Anorexia nervosa has the highest mortality rate of any mental disorder – new hopes

Eating disorder researchers at The University of Texas Health Science Center at Houston (UTHealth) have discovered a neurocircuit in mice that, when activated, increased their stress levels while decreasing their desire to eat. Findings appear in Nature Communications.

The scientists believe their research could aid efforts to develop treatments for a serious eating disorder called anorexia nervosa, which has the highest mortality rate of any mental disorder, according to the National Institute of Mental Health.

People with anorexia nervosa avoid food, severely restrict food, or eat very small quantities of only certain foods.

Even when they are dangerously underweight, they may see themselves as overweight.

“We have identified a part of the brain in a mouse model that controls the impact of emotions on eating,” said Qingchun Tong, PhD, the study’s senior author and an associate professor in the Center for Metabolic and Degenerative Disease at McGovern Medical School at UTHealth.

Because mice and humans have similar nervous systems, Tong, the Cullen Chair in Molecular Medicine at UTHealth, believes their findings could shed light on the part of the human brain that regulates hunger.

The investigators believe they are among the first to demonstrate the role of this neurocircuit in the regulation of both stress and hunger.

Because mice and humans have similar nervous systems, Tong, the Cullen Chair in Molecular Medicine at UTHealth, believes their findings could shed light on the part of the human brain that regulates hunger. The image is in the public domain.

While previous research has established that stress can both reduce and increase a person’s desire to eat, the neural mechanisms that act on the regulation of eating by stress-related responses largely remain a mystery.

Tong’s team focused on a neurocircuit connecting two parts of the mouse brain: the paraventricular hypothalamus, an eating-related zone in the brain, and the ventral lateral septum, an emotional zone in the brain.

The neurocircuit acts as an on/off switch.

When researchers activated the neurocircuit, there was an increase in anxiety levels and a decrease in appetite.

Conversely, when the investigators inhibited the neurocircuit, anxiety levels dropped and hunger increased.

The scientists used a research technique called optogenetics to turn the neurons in question on and off.

Yuanzhong Xu, PhD, the study’s lead author and an instructor at McGovern Medical School, said additional preclinical tests are needed to confirm their findings.

Coauthors from UTHealth include Yungang Lu, PhD; Ryan Cassidy; Leandra Mangieri, PhD; Canjun Zhu, PhD; Zhiying Jiang, PhD; Xugen Huang, PhD; and Nicholas Justice, PhD. Also contributing to the paper were Yong Xu, MD, PhD, and Benjamin Arenkiel, PhD, of Baylor College of Medicine.

Tong and Justice are on the faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences.

Funding: The study titled “Identification of a Neurocircuit Underlying Regulation of Feeding by Stress-Related Emotional Responses” was supported in part by National Institutes of Health grants (R01DK114279, R21NS108091, 5F31DA041703, and R01DK109934).

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Anorexia Nervosa (AN) is an eating disorder (ED) characterized by self-starvation driven by weight, shape and eating concerns and extreme dread of food, eating and normal body weight (American Psychological Association [APA], 2013; Walsh, 2013; Treasure et al., 2015b).

The annual United Kingdom female incidence of AN is approximately 14 cases per 100,000 (Micali et al., 2013), with up to 4% of women and 0.24% of men meeting the broad definition of AN in their lifetime (Smink et al., 2013).

The peak age of onset for girls is 15–25 years and for boys is 10–14 years (Micali et al., 2013). AN is associated with poor prognosis and the highest mortality rates of all psychiatric disorders (Smink et al., 2013).

The treatment of choice for AN is talking therapy (National Institute for Health and Care Excellence [NICE], 2017). Yet the disorder has poor rates of remission and high levels of relapse. Current psychological interventions facilitate small change, with better interventions needed (Bulik, 2014; Startup et al., 2015).

