg of medroxyprogesterone acetate given daily for the first 10 days of every month	18 months	38	16.9 ± 0.2 (SE)	n.av.	At 18 months follow-up (n=20, estrogen group; n=17, placebo group), the estrogen group showed a significant decreased in STAIC-trait scores. There were no differences in BMI changes between groups.
		2. Placebo			34	16.2 ± 0.2 (SE)
Leppanen et al., 2017 (60, 61)	Double-blind placebo controlled	1. Oxytocin	40 IU Oxytocin intranasally prior to stiudy tasks for interpretation and expression of emotions	Single application versus placebo	15	25 (median)	n.av.	Oxytocin did not have signiifcant effect on emotion expression or interpretation; oxytocin did not affect food intake
		2. Placebo			15	24 (median)
Russell et al., 2018 (59)	Double-blind placebo controlled	1. Oxytocin	36 IU intranasally daily	4–6 weeks	16	23.0 ± 7.6	Restricting/binge-purge	Oxytocin had no effect on weight gain
		2. Placebo			17
DiVasta et al., 2019 (50)	Double-blind placebo controlled	1. DHEA + Estrogen	DHEA 50 mg + 20 mcg ethinyl estradiol/.1 mg levonorgestrel daily	12 months	35	Range 11–18 years	Restricting/binge-purge	DHEA + Estrogen did not improve bone health
		2. Placebo			35
Fazeli et al., 2018 (46)	Double-blind placebo controlled	1. Relamorelin (ghrelin agonist)	100 ug every day, subcutaneous injection	4 weeks	10	28.9 ± 2.4	n.av.	Relamorelin was associated with faster gastric emptying, but there was only a trend toward higher weigh gain
		2. Placebo			12	28.9 ± 1.9
Kimball et al., 2019 (52)	Double-blind placebo controlled	1. Testosterone	300 ug testosterone patch	24 weeks	42	28 ± 7	n.av.	Testosterone was assocated with significantly worse weight gain compared to placebo
		2. Placebo			46	27 ± 7
Other
Levinson et al., 2015 (62)	Double-blind placebo controlled	1. D-cycloserine	250 mg 1 hr before exposure therapy session	4 exposure therapy sessions	20	26.1 ± 10.5	Restricting/binge-purge	D-cycloserine group showed a significantly greater increase in BMI than those in the placebo group
		2. Placebo			16	24.6 ± 9.0
Israely et al., 2017 (64)	Double-blind placebo controlled crossover	1. Tyrosine	100mg/kg/day	3 weeks	19	n.av.	n.av.	Tyrosine shortened the reaction time on memory tasks and improved depression ratings.
		2. Placebo
Manos et al., 2018 (63)	Double-blind placebo controlled	1. Omega-3 Fatty Acid	2,120 mf eicosapentaenic / 600 mg docosohexaenoic acid	12 weeks	12	15.0 ± 1.3	Restricting	No group difference on weight gain
		2. Placebo			12	14.4 ± 1.8

3. Narrative Review Results

3.1. Medications to Stimulate Eating

The ability of severe food refusal seen in anorexia nervosa may be due to both active avoidance, but also an inadequate biological drive to eat. Using medication that would stimulate eating therefore could help overcome food avoidance. Early studies investigated agents such as the antihistamine cyproheptadine or the alpha 2 adrenergic agonist clonidine, which had increased feeding in basic science studies, but did not prove to be successful. Opiates and opiate antagonists are associated with the hedonic aspects of salient stimuli and it was hypothesized that they could interrupt the self-reinforcing properties of food restriction and in turn stimulate eating in anorexia nervosa. An older study using the opiate antagonist naltrexone improved binge/purge frequency in the binge-eating/purging subtype of anorexia nervosa, but other studies using opiate system targeting medications are lacking [15]. Depression research has now started to investigate the opioid system with specific ligand agonist and antagonists to the mu, delta or kappa receptors, which could be an important direction in anorexia nervosa research as well [16]. Cannabinoids also stimulate appetite, but an early study in adults with anorexia nervosa did not show benefits from 9-tetrahydrocannbinol but caused dysphoria and sleep disturbance. Andries et al. showed more recently in a double-blind placebo controlled crossover in 24 individuals with restricting or binge eating/purging type anorexia nervosa that the tetrahydrocannabinol dronabinol was associated with weight gain in women with severe relapsing AN although the weight increase was modest [17]. Cannabis and the hemp product cannabidiol (CBD) have been receiving increasing attention in the recent years with legalization of those substances for medical and recreational use. This has sparked the growing of a multitude of novel strains, which could prove beneficial for weight gain or other behaviors relevant to anorexia nervosa [18, 19]. However, specific research is largely lacking. Other agents that frequently stimulate eating and lead to weight gain presumably via histamine receptors, are the newer antipsychotic medications, often referred to as atypical antipsychotics [20]. Those medications are discussed in more detail below, but their general propensity to stimulate eating has not been observed in anorexia nervosa to the extent that it has been reported in other populations.

