The True Neural Cause of Anorexia Nervosa: Why Medication Doesn't Work
Anorexia: A Complex Phenomenon
Anorexia nervosa (AN) is an insidious disease, featuring self-imposed restrictive eating, emaciation and an array of psychological symptoms. Apparently immune to hunger cues, anorexics very rarely binge-eat and remain in a negative energy balance. This distinguishes the disorder from bulimia and binge-eating disorder, both of which involve a strong degree of food addiction, impulsivity and a pull towards palatable foods that anorexics lack entirely (Glazer et al., 2019).
Even if full nutritional and physical recovery is achieved, anorexics are extremely prone to relapsing because the root cause of their disorder lies in their mindset and psychology. Only 50% of anorexics achieve long-term weight restoration (Couturier, 2006), and 40% of those who do admit to still focusing intently on their weight (Startup et al., 2013).
While environmental factors like stress and the societal pressure to be 'skinny' can trigger the onset of active AN, anorexics are born with a genetic disposition that renders them vulnerable. An individual with the intrinsic neural makeup of an anorexic is a ticking time-bomb. Regardless of when, a stressor or difficult life period will most likely come along and precipitate the onset of ritualized calorie-counting.
In this article, I intend to shed light on the true neural cause of AN and the reason why current treatment paradigms fail to treat it effectively. There is hope; the overlap between psychology and neuroscience is ever-growing, and flawed psychiatric dogmas are being dispelled. Only by observing AN from a new and unjaded perspective can we succssfully teach anorexics how to thrive in life and leave restriction behind.
A Specific Mentality Precedes (and Causes) Anorexia
Witnessing a loved one plunging into the grips of active AN is not only devastating but also wildly frustrating, since the sufferer will reject interventions and adhere rigidly to food restriction. Even witnessing just one anorexic with a skeletal frame refusing to eat will lead to you wonder how and why someone starving can deny their body of such primitive needs.
After all, many people suffer from body dysmorphia and the plaguing desire to be slim, but the vast majority turn to temporary dieting and inevitably binge when hunger takes over. Many people cannot even lose 2 pounds after festive over-eating; food is too attractive, and willpower insufficient.
In the face of intense emotional stress, only a tiny percentage of people develop AN (0.3% of women). What separates anorexics from healthy individuals, chronic dieters, obese binge-eaters and bulimics (1-3% of women), none of whom could maintain starvation for years even if paid millions of dollars (Hudson et al., 2007)?
The answer lies in the stereotypic disposition that can be observed in patients years before the illness starts, which SSRI therapy cannot treat. Anorexics are perfectionistic, harm-avoidant, intelligent and (crucially) capable of adhering to long-term goals (Winecoff et al., 2015). I will focus on the different facets of said mentality, elucidating why each personality trait primes the individual for such an unwavering adherence to self-starvation.
1. Perfectionism and Motivation
Understanding the neural and psychological factors that underpin the ability to a). self-starve and b). gain immense satisfaction and comfort from doing so is the only way to comprehend and treat the anorexic mentality. When considering AN risk factors, much past research has failed to distinguish between pre-existing personality (trait-related) factors and psychological manifestations of the disease.
Longterm malnutrition will produce transient psychological symptoms and abnormal behaviors; high plasma cortisol levels (hypercortisolemia) can be considered a hallmark of active AN, since starvation affects adrenocortical function and increases activity of the hypothalamic-pituitary-adrenal axis (Tomiyama et al., 2010). However, it is certain that neural abnormalities precede AN and are causal to the disorder.
Anorexics are prone to a marked degree of perfectionism, which manifests itself in different ways before and during the illness. Excelling in whatever they channel their unwavering focus into, many anorexics commit to hours of sports during their childhoods and enjoy competing. It is predicted that around 60% of anorexics were competitive athletes prior to the development of restrictive eating habits (Davis et al.,1994).
Both academic excellence and a strong work-centered drive are typical prerequisites to AN; a Swedish 2015 involving 1,800,643 individuals found a marked positive correlation between high school grades and the teenage onset of AN (Sundquist et al., 2016).
2. Immunity to Palatable Foods
Millions of years of evolution have primed us to crave and enjoy hyper-palatable foods to promote our survival. Despite possessing underweight BMIs, anorexics respond paradoxically to such appetitive stimuli and actively prefer low-fat and low-sugar foods. When asked to rate different foods, they show a strong preference for low-caloric-density options such as cucumber and rate these as tastier than healthy controls do (Holsen et al., 2012).