Although early intervention is key to recovery, there is an average delay of 18 months from symptoms emerging to treatment, followed by multiple relapses even following treatment, each lasting 6 years (PricewaterhouseCoopers, 2015).

Costs of AN and other EDs to the individual, family and carers, and society are therefore substantial.

Time spent caregiving for somebody with severe AN is almost twice that for somebody with a physical health disorder (e.g., cancer) or other mental health difficulty (e.g., psychosis; (Viana et al., 2013).

The annual cost to the United Kingdom economy is estimated to be £17.9 billion, offering a “compelling case for change” in services and treatment (PricewaterhouseCoopers, 2015, p. 9). There is now significant work underway in this vein; for example, the First Episode and Rapid Early Intervention for Eating Disorders (FREED; Brown et al., 2018).

Risk and Maintenance Factors Associated With AN

Anorexia Nervosa has been associated with numerous broad ranging risk and maintenance factors.

 Risk factors are variables which predict subsequent development of later pathology, in an individual currently disorder and symptom-free (Stice, 2002).

Risk factors can have effects mitigated by protective factors or amplified by potentiating factors. Maintenance factors predict symptom persistence versus remission over time in individuals already symptomatic for a disorder (Stice, 2002).

Clinical implications of risk and maintenance factors differ; risk factors are relevant to the development of preventative programs and maintenance factors to treatment interventions (Stice, 2002). While we do not fully review evidence for risk and maintenance factors for AN herein; we briefly indicate those most well-accepted and summarize them diagrammatically in Figure 1.

This reveals complex interactions between genetic, biological, psychological, and socio-environmental factors in the development and maintenance of AN, with some factors proposed to represent both risk and maintenance factors.

Current Clinical Perspectives, Models, and Treatment for AN to Date

Psychological models to date use existing psychological theory to address relevant risk or maintaining factors within clinical treatment for AN. Recent guidance published by National Institute for Health and Care Excellence [NICE] (2017) recommends the following psychological interventions be considered for adults with AN: Eating Disorder Focused Cognitive-Behavioral Therapy (CBT-ED); Maudsley Anorexia Nervosa Treatment for Adults (MANTRA); Specialist Supportive Clinical Management (SSCM); and Focal Psychodynamic Therapy (FPT).

CBT-ED traditionally focuses on symptom-based accounts suggesting both control and overvaluation of weight/shape maintain AN. Later revisions include: clinical perfectionism; low self-esteem; mood intolerance; and, interpersonal difficulties as additional treatment foci (Fairburn et al., 1999, 2003, 2009, 2015). Using cognitive and behavioral techniques, it seeks to increase motivation to change, directly enhance weight gain while tackling concerns about weight and shape and prepare for set-backs to maintain gains made (Fairburn et al., 2009).

MANTRA outlines a broader range of putative maintenance factors as treatment targets (Schmidt and Treasure, 2006; Wade et al., 2011; Schmidt et al., 2012, 2015; Treasure and Schmidt, 2013). Four core factors are included: (1) Rigid, detail-focused, and perfectionist information processing style; (2) Socioemotional difficulties (e.g., avoiding experience and expression of emotions within close relationships); (3) Positive beliefs about the value of AN; and (4) Close others exhibiting high expressed emotion or accommodating/enabling AN behaviors. These factors intensify once in a starved state, further maintaining them. The authors argue that CBT models miss important factors because key difficulties underlying EDs rarely concern ED-related themes (only 1%); with issues of interpersonal difficulties being more significant, including rejection and abandonment (42%); negative self-perception (22%); and emotional experience (20%; Sternheim et al., 2012).

Focal Psychodynamic Therapy employs three phases of treatment focussing upon relationships and breaking pro-anorexic belief and behavior patterns (Zipfel et al., 2014). Firstly, it concentrates upon relationship building, therapeutic alliance, identifying pro-anorectic behavior/beliefs and self-esteem. Secondly, relevant relationships are examined and links with AN beliefs/behaviors made. Finally, this is transferred to everyday life and a therapeutic ending.

