Progress in Developing Pharmacologic Agents to Treat Bulimia Nervosa
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CNS Drugs (2019) 33:31–46 https://doi.org/10.1007/s40263-018-0594-5 REVIEW ARTICLE Progress in Developing Pharmacologic Agents to Treat Bulimia Nervosa Susan L. McElroy1,2 · Anna I. Guerdjikova1,2 · Nicole Mori1 · Francisco Romo‑Nava1,2 Published online: 6 December 2018 © Springer Nature Switzerland AG 2018 Abstract This paper reviews past and current progress in developing pharmacologic agents for the treatment of individuals with bulimia nervosa (BN). We searched the literature and clinical trial registries for compounds studied in BN, the related condition, binge eating disorder (BED), and preclinical models of binge-eating behavior. Drug classes evaluated included antidepressants, antiepileptic drugs, stimulants and other medications for attention-defcit/hyperactivity disorder, opioid antagonists, and weight loss agents, among others. The only available drugs with established efcacy in BN at this time include antidepres- sants (especially selective serotonin reuptake inhibitors [SSRIs]) and the antiepileptic topiramate, though the efcacy of these compounds is modest at best. The only medications we found currently receiving empirical study in people with BN were fuoxetine, other serotonergic antidepressants, intranasal naloxone, lisdexamfetamine dimesylate, phentermine–topiramate combination, the antiandrogenic oral contraceptive ethinyl estradiol plus drospirenone, and prazosin. Preclinical models sug- gest that nociceptin receptor antagonists, the selective serotonin 5-HT2C receptor agonist lorcaserin, monoamine stabilizers, and selective orexin-1 receptor antagonists might be helpful. We found no evidence of a drug developed specifcally for the treatment of individuals with BN. Future areas for research in the pharmacotherapy of BN are suggested. Importantly, until drugs are developed specifcally for eating disorders, drugs developed for other conditions that are centrally acting and associ- ated with benefcial psychotropic efects and/or reduced appetite or weight loss might be considered for repurposing in BN. 1 Introduction Key Points Bulimia nervosa (BN), characterized by recurrent binge- Empirical study into the pharmacologic treatment of eating episodes and regular inappropriate compensatory bulimia nervosa (BN) has substantially lagged behind weight loss behaviors, is an important public health problem. that into other serious mental disorders. Indeed, only It is present in approximately 1.0% of the general world- one drug (the selective serotonin reuptake inhibitor wide adult population as a lifetime diagnosis and 0.4% as a fuoxetine) has regulatory approval for the treatment of 12-month diagnosis [1]. Among adolescents from the USA, individuals with BN. the lifetime prevalence estimate of BN is 0.9% [2]. BN is Few studies of pharmacologic agents in individuals with more common in females than males, with 1.5% of adult BN are presently ongoing. women [3] and 1.3% of adolescent females [2] from the USA experiencing BN during their lifetime. Median age of onset Pharmacotherapy agents with efcacy in other condi- of BN is late teens to early 20s in adults [1] and 12.4 years tions characterized by binge eating (e.g., binge eating in adolescents [2]. Though a substantial proportion of indi- disorder [BED]) or hyperphagia (e.g., Prader–Willi viduals with BN recover over the long term, the disorder is syndrome) should be considered for evaluation in BN, recurrent or chronic in others [4–6]. though assessment of safety will be crucial. BN is associated with substantial psychiatric and medi- cal comorbidity, including mood, anxiety, substance use, * Susan L. McElroy and attention-defcit/hyperactivity (ADHD) disorders, sui- [email protected] cidality and self-injurious behavior, dental complications, electrolyte abnormalities, obesity, and increased mortal- 1 Lindner Center of HOPE, Mason, OH, USA ity [1, 3, 7]. BN is further associated with impairment in 2 University of Cincinnati College of Medicine, Cincinnati, OH, USA Vol.:(0123456789) 32 S. L. McElroy et al. role functioning, reduced health-related quality of life, and ongoing in France to evaluate the efcacy of SSRIs in 45 increased healthcare utilization and costs [1, 3, 8]. participants with BN according to brain serotonin profle Though psychotherapy is viewed by many to be the as determined by positive emission tomography using the treatment of choice for BN [9, 10], patients with BN often specifc brain serotonin 5-HT1A receptor ligand [18F]MPPF receive pharmacotherapy [11]. However, only one drug, the (NCT02359513). selective serotonin reuptake inhibitor (SSRI) fuoxetine, has Other antidepressants beyond fuoxetine have been shown regulatory approval for the treatment of BN (in the