SPECIAL REPORT: TREATMENT RESISTANCE
Anorexia nervosa (AN) is a severe psychiatric disorder characterized by restricted eating, significant weight loss, and a profound fear of weight gain. AN and the related disorder, bulimia nervosa, have a lifetime prevalence of 1% to 2% of the population.1 Weight loss in AN results in serious medical consequences and higher levels of care are often necessary to restore weight. AN has the highest risk of mortality of any nonsubstance-use psychiatric disorder and, too often, a poor prognosis.2 Reluctance to recover is sustained by ego-syntonic symptoms that reinforce the illness.3 Only 13% to 50% of patients are considered recovered 1 to 2 years posttreatment, and a sizeable subset (20% to 30%) go on to develop a chronic and unremitting course of AN.4
Limited effectiveness of both pharmacological and psychological treatments contributes to this chronicity. Family-based therapy, which works in alliance with parents to maintain eating and restore weight, has had some success in adolescent patients, but not all younger patients achieve adequate benefit. For older patients with AN, evidence-based therapies remain underdeveloped.
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Historically, AN has been considered a consequence of psychosocial factors.5 However, considerable recent evidence supports powerful genetic and neurobiological contributions to AN behavior.6,7 Many affected individuals have an anxious, obsessive, inflexible, and perfectionist temperament that presents in childhood before the onset of AN, becomes exaggerated during illness, and persists in a mild-to-moderate form after recovery. Comorbid depression is common, as is denial of illness and lack of motivation to change.3
Recent studies have shed new light on underlying mechanisms driving such AN symptoms.8,9 For example, when people are hungry, activation of brain circuits normally makes them feel irritable and uncomfortable and makes food more rewarding and motivating. These neural processes appear to be miscoded in AN and sensitized with weight loss.8 Instead, when these individuals become hungry and are presented with food, they experience brain circuit activity associated with considerable anxiety; further, dopamine-related brain mechanisms that motivate and initiate eating fail to activate. Such findings open the door to identifying new targets and new pharmacological approaches in AN.
Status of Medication Use
It is important to note that there are no US Food and Drug Administration (FDA)–approved medications to treat AN. Nonetheless, given the risk of significant physical and psychological consequences of this disorder, off-label prescribing of some agents has become widespread.
For patients with AN who show signs of treatment resistance, the most common medication intervention is atypical antipsychotics. Although promising case reports, open trials, and chart reviews began appearing in the late 1990s, the controlled-trial literature on atypical antipsychotics in AN remains disturbingly limited, which is a testament to the notorious difficulties in recruiting and retaining patients with AN in medication trials. To date, there have been 8 randomized, placebo-controlled trials (RCTs) involving placebo groups. Only 1 of these involved more than 40 patients, and the total number of randomized patients in all trials was less than 350.10,11
Olanzapine is by far the most studied medication for AN, with 5 trials taking place between 2007 and 2019. All but 1 were considered positive, although the degree of benefit typically was small. Two trials involving use of quetiapine had mixed results, and 1 trial with risperidone was negative.10 In the closest thing to a landmark medication study in AN, Attia et al reported results of a relatively large, multisite RCT of olanzapine in adult outpatients in 2019.12 Five sites in North America randomized 152 patients to olanzapine or placebo during a 6-year recruitment period. The 16-week trial used a target olanzapine dose of 10 mg/d (mean, 7.77 mg/d), and investigators found a significant increase in weight for the olanzapine group versus placebo. However, the difference in weight gain (ie, 1 lb of body weight/month for a woman of average height) was modest between the groups; patients using olanzapine gained an average of approximately 1.5 lb of body weight/month. Weight restoration is the primary outcome in any AN trial, but use of a medication hopefully also will impact the powerful thought processes and psychiatric symptoms that drive the illness. Importantly, the authors reported that use of olanzapine showed “no significant benefit for psychological symptoms.”12
Despite these limitations, expert articles and guidelines most likely recommend olanzapine as the antipsychotic of choice to treat AN, because so few RCTs have involved use of other medications. In our experience, a few types of patients may particularly benefit from olanzapine. For individuals who desire some degree of weight restoration but are struggling due to lack of appetite or drive to eat, olanzapine may provide improvement. In addition, patients with very high anxiety presenting more as fear than cognitive rigidity may benefit from the sedative-like properties of olanzapine.
However, there are substantial roadblocks to successful use of olanzapine for AN. The quality that led to early interest in and dominant study of olanzapine—its well-known propensity to cause weight gain—makes it unacceptable to the vast majority of patients with AN. At best, many of these individuals are ambivalent about weight gain, and even those who have accepted it as a necessary aspect of recovery frequently fear loss of control over the process. It is critical to understand that improvement in body image for AN patients can significantly lag weight restoration. If a medication adds weight but has little impact on thought process, the patient may experience an intolerable emotional state that greatly heightens the risks of nonadherence and resumption of weight loss.
With 14 atypical antipsychotics available for use in the United States, it is astonishing that so few have been studied in RCTs of AN. Given the highly complex and variable receptor-binding properties of this class, leading to clinically relevant heterogeneity—for example, some atypical antipsychotics are known to treat depression better than others—it is premature to conclude that atypical antipsychotics have only minimal benefit for AN based on results reported with use of 3 of the earlier medications. Lack of RCTs with newer, relatively weight-neutral antipsychotics, especially those having a somewhat different mechanism of action (eg, aripiprazole), may be a serious oversight.