In summary, agents that promote weight gain in other populations have not been very successful in anorexia nervosa based on the available research. An important obstacle is that individuals with anorexia nervosa often explicitly resist and refuse taking a medication that is to primarily stimulate weight gain because of their fear of losing control over eating.

3.2. Medications to Treat Mood and Anxiety

Tricyclic antidepressants, first developed in the 1950s, have been used for anxiety, depression and obsessive-compulsive disorder and also tried in anorexia nervosa. Early on, the hypothesis was raised whether anorexia nervosa is a form of depressive or anxiety disorder, which made application of those medications a reasonable approach. However, those medications have not been able to improve outcome of anorexia nervosa [21].

The most frequently prescribed psychiatric medications, the so called serotonin reuptake inhibitors (SSRIs) have FDA indications for depression, anxiety and OCD and seemed an ideal medication class to use in anorexia nervosa to reduce eating disorder related anxiety and support recovery. In addition, in about half of individuals on any SSRI the medication promotes some weight gain [22]. However, the results have been overall disappointing. After some promising reports using the SSRI fluoxetine, larger controlled studies did not reveal benefits for weight gain, or weight maintenance [23–25] or relapse prevention of anorexia nervosa. The overall largest study that was done by Walsh et al. followed in a double blind design individuals with anorexia nervosa over 52 weeks, with 49 participants on active drug fluoxetine and 44 on placebo [26]. Other studies tested citalopram, sertraline or paroxetine, with no clear benefits for weight gain, although there was some indication that those medications might have helped with body dissatisfaction and mood [27, 28].

Benzodiazepines are the classic fast acting anxiolytic medications that enhances gamma aminobutyric acid (GABA) action in the brain but they also affect dopamine circuitry as well as neuroimmune function and differences across the various medications have been identified [29, 30]. One study by Steinglass et al. used the benzodiazepine alprazolam, in a double-blind placebo controlled crossover design in 20 individuals with either restricting or binge eating/purging type anorexia nervosa. However, this medication applied in an inpatient setting did not find this drug beneficial in the treatment of anorexia nervosa [31]. No other studies exist that researched the effects of benzodiazepines in anorexia nervosa.

3.3. Medications to Target Irrational Perception and Cognitive Flexibility

The perception of being fat while being severely underweight can be seen as an apparent loss of touch with reality. In fact, research has shown that at least in a subgroup of individuals with anorexia nervosa body image misperception has a psychotic quality [32]. Targeting a psychotic or delusional quality of body image perception has led to the use of antipsychotic medication that typically target the dopamine receptor system, and specifically block the dopamine D2 receptor. The results have been mixed. The early studies using pimozide, haloperidol, or sulpride provided some support for benefits for weight gain, body image distortion and drive for thinness, but no supporting controlled studies have been published [21].

The atypical antipsychotic medications have a better side effect profile compared to older agents, which may be due to their serotonergic properties. In a single-blind study, Ruggiero et al found amisulpride superior with respect to weight gain over a three-month period compared to clomipramine and fluoxetine but there were no group differences for fear of weight gain or body image distortion [33].

