Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

Study Overview
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Brief Summary
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This is a study of a new medication for the treatment of cognitive impairments (thinking difficulties) and negative symptoms in people with schizophrenia. The new medication is rasagiline. Rasagiline is a drug which has been approved by the Food and Drug Administration for the treatment of Parkinson's disease. It is used to treat cognitive problems.

Detailed Description
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The study will consist of two phases: a 4-week continued stability phase (lead-in phase) and a 12-week double-blind treatment phase. In the lead-in phase, subjects receiving antipsychotic medication, who manifest moderate to severe and persistent negative symptoms, will remain on their maintenance regimen for at least four weeks. The treatment phase will be a 12-week, parallel groups, double-blind, placebo-controlled trial of adjunctive rasagiline (1 mg/day), a selective MAO-B oxidase inhibitor.

Official Title
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Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: rasagiline (Pharmacodynamics)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects will meet DSM-IV criteria for schizophrenia or schizoaffective disorder. Current treatment with one or more second generation antipsychotics, except ziprasidone On same second generation antipsychotic(s)for at least 56 days On same dose of second generation antipsychotic(s)for at least 30 days 22-item SANS: Total score (i.e.all items minus global items and poverty of content of speech)greater than 20 or global Rating of Affective Flattening greater than or equal to 3 or global Rating of alogia greater than or equal to 3 BPRS: Sum of the four positive symptom items less than or equal to 16 (items 4,11,12,15) BPRS: Sum of the four Anxiety/Depression Factor items less than or equal to 14 (items 1,2,5,9) Simpson-Angus Scale: Total score less than or equal to 8 Exclusion Criteria: DSM-IV Major Depressive Disorder within last 6 months Current treatment with ziprasidone DSM-IV diagnosis of alcohol or substance dependence within the last 6 months DSM-IV criteria for alcohol or substance abuse within the last month evidence of illicit substance use, as identified with urine toxicology screen History of an organic brain disorder, mental retardation,epilepsy, or a medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol. See those listed below Uncontrolled hypertension defined as BP exceeding 145/90 on 3 consecutive readings despite adequate treatment, pheochromocytoma, melanoma, hepatic insufficiency Pregnancy or lactation in females Pheochromocytoma Melanoma Hepatic insufficiency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Rasagiline<br>Treatment with Rasagiline | Drug: rasagiline (Pharmacodynamics)<br>* Rasagiline 1 mg/day for 12 weeks<br>|
| Placebo Comparator: Inactive pill<br>Treatment with Placebo | Drug: Placebo<br>* Placebo 1 tablet each day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Negative Symptoms | The Scale for the Assessment of Negative Symptoms (SANS) rating scale was used to assess the negative symptoms of schizophrenia. Scores on the subscales are combined (summed) to compute a total score. There are a total of 17 subscales. Each subscale ranges from 0=Not at all to 5=Severe. Every 4 weeks the summed subscale scores provide a total score for that week (0-85). Higher scores indicate more severe negative symptoms. | Every 4 weeks over a 12 week period | 
| Cognitive Testing - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score | The RBANS is a brief, individually administered test designed to evaluate neuropsychological status of adults, ages 20-89. The 12 subtests measure attention, language, visuospatial/constructional abilities, and immediate and delayed memory. The raw scores from the subtests are scaled together to create index scores, and these are summed for conversion to a total scale score. Higher score equals a better outcome. The total index score range for the RBANS is 40-160. | Beginning of treatment phase (week 0) and end of treatment phase (week 12) | 
| Cognitive Testing - N-Back Neurocognitive Task | The N-Back task is a sequential letter working memory task. D-prime was used to measure accuracy on the 0-back, 1-back, and 2-back conditions. D-prime scores range from 0 to 8.6. Higher scores are better. As memory load increases from 0 to 1, from 1 to 2, D-prime scores are expected to be lower. | Beginning of treatment phase (week 0) and end of treatment phase (week 12) | 
| Cognitive Testing - Probabilistic Learning Task | To assess reward learning, participants used performance feedback to choose the most frequently rewarded item in each of three pairs of stimuli (one pair had reward probabilities: 80% vs 20%; one pair had reward probabilities of 70% vs 30%; one pair had the probabilities of 60% vs 40 %) (PL; Frank et al, 2004). A total of 240 trials were administered so each pair was seen 80 times. Higher scores represent more frequent choices of the optimal stimulus in each pair. The frequencies with which participants repeated an item choice that was rewarded on the previous presentation (win-stay) is also presented as a percentage. Similarly, the lose-shift score is the percentage of times that participants changed their choice for unrewarded items (lose-shift). The win-stay score serves as a measure of the impact of positive feedback on subsequent choices while the lost-shift score serves as a measure of the impact of negative feedback on subsequent choices. | Beginning of treatment phase (week 0) and end of treatment phase (week 12) | 
| Cognitive Testing - Delayed Discounting | The monetary choice questionnaire for hypothetical monetary rewards was used to assess delayed discounting (Kirby et al, 1999). The measure includes 27 items in which participants choose between a smaller, immediate reward (SIR) and a larger, delayed reward (LDR). There are three LDR sizes: small ($25-35), medium ($50-60) and large ($75-85). By examining the pattern of choices that participants make across the set of 27 items it is possible to calculate their delay discounting rate, termed K. The discount rate determines the steepness of the reduction in the present value of a reward with increases in the delay to the possible receipt of that reward. Thus, higher values in K represent greater discounting of the value of future rewards. With this measure K values can range between a low of 0.00016 to a high of 0.25. Higher K values have been linked to measures of impulsivity. Shown in the table are the K values observed when the future rewards were small, medium, or large. | Beginning of treatment phase (week 0) and end of treatment phase (week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extrapyramidal Symptoms | The Simpson Angus Scale (SAS; Simpson and Angus, 1970) was used to assess extrapyramidal symptoms (EPS). The assessment consists of 11 items, each rating the severity of potential symptoms of movement disorders. Total scores are calculated by summing the scores of each of the 11 items for a potential total score of 0-44, with higher scores indicating more severe EPS. | Baseline (Week 0) and End of Study (Week 12) | 
| Number of Participants With Akathisia | The Barnes Akathisia Scale (BAS; Barnes, 1989) was used to assess akathisia, a type of extrapyramidal symptom. The global clinical assessment of akathisia score is rated on a scale from 0=Absent to 5=Severe Akathisia. | Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | 
| Change in Persistent Positive Symptoms | The Brief Psychiatric Rating Scale (BPRS) positive symptom item total score was used to assess positive symptom change. The BPRS positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from 1=Not Present to 7=Very Severe. The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating. | Every 4 weeks for 12 weeks. | 
| Depressive Symptoms | The Calgary Depression Scale (CDS; Addington et al, 1997) total score was used to assess depressive symptoms over the course of the study. Total scores were calculated by summing the scores of each of the 9 items. Total scores can range from 0-27, with higher scores indicating more severe depressive symptoms. | Every 4 weeks for 12 weeks. | 
| Global Change in Illness Severity | The Clinical Global Impression (CGI) severity of illness item was used to assess global changes. Scores on this item range from 1=Normal, not at all ill to 7=Among the most extremely ill. | Every 4 weeks for 12 weeks. | 
| Number of Participants Exhibiting Side Effects | The Side Effect Checklist (SEC) was used to assess side effects. The SEC is comprised of 22 common side effects, which are rated on a 1 (none)-4 (severe) scale. Side effects are determined to be clinically significant if there is a two or more point increase in severity from baseline, or any side effect that receives a severity rating of 4 (severe) at any point in the treatment phase of the study. | Every week for 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognitive impairments, Negative symptoms