Mary Ellen Trunko, MD

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.

 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.

 Reluctance to recover is sustained by ego-syntonic symptoms that reinforce the illness.

 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.

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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Hewa Artin, MD; Michelle F. Sloan, MD; Zafiris J. Daskalakis, MD, PhD

Reducing Heterogeneity in Non–Treatment-Resistant and Treatment-Resistant Schizophrenia

Frederick Charles Nucifora Jr, PhD, DO, MHS

Historically, AN has been considered a consequence of psychosocial factors.

 However, considerable recent evidence supports powerful genetic and neurobiological contributions to AN behavior.

 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.

Recent studies have shed new light on underlying mechanisms driving such AN symptoms.

 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.

 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.

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.

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.

 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.

 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.”

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.

 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-HT2

 antagonist. Aripiprazole, in contrast, is a D

 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 D

 receptor activity, which may improve brain function, reduce anxiety, and aid in the psychotherapeutic process.

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).

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.

 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.

 Comorbid conditions have been associated with greater illness severity and mortality.

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.

 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.

 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.

 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. 

 is a professor in residence of psychiatry at the University of California, San Diego. 

 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. 

 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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Articles

Only 13% to 50% of AN patients are considered recovered 1 to 2 years posttreatment, and 20% to 30% go on to develop a chronic and unremitting course of AN. How can we improve these outcomes?

Pharmacological Management of Treatment-Resistant Anorexia Nervosa

Bulimia nervosa (BN) is a serious disorder characterized by recurrent large-volume eating episodes that are marked by a loss of control (binge eating), regular compensatory behaviors that are intended to prevent weight gain (purging), and over-valuation of body shape and weight. BN is associated with psychiatric comorbidity, significant psychosocial impairment, medical complications, and increased mortality.

Clinical guidelines for the evidence-based treatment of BN highlight first-line, outpatient psychotherapeutic and pharmacological approaches. Self-help, enhanced cognitive-behavioral therapy (CBT), and interpersonal psychotherapy are considered first-line psychotherapeutic interventions. Antidepressants, most notably SSRIs and specifically fluoxetine, which is FDA-approved for use in BN, are recommended adjunctive first-line treatments. Limited data suggest that CBT-BN alone and CBT-BN plus antidepressants are more efficacious than antidepressants alone.

 Despite these available treatment options, roughly 30% of cases are chronic and unremitting. Even for those who do initially respond to treatment, estimated rates of relapse in BN range from 25% to 63%.

Melia is a patient with treatment-refractory, complex BN, who presents for treatment at our eating disorders program. A 20-year-old college student, she plans to attend law school after graduation.

Her eating disorder began in her freshman year, when she started “using food to cope” after a difficult breakup and domestic violence. Before admission, she was eating salads or diet frozen entrÃ©es for most meals and binge eating and purging 3 to 5 times a day. She has a history of self-harming behaviors and 2 suicide attempts.

She reports frequent shoplifting, occasional binge drinking to the point of blacking out, and recurrent unsafe sex with men she meets at bars. She previously had attempted outpatient, partial hospital, and residential treatment but had been unable to sustain recovery. She also had several trials of antidepressant medication without response for depression, anxiety, and eating-disordered symptoms.

Melia reports that she feels “very stressed” at school and has high standards for herself. She has had to withdraw from school several times to pursue treatment.

Improving outcomes for individuals with treatment-resistant BN such as Melia hinges on:

 Developing an understanding of what factors make treatment failure or dropout more likely

 Generating hypotheses about the mechanisms of non-response

 Proposing and evaluating treatments that address these hypothesized mechanisms

In general, first-line psychotherapeutic treatments-whether delivered in person or via telemedicine-result in remission in only 30% to 50% of adult patients with BN.

 These first-line treatments are often particularly ineffective for the large subset of patients who struggle with a range of other dysregulated behaviors. To date, despite some inconsistency in the literature, predictors of worse outcome or treatment dropout include longer duration and more severe eating disorder symptom profiles, comorbid psychopathology such as depression or substance use, and characteristics of personality pathology such as affective instability and impulsivity.