The atypical antipsychotic most frequently studied in anorexia nervosa is the thienobenzodiazepin olanzapine. It is a dopamine D2 receptor antagonist and an inverse agonist at the serotonin 2A and histamine H1 receptor. Olanzapine is associated with substantial weight gain in populations with psychosis or mania, presumably mediated by the histamine receptor. Earlier open label studies suggested improved weight gain in anorexia nervosa and possibly reduced fear of eating and weight gain, while one study did not show benefit over the typical antipsychotic chlorpromazine [34]. Several double blind controlled studies have now been conducted using olanzapine. One trial by Bissada et al. conducted over 10 weeks (16 patients on active drug and 18 on placebo, daily dose range 2.5 to 10mg), indicated faster and greater weight gain compared to placebo [35]. Another randomized controlled study by Attia et al. (11 patients on active drug, 10 on placebo, 10 weeks duration, dose range 2.5 to 10mg daily) found that the active drug was associated with small but significantly greater weight gain compared with placebo in an outpatient setting [36]. A very recent multi center follow up study, also by Attia et al., in a large group of individuals with anorexia nervosa (75 patients on active drug, 77 on placebo, 16 weeks duration, mean daily dose range 7.77mg) replicated those results. The study showed modest but significant therapeutic effect of olanzapine compared with placebo on weight gain in adult outpatients with anorexia nervosa, an increase in BMI over time in the olanzapine group 0.259±0.051 compared to 0.095±0.053 per month in the control group over a 4 month period. However, there were no significant benefits for psychological symptoms [37]. Studies that tested whether olanzapine is beneficial to enhance psychotherapy did not show clear benefits from the drug [38–41], questioning whether the medication is beneficial for weight gain when applied with additional treatments. It is possible that a therapeutic ceiling effect is reached quickly when used in conjunction with psychotherapeutic interventions.

The atypical antipsychotic quetiapine is a relatively weak antagonist at the dopamine D1 and D2 as well as serotonin 1A and 2A receptor sites, but a strong histamine H1 receptor antagonist. Quetiapine is known to reduce anxiety and is often associated with weight gain, which could stimulate metabolic processes to enhance weight restoration in anorexia nervosa. A few smaller studies suggested improved weight gain related to the medication, but a double-blind, controlled follow up study by Powers et al. in a very small outpatient sample (4 patients on active drug, 6 on placebo, 8 weeks duration, mean daily dose 178mg) did not find benefits from quetiapine on treatment outcome for anorexia nervosa core symptoms [42]. The small sample size, however, makes this negative study prone to type 2 errors.

Similarly, risperidone, a dopamine D2, serotonin 1A, 2A, and histamine H1 receptor antagonist did not show benefits from the drug over placebo in a double-blind, controlled study by Hagman et al., (18 patients on active drug, 22 on placebo, 17 weeks duration, mean daily dose 2.5mg) although earlier case reports had indicated some promise [43].

The atypical antipsychotic aripiprazole and its more recent successor brexiprazole are different compared to other atypical antipsychotics, as they are dopamine D2 and serotonin 1A receptor partial agonists, while having serotonin 2A receptor antagonistic properties. No controlled studies exist, but case series on adults and youth and a recent retrospective chart review in adolescents with anorexia nervosa (22 patients on aripiprazole, 84 not on the medication, mean daily dose 3.6mg) suggested improved weight gain in youth with anorexia nervosa (change from admission age adjusted BMI percentile aripiprazole group from 4.2 to 36.2, compared to the control group with BMI percentile gain from 3.1 to 28.6) who were treated in a high level of care inpatient or partial hospital treatment setting [44].

In summary, olanzapine has the strongest evidence to support weight gain in anorexia nervosa in the outpatient setting, although the amount is modest. In high level of care settings effects may not be pronounced enough to be significant. The other atypical psychotic medication studies showed a mixed picture, indicating some benefits, but maybe only at earlier stages in treatment. This is interesting and could hint at the changing dopamine receptor profiles through illness and recovery. The dopamine system adapts to nutritional and hormonal state, and medication that can adapt to changing neurotransmitter receptor dynamics could be specifically beneficial to target illness behaviors. A new category of dopamine agents are the so called dopamine stabilizers that adapt to the synaptic dopaminergic tone with dopamine agonistic and antagonistic properties [45]. Those agents, that include aripiprazole and brexiprazole are such dopamine stabilizers and could have a role in anorexia nervosa treatment across illness stages and associated neurotransmitter adaptations. The referenced retrospective chart review in adolescents with anorexia nervosa suggests that this group of medications could be beneficial to support recovery even in high level of care settings.

