A Double-blind, Placebo Controlled Trial of Risperidone for the Treatment of Anorexia Nervosa

Study Overview
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Brief Summary
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The aim of this pilot study is to determine the safety and efficacy of risperidone for the treatment of anorexia nervosa. Hypothesis 1: Subjects on risperidone will show a more significant decrease in body image distortion and Eating Disorder Inventory -2 scores than subjects on placebo. Hypothesis 2: Subjects on risperidone will reach and maintain at or above 90% Ideal body weight sooner than controls.

Detailed Description
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The lack of effective medications for the symptoms of anorexia nervosa (AN), combined with early promising findings in case reports (Risperidone and Olanzapine) and one open study of olanzapine have led to increased use of these medications for individuals with AN. This double-blind placebo controlled study of risperidone will attempt to determine if risperidone is effective in decreasing core symptoms of anorexia nervosa and decreasing the length of time required to reach and maintain at or about 90% Ideal body weight. The safety of risperidone in this population will also be examined through monitoring of Extrapyramidal Symptoms, Tardive Dyskinesia, Electrocardiograms's, Resting Energy Expenditure, liver enzymes and other blood chemistry. Other possible variables which may mediate the recovery process or be impacted by risperidone,such as leptin and anxiety symptoms are also being measured.

Official Title
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A Double-blind, Placebo Controlled Trial of Risperidone for the Treatment of Anorexia Nervosa

Conditions
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Anorexia Nervosa

Intervention / Treatment
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* Drug: Risperidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary Diagnosis of Anorexia Nervosa Female, age 12-21 Active in a level of care for AN at The Children's Hospital, Denver As long as there is a primary dx of AN, co-morbid diagnoses may be included. If taking an antidepressant, must be on a stable dose for 3 weeks prior to entering the study, and dose of antidepressant may not be changed during Phase 1 of the study. If choosing to discontinue antidepressant medication, must be off the medication for 3 weeks prior to beginning the study. If sexually active, must use birth control during the study and have a monthly pregnancy test. Exclusion Criteria: Previous enrollment in this study on a prior admission Previous allergic reaction to risperidone or other atypical neuroleptic Positive pregnancy test Neurologic disorder other than benign essential tremor Taking a psychotropic medication other than antidepressant and discontinuing the medication is not recommended. Active hepatic or renal disease Wards of the state Males