Specialist SSCM (McIntosh et al., 2006) was originally developed as a comparison ‘treatment as usual’ for use in clinical trials. It combines clinical management and supportive psychotherapy to provide practical support and is not formulation-based; rather it focuses on psycho-education, resumption of eating and normalization of weight.

These treatment developments since the publication of previous NICE guidelines (National Institute for Health, and Care Excellence [NICE], 2004) represent obvious innovation in the application of empirical research to treatment models and clinical practice.

However, of these, there remains no clear front runner and it is uncertain which treatment best suits which sufferer of AN.

Results from randomized controlled trials (RCTs) indicate that these speciality out-patient treatments do not out-perform each other or control comparisons post-therapy or at follow-up (Carter et al., 2011; Schmidt et al., 2012, 2015; Zipfel et al., 2014; Fairburn et al., 2015).

They demonstrate only small non-significant effect sizes of change (Watson and Bulik, 2013), with around 20% of people weight-restored after 1 year (Schmidt et al., 2012, 2015; Zipfel et al., 2014).

Therefore, non-specific control interventions seeking to manage clinical symptoms (e.g., SSCM) appear as effective as complex, empirically driven models, prompting the inclusion of SSCM in NICE guidelines.

This falls short of advances made in outcomes from interventions developed for other Axis I disorders, including CBT for depression, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and Bulimia Nervosa (Butler et al., 2006).

Anorexia Nervosa is notoriously considered ‘difficult to treat’ and, as described, treatment outcomes indicate an unexplained discrepancy between theoretical models based on empirical data findings and clinical application.

It may be that even where causal models are available and appear robust, it cannot be assumed that derived interventions effectively manipulate targets.

Evidence of the impact of interventions upon proposed maintenance factors is absent in the field and not understanding how change is facilitated is a barrier to developing evidence-based interventions for AN (Pennesi and Wade, 2016).

Furthermore, speciality interventions developed to date tend to have complex hypotheses with many diverse target variables.

This potentially falls into the trap of an unhelpful ‘everything is relevant’ approach common in mental health research and results in the inclusion of many possible risk or maintenance factors into a causal model (Kendler and Campbell, 2009).

It produces heterogeneity across the delivery of an intervention creating difficulty in drawing links between outcomes and causal processes. In addition, while earlier models have sought to describe and address the current clinical presentation of AN, it is imperative that models offer strong theoretical bases and robust consideration of how AN has arisen; a paradigm that the ED field has not optimally employed (Pennesi and Wade, 2016). Previous models may fail to sufficiently consider and adequately account for etiology and phenomenology of EDs (Fox, 2009; Waller et al., 2010).

Like others, we therefore propose that any explanation for AN must include reference to phenomenological and interpretive aspects of the presentation (Amianto et al., 2016). Moreover, the definition and extrication of risk and maintenance factors is complex, especially for AN which is compounded due to its mixed psychological and physical presentation, and there is a paucity of research examining risk and maintenance factors by differential ED diagnoses (cf. Stice, 2002; Jacobi et al., 2004; Jacobi et al., 2011).

Risk factors can be potentiated once in the ill state, or mediated by other variables and maintenance factors can be generated as a consequence of AN, perpetuating the disorder (Wonderlich et al., 2005). Thus, key foci for clinical interventions are difficult to discern and may alter as the disorder progresses.

Building an explanatory developmental framework attempting to understand how factors link together to cause and maintain AN makes it unnecessary to distinguish between risk and maintenance factors and is therefore desirable.

We propose that an integrative account of the emergence of risk and maintenance factors and their interplay (including how this is potentiated once AN is established) is required to gain the necessary depth of understanding of the development and presentation of AN to develop and inform interventions.

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Source:
UT Houston
Media Contacts: 
Rob Cahill – UT Houston
Image Source:
The image is in the public domain.