. Patients with BN have high rates of comorbidity with other psychiatric conditions, including mood, anxiety, and impulse-control disorders. Impulsive behaviors and comorbid disorders defined by behavioral dysregulation are common in BN, including substance use disorders (approximately 37%), ADHD (about 35%), borderline personality disorder (approximately 28%), self-injurious behavior, risky sexual activity, and shoplifting.

 Moreover, BN is associated with suicidality independent of comorbidities.

 The range and extent of co-occurring psychopathology are associated with poorer treatment outcome and thus can present profound challenges to the application of evidence-based treatment. Unfortunately, strictly controlled treatment trials often exclude those with significant comorbidity, which leaves a void in our understanding of best practices for our most complex patients.

 Individuals with BN report significantly higher levels of emotion intensity, deficits in emotional awareness, and increased use of dysfunctional strategies for emotion regulation.

 Impulsive behaviors may function to regulate dysphoric, extreme mood states. Paradoxically, these behaviors may evoke more negative emotion, which leaves the patient trapped in a cycle of dysregulated emotions and behaviors.

Limited development of effective, evidence-based medication strategies.

 Another potential factor in poor treatment response may be the lack of development of medication strategies that might help patients regulate affect. Randomized controlled trials in the 1980s and early 1990s established antidepressants as superior to placebo in reducing symptoms of BN. The largest studies by far involved fluoxetine-hence, the FDA indication. Subsequently, the antiepileptic drug topiramate was shown to treat BN symptoms more effectively than placebo.

It is important, however, to understand the nature of these trials in determining clinical applicability. Positive response was often defined as a 50% or more reduction in weekly binge and/or purge episodes. While impressive, this decrease left many patients still meeting DSM criteria for BN at completion of the studies, and full remission rates were much lower.

Up to one-half of patients who present for treatment of BN would have been excluded from the studies, primarily for comorbidities. Finally, most trials were small and short term.

 This may be especially concerning with regard to topiramate, which has fairly widespread use in BN despite well-known tolerability issues and the potential adverse effect of unhealthy weight loss in BN patients striving for thinness. It may surprise some clinicians to know that this approach is based on randomization to topiramate or placebo of only approximately 130 patients, for a period of just 10 weeks.

 Despite the apparent limited benefit of medications in BN, there has been virtually no research in this area for more than a decade.

Improved understanding of the neurobiology and associated features of BN may provide both an explanation for poor response to evidence-based treatment, and a framework for improved treatment approaches. Impaired inhibitory control and aberrant reward responsivity and reward-based learning may contribute to the affective dysregulation, binge eating, purging, and other impulsive behaviors often reported by individuals with BN. Extant neuroimaging findings in BN suggest abnormal functioning of the corticostriatal and corticolimbic circuits that support these processes, and this altered functioning has been linked to increased bulimic symptom frequency.

 Dysfunction in these circuits may leave patients with powerful urges to inappropriately initiate or continue eating or to purge, and, in combination with impaired learning, may interfere with response to treatment.

Designing successful interventions requires consideration that abnormal neurobiological functioning may contribute to BN and associated behaviors, and these behaviors appear to serve the purpose of temporarily reducing intolerable emotional intensity. Specifically, treatments for refractory BN may include a focus on skills and strategies designed to help patients regulate emotions and cope with altered inhibitory control and reward sensitivity.

Developments in psychotherapeutic strategies.

 Psychotherapeutic interventions for treatment-resistant BN may specifically focus on skills that help patients cope with their dysregulated emotions, thereby reducing impulsive behaviors. Recent treatments developed to address emotion dysregulation within BN include integrative cognitive-affective therapy, adaptations of CBT, and dialectical behavior therapy (DBT).

DBT originally was developed for patients with intense emotion dysregulation, borderline personality disorder, and/or suicidality, and has been adapted and studied for use with eating disorders.

 With its heavy emphasis on skill development for tolerating distress and regulating emotions, along with its structured approach to treating complex comorbidities, DBT may be particularly effective in mitigating biologically driven vulnerabilities to unstable affect and maladaptive, impulsive behaviors.

 Considering the prevalence and morbidity of BN, along with the limited efficacy of antidepressants and safety concerns about topiramate for many patients, the lack of new research into pharmacological treatments during the past decade and present day is notable. Recently, a few encouraging but very small open series and case reports have been published. Some of these have utilized antiepileptic drugs-namely, zonisamide and lamotrigine, which warrant further exploration for treatment-refractory BN.

