Use of atypical antipsychotics in individuals with anorexia nervosa
Introduction
Anorexia nervosa (AN) is a life-threatening mental health condition characterized by severe cognitive distortions and obsessive preoccupations regarding eating, weight gain, food, and/or body image, which often prolong treatment and delay recovery.1-4 While eating disorder (ED)-focused Family-Based Therapy (FBT) and weight restoration are mainstays of treatment among individuals with AN, interest exists in evaluating the role of atypical antipsychotics to target cognitive distortions and obsessive preoccupations.5-8
While treatment guidelines do not provide clear recommendations regarding antipsychotic choice, the timing of initiation, or duration of treatment, atypical antipsychotics are among the most commonly prescribed psychotropic medications in individuals with AN.2-4 Olanzapine, risperidone, quetiapine, and aripiprazole are described in the literature, with mixed efficacy and safety profiles.4,8-11 Through an illustrative case review, this manuscript will highlight practical and evidence-based pearls to apply to this important patient population.
Illustrative Case
“I don’t deserve to eat. I hate my body.”
CM is an 18-year-old cisgender female admitted to the hospital with concerns about abdominal discomfort, constipation, calorie restriction (600-800 cal/d), excessive exercise (3 hr/d), fear of gaining weight, and negative thoughts of self-image. CM reports significant food and calorie restriction that started 8 months ago, precipitated by social stressors, including online bullying and perceived enhancement of athletic performance as a competitive skier. She eats a small breakfast and dinner daily, identifying “carbs, dessert, and soda” as fear foods and “veggies and watermelon” as safe foods. Her last menstrual cycle was more than 4 months ago. Upon further assessment, you learn that she has lost 17 kg in the past 3 months. Her body mass index (BMI) is currently 17 kg/m2, and she was 20 kg/m2 3 months ago. Currently, she is at 55% of her ideal body weight (IBW) (41 kg) and in the 30%ile based on weight.
CM’s initial treatment is as follows: (1) monitor for electrolyte imbalances, fluid retention, dehydration, and refeeding syndrome; (2) a meal plan starting at 1750 kcal/day, increase by 250 kcal/day as tolerated; (3) give oral supplement at 100% of calories for uneaten foods; (4) supervise meals and snacks and provide meal support; (5) goal weight gain 0.2 kg/day; and (6) initiate supportive medications, including a daily multivitamin, thiamine, zinc, and polyethylene glycol.
“My eating disorder is telling me I’m disgusting.”
After acute medical stabilization, CM is transferred to the day treatment ED program for FBT and structured support with nutrition. Despite ongoing reports of intrusive, perseverative ED thoughts, CM’s weight trend is positive in the initial weeks of treatment. Notably, her BMI is 19 kg/m2 and 70% of IBW (50 kg) and 45%ile based on weight. As treatment progresses, CM endorses symptoms of anhedonia, sleep disturbance, fatigue, restlessness, guilt, depressed mood, and anxiety, for which escitalopram 5 mg by mouth daily is initiated. At the time of antidepressant initiation, BMI is 21 kg/m2 and 80% of IBW (55 kg) and 50%ile based on weight.
One month into ED treatment, CM reports ongoing body image distress, fear of weight gain, and self-injurious behavior related to recently learning her weight. Of note, food-avoidant behaviors have increased, with CM reporting a heightened difficulty eating fear foods, completing meals, and engaging in FBT. Escitalopram was increased weekly to a dose of 20 mg by mouth daily to target ongoing symptoms of depression and anxiety. CM denies side effects at this dose and does report some improvement in depressed mood. Overall, CM’s weight trend has been neutral, with a recent negative trend. Her BMI is 20 kg/m2 and is 75% of IBW (52 kg) and 47%ile based on weight. Given concerns for heightened food-avoidant behavior, challenges engaging in FBT, and a negative weight trend, the treatment team decided to start aripiprazole 2.5 mg by mouth daily, targeting cognitive distortions and rigidity regarding food and body image.
Evidence-Based Discussion
Eating Disorder Guidelines
The goals of ED treatment include weight restoration, return to a healthy growth trajectory, normalizing eating behaviors, and establishing a positive relationship with food and body image.3,4 In select cases, psychotropic medications can be useful adjuncts to weight restoration and FBT.3,4 It is estimated that more than 50% of individuals with AN are prescribed psychotropic medications, with selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics among those most prescribed.2,3,12 While SSRIs are often prescribed to target co-occurring symptoms of depression, anxiety, or obsessive-compulsive or trauma-based disorders, atypical antipsychotics are often prescribed to support weight gain and target cognitive distortions and obsessive preoccupations regarding eating, weight gain, food, and/or body image.8-11
Despite high rates of atypical antipsychotic prescribing in clinical practice, ED treatment guidelines do not provide specific recommendations regarding their use.3,4 Instead, ED treatment teams must make decisions based on updated primary literature (Table), patient-specific factors, and formulary availability.