Drawing conclusions from patients' self-reported attraction to such foods would be spurious, since they could be secretly desiring a substantial meal but scared of weight gain. However, the presence of this abnormal response in the face of palatable and high-calorie foods can also be observed at the neural level.
Healthy control individuals find a 10% sucrose solution pleasant and slightly addictive; following consumption, an increase in activity can be seen in brain regions that pertain to gustatory reward processing (the caudate, putamen, cingulate cortex and insula). In unwell and weight-restored (WR) anorexics, an abnormally low response is seen in these areas (Wagner et al., 2008).
This points towards the possibility of anorexics possessing an inherent, preexisting resilience to palatable foods that other individuals do not have (notably bulimics, who are assumedly subject to the same self-imposed goal of weight loss, yet simply cannot maintain starvation without bingeing). However, such results must be interpreted with great caution, because malnutrition leads to potentially-permanent changes in brain morphology.
Some people who abuse drugs such as methamphetamine never regain their normal appetite cues and reward processing; it is conceivable and likely that a stressor as intense as years of starvation could render an anorexic permanently brain-damaged. In this way, the aforementioned abnormal responses to palatable foods may be a scar from the illness rather than being causal to its etiology.
3. Generalized Lack of Hedonic Drive
Often described as ascetic (capable of extreme self-discipline), anorexics' apparent lack of pull towards temptation extends far beyond the realm of food. They are often socially anhedonic (when unwell and when WR), garnering little pleasure from spending time with others and exhibiting a low degree of venturesomeness (Tchanturia et al., 2012).
It appears that two main factors contribute to this phenomenon: a). the sense of wellbeing that they achieve from goal accomplishment (whether academic or food-based), seeing pastimes as mindless obstacles in the way of success and b). an absence of impulsive tendencies. To clarify, impulsivity can be considered an umbrella term that not only underpins states of repetitive action (such as OCD rituals and binge eating), but also a general willingness to be spontaneous.
People higher up the impulsivity scale are easily pulled towards the many types of salient stimuli that surround us. Bulimics are, of course, an archetypal example of heightened impulsivity, since the disorder can be considered an addiction to palatable foods. Significantly more bulimics fall into alcohol, gambling and drug addictions than healthy controls, with no such pattern seen in anorexia (Goodman, 2008).
Since restriction oddly stabilizes an anorexic's mood and renders them satisfied, a great degree of discomfort and dysphoria is experienced in the face of anything that threatens their advancing weight-loss trajectory. Anorexics often display a long-term and unwavering preference for solitude, strangely appearing to lack the innate human need for light-hearted socializing. Since they are also remarkably immune to risk-taking, it seems that a generalized atypical response to interesting stimuli is a prerequisite to the onset of AN (Hinvest et al., 2011). Keep reading to discover the probable neural basis of this and the reason why medication does not help.
4. A Tendency to Enjoy Physical Exercise
Unwell anorexics expend more energy in the form of walking and running than healthy controls (Casper et al., 1991), despite this going against the body's natural mechanisms to promote survival.
Anorexics fidget, pace, walk and climb stairs obsessively. Is such motoric restlessness completely voluntary, and nothing more than an attempt to expend calories, or could anorexics be particularly prone to such movements? After all, children who later become anorexic typically thrive in competitive sports, and the compulsive movements of AN mimic those induced by amphetamines.
Before conjectures can be made about the potential neural blueprint for this phenomenon, it must be remembered that starvation itself induces endocrinological changes that promote restlessness and a 'drive for activity'. Prolonged fasting heightens cortisol levels (hypercortisolaemia), in addition to stimulating the sympathetic nervous system and increasing dopamine and norepinephrine activity (Tomiyama et al., 2010); this is all an attempt to increase the motivation and perceived energy of the individual, which in normal circumstances would allow them to keep seeking food despite a weak nutritional status.
The Traditional View of Anorexia
Certain parallels can be drawn between obsessive-compulsive disorder (OCD) and AN; both disorders dysphoria-inducing intrusive thoughts and the carrying out of rituals to soothe one's mood. OCD is, in fact, fifteen times more prevalent among unwell anorexics than in the general population (Serpell et al., 2002). Much research into the neural cause of AN has, therefore, assumed that anorexia is simply the result of an OCD mentality channeled into food control. In line with this, AN is currently pharmaceutically treated in the same way as OCD; the issue is, medications that successfully halt repetitive OCD behaviors are ineffective in preventing AN relapses.