 Similar to topiramate, zonisamide has an adverse-effect profile that may limit its use in patients with eating disorders.

Lamotrigine, with its relative weight neutrality, greater tolerability, and demonstrated benefit in other conditions characterized by affective dysregulation and impulsivity (eg, bipolar disorder), may hold the most promise. The decreases in emotional and behavioral dysregulation associated with lamotrigine may blunt or delay impulsive urges enough to allow patients to use skills, ultimately permitting engagement with empirically supported psychological treatments.

 However, controlled trials of lamotrigine are needed.

Recent FDA approval of lisdexamfetamine (a CNS stimulant) for binge eating disorder has heightened interest in potential use of such medications in BN. Some investigators hypothesize that CNS stimulants may address inhibitory control deficits or deficient reward systems in dysregulated eating disorders in a similar manner as in ADHD. A retrospective series published earlier this year showed large reductions in binge and purge symptoms in 6 patients with chronic BN.

 While this is intriguing, substantial risks associated with use of these controlled substances in dysregulated BN may make CNS stimulants prohibitive.

The relatively weight-neutral atypical antipsychotic aripiprazole showed benefit as augmentation to antidepressants in 2 small groups of treatment-refractory BN case reports.

 It is interesting to speculate whether the partial-agonist properties of aripiprazole may improve stabilization of dopamine/serotonin neurotransmitter systems, which have shown abnormalities in BN.

Although consensus exists among practitioners that co-occurring disorders must be addressed in BN treatment, when and how to do so remains a subject of much debate and is a critical consideration in treatment planning. Medication management of comorbidities such as MDD, bipolar disorder, and anxiety disorders is beyond the scope of this article, but is an important aspect of comprehensive care that may improve the capacity of BN patients to engage in treatment. Evidence-based protocols (eg, CBT for depression, prolonged exposure for PTSD) exist for most comorbidities, but it can be difficult to know how to integrate those treatment protocols with the treatment of the primary eating disorder.

Treatment can take place sequentially, or it can follow an integrated approach that treats all conditions concurrently. Sequential treatment may be advantageous in that it allows the clinician to address safety concerns presented by the eating disorder first, may reduce barriers to the effectiveness of the other treatment, and may be logistically more practical. However, treating one cluster of symptoms may result in worsening of other behaviors, and this cycling may prevent recovery from both disorders. Thus, more recently, concurrent or integrated treatments across comorbidities have become the preferred approach. Regardless of the chosen timing, comorbid conditions should be addressed with evidence-based treatment.

For Melia, the combination of DBT and lamotrigine was very effective. Melia had begun to learn DBT skills in past treatment episodes, but reported difficulty applying the skills because her impulsivity was so strong that she felt there was “no time” between an urge and a behavior to attempt to use the skills. With the addition of lamotrigine, she still experienced urges to binge, purge, shoplift, and self-harm, but she demonstrated increased ability to delay urges long enough to call her therapist for skills coaching. DBT hierarchy helped her therapist organize and prioritize Melia’s treatment targets.

DBT has a focus on helping the patient build a “life worth living” outside the disorder. For Melia, this was difficult because she felt that anything short of immediately completing school with top grades and going to law school would be failure. During treatment, she was able to be less judgmental of herself, and she got a temporary job as a paralegal while she focused on recovery. Her depression and anxiety also improved, and she gained more insight into balancing career and other life goals. Ultimately, she graduated college with plans to attend law school.

Despite significant progress in our understanding of the biological substrates of BN during the past decade, traditional evidence-based treatments fail to help many patients achieve full remission of symptoms. Development and rigorous evaluation of new treatment approaches-particularly those that target characteristics of chronic, treatment-refractory BN-remain crucial tasks in decreasing suffering for patients such as Melia.

Dr. Anderson is Clinical Associate Professor, Dr. Reilly is Postdoctoral Fellow, Dr. Berner is Postdoctoral Fellow, Dr. Trunko is Clinical Associate Professor, and Dr. Kaye is Professor and Director, Eating Disorders Center, Department of Psychiatry, University of California, San Diego, CA.