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>double blind study of risperidone for anorexia nervosa. this is the subject group that receives placebo. | Drug: Placebo<br>* Comparison of risperidone versus placebo for the treatment of symptoms related to anorexia nervosa.<br>* Other names: placebo - inactive pill;|
| Active Comparator: risperidone<br>Study is double blind, placebo controlled. This is the subject group on active medication | Drug: Risperidone<br>* risperidone titrated 0.5 to 4 mg over study enrollment. Mean Length of Phase 1 is currently 10 weeks.<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Eating Disorder Inventory-2 Drive for Thinness Subscale (DT) | Eating Disorder Inventory -2 - Subscale : Drive for Thinness Subscale (DT). Lower scores are better on this scale and indicate less cognitive focus on drive for thinness. The EDI 2 is a 91 item scale with 8 subscales - (Drive for thinness, Bulimia, body dissatisfaction, ineffectiveness, perfection, interpersonal distrust, interoceptive awareness and maturity fears.). The DT subscale was used for this outcome. Respondents rate each item as usually , often, sometimes, rarely or never. Subscale scores are computed by summing all item scores for each subscale. There are 7 items in the DT subscale (questions 1,7,11,16,25,32 and 49). the subscale score range is 0-21. The EDI-2 was completed by subjects at baseline and then monthly during study participation (range 0 -18 weeks). Change in the DT subscale score was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. | month | 
| Change in Eating Disorder Inventory (EDI)-2 Score for Body Dissatisfaction (BD) | change in Eating Disorder Inventory (EDI) 2-score for Body Dissatisfaction (BD). Lower scores are better on this scale. Higher scores indicate the subject has greater body dissatisfaction. BD is one of the 8 subscales of the EDI-2. 9 of the 91 questions in the EDI-2 scale constitute this subscale. The score range is 0-27. Subjects completed the EDI-2 at baseline and monthly during study participation (range 0 to 18 weeks). Change in the BD subscale score during the study was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. | monthly | 
| Hazard Ratio for Time to Reaching Ease Of Eating Level 3 From Start of Study (Normal Eating Behavior) | The Ease of Eating Scale (EOES) is a 14 item scale which measures Food avoidance behaviors (FABs). The scale is rated by staff observing a subject eating a meal or snack. 0 = normal eating behavior, maximum score 28. Higher scores indicate more food avoidance behaviors, such as taking small bites, taking > 30 seconds between bites (slow eating), etc. EOE was completed for each meal a subject ate in the program and scores were averaged for each week in the study and entered in the data base. Change in EOES score was calculated by evaluating change over time. This measure was only used in Phase 1 of the study, for days the subjects were in the treatment program. | weekly up to study endpoint: reaching target weight and maintaining for 1 month | 
| Color A Person Test (CAPT) | Color A Person Test (CAPT) - Subjects color an outlined image of a body to indicate body dissatisfaction (red (5)= very dissatisfied, Yellow, dissatisfied, black, neutral, green satisfied, blue very satisfied (1). The outline is divided into16 sections for scoring. The CAPT was completed at baseline and monthly during study participation. Total CAPT scores were calculated by adding the total score and dividing by 16. Score range is 1-5. Lower scores indicate less body dissatisfaction. Change in the CAPT score during the study was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. | monthly | 
| Body Image Software (BIS): Average Distortion | Body Image Software (BIS) - the subject adjusts a digital image of themselves on the computer using the direction to adjust their image to how they see themselves right now, this determines their perception of their current image. Accuracy is measured by a smaller score between desired image and actual image. Change in the BIS Average Distortion score during the study was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. There are no identifiable minimum/maximum values as there would be in a questionnaire scale. There are no subscales. The BIS program calculates the difference between their actual image and the size of the image they have adjusted the digital image to based on their perception of how they see themselves right now | monthly | 
| Body Image Software (BIS): Average Desired Thinness | Body Image Software (BIS) - the subject adjusts a digital image of themselves on the computer to their desired image. The BIS program calculates the difference between their actual image, and how much they have adjusted the image to represent their desired image. Accuracy is measured by a smaller score between desired image and actual image. Change in BIS - Average Desired Thinness score was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. There are no identifiable minimum/maximum values as there would be in a questionnaire scale. . There are no subscales. | monthly | 
| Body Image Software (BIS) - Point of Subjective Equality (PSE) | Body Image Software (BIS) - the subject adjusts a digital image of themselves on the computer to their desired image, and also completes a task that determines their perception of their current image. Accuracy is measured by a smaller score between desired image and actual image. Change in BIS -PSE was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. There are no identifiable minimum/maximum values as there would be in a questionnaire scale. Interpreting the PSE is how it compares to a PSE = 0, which is no distortion in body size. | monthly | 
| Body Image Software (BIS) - Difference Limen (DL) | Body Image Software (BIS) - the subject adjusts a digital image of themselves on the computer to their desired image, and also completes a task that determines their perception of their current image. Accuracy is measured by a smaller score between desired image and actual image. Change in BIS-DL was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. There are no identifiable minimum/maximum values as there would be in a questionnaire scale. There are no subscales. Interpreting the DL occurs by referencing it to DL= 0, which would reflect a total inability to detect size differences, which has never occurred in studies using the BIS program. | monthly | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach 90% Ideal Body Weight (IBW) and Maintain for 1 Month, Stratified by >=80% at Start of Study | The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. These estimates were produced using Kaplan-Meier probabilities. This was measured weekly from 0-18 weeks. | weekly | 
| Change in Ratings of Anxiety Symptoms on the Multidimensional Anxiety Scale for Children (MASC) | The Multidimensional Anxiety Scale for Children (MASC) is a self report measure completed by the subject that measures anxiety symptoms. Higher scores indicate greater anxiety. A score of over 50 is significant for anxiety Change in MASC scores was calculated using an estimate of change in score between week 0 and week 7 derived from the mixed effect model across all time points. | monthly to study end point | 
| Change in Leptin Levels | Leptin levels were measured by serum blood draws, results reports in nanograms / ml (ng/ml). | Week 0 and week 7 | 
| Change in Prolactin Levels | Prolactin serum blood levels, measured in nanograms / ml | week 0 and week 7 | 
| Time to Reach 90% IBW and Maintain for 1 Month, Stratified by IBW <80% at Start of Study | The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. These estimates were produced using Kaplan-Meier probabilities. | 0 - 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anorexia Nervosa, Risperidone, Atypical Neuroleptics, Dopamine, Leptin, Body Image, Adolescents