Aripiprazole
Aripiprazole has gained interest in the treatment of individuals with AN given its favorable side effect profile, positive effects on ED cognitions (Table), and unique mechanism of action.7,37 As a D2 partial agonist, dopamine receptor downregulation is thought to contribute to reward system responsiveness, habituation to refeeding, decreased conditioned fear response, and reduced cognitive rigidity and body image distortion.5,13,37 While studies are limited by small sample sizes and lack of rigorous study methodology, aripiprazole has demonstrated improvements in ED cognitions and weight gain in 3 case series5,13,14 and 1 retrospective case-control study.38 Among a group of 9 patients who were previously treated with an antipsychotic, aripiprazole was associated with an increase in medication compliance, improved medication tolerability, and improved ED outcomes.13 Reasons for prior antipsychotic discontinuation included increased appetite with olanzapine and galactorrhea, sedation, or increased appetite with risperidone.13 With studies reporting good tolerability and low rates of adverse effects (eg, sedation, nausea), low-dose aripiprazole (≤5 mg/d) is a leading choice in clinical practice.
Olanzapine
Olanzapine is the most well-studied antipsychotic among individuals with AN (Table) and is frequently used in clinical practice. Among 7 double-blind, randomized, controlled trials,15,16,18,20,21,23,26 olanzapine was associated with mixed results for weight gain and ED cognitions. Increases in fasting blood glucose and sedation were common reasons for treatment discontinuation.23,26 Ten open-label or retrospective studies11,17,19,22,24,25,27-30 demonstrated variable improvements in weight but with mixed effects on ED symptoms. Of note, high rates of side effects were reported with sedation, dyslipidemia, hyperprolactinemia, and elevations in liver function tests (LFTs) among the most common reasons for treatment discontinuation. In 1 retrospective study, aripiprazole was associated with greater improvements in ED symptoms and tolerability compared to olanzapine.11 Altogether, the use of olanzapine should be considered carefully, given the mixed results and the risk of adverse effects.
Quetiapine
Overall, quetiapine has not demonstrated significant improvements in ED cognitions, weight gain, or mood (Table).33,34 While 1 open-label study demonstrated some improvements in weight and ED symptoms,31 subsequent studies have not demonstrated benefit.32-34 In the only double-blind, placebo-controlled study,34 no difference in ED symptoms or BMI compared with placebo was observed. Sedation, orthostasis, constipation, dry mouth, and difficulty concentrating were noted at the beginning of treatment but were generally transient.31-33 While the use of quetiapine could be considered in this patient population to support concurrent symptoms (eg, bipolar disorders), quetiapine should not be routinely considered for AN-associated cognitions.
Risperidone
Two studies suggest a lack of benefit for risperidone in those with AN, with no improvement in ED cognitions and weight gain (Table).35,36 In a double-blind, placebo-controlled study,35 risperidone did not demonstrate improvements in core ED symptoms or time to reach 90% of IBW. While overall well-tolerated, it is notable that risperidone was associated with a significant elevation in serum prolactin by week 7 of treatment. Additionally, a naturalistic, placebo-controlled study36 did not demonstrate a difference in BMI, ED symptoms, mood, or rehospitalization rates among those prescribed low-dose risperidone. Overall, risperidone is an undesirable choice, given the lack of robust literature and current data, suggesting a lack of benefit in individuals with AN.
Recommended Strategies for Appropriate Medication Use in ED
Antipsychotics may be used to augment treatment in patients with severe ED cognitive symptoms, thought distortions, or obsessive preoccupations that interfere with engagement in treatment. Exact timing of initiation is not well-understood but likely can be considered early in weight restoration.
Olanzapine is the most widely studied antipsychotic, but clinicians should consider the benefits versus risks, including sedation, dyslipidemia, hyperprolactinemia, and elevations in LFTs. Aripiprazole has growing evidence, particularly in adolescents. Low doses should be used to optimize D2 partial agonism effects. Based on identified improvements in ED cognitions, aripiprazole could be considered a reasonable alternative to olanzapine with lower rates of side effects. Quetiapine and risperidone should be avoided for ED symptoms and weight gain.
Routine monitoring should include evaluation for extrapyramidal side effects and tardive dyskinesia, lipid panels, fasting blood glucose/HgbA1c, waist circumference, and an electrocardiogram in some high-risk cases. Metabolic monitoring should occur at baseline (before antipsychotic initiation) and then at 3, 6, and 12 months. Weight and waist circumference should be measured at each office visit.39-41 An Abnormal Involuntary Movement Scale (AIMS) should be completed every 6 months.39
Consider short-term use (eg, 8-12 weeks), with ongoing evaluation for need as patient continues to engage in other evidence-based interventions (eg, FBT, weight restoration). The duration of use may also be influenced by other comorbidities (eg, mood disorder).
Conclusion
Atypical antipsychotics can be considered in some patients with AN, and difficult-to-treat ED cognitions or thought distortions that may interfere with participation in FBT and/or weight restoration. Olanzapine is well-studied, and there is growing literature to support the use of aripiprazole. Once an atypical antipsychotic is started, its ongoing need should be reevaluated with consideration to discontinue within 3 months of weight restoration. Routine monitoring for side effects is important to ensure safe use (eg, AIMS, metabolic monitoring).
Contributor Notes
Disclosures: The author has no conflicts of interest to disclose.