The authors report no conflicts of interest concerning the subject matter of this article.

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Dialectical behavior therapy may be particularly effective in mitigating biologically-driven vulnerabilities, and zonisamide and lamotrigine may play a role.

Treatment-Resistant Bulimia Nervosa: Clinical Implications and Future Directions

Bulimia nervosa (BN) is a disorder with a complex cause. The disorder is most commonly seen in women, generally with onset in adolescence. It is characterized by binge eating (consumption of an unusually large amount of food accompanied by feeling a loss of control), inappropriate compensatory measures to prevent weight gain (including purging by vomiting, abuse of laxatives and diuretics, strict dieting, and excessive exercise), obsessive fears of being fat, and negative self-evaluation influenced largely by body shape and weight.

BN is often associated with anxiety, depression, obsessionality, substance abuse, and poor impulse control.

Antidepressants are the mainstay of pharmacological treatment for BN. In the 1980s and early 1990s they were established as more effective than placebo in treating BN in double-blind, placebo-controlled trials that tested a variety of medication classes, including tricyclic antidepressants, monoamine oxidase inhibitors, and more recently, SSRIs.

Success was most commonly measured by a decrease in the number of bingeing and purging episodes, and although the studies varied widely, many patients achieved short-term reductions of 50% to 75% in one or both areas.

Much less attention has been focused on whether antidepressants are as useful in reducing mood and impulse control problems often comorbid with BN.

While the observed reductions in eating-disordered behaviors were significant, it is important to realize that many patients who responded to medication continued to binge and purge at a frequency that still met criteria for a diagnosis of BN at the end of the studies. Only a minority of patients attained remission of the bingeing and purging symptoms.



Another caveat concerns the clinical applicability of trial data, because some have estimated that one-third to one-half of patients who present for treatment of BN would have been excluded from treatment studies because of accompanying substance abuse, personality disorders, current or earlier use of psychotropic medication, and other factors.


With their relatively benign adverse-effect profiles, SSRIs are the first-line pharmacological treatment of BN.

 Fluoxetine is the most studied of the antidepressants in this country, and the only medication approved by the FDA for treatment of BN. The indication was granted in 1996, after 2 large, multicenter, controlled trials convincingly demonstrated that fluoxetine was more efficacious than placebo for treatment of BN.

The first, an 8-week study that included nearly 400 patients, showed a response at a relatively high dosage of 60 mg/d, while a dosage of 20 mg/d was no different from placebo.

The second trial, with a duration of 16 weeks, revealed that a starting dosage of 60 mg/d was generally well tolerated in this patient population.



Trials with other SSRIs have been scant. Several conducted with fluvoxamine had problems with tolerability and mixed results regarding efficacy.

In a large randomized trial involving 267 patients, fluvoxamine was no better than placebo for short- or long-term (1 year) treatment of outpatients with BN. The investigators acknowledged that the dosage range of 50 to 300 mg/d may have been too low to show a treatment effect with this illness; however, titration to higher doses may have led to even more adverse events.

Overall, there is little evidence for the use of fluvoxamine as an SSRI of choice for the treatment of BN.

Results with sertraline have been more promising, although the results of only one small randomized trial with 20 patients have been reported. Of interest, significant improvement versus placebo occurred with only 100 mg/d, in contrast with the relatively high doses required for fluoxetine.

The reason for this finding is unknown, but replication on a larger scale would be beneficial.

Little work has been undertaken in controlled trials to compare various SSRIs for BN. One randomized controlled trial of 6 weeks' duration that involved 91 inpatients was designed to explore a genetic basis for drug response. No such basis was elucidated, but the authors reported that fluoxetine, fluvoxamine, citalopram, and paroxetine were all superior to placebo.

Findings from a smaller controlled study in which patients were randomized to either citalopram or fluoxetine indicate that both groups had significant improvement in eating psychopathology.


Success with the SSRIs lends support to the theory of altered serotonin activity in BN. Nonetheless, neurotransmitter dysregulation in the disorder is more complex, and it has been known for some time that the noradrenergic system is implicated as well.

some tricyclic antidepressants with prominent noradrenergic effects, including desipramine and imipramine, were shown to reduce binge eating and purging.

