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.

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.

Inclusion Criteria:

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

Exclusion Criteria:

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

This study aims to include a small number of participants, and privacy and confidentiality will need to be considered against the benefits of data sharing.