3.4. Agents to Target Endocrinological Alterations

Anorexia nervosa is associated with multiple endocrinological abnormalities, which could affect brain function and behavior [46]. The gut hormone ghrelin is produced in stomach and pancreas to stimulate food intake, and a recent study by Paslakis et al. could link this hormone to decision making in anorexia nervosa [47]. A recent controlled trial by Fazeli et al. showed improved gastric emptying but only trend level weight gain benefits from application of the ghrelin agonist relamorelin (10 patients on active drug, 12 on placebo, 4 weeks duration, mean daily dose 100ug) [48]. It is unclear whether a longer duration of medication application beyond 4 weeks might have led to significant results. Sex hormone levels are low in anorexia nervosa and frequently leading to amenorrhea as well as low bone density. Those hormones such as estrogen and testosterone have also multiple behavioral effects. In one randomized controlled trial by Misra et al. estrogen application reduced trait anxiety but had no specific effects on eating disorder behaviors or weight (38 patients on active drug, 34 on placebo, 18 months duration, 100ug twice weekly) [49], although Klibanski et al. had not found estrogen effective to improve bone mass or body weight earlier. Dehydroepiandrosterone (DHEA) is a steroid hormone intermediary in the production of sex hormones. A small but controlled study by Bloch et al. indicated improved weight gain over placebo in the DHEA group and Gordon et al. found that DHEA may improve bone health in anorexia nervosa [50, 51]. Unfortunately, a recent large study by DiVasta et al. that compared DHEA plus estrogen against placebo in adolescent anorexia nervosa (35 patients on active drug, 35 on placebo, 12 months duration, mean daily dose DHEA 50 mg + 20 mcg ethinyl estradiol/.1 mg levonorgestrel) showed no benefits of hormone replacement on bone development [52]. Miller et al. had found in a pilot study that testosterone improved spatial cognition and mood [53], but a recent large controlled study by Kimball et al. (42 patients on active drug, 46 on placebo, 24 weeks duration, mean daily dose 300 ug testosterone patch) showed that testosterone application in anorexia nervosa is associated with worse weight gain and application of this hormone seems contraindicated in the disorder [54]. Another hormone, human growth hormone was hypothesized to be beneficial for AN but was not superior to placebo in a pilot study with respect to weight recovery, although cardiovascular normalization occurred faster [55]. Another hormone, oxytocin, is produced by the hypothalamus and affects social behavior and cognition. Social cognition, the cognitive processes about how we relate to others, has been found impaired in anorexia nervosa when ill and after recovery. Research is inconclusive whether oxytocin is altered in anorexia nervosa and whether it is part of the disorder’s pathophysiology [56, 57]. A series of double-blind studies by Kim et al. indicated that oxytocin may reduce attention bias to disgust in both anorexia nervosa and control groups, suggesting that in anorexia nervosa, oxytocin reduced attention bias to food and body-related stimuli but it had no effect on emotion recognition or food intake [58–60]. Other studies by Russell or Leppanen et al. did not support the use of oxytocin for weight gain in anorexia nervosa or behavior domains such as anxiety [61–63].

3.5. Other Agents

Various agents targeted learning, anxiety or neural protection. Serum zinc levels are low in anorexia nervosa and could be causing alterations in neurotransmitter function and learning, but supplementation studies were inconclusive [21]. The glutaminergic NMDA agonist d-cycloserine had previously been shown to augment fear extinction in classic anxiety exposure treatment and in a randomized controlled study that used food exposure and d-cycloserine or placebo (20 patients on active drug, 16 on placebo, 4 exposure sessions, 250 mg 1 hour before exposure therapy session), the active treatment group showed greater weight gain after four exposure sessions and at one-month follow-up [64]. This approach could hold promise or future studies, but no follow up studies have been published.

Omega-3 fatty acids are important building blocks for brain development and restoring a deficiency due to malnutrition in anorexia nervosa had been hypothesized to maybe improve illness behavior such as high anxiety. Manos et al. conducted a controlled study over a 12-weeks period supplementing 2,120 mg eicosapentaenoic acid/600 mg docosohexaenoic acid daily (12 patients on active drug, 12 on placebo), but active supplementation could not be distinguished from placebo as trait anxiety decreased in both groups similarly [65]. Another recent nutritional supplement study compared the amino acid tyrosine, a precursor for dopamine, with placebo in a double blind cross over design (19 patients, 3 weeks duration, 100mg/kg/day) and reported improved depression ratings [66]. Overall, the benefits of nutritional supplements in treatment for anorexia nervosa remain uncertain and the small study sizes have been prone to error.