This class of drugs may be associated with greater adverse effects in BN and thus these drugs are rarely used.

However, it is surprising that no controlled trials have been conducted with the newer generation noradrenergic antidepressants. Small open trials in Austria and Italy used reboxetine, a selective noradrenaline reuptake inhibitor not available in the United States. Results showed a decrease in bingeing and purging symptoms as well as other psychological variables.



There are no reports of venlafaxine as a treatment for BN; however, a retrospective review found some efficacy for this serotonin-norepinephrine reuptake inhibitor (SNRI) in patients with the related condition of binge-eating disorder.

The other currently prescribed SNRI, duloxetine, has appeared in a single case report of treatment-refractory BN, in which the patient achieved remission of bingeing and purging symptoms on a high dosage of 120 mg/d.

Clearly, controlled trials are needed to assess the efficacy of SNRIs for treating BN.

Bupropion is another antidepressant worth mentioning. In 1988, the immediate-release formulation was found to be effective in reducing BN symptoms in a controlled study; however, 4 of 69 patients who received the drug had generalized seizures, resulting in its contraindication by the FDA for use in eating disorders.

Subsequently, the investigators of the study reported doing an intensive examination of the patients who had experienced seizures. They found no common features in these patients' medical histories, laboratory results, concomitant medication use, or other variables that might explain predisposition to seizure, and concluded that the increased incidence of seizures could not be explained.

Although no study has attempted to replicate these findings using the lower doses and longer-acting forms of the drug more commonly prescribed today, clinicians in the eating disorders field generally avoid using bupropion when treating patients with BN.

Antidepressants were initially proposed for treatment of BN because of the frequent accompanying mood symptoms of these patients. However, such medications also have proved helpful in patients with BN without comorbid anxiety and depressive disorders; they appear to independently target symptoms of binge eating, purging, and preoccupation with shape and weight.

This result, along with a generally more rapid onset of action and, for fluoxetine, a higher dosage requirement than is seen with treatment of depression, suggests that drug action for BN symptoms may occur by a different mechanism, perhaps relating in part to underlying variance in the serotonergic abnormalities found in BN patients versus those with major depression.

Such a possibility has led to case reports and small trials of novel medica-tions, most notably topiramate and ondansetron.




The anticonvulsant topiramate has been linked to appetite suppression and weight loss, and interest in its use in BN followed suggestions of efficacy in patients with binge eating disorder.

 Results from the first randomized, double-blind, placebo-controlled trial of topiramate in BN were reported in 2003. The 10-week trial of 69 patients began with a dosage of 25 mg/d titrated to a maximum of 400 mg/d (median 100 mg/d). Topiramate was found to be more efficacious than placebo in decreasing frequency of bingeing and purging behaviors (to a similar degree as that seen in antidepressant trials) and in improving other psychological measures, including anxiety, self-esteem, eating attitudes, and body image. Adverse events were generally mild to moderate, resolved with time or dose reduction, and did not usually lead to withdrawal from the study.

A 10-week controlled trial in 2004 found similar results with regard to reductions in bingeing and purging behaviors, and a decrease in weight was reported in the topiramate group.

 

There was an unusually low dropout rate among the 60 participants, possibly because the study enrolled only patients with moderate BN, or because the dose was increased slowly and remained relatively low (25 to 250 mg/d).

Despite the report that there were few intolerable adverse effects in these small studies, adverse reactions to topiramate are common in clinical psychiatric practice, which tends to limit its use.




Another novel agent proposed for treatment of BN is the antiemetic ondansetron, a selective 5-HT3 antagonist approved for the prevention of nausea and vomiting in cancer patients undergoing chemotherapy or radiation treatment. It targets serotonin release from enterochromaffin cells in the gut that may cause the symptoms by stimulating afferent branches of the vagus nerve and thereby initiating the vomiting reflex. One group of investigators has postulated that an escalating cycle of bingeing and purging behaviors in chronic BN results at least in part from a desensitization in the threshold for activation of vagal afferent fibers, with dysregulation of satiety mechanisms.

The results of a randomized, double-blind trial of 25 patients with severe, chronic BN showed that ondansetron was more effective than placebo in reducing binge eating and purging by vomiting during a 4-week period.

