Eating disorders are not a homogenous group but rather represent several distinct entities that present with different symptoms and involve different brain circuits. This article focuses on the known neurobiology associated with three of the most prevalent disorders—anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED)—and discusses the best-available targeted treatments.
Eating disorders affect all races, ethnic groups, and genders. In a 2007 study based on data from the United States National Comorbidity Survey Replication, lifetime prevalence estimates of AN, BN, and BED were 0.9%, 1.5%, and 3.5%, respectively, among women, and 0.3%, 0.5%, and 2%, respectively, among men.1 Although BED is the most common eating disorder, it was only formally recognized as a distinct eating disorder in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).2 During binge eating episodes, people eat rapidly until uncomfortably full and typically eat alone due to feelings of embarrassment. Episodes are followed by feelings of disgust or guilt and cause marked distress in the person. In BN, the binge episodes are followed by the recurrent use of inappropriate compensatory behaviors such as purging, excessively exercising, or misusing laxatives.2 Most people with eating disorders experience comorbid mental disorders, including major depressive disorder, anxiety disorders (particularly social anxiety), substance use disorders, posttraumatic stress disorder, bipolar disorder, obsessive-compulsive disorder, borderline personality disorder, and obsessive-compulsive personality disorder.2
AN has the highest mortality rate among all psychiatric illnesses.3 A meta-analysis of 36 studies found that the weighted annual mortality for AN was 5.1 deaths (95% confidence interval, 3.99-6.14) per 1,000 person-years, and 1 in 5 people with AN who died had committed suicide.3 AN is defined by restriction of energy intake relative to body requirements, which results in significantly low body weight. There is an intense fear of gaining weight despite the person's malnourished state, and the person has a disturbance in perceived body shape. The person's low body weight is not recognized as problematic and he or she does not recognize the severity of the progressing malnutrition or the signs of end organ failure. Extreme AN is defined as a body mass index of less than 15 kg/m2 and is associated with severe medical consequences.2
Children who later develop eating disorders often express certain temperament traits, which are genetically determined ways of responding to the environment.4 These traits are thought to present premorbidly to the eating disorder and persist after recovery; however, more studies are needed to confirm this hypothesis. High harm avoidance is a trait associated with all eating disorders. Other temperament traits associated with eating disorders include negative emotionality, perfectionism, inflexibility, and obsessive behaviors regarding order, exactness, and symmetry.5 People with AN have inhibitory self-control and reward mechanisms that manifest as a high punishment sensitivity and a low reward reactivity. This means that they are more motivated to avoid punishment than to be rewarded. Other common temperament traits, which are more often associated with BN and BED, include impulsivity, sensation seeking, and lack of planning and persistence.6
People with eating disorders have difficulties with “set shifting” and cognitive flexibility. Set shifting refers to the ability to move between multiple tasks and is a component of executive functioning. Studies have found that people with AN and BN have set shifting deficits and tend to be cognitively rigid.4,5 The difficulty with set shifting does not improve with recovery from an eating disorder, suggesting that it is a trait.4 It is important to note that a person's eating disorder symptoms and diagnosis may change over time (often from AN to BN),7 but temperament traits tend to remain constant and persist after recovery.4 Addressing underlying temperament traits in psychotherapy may be helpful in the multidisciplinary treatment of eating disorders.
Neurobiology of Anorexia Nervosa
The effects of malnutrition on the brain present as difficulty sustaining attention and concentration, psychomotor slowing, poor problem-solving, depression, and lack of insight.
Eating disorders can cause changes in brain volume. Brain imaging has shown that the insula, which processes taste and interoception, is enlarged in people with AN.8 The insula is an important structure that is thought to be disturbed in AN, leading to distortions in body image, lack of recognition of hunger/fullness cues and the symptoms of malnutrition, diminished motivation to change, alexithymia, and food aversion due to alterations in the taste-reward system.4 Severely malnourished people are often not able to initially benefit from psychotherapy due to cognitive impairment and may require nutritional refeeding as the primary treatment intervention.
AN may be associated with high anxiety premorbid to the illness, which persists after weight restoration. This anxiety is associated with altered brain functioning in the dorsal caudate and limbic regions of the brain and involves abnormalities in both the dopamine and serotonin neurotransmitter systems. Dopamine dysfunction in AN has been found to be associated with altered reward sensitivities and altered motivation and executive functioning.6 In a 2012 study using positron emission tomography, healthy controls reported feelings of pleasure and euphoria when dopamine was released in the dorsal caudate, whereas those with AN reported increased anxiety.9 People with AN experience anxiety in anticipation of eating (which worsens with malnutrition), encode food as dangerous, and have an exaggerated brain response to food.10 Malnutrition can lead to decreased serotonin, which has a calming effect in people with AN.5,6 Avoidance and restriction of food by people with AN is a self-regulation mechanism and serves to lower their overall anxiety levels.6 Therefore, the drive for thinness is reinforced not only by inflexible and perfectionistic temperament traits, but also by progressive malnutrition.