Why? First, we must consider the likely root cause of OCD. It is believed that abnormal neurotransmitter signaling in the corticortico-thalamo-striatal-cortical circuitry underpin the impulsivity and compulsions implicated in the disorder (Rosenberg et al., 2001). While glutamate and dopamine activity contributes to symptomology, abnormally low serotonin levels in the caudate and putamen (dorsal striatum) are thought to be key drivers of the onset of symptoms. For this reason, OCD is treated relatively successfully with selective serotonin reuptake inhibitors (SSRIs). Around 60% of patients experience significant relief from paroxetine, fluoxetine (Prozac), sertraline and fluvoxamine (Bloch et al., 2010).
The low-serotonin hypothesis of OCD can be put to further test through employing animal models and altering the orbitofrontal cortex (OFC). This brain region directly projects to the dorsal striatum to release serotonin, so disturbed OFC function results in lower striatal concentrations of serotonin. Intentionally disturbing the OFC in rats precipitates obsessive pressing of a level to obtain a food reward, which ends upon the administration of paroxetine (Schilman et al., 2010).
Anorexia: Far From Being OCD
Despite both disorders symptomology in common and the development of both often aligning with teenage stress, AN cannot be considered one mere possible outcome of OCD. While many different types of compulsive behaviour can be seen in OCD, this is not true of AN; obsessions with contamination and security and consequent rituals are not seen in AN (Cottraux et al., 1996). Most manifestation of obsessive behavior in AN pertain to order and symmetry, with autism interestingly being a frequent comorbidity.
Anorexics are far disturbed by images of disordered and 'messy' rooms than healthy controls, but respond normally to ones of orderly scenes (Suda et al., 2014). The reality is that AN involves perfectionism, an obsession with weight loss and adherence to an austere lifestyle, while less 'meditated' impulsivity drives OCD (and bulimia, too; both involve causal low serotonin levels).
Many pharmaceutically-funded studies on the success of SSRIs in treating AN are open-label studies, meaning that subjects are aware that they have been given the drug. Within psychiatry, this type of study is entirely void of legitimacy because the placebo effect experienced by someone who knows they have been given a mood-altering drug will be extremely marked.
When popular SSRIs are administered to unwell and weight-restored anorexics in double-blind, placebo-controlled trials, they fail to prevent relapse rates. In fact, a 2006 study on fluoxetine saw patients finishing with a lower mean BMI after taking the drug compared to the placebo group, suggesting it could even worsen the neurotic AN mentality (Walsh et al., 2006). Sertraline does not decrease post-recovery relapse rates nor does it lower scores in a perfectionism test (Holtkamp et al., 2005).
The Surprising Role of Serotonin in Anorexia
It is clear that the AN mentality is not driven by low levels of serotonin, since SSRIs fail to successfully treat and prevent relapses. Interestingly, it is believed than an overdrive (excess) of serotonin may, instead, play a causal role in the pathophysiology of the disorder. High intrasynaptic concentrations of serotonin can contribute to harm-avoidance, perfectionism and reduced appetite; the latter may explain patients' apparent iron willpower in the face of food temptation (Frank et al., 2001).
Tryptophan is the precursor to serotonin and can be obtained through diet; it is present in fish, seeds, oats, turkey, eggs and cheese. Since low level of this amino acid are found during prolonged starvation, AN involves lowered serotonin concentrations. Fascinatingly, acute tryptophan depletion (i.e. abstaining from tryptophan while still consuming other amino acids) significantly lowers self-reported anxiety in anorexics, compared to a placebo (Walter et al., 2003).
Since most anorexics eat normally before falling ill, it would be hasty to conclude that anorexics feel better when starving solely because of this imbalance (and that AN is simply an attempt to self-medicate an overdrive in serotonin). Anorexics' keen goal-adhering capabilities play a key role in sustaining AN, in addition to the societal concept of the 'perfect' body type.
However, it does seem that this intrinsic abnormality in serotonergic signaling is a prerequisite to AN; it would explain why starvation provides the anorexic with such a strong sense of peace and mental stability that goes further than the satisfaction gained from the consequent weight loss. Anyone who has observed an anorexic in the throes of the illness will tell you that the disorder extends far beyond a 'desire to diet'; the complexity of the neurobiology underpinning it can be grasped from mere observation of a starving patient refusing to eat a spoon of yogurt.
In addition to indicating why anorexics may become so dysphoric following eating, high serotonin levels would also be conducive to the self-disciplined and perfectionistic facet of AN.
Unusual Dopamine Activity in Anorexia
Anorexics are academically-inclined, productive and show a strong affinity for physical exercise and movement. As I have already discussed, this proclivity for goal-oriented focus contributes to the anorexic's ability to maintain such an austere lifestyle.
