Rasagiline in the Treatment of Persistent Negative Symptoms of Schizophrenia

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.

Time frame: Every 4 weeks over a 12 week period

Population: Number of participants available for symptom efficacy analyses.

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.

Time frame: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Time frame: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Time frame: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points. Results for lose shifts are calculated for 24 Rasagiline and 22 Placebo participants, due to missing data created by participants who had zero losses (and hence no need to shift) during both the 3rd and 4th blocks of trials.

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.

Time frame: Beginning of treatment phase (week 0) and end of treatment phase (week 12)

Population: Subjects completing the cognitive testing at both time points.

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.

Time frame: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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.

Time frame: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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.

Time frame: Baseline (Week 0) and End of Study (Week 12)

Population: SAS scores were collected at baseline on 28 Rasagiline and 29 Placebo patients. End of study scores were collected on 27 Rasagiline and 27 Placebo patients, including 5 patients who withdrew before Week 12 (1 Rasagiline patient at Week 4, 1 Placebo participant each at Weeks 3 and 6, and two Placebo participants at Week 8).

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.

Time frame: Every 4 weeks for 12 weeks.

Population: Number of participants available for symptom efficacy analyses.

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.

Time frame: Every week for 12 weeks

Population: One placebo patient for whom a baseline side effects checklist was excluded from these analyses.

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.

Time frame: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.

Population: Barnes Akathisia Scales at baseline and end of study were collected for 26 participants each in the rasagiline and placebo groups. End of study ratings were collected at week 12, except for 4 placebo participants (1 participant each at weeks 3 and 6, and two at week 8).