Another prominent symptom found in people with AN is ruminating thoughts. Ruminations are defined as repetitively focusing on symptoms of distress and on the possible causes or consequences of these symptoms. Studies suggest links between ruminating thoughts and anxiety, binge eating, binge drinking, self-injury, and depression.11,12 One of the American Psychiatric Association criteria for residential level of eating disorder care is that the patient is preoccupied with intrusive repetitive thoughts 4 to 6 hours a day.13 Ruminations have been found to be associated with increased activity in the amygdala; thus, blocking dopamine transmission in the mesolimbic area of the brain with medication could lead to fewer eating disorder ruminations.
Neurobiology of Bulimia Nervosa
People with BN, and to some degree people with AN binge/purge subtype, tend to have problems with impulse control. They may more readily engage in greater novelty and pleasure-seeking behavior and be less concerned with behavioral consequences. In BN there appears to be dysregulation between the ventral limbic brain circuits that produce reward and the dorsal cognitive circuits that control attention, planning, and regulation. In imaging studies, patients with BN show differences in activation of their prefrontal cortex when compared to controls.14–19 They demonstrate higher activity in the prefrontal cortex when presented with images of food and lower activity during executive control tasks, which is a marker for impulsivity.20
Studies show that in people with BN, reduced dopamine activity leads to increased episodes of bingeing and purging.21 The binge-purge cycle works in the following manner. There is often a period of restriction of caloric intake, followed by an impulsive binge episode (often on high-caloric, high-sugar foods). This results in decreased dopamine levels in the nucleus accumbens after the fast and enhanced dopamine levels after a binge episode. Unlike in AN, the dopamine release during a binge episode is thought to cause a feeling of pleasure, which is rewarding and increases the probability of future binges.
Neurobiology of Binge-Eating Disorder
People with BED tend to have greater attentional biases toward food, altered reward sensitivities, and altered brain activation in regions associated with impulsivity and compulsivity.20 It is hypothesized that initially these patients have increased reward sensitivities related to food, which leads to an over-exuberate dopamine release. This leads to increased bingeing episodes and increased weight gain. With increasing body weight, this reward sensitivity becomes dysregulated such that increased consumption of food is required to elicit the same dopamine reward response.22
On imaging studies, people with BED show altered brain activation in regions associated with impulsivity and compulsivity.20 Decreased dopamine in the prefrontal cortex results in a greater degree of impulsivity whereas decreased dopamine in the striatum is associated with more compulsive eating. It is hypothesized that the increased impulsivity may underlie the diminished control observed during binge eating episodes in patients with BED. Other neuroimaging studies suggest altered function of prefrontal, insular, and orbitofrontal cortices and in the striatum as well.20 Decreased dopamine, particularly in the dorsal lateral striatum, has been shown to lead to compulsive food consumption and drug use.
Medications for Anorexia Nervosa
There are no medications approved by the US Food and Drug Administration (FDA) for the treatment of AN, and antidepressant medications generally do not help in the early stages of treatment. Chronic malnutrition causes deficiency of essential amino acids (ie, only found in foods) such as tryptophan, which is the precursor to the neurotransmitter serotonin. This leads to inadequate synthesis of serotonin and dysregulation of serotonergic systems in several areas of the brain. Selective serotonin reuptake inhibitors (SSRIs) are generally ineffective in people with low body weight due to reduced serotonergic activity.5,6
Medications may be used in the treatment of AN to target two prominent symptoms—cognitive rigidity and ruminating thoughts—both of which are related to dysregulation of dopamine. Increases in dopamine in the anterior cingulate cortex and prefrontal cortex are associated with more flexible and less-rigid thinking patterns.23 A study using dopamine D2 stimulation in people with low dopamine synthesis improved cognitive flexibility as tested with the Wisconsin Card Sorting Test.23 Dopamine D2 agonists may help with cognitive rigidity during a low dopamine state, as is hypothesized for AN.23 Decreasing dopamine in the mesolimbic pathways has been associated with decreases in ruminating thoughts among people with eating disorders.24
In considering these target symptoms together, second-generation antipsychotic medications may have a unique, although modest, role in the early treatment of patients with AN. Dopamine D2 antagonists such as olanzapine and quetiapine may exert therapeutic effects in patients with AN by blocking dopamine in the mesolimbic pathways, thus slightly decreasing ruminations. Dopamine partial agonists, such as aripiprazole, may present an interesting option for treatment. Aripiprazole is a medication that works via dopamine “stabilization,” as it can decrease or increase neuronal firing in the brain depending on the dopamine “environment.”25 For instance, in regions of the brain where there are high dopamine concentrations, such as the mesolimbic pathways, aripiprazole may block dopamine and lead to a decrease in thought ruminations. In regions of the brain in a person with AN in which there is a decreased amount dopamine, such as the prefrontal cortex, aripiprazole may increase dopamine firing and could lead to improvements in cognitive flexibility.