Altered dopaminergic activity in the midbrain and basal ganglia are known to precipitare various forms of obessive behaviour. Strong psychostimulants (e.g. methamphetamine) and agonists at dopamine receptors (e.g. apomorphine) can precipitate compulsivity in normal people (Goodman et al., 1990). The major dopamine metabolite (homovanillic acid) has been found to be significantly higher in the cerebrospinal fluid of anorexics, compared to bulimics and healthy controls (Castro-Fornieles et al., 2008).
Additionally, recovered anorexics experience significantly stronger symptoms of anxiety than controls when given amphetamine; the drug's principal mode of action is to increase dopamine release in the nucleus accumbens. The validity of such results is contestable, since many anorexics are cautious individuals and likely to be nervous after consuming a strong stimulant, but this nonetheless points towards the possibility of an overdrive in dopamine contributing to AN.
Interestingly, however, antipsychotic drugs (classical and atypical) that act as antagonists at different dopamine receptors fail to lower perfectionism scores in anorexics and prevent relapses (Kaye et al., 2009). We, therefore, cannot conclude that heightened dopamine concentrations are an obligatory prerequisite to AN; if this were the case, significant relief from the 'neurotic', goal-obsessed mentality would be instantly softened by such pharmacotherapy.
Rather, a more complex reward system dysfunction is most probably implicated, perhaps a). involving several dopamine receptor subtypes or b). involving heightened levels in some brain regions and low levels in others.
A New Way to View Anorexia
After spending a while immersed in scientific details, sometimes it helps to temporarily leave them behind and allow first principle thinking to take over. What exactly is the phenomenon that we call AN? How can we treat it when its pathophysiology is so complex and psychiatry so flawed?
Based on my experience with anorexic patients and an extensive amount of research, I firmly believe that we should deem AN the following: the result of self-discipline, motivation and a keen goal-oriented drive that has been channeled into food. The root cause of the disorder extends far beyond the mere desire to be slim, hence why therapy sessions tackling body dysmorphia also often fail to change the patient's eating habits. As we have seen, most anorexics excel far beyond their peers in school work and sports, due to them possessing this 'edge' (which is, itself, a double-edged sword).
Treating potential neurochemical factors that contribute to AN is unlikely to yield any significant success, when the truth is that driven, obsessive individuals who are prone to AN are always likely to relapse if vulnerable or unoccupied. They possess a mentality that would have served them immensely well in the hunter-gatherer period, when being committed and austere would have conferred them with an advantage in building a home and protecting their children. In those times, there was no social media, no concept of an 'attractive figure' nor the time or luxury to fall into the addiction of controlling one's caloric intake.
Speaking about the origins of the AN mentality is all well and good, but how can we be analytical and better treat anorexics? Inherently highly-strung, ambitious and self-critical, it takes a lot more than 'body positivity' to convince an anorexic to switch their lifestyle away from something so satisfying to them: weight loss, with the goal of absolute adherence. However, since the AN disposition is also correlated with intelligence, thorough hard work and success, anorexics can learn to thrive without restricting.
How Can An Anorexic Avoid Relapses?
In order for someone to exist in society with the AN mentality and not succumb to the lure of restricting, they must be living a life that is intensely rewarding to them. They must be engaging in a type of hobby, job or greater purpose that can consume them, become an addiction, and provide them with regular rewards and signs of progress in the same way that restriction and weight loss do.
Many treatment options focus on dulling the AN mentality and lowering their obsessiveness, but there is a strong duality to everything; these same traits that produce the nightmare that is the modern illness 'AN' are, in themselves, also capable of working well for the anorexic if food restriction can be avoided.
The issue is as follows: in this artificial, modern reality paradigm, mental sharpness and a propensity to overthink and obsess no longer serves us. We have food available in abundance, our families and children do not typically require our protection, and real, physical fighting is rare. In fact, none of us live in accordance with the neural makeup that we have acquired from our ancestors, hence why we suffer from seemingly absurd mental health issues such as panic attacks during exams and depression during otherwise-blissful summer holidays. Our brains are on alert in ways that are no longer necessary.
We all must strive to learn how to exist as we are in this modern society, without falling deeply into damaging addictions, lifestyles or eating disorders. Unfortunately, this will be more difficult for an anorexic than for the average person, but it is perfectly possible for an anorexic to recover, throw themself into a new lifestyle that serves their previously-unmet psychological needs, and never fall back into the grips of the illness.
Have you suffered from anorexia nervosa?
Wonderful video from Rebecca Leung describing her adherence to the new goal, recovery
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