Past criticisms of potential ondansetron use have included expense and short half-life. While the drug is now available as a generic, the problem of multiple daily dosing still remains. If an extended-release version of ondansetron becomes available, larger and longer studies that include an assessment of the impact on psychological features of BN could be of interest.




A few other medications have been studied in a limited number of small trials. Endogenous opioids are believed to be involved in the regulation of food intake, and the opioid antagonist naltrexone attracted attention in the late 1980s after it was observed to decrease appetite in some patients recently detoxified from opioid dependence. Unfortunately, when subsequently tested in patients with BN, the standard naltrexone doses used in addiction were found ineffective. There appeared to be some efficacy in open-label studies at 200 to 300 mg/d, but because this dosage is high enough to raise concerns of liver toxicity, naltrexone is not recommended.



Lithium carbonate was no more effective than placebo for symptoms of BN in one controlled trial. Mean plasma concentrations at the low end of the usual therapeutic range may have affected outcome

; nonetheless, lithium use entails a potential toxicity risk for patients who continue purging. Carbamazepine did not prove beneficial in an early controlled trial with 6 patients.



A future direction of research may involve the atypical antipsychotics, which have not been formally studied for use in BN. Interest in this medication class stems from preliminary data that show efficacy in some patients with anorexia nervosa, as well as reports of efficacy when used as an augmenting agent in depression and anxiety disorders.



At the University of California San Diego Center for Eating Disorders Treatment and Research, we occasionally use low-dose atypical antipsychotics to augment antidepressants in some of our patients who have more chronic and severe BN and whose disorder has proved refractory to the established treatments (typically, these patients also have not achieved remission of comorbid depression or anxiety on various antidepressants). These patients often are also of relatively low weight and display the rigid, restrictive thought processes more typical of patients with anorexia nervosa.

While case reports and small open trials of anorexia nervosa, mostly with inpatients, have focused on olanzepine, quetiapine, and risperidone, in consideration that the weight gain sometimes attributed to these medications may benefit emaciated patients, we have found use of these particular medications in our BN outpatients to be problematic. Even in cases where patients accept the need to attain a higher target weight, fear of uncontrollable weight gain prevents most patients from agreeing to a medication trial, and those who do rarely remain adherent. In addition, some investigators have expressed concern that these medications, especially olanzapine, might exacerbate binge eating symptoms in patients with eating disorders.

We have had more success in starting patients on the generally weight-neutral antipsychotics aripiprazole and ziprasidone. Our patients who find these medications helpful describe a reduction in distress around eating, more willingness to attempt their prescribed meal plans, fewer obsessional thoughts about food, exercise, weight, and body image, and less tendency to dwell on these thoughts when they do occur. For some, reductions in bingeing, purging, and restrictive eating behaviors have been demonstrated clinically. Mood tends to improve as well. However, it must be emphasized that without trial data, use of the atypical antipsychotics in BN remains experimental. Any desired benefit must be weighed against potential adverse effects, including the unlikely but possible risk of tardive dyskinesia.




There are minimal controlled trial data on long-term efficacy of pharmacotherapy for BN. A relatively large study designed to isolate long-term potential benefits of antidepressant medication, conducted in 2002, was hampered by significant rates of attrition in both study drug and placebo arms. The trial began with 232 patients who received an 8-week course of fluoxetine, 60 mg/d, under single-blind treatment conditions. Of this group, 150 patients were considered responders (ie, a 50% or greater decrease in weekly vomiting episodes), and were randomly assigned to continued fluoxetine treatment or placebo for a 1-year double-blind relapse prevention phase.

Findings included a lower rate of relapse for the fluoxetine group, but the investigators noted a worsening on all measures of efficacy over time. They concluded that pharmacotherapy alone may not be adequate treatment after acute response for most patients.

Perhaps even more concerning was a less than 20% acute-phase remission rate in this study. This result, which is described as consistent with data from other trials, reveals that the vast majority of responders were still bingeing and purging at the beginning of maintenance therapy, which indicates that the idea of relapse prevention may be dubious for most trial participants.



Bulimia nervosa is a disorder with a complex cause. The disorder is most commonly seen in women, generally with onset in adolescence.

Mary Ellen Trunko, MD

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