Several retrospective studies and a few small, randomized control trials have demonstrated these findings to be true. In a 2015 retrospective study, Marzola et al.26 showed aripiprazole to have effectiveness in reducing eating-related preoccupations and rituals with a large effect size in 75 patients with AN. In 2013, Brambilla et al.27 showed olanzapine at a dose of 2.5 to 5 mg daily decreased depressive symptoms, reduced aggression, and promoted greater increases in weight in patients with the AN binge-purge subtype. Case reports, such as by Trunko et al.,28 have shown that treating patients with AN with low-dose aripiprazole (2.5–5 mg daily) led to improvements in mood, anxiety, and cognitive flexibility. Taken together, these studies can offer some encouragement for the use of a dopamine antagonist or dopamine partial agonist, but clinically this effect is subtle and sample sizes are small and studies generally not fully controlled. The mainstay of AN treatment continues to be nutritional refeeding and psychotherapy, but in certain instances these medications may be helpful as an adjunct.
Medications for Bulimia Nervosa
In the treatment of people with BN, SSRIs such as fluoxetine are the treatment of choice. Fluoxetine is the only FDA medication approved for the treatment of BN and typically requires doses of 60 to 80 mg daily.29 SSRIs can also be used to treat highly comorbid conditions such as depression and anxiety in people with BN. Two major systematic reviews30,31 included 19 and 12 placebo-controlled trials, respectively, comparing the use of antidepressants with placebo in people with BN. The reviews found that antidepressants reduced the binge-purge cycle by 50% to 80%30 and significantly prolonged remission.30,31
Patients suffering from comorbid BN and mood dysregulation due to borderline personality disorder or bipolar disorder may benefit from treatment with lamotrigine.32 The antiepileptics topiramate and zonisamide have also been used to decrease bingeing episodes in BN and BED, but use is often limited by cognitive side effects and potential weight loss, which should be monitored.33 Naltrexone alone or in combination with fluoxetine has been shown to decrease bulimic symptoms.34 Naltrexone may be helpful when alcohol use disorder is co-occurring with BN.34
Medications for Binge-Eating Disorder
Psychological and behavioral treatments for BED, namely cognitive-behavioral therapy and interpersonal psychotherapy, are the most strongly supported interventions.35 Several studies have explored the use of psychiatric medications in BED with and without concomitant psychotherapy interventions and have had mixed success.36 Antidepressants are often the first choice when treating BED with medication, because comorbid depressive disorder is common. It is important to select an antidepressant that is not associated with weight gain. Bupropion, a norepinephrine and dopamine reuptake inhibitor, may target depression and some symptoms of impulsivity in BED, as well as contribute to weight loss. Of note, bupropion is contraindicated in AN and BN due to increased risk for seizures. The antiepileptics topiramate and zonisamide have been shown to be effective in BED, but their use is limited by the side effect profile.36
Lisdexamfetamine is the only medication that is FDA-approved for the treatment of moderate to severe BED. It exerts therapeutic effect by blocking the reuptake of norepinephrine and dopamine in the prefrontal cortex. This medication has shown benefit not only in appetite suppression (and reducing binge episodes), but also by improving symptoms of impulsivity, which serves to further reduce bingeing behaviors. Due to the side-effect profile and potential for misuse of lisdexamfetamine, it should not be used in people who have hypertension or substance use disorders.36
Evidence from neuroimaging studies suggests that eating disorder symptoms involve dysfunction in circuits underlying reward and inhibition. Eating disorders are chronic and debilitating, and current medication options are often minimally effective, at best, in treatment. Further research is needed in the development of targeted pharmacologic therapies to treat these potentially life-threatening diseases.
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