4. The Case for a Different Approach to Medication Studies and Treatment in Anorexia Nervosa

4.1. Multiple Systems are Involved in Anorexia Nervosa Pathophysiology.

Anorexia nervosa is a psychiatric disorder with a complex bio-psycho-social background. Various models have discussed how biology and behavior might be involved in the etiology of anorexia nervosa [67, 68]. A recent model for the development of anorexia nervosa proposed that there is a disease progression from a conscious motivation to change eating and losing some weight, to a vicious cycle that includes changes in neurotransmitter systems and hormonal function, which instead of stimulating food intake, drive anxiety in anorexia nervosa and further food avoidance [69]. That model (shown in Figure 1., used with permission) is based on empirical human behavior and brain imaging data, and integrates basic neuroscience. An important message that this model conveys is that the various neurotransmitter and endocrine alterations that occur during the illness likely interact with behavioral traits and promote the vicious cycle of weight loss in anorexia nervosa. Although those biological alterations often normalize with weight recovery, they may interfere with normal cognitive-emotional and food seeking behavior during the ill state and impede recovery and weight restoration [46]. This possibility led this author to the hypothesis that maybe more than one biological system needs to be targeted simultaneously to stabilize brain homeostasis to support healthy behavior as opposed to food restriction that frequently leads to death.

Figure 1.

A schematic model for disease development and maintenance in anorexia nervosa. After deciding to change eating behavior and lose weight, endocrine changes occur that signal the need to eat; the dopamine system gets activated to support the motivation to seek out food; perfectionism and high anxiety mediate the transition to developing AN core behaviors while the original conscious motivation is sustained. Weight loss briefly alleviates anxiety and reinforces food restriction. However, gut hormones and dopamine that stimulate food seeking, elevate anxiety and subsequently elevate AN core behaviors. Anxiety triggers a food-control circuitry from ventral striatum to hypothalamus that depends on dopamine D1 receptors, which have been sensitized in the context of food restriction. Anxiety gets further elevated in the illness process due to the possibility of loss of control and weight gain, and this becomes a self-reinforcing process. Ongoing food restriction and weight loss perpetuate the cycle. Reproduced from [69] with permission of Elsevier.

4.2. The Call for Reconceptualization of the Underlying Pathophysiology

The severity of the illness and the lack of effective treatments has led to several researchers calling for reconceptualization of anorexia nervosa’s psychopathology. Bulik et al. have focused on studying metabolic aspects of anorexia nervosa and a very recent genetic study supported this, showing that the genetic background of anorexia nervosa shows an interplay of genetic risk loci that have been found associated with both metabolic and psychiatric disorders [70, 71]. A genetic study by Steiger et al. on DNA methylation showed that in a group of underweight individuals with anorexia nervosa genes involved in lipid and glucose metabolism, serotonin neurotransmitter system and immune function were both altered compared to controls, while those abnormalities tended to be normalized in a group of individuals who had recovered from anorexia nervosa. Monteleone et al. also called for a re-conceptualization using a different approach and performing a so-called network analysis and a large behavioral assessment battery [72]. They found that aside from eating disorder core symptoms, depressive and anxiety symptoms are closely related to the illness and may need to be incorporated in the overall conceptualization of the illness. Taken together, there is now increasing evidence that several body systems are involved in the pathophysiology of anorexia nervosa. Importantly, those systems affect brain neurotransmitter function and thus likely also behavior. Those studies and the lack of effective treatments for anorexia nervosa suggest that we need innovative approaches to treatment that may go beyond a one disorder – one treatment approach and may in fact be comprised of several interventions to improve outcome of anorexia nervosa [73].

4.3. Single Versus Multi Intervention Research

Psychiatric disorders involve complex interactions of predisposing behavioral traits, environmental factors, normal or pathologic developmental changes, hormonal variations, etc. that in combination may trigger illness and contribute to short and long term outcome [74]. Pharmacological or psychotherapy trials typically target a narrow range of systems or circuitries and usually only one intervention is tested at a time. This is to be scientifically rigorous and identify specific behaviors that can be changed using a certain biological or psychological approach and ideally target a specific brain circuitry. However, one treatment target is often not enough. For instance, depression and anxiety research had shown that a combination of psychotherapy and medication treatment is beneficial for a subgroup of patients who show treatment resistance, although head to head trials are sparse [75]. Furthermore, while polypharmacy, using more than one medication at a time for a condition is usually not recommended, it has been recognized that such an approach can be helpful and for instance reduce rehospitalization for individuals with schizophrenia [76].

