An Open Trial of a Novel Pharmacotherapy for Habit Modification in Anorexia Nervosa

Обзор

The purpose of this study is to test the feasibility and tolerability of donepezil in a small group of patients with anorexia nervosa (AN). Study participants will be receiving care at the New York State Psychiatric Institute Eating Disorders Unit. Study medication will be increased from 1 mg per day to a maximum of 5 mg per day for up to 8 weeks. Participants will be closely monitored for side effects by a research psychiatrist every week, in addition to the regular clinical monitoring they receive during inpatient treatment. The study will also include assessments of habit strength to measure any changes in maladaptive eating habits over the course of the treatment.

Подробное описание

Anorexia nervosa (AN) is a serious mental illness affecting up to 4% of women in the United States, with a chronic course and a mortality rate 6 times that expected for young women (Arcelus et al., 2011). The core, salient behavior in AN is maladaptive food restriction that persists even after full weight restoration treatment (Steinglass et al., 2023). Pharmacologic approaches to the treatment of AN, to date, have attempted to capitalize on side effect profiles (e.g., weight gain) or efficacy in related disorders (e.g., depression) but have yielded disappointing results (Muratore and Attia, 2022). This program of research leverages advances in mechanism research, which has identified the importance of habit systems in AN (Conceição et al., 2023), to test whether a medication can target habitual restrictive intake and thereby help patients with AN.

Donepezil is an acetylcholinesterase inhibitor and an FDA-approved medication that has been shown to reverse habitual behaviors like excessive exercise and food restriction in a rodent model of AN. Donepezil has been studied for its potential effect in mitigating compulsive, habit-like symptoms in other clinical populations, with no adverse events (Bergman et al., 2016; Cubo et al., 2008). These data suggest that donepezil may be effective in reducing maladaptive behaviors in compulsive disorders. There is no control product in this study.

Study medication will be initiated at 1mg, to be taken before bed. Dosing will follow a flexible titration. The expected titration will be 1 mg for 2 weeks, 2.5 mg for 2 weeks, then 5 mg for 4 weeks. The target dose of 5 mg/day is lower than the approved dose for dementia and the dose used in a study of adults with Obsessive Compulsive Disorder (OCD) (Bergman et al., 2016). Doses may be lowered from those recommended by the protocol if side effects are significant.

The primary objective of this study is to test the feasibility and tolerability of donepezil among patients with AN. The exploratory objectives are to test the utility of donepezil to modify the habitual behaviors characteristic of AN.

Вмешательства

• Препарат Donepezil
  Study medication will be initiated at 1mg, to be taken before bed. Dosing will follow a flexible titration. The expected titration will be 1 mg for 2 weeks, 2.5 mg for 2 weeks, then 5 mg for 4 weeks. Doses may be lowered from those recommended by the protocol if side effects are significant.

Первичные конечные точки

• Side Effects Form [Срок оценки: From enrollment to the end of treatment at 8 weeks]
• Clinical Global Impressions Scale [Срок оценки: From enrollment to the end of treatment at 8 weeks]

Вторичные конечные точки (2)

• Self-Report Habit Index [Срок оценки: From enrollment to the end of treatment at 8 weeks]
• Food Choice Task [Срок оценки: From enrollment to the end of treatment at 8 weeks]

Критерии участия

Критерии включения

• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study (Clinical interview).
• Aged 18-60 years (Clinical interview).
• Diagnosed with anorexia nervosa (EDA-5).
• BMI ≥ 15 kg/m2 (Clinical team medical record)

Критерии исключения

• Score of High Risk on the Columbia Suicide Severity Scale (C-SSRS).
• Pregnancy (Serum pregnancy test on admission).
• Current diagnosis of schizophrenia, schizophreniform disorder, bipolar (type I), or substance use disorder (SCID).
• Bradycardia (below 60 bpm) (vital signs measurement by the clinical team)
• Corrected QT interval (QTc) greater than 480 ms at baseline (EKG).
• Antipsychotic medication (antidepressants at a stable dose are allowed) (clinical interview).
• Known allergic reactions to components of the donepezil (e.g., known hypersensitivity to donepezil hydrochloride) (clinical interview).
• History of peptic ulcer disease (clinical interview).
• History of arrhythmia (clinical interview).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Другое

Центры проведения

США · 1 центр

• New York State Psychiatric Institute — New York

Публикации

• Attia E, Kaplan AS, Walsh BT, Gershkovich M, Yilmaz Z, Musante D, Wang Y. Olanzapine versus placebo for out-patients with anorexia nervosa. Psychol Med. 2011 Oct;41(10):2177-82. doi: 10.1017/S0033291711000390. Epub 2011 Mar 22. PMID 21426603
• Conceicao ISR, Garcia-Burgos D, de Macedo PFC, Nepomuceno CMM, Pereira EM, Cunha CM, Ribeiro CDF, de Santana MLP. Habits and Persistent Food Restriction in Patients with Anorexia Nervosa: A Scoping Review. Behav Sci (Basel). 2023 Oct 25;13(11):883. doi: 10.3390/bs13110883. PMID 37998630
• Cubo E, Fernandez Jaen A, Moreno C, Anaya B, Gonzalez M, Kompoliti K. Donepezil use in children and adolescents with tics and attention-deficit/hyperactivity disorder: an 18-week, single-center, dose-escalating, prospective, open-label study. Clin Ther. 2008 Jan;30(1):182-9. doi: 10.1016/j.clinthera.2008.01.010. PMID 18343255
• Steinglass JE, Fei W, Foerde K, Touzeau C, Ruggiero J, Lloyd C, Attia E, Wang Y, Walsh BT. Change in food choice during acute treatment and the effect on longer-term outcome in patients with anorexia nervosa. Psychol Med. 2024 Apr;54(6):1133-1141. doi: 10.1017/S0033291723002933. Epub 2023 Oct 2. PMID 37781904
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• El Mestikawy S, Wallen-Mackenzie A, Fortin GM, Descarries L, Trudeau LE. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci. 2011 Apr;12(4):204-16. doi: 10.1038/nrn2969. PMID 21415847
• Bergman J, Miodownik C, Lerner PP, Miodownik E, Shulkin A, Lerner V. Donepezil as Add-on Treatment for Resistant Obsessive-Compulsive Disorder: Retrospective Case Series. Clin Neuropharmacol. 2016 Jul-Aug;39(4):194-6. doi: 10.1097/WNF.0000000000000160. PMID 27223667
• Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry. 2011 Jul;68(7):724-31. doi: 10.1001/archgenpsychiatry.2011.74. PMID 21727255

Идентификаторы

NCT: NCT06518941 · NKI2024-90

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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