USA to be superior to placebo for reducing the frequency of both and other countries). Moreover, no drug has been devel- binge-eating and purging episodes in BN [19, 20], and oped specifcally for the treatment of an eating disorder, guidelines have concluded that antidepressants are efca- which may refect in part the limited knowledge about the cious for BN [9, 21]. This includes SSRIs other than fuox- pathophysiology and molecular genetics of these disorders etine, tricyclic antidepressants, monoamine oxidase inhibi- [12–14]. New medications with novel mechanisms of action tors, and atypical agents such as mianserin, trazodone, and are sorely needed for the treatment of individuals with BN. bupropion. A 2003 meta-analysis of 19 antidepressant RCTs We review past and ongoing research with specifc medi- in people with BN showed antidepressants were modestly cations or medication classes in treating individuals with superior to placebo for stopping binge-eating episodes [22]. BN. We searched PubMed and clinical trial registries to This meta-analysis showed antidepressants were also safe for identify medications evaluated in BN. Because we found so treatment of BN, with the important exception of bupropion. few, we also searched PubMed and clinical trial registries to Though efcacious for reducing binge eating and purging, identify drugs evaluated in patients with binge-eating dis- this agent was associated with an increased risk of seizures order (BED). Although BED is a diagnostic entity distinct [23] and is therefore contraindicated for the treatment of BN from BN, it is also characterized by recurrent binge-eating (and anorexia nervosa). episodes as a core feature, the binge-eating episodes for both To our knowledge, three randomized, placebo-controlled, disorders are similarly defned in modern nosologic systems relapse-prevention trials have been undertaken with antide- [15, 16], and there is substantial diagnostic shift between pressants in BN. In the frst RCT, though desipramine was the two disorders [4]. Although not yet defnitively proven, superior to placebo for reducing binge eating in the initial a drug that reduces binge eating in BED might also reduce acute phase of the study, not enough patients completed binge eating in BN. Finally, we also searched PubMed for the maintenance phase to determine whether the drug also drugs evaluated in preclinical models of binge eating, though had long-term efcacy [24]. In the second RCT, 72 patients whether fndings from these models generalize to individuals with BN successfully treated with intensive inpatient psy- with BN remains unclear [17]. chotherapy were randomized to receive fuvoxamine (n = 33) This search found a broad array of drugs evaluated in the or placebo (n = 39) as outpatients for 12 weeks [25]. Fluvox- treatment of BN and related conditions, including antide- amine was begun 3 weeks before hospital discharge, for a pressants, antiepileptic drugs, stimulants and other ADHD total of 15 weeks of treatment. Relapse rate was signifcantly medications, agents with hormonal properties, and weight lower with fuvoxamine than placebo, as evidenced by (1) loss drugs, among others. We summarize these data and sug- 10 versus 46% deterioration on the Psychiatric Status Rating gest future areas for research. Scale for Bulimia Nervosa; (2) 111 versus 270% increase in self-reported binge-eating episodes in the last week, and (3) 50 versus 175% increase on the Structured Interview for 2 Antidepressants Anorexia and Bulimia Nervosa subscale of bulimic behavior. In addition, at the end of the relapse prevention, signifcantly As noted, the SSRI antidepressant fuoxetine is the only more patients in the fuvoxamine group than the placebo medication with regulatory approval (in the USA and other group reported no binge-eating episodes in the past week countries) for the treatment of BN. In the largest randomized (p < 0.05). However, the dropout rate was high (33%), with controlled trial (RCT) of fuoxetine in BN, 387 women 14 (38%) fuvoxamine recipients and fve (14%) placebo with BN were randomized to receive fuoxetine 60 mg/ recipients stopping treatment prematurely. day, fuoxetine 20 mg/day, or placebo for 8 weeks at 13 In the third study, 232 outpatients with purging-type BN sites [18]. Fluoxetine 60 mg/day was superior to placebo received single-blind treatment with fuoxetine 60 mg/day for reducing binge-eating and vomiting episodes, whereas for 8 weeks; 150 (65%) met response criteria and were ran- fuoxetine 20 mg/day had an intermediate efect [18]. Fluox- domly assigned to continue fuoxetine 60 mg/day (n = 76) etine 60 mg/day was also superior to placebo for reducing or switch to placebo (n = 74) for 52 weeks [26]. Fluoxetine- depression, carbohydrate craving, and pathological eating treated participants had a signifcantly