Several studies found that prescription of psychotropic medications is frequent in anorexia nervosa despite the lack of FDA approved medication specific to the disorder [77, 78]. Whether all polypharmacy is to be avoided in anorexia nervosa or whether there are medication combinations that do promote improved outcome needs further research as recognized in psychiatry in general [8]. For instance, the above studies were not designed to discern whether those on medication were more severely ill, or had higher comorbidity. The finding that depression and anxiety predict negatively treatment outcome in anorexia nervosa and comorbid psychiatric disorders in general are associated with higher mortality in the disorder would support the use of medication to target those conditions [79, 80]. Research may have to adapt and focus more on outcome measures that go beyond weight gain and include quality of life, and mood and anxiety measures when studying medication interventions in anorexia nervosa. This is crucial to try to prevent weight loss and relapse after significant resources have been invested in high level of care settings to nutritionally rehabilitate a person with anorexia nervosa.

4.4. Potential Targets for Novel Research Directions

Figure 2. shows a schema of potential treatment targets and how we might be able to manipulate those therapeutically. Importantly, it is possible that a combination of treatments is or will be necessary to make treatment outcome in anorexia nervosa more successful.

Figure 2.

Therapeutic targets for a multi-intervention approach. Research will have to study combination treatments and target several systems simultaneously to develop innovative treatment approaches.

Well known treatment strategies include a multidisciplinary team with psychiatrist, psychotherapist and dietician to support the process of nutritional rehabilitation. Frequently prescribed in clinical practice are SSRIs to treat comorbid anxiety, depression or obsessive compulsive disorder, but as pointed out above, research is lacking that specifically studied medication effects on comorbid conditions as mediators or moderators for illness outcome.

Benzodiazepines are also frequently prescribed but little information exists on using this class of medication as an adjunct treatment. Benzodiazepines are commonly only distinguished by their half-life, but there are also differences by individual benzodiazepine regarding pharmacodynamics and behavior effects, which has not been well researched [29]. The only benzodiazepine formally studied in anorexia nervosa is clonazepam in a small pilot trial [31]. Recent studies indicate that benzodiazepine subtypes not only differentially bind to GABA receptor subunits, but also affect the immune system differentially. For instance, lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, act as neuroimmune-modulators during psychosocial stress but via different mechanisms [30]. The immune system has received renewed attention for its ability to modulate neurotransmitter function and subsequently behavior [81]. It is possible that altered cytokine levels have important functions in perpetuating the illness when underweight. Thus, treating anxiety via modulation of the immune system aside from GABA receptor stimulation could be a factor to improve brain health and outcome in anorexia nervosa. There is concern about the addiction potential of benzodiazepines, but research has shown that not all subtypes have similar tolerance potential, and research in clinical populations on this question is clearly lacking [29, 82]. One could also argue that when weighing the modest risk of addiction from an overall safe medication against high risk from death from severe food restriction, treating the latter should be of higher concern.

The described recent genetic studies have indicated involvement of metabolic systems and research will have to investigate whether there are factors of abnormal body homeostasis that “make severe weight loss possible” and that hinder weight gain. Olanzapine in the outpatient setting may have beneficial effects and research should test whether it is metabolism or appetite regulation that are targeted by olanzapine or whether other systems and mechanisms are at play. Hormones that affect body homeostasis, digestion, stress and sex drive are altered in anorexia nervosa and can affect brain function and neurotransmitter systems [46]. Their replacement has not shown strong benefits as laid out above. However, it is possible that normalizing hormonal function could at least improve some symptoms and quality of life by for instance improving gastric motility. Gastrointestinal discomfort is one of the most common complaints during anorexia nervosa treatment and specific hormonal or maybe enzymatic interventions should be researched to improve quality of life and facilitate the recovery process [83]. Those symptoms also often stimulate body image distortion, and relieve from the gastrointestinal discomfort could reduce core eating disorder symptoms.