Over the past decade, and with the 2019 olanzapine trial notwithstanding, nearly all additions to the literature on the use of atypical antipsychotics in patients with AN have involved aripiprazole. Five peer-reviewed articles from 4 different sites in 3 countries have described very interesting findings from case series and retrospective chart reviews.13,14 These reports often show benefit for weight gain, but most notably, they have included remarkably similar descriptions of an impact on thought processes related to AN, particularly the loosening of rigid and entrenched rules and distortions. Observations have included reduced eating-specific anxiety and distress; less rigid food choices; diminished obsessional thoughts about food, exercise, weight, and body image; and fewer eating disorder (ED) rituals. Additionally, many patients reported reduced symptoms of depression and non-ED–related anxiety, which will be discussed in the next section. Therefore, regardless of any direct impact on weight, aripiprazole may indirectly enhance weight restoration by improving cognition and thereby promoting a better response to psychological and dietary treatments. RCTs are needed to further investigate these findings.
What may account for this possible difference between olanzapine and aripiprazole in AN? Olanzapine—as well as most other current atypical antipsychotics, including quetiapine and risperidone—is a 5-HT2A/D2 antagonist. Aripiprazole, in contrast, is a D2 and 5-HT1A partial agonist, meaning it acts differently at dopamine and serotonin receptors. Theoretical arguments have addressed how use of aripiprazole at lower doses (typically, 1-5 mg/d, with occasional titration up to 10 mg/d) may facilitate learning and behavior change in individuals with AN.
For example, basic research has indicated that dopamine receptor stimulation may be beneficial in suppressing previous fears after extinction training. Moreover, neurobiological research suggests that AN is associated with heightened responsiveness in brain reward circuits, which may be due to a hypersensitive dopamine system. Aripiprazole may downregulate D2 receptor activity, which may improve brain function, reduce anxiety, and aid in the psychotherapeutic process.9,13,15
Additionally, almost all patients described in this research on aripiprazole use were being treated concurrently with antidepressants. In contrast, no RCT has formally studied atypical antipsychotic augmentation of antidepressants in AN. Although some RCTs allowed patients already on antidepressants to continue them, use was not systematic or evaluated, and the overall numbers were too small to yield meaningful results. We believe that, particularly for medications such as aripiprazole with known significant effects as augmenters, combination treatment may be 1 key to showing a more robust response in controlled trials. On a practical note, adherence also has improved with use of aripiprazole, because it often is better tolerated. Still, some patients encounter akathisia, which we have been able to minimize by initiating therapy with very low doses (eg, as low as 0.5 mg/d in some patients).
Impact of Psychiatric Comorbidities
AN is associated with high levels of comorbid conditions. More than 40% of individuals with AN have a lifetime comorbid anxiety or mood disorder, over 30% have an impulse control disorder, and about 27% have a substance use disorder.16 Recent data showed that individuals with AN had a 25% risk of receiving any noneating disorder diagnosis during the first 2 years of longitudinal follow-up and a 55% risk of developing comorbid conditions 2 decades after inclusion.17 Comorbid conditions have been associated with greater illness severity and mortality.18,19
Research on eating disorders traditionally has not focused on comorbidities, but new data highlight the need for treatment of those conditions. Whether eating disorder outcomes will be affected by treatment of comorbid psychiatric illnesses is uncertain, but improving quality of life and reducing suicide rates are similarly important goals.
Few medications specific to AN have been approved by the FDA, yet affected patients frequently receive prescriptions for psychotropics.20,21 However, studies on pharmacological interventions in AN commonly have not been designed to discern whether individuals taking these medications had more severe illness or higher comorbidity than did others. Because depression and anxiety predict more negative treatment outcome in AN, and comorbid psychiatric disorders are associated with higher mortality among this patient population, use of medication to target these conditions is supported.18,22 Research may have to adapt and focus more on outcome measures that go beyond weight gain; these may include the study of quality of life, mood, and anxiety measures in relation to use of medical interventions. These measures are crucial in preventing weight loss and relapse after significant resources that involve a high level of care have been used for nutritional rehabilitation.
A recent patient with severe AN in our program also had severe, comorbid obsessive-compulsive disorder (OCD). She had many magical thinking–related obsessions that substantially limited her will to live and contributed to overwhelming major depressive disorder with suicidality. The patient was treated with olanzapine to reduce distress and had been on various antidepressant and antianxiety medications, but she never received an adequately dosed trial of a selective serotonin reuptake inhibitor to treat OCD. During weight restoration, we initiated sertraline, which was titrated to 200 mg/d. After 4 months of treatment, the patient experienced significant relief from symptoms of OCD and could start participating in social activities. AN was still a significant struggle, but the patient experienced improvement in daily life activities and overall functioning.
While olanzapine has shown benefit for AN in RCTs, weight restoration tends to be minor, AN cognitions do not appear to improve significantly, and most patients are unaccepting of a medication known to cause weight gain. RCTs of additional atypical antipsychotics, especially those that have a somewhat different mechanism of action (eg, aripiprazole), used alone and in combination with antidepressants are needed. Research into strategies to better treat psychiatric comorbidities in patients with this disorder may reduce treatment resistance. Finally, early investigations to treat AN and its comorbidities with novel biological treatments (eg, psilocybin, ketamine, cannabinoids, and neuromodulation techniques of repetitive transcranial magnetic stimulation and deep brain stimulation) are ongoing.23-26
Dr Trunko is an associate clinical professor of psychiatry at the University of California, San Diego, and medical director of the UCSD Eating Disorders Treatment and Research Program. Dr Frank is a professor in residence of psychiatry at the University of California, San Diego. Dr Schwartz is director of medical and clinical services at the USCD Eating Disorders Treatment and Research Program, and clinical professor of psychiatry at the University of California, San Diego. Dr Kaye is the founder and executive director of the UCSD Eating Disorders Treatment and Research Program, and professor of psychiatry at the University of California, San Diego.
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