The poor insight into the illness and some individuals reporting a psychotic quality of body image distortion suggests that medication that can improve insight and learning could be instrumental in facilitating treatment as psychotherapy involves learning new behaviors. The illness is associated with a multitude of alterations in neurotransmitter metabolism and neurotransmitter receptor availability and medication that improves or reinstates a balance between neurotransmitter systems could be highly beneficial in supporting emotional stability. A new group of medications has been identified, the so-called dopamine stabilizers, which could have a critical role in supporting brain health in anorexia nervosa. Those agents include aripiprazole, brexiprazole and cariprazine [84]. Animal models have shown that weight loss is associated with physiological changes in the body and the brain reward circuitry, including dopamine release and receptor function. Anorexia nervosa is also associated with low gonadal hormones and basic science has suggested that females at low weight and low sex hormone levels show altered learning including reward learning [85–88]. Dopamine D1 and D2 receptor stimulation can facilitate learning and fear extinction especially in females in a low estrogen state [89–91]. Psychotherapy of anorexia nervosa is designed to reinstate normal eating behavior and extinguish fears of getting fat by exposure to food stimuli and eating and dopamine agonists could facilitate this process [92]. Application of dopamine receptor antagonists such as antipsychotics that block the dopamine D2 receptor may increase dopamine system activity but application of dopamine receptor agonists could result in reduced response sensitivity [93, 94]. Such dopamine receptor down-regulation in anorexia nervosa then might aid in habituation to re-feeding and fear extinction [87], reduce conditioned fear response [95, 96], and reduce cognitive rigidity [97] and body image distortion [32]. Human brain imaging studies support so far, the hypothesis of elevated dopamine system responsiveness in anorexia nervosa and the potential usefulness of dopamine agonists [98, 99]. Furthermore, most recent basic research in mice found dopamine D2 receptor overexpression in an anorexia nervosa rodent model, showing that this receptor was associated with weight loss and altered glucose metabolism [100]. Those studies lend further support to the hypothesis that the dopamine system may have a central role in the pathophysiology of anorexia nervosa.

Lastly, novel interventions that include transcranial treatments such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) could support normalization of altered electric and chemical neuronal activation and signal transduction and facilitate psychotherapy by improving neuroplasticity [101].

4.5. Patient Oriented Precision Psychiatry

We are still far from a comprehensive disease model that can be used for guidance what novel interventions to apply in anorexia nervosa in general or how interventions could be tailored to specific patients based on their individual neurobiological background. Developing research to test combinations of treatments that target several biological systems may be key to identify more effective treatment models. Furthermore, conducting studies that are able to investigate biological and associated psychological and environmental factors in individual patients will be challenging, yet essential. There are several steps how we could move toward this goal. A path toward successful new interventions could be large scale longitudinal studies that use cellphone based Apps and the combination of in person visits, biological and behavioral assessments [102]. Such studies hold much promise to identify general and person specific targets to improve treatment outcome. This would also help develop registries of individuals with anorexia nervosa to follow them over years and while they go through illness or recovery and various treatment approaches. Another important direction is to use improved animal models for anorexia nervosa in parallel to human research. Recent studies have shown that use of mice may be more reflective of human neurobiology compared to other rodents [100]. This research will help better understand the interactions of neurotransmitter, metabolic and immune systems in the underweight state and whether specific interventions can promote weight gain and recovery to translate into human studies.

5. Conclusion

Despite the lack of approved medications for anorexia nervosa, there are some promising directions forward. Especially the dopamine system in conjunction with medications to modulate GABA neurotransmission could be beneficial to improve learning and behavior change, as well as normalize altered metabolism in anorexia nervosa. Those medication interventions, however, are unlikely to lead to large treatment improvements alone but may be best used in combination with psychotherapeutic and other pharmacological interventions. This hypothesis has to be studied systematically and in conjunction with improved animal models for anorexia nervosa.

6. Expert Opinion

Pharmacological treatment in anorexia nervosa is associated with a variety of hurdles. Individuals with anorexia nervosa frequently are hesitant to engage in any treatments as the idea of weight gain and recovery is experienced as anxiety provoking. Thus, the provider’s first step in the process of making decisions on prescribing medications is developing a very strong therapeutic bond where the patient learns to trust and feels safe enough to accept recommendations at all.

After a careful psychiatric assessment and discussion of diagnoses identified and treatment alternatives, a review of the current medication regimen will then identify what medication is currently helping, or what has helped in the past and for what. The next step is to identify treatment targets and what the patient would like to benefit from using medication. This is a crucial step as weight gain for instance is not something that many patients can immediately commit to, and help with anxiety or depression could be a good first step. Personally I am cautious with medication recommendation if a person has a recent onset of anorexia nervosa or has not had psychotherapeutic interventions before, except there is severe and longstanding comorbidity. However, medication indication needs to be assessed ongoing and revisited.

The frequently encountered premorbid generalized anxiety disorder or a depressive disorder is often of clinical significance [80]. Despite the lack of formal studies, SSRIs are often reported as beneficial by the individual and improving quality of life, although having maybe no effect on weight gain. Patients with anorexia nervosa who tend to be terrified of taking a medication that is associated with weight gain find medications such as the selective serotonin or serotonin/noradrenaline reuptake inhibitors as first line agents for anxiety and depression less anxiety provoking than other medications and they are usually well accepted. However, some may get some appetite suppressant effect out of noradrenaline reuptake inhibitors and caution is advisable.

Benzodiazepines can be very helpful in reducing worries or panic attacks and help patients to stay engaged in treatment. Individuals with personality traits of unstable emotions such as borderline personality disorder can often benefit highly form those medications to avoid self-harm or suicidal behaviors. The explicit goal in the treatment contract is to use those medications only temporarily and eventually replace them with SSRIs and work in psychotherapy. Reality, however, is that some individuals are very unstable, and medication may be necessary for some time. This has been my experience especially for individuals with very unstable support systems. The addiction potential of benzodiazepines has to be considered, especially in patients with an alcohol or substance use disorder history. However, especially individuals with restricting type anorexia nervosa show a high motivation to not take those medications. Basic science has shown that lorazepam has a lower tolerance potential than other benzodiazepines and is my preferred agent in that medication group if clinically indicated [29]. An alternative rescue medication for acute distress can be the antihistamine hydroxyzine that is without obvious biological addiction potential, but it tends to be less effective. Key is to set the stage at the beginning of prescribing for how long the provider envisions prescription of the medication, what the specific treatment goals are and what the plan is to gradually wean off the benzodiazepine or replace with other interventions.

The recent studies by Attia et al. [36, 37] suggest that olanzapine should be considered as a medication for outpatients with anorexia nervosa. That study used between 2.5mg and 10mg olanzapine daily and may affect metabolism to promote weight gain. The dopamine D2 receptor partial agonist aripiprazole might be beneficial in anorexia nervosa treatment for individuals in higher level of care to facilitate psychotherapy [44]. We have started to regularly suggest a trial of aripiprazole to individuals with anorexia nervosa who have great difficulties with engaging in treatment, have been relapsing and being overwhelmed by preoccupations with fear of weight gain and drive for thinness [44]. The patients themselves anecdotally reported that they “feel less anxious around food”, their “rational mind” is better and therapists have reported that patients are more engaged in treatment. Typically one can start at 1mg by mouth at bedtime and increase to 1mg twice a day. The split dosing reduces side effects and some patients report immediate effects from the medication. When underweight, the medication may be increased gradually to 2.5mg twice a day. When patients reach normal weight then a higher dose may be beneficial, typically between 5 mg and 10 mg at bedtime, once a day dosing. Whether newer dopamine stabilizers such as cariprazine or brexipazole may be beneficial will be a target for future study.

Article highlights box.

• Anorexia nervosa has the highest mortality among the psychiatric disorders and new research directions are needed to develop more effective treatments.

• Novel research indicates specific alterations in neurotransmitter function, hormone release and metabolic processes in anorexia nervosa that could be targeted therapeutically.

• The high mortality of anorexia nervosa and the lack of effective treatments suggest that research should be conducted that tests combinations of treatments and how pharmacological interventions could facilitate psychotherapeutic approaches.

• Basic science research needs to be further developed that parallels human studies and vice versa to better understand the interactions between neurobiology and behavior.

• Despite the lack of FDA approved medications for anorexia nervosa, the prescribing clinician should carefully assess and treat comorbid conditions with the rationale that this will help improve quality of life and hopefully make recovery from the eating disorder more successful, although the latter is uncertain.

• New understanding of the actions of atypical antipsychotic or benzodiazepine medications may open new avenues to add in the treatment of anorexia nervosa.