Cognitive Enhancement in Bipolar Disorder

Study Overview
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Brief Summary
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The purpose of this study is to examine whether the medication pramipexole (Mirapex) may be able to improve cognitive problems (i.e. difficulties with thinking, memory, and concentration) that may be associated with bipolar disorder.

Detailed Description
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To address the primary aim, the study is an eight-week, randomized, double-blind, placebo-controlled treatment trial of pramipexole in 50 euthymic bipolar I and II disorder (BPD) patients, who demonstrate cognitive impairment.

Official Title
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Cognitive Enhancement in Bipolar Disorder

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: pramipexole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects between 18 and 65 years of age, who meet Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for BPD I or II (by SCID) and confirmed in the diagnostic consensus conference will be included. Subjects must also meet criteria for euthymia described above. All subjects must be taking a standard mood stabilizer at a stable therapeutic dose (i.e. lithium, carbamazepine, valproate, lamotrigine). Exclusion Criteria: Subjects with a history of central nervous system (CNS) trauma, neurological disorder, Attention Deficit Hyperactivity Disorder (ADHD), or learning disability will be excluded. Subjects with a DSM-IV diagnosis of current or recent substance abuse or dependence (in the previous 1 month) will be excluded. Moreover, subjects with rapid-cycling during the past year will be excluded (based on SCID). Any subject with an active, unstable medical problem that may interfere with cognition will be excluded based on the investigator's judgment. While medication status is an important consideration in any study of bipolar disorder, the exclusion of patients taking any medication is not practical, given the high prevalence of combination pharmacotherapy for bipolar disorder. To help control for medication effects on cognition, we plan to limit the types of medications allowed by excluding certain medications with a known impact on cognitive performance. Subjects taking clozapine will be excluded due to it's potential overlapping mechanisms of action with pramipexole. Subjects taking prescription or over-the counter medications may also be excluded if these medications have been shown to impact cognition (i.e. diphenhydramine). The use of benzodiazepines, sedatives, or sleeping pills, within 6 hours of neurocognitive testing will not be allowed. In addition, patients taking topiramate, tricyclic antidepressants, or anticholinergic medications that are known to impact cognition will be excluded from participation. Subjects taking any medications that are known to interact with pramipexole (i.e. Zantac, Tagamet, Reglan, Benemid, Probalan, Compazine, Phenergan, quinidine, selegiline, verapamil, and any other medication with a known interaction) will also be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: Active pramipexole<br>Day 1: Random assignment to drug or placebo and dosage starting at 0.125 mg BID, which will be increased every week to a target dose of 1.5 mg/day. Targeted maximum dose of 1.5 mg/day is expected to be reached by week 4, however, dosing will be flexible based upon side effects reported. The maximum dose will be 1.5 mg/day. | Drug: pramipexole<br>* po pramipexole versus matching placebo minimum 0.125 mg bid and maximum 0.75 mg bid<br>* Other names: Mirapex;|
| Placebo Comparator: Placebo pramipexole<br>Day 1: Random assignment to drug or placebo and dosage starting at 0.125 mg BID, which will be increased every week to a target dose of 1.5 mg/day. Targeted maximum dose of 1.5 mg/day is expected to be reached by week 4, however, dosing will be flexible based upon side effects reported. The maximum dose will be 1.5 mg/day. | Drug: pramipexole<br>* po pramipexole versus matching placebo minimum 0.125 mg bid and maximum 0.75 mg bid<br>* Other names: Mirapex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 8 in Weschler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Span Subtest (Digits Forward) | The examinee is read a sequence of numbers and must recall the numbers in the same order. Measures auditory attention and verbal working memory. The standard scores were reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Weschler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Span Subtest (Digits Backward) | The examinee is read a sequence of numbers and must recall the numbers in reverse order. Measures auditory attention and verbal working memory. The standard scores were reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Weschler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Symbol Coding Test | Using a key, the examinee copies symbols that are paired with numbers within a specified time limit. Measures visual scanning and graphomotor speed. The standard scores were reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Stroop Color-Word Test | The Stroop Color-Word Test consists of a word page with words printed in black ink, a color page with 'Xs' printed in color, and a color-word page where the color and the word do not match. The examinee reads the words or names the ink colors as quickly as possible within a time limit. Measures selective attention and inhibitory control. The raw scores (total number of words read) for each trial were reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Trail Making Test Part A | The examinee is instructed to connect a set of 25 dots as quickly as possible while maintaining accuracy. Measures attentional resources and is a measure of the frontal lobe executive functions of visual search, set-switching and conceptual flexibility. The total time in seconds was reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Trail Making Test Part B | The examinee is instructed to connect a set of 25 dots, alternating between numbers and letters, as quickly as possible while maintaining accuracy. Measures attentional resources and is a measure of the frontal lobe executive functions of visual search, set-switching and conceptual flexibility. The total time in seconds was reported for this measure. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in d2 Test of Attention | The d2 Test of Attention consist of 14 lines, each comprised of 47 characters, for a total of 658 items. The examinee must scan each line and cross out all the d's with two dashes. The subject is allowed 20 seconds per line. Measures rapid processing of visual information and motor speed. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Hopkins Verbal Learning Test | The examinee is required to recall a list of 12 words over 3 immediate learning trials, a delayed recall trial and a recognition trial. Measures learning and retention of verbal material. The total number of words recalled during the delayed recall trial was reported. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 
| Change From Baseline to Week 8 in Controlled Oral Word Association Test (COWAT) Letter Fluency | The examinee is required to say as many words as they can think of in one minute that begin with a given letter of the alphabet. The task contains three trials. Measures phonetic verbal fluency. The raw score (total words recorded across the three trials) was reported. Values indicate the change from baseline to week 8, with positive values reflecting higher scores at week 8 and negative values reflecting lower scores at week 8. | Change from Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind: Change From Baseline in Hamilton Rating Scale for Depression (HAM-D-21) Total Score at Endpoint | The Hamilton Depression Rating Scale is a clinician-rated scale used to rate depression severity. The items are rated on either a 5-point (0 to 4) or a 3-point (0 to 2) scale. The 5-point scale uses a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). Higher scores indicate worsening. The responses are summed to yield the HAM-D-21 score that ranges from 0-64. | Change from Baseline to Week 8 | 
| Double-blind: Change From Baseline in Clinician-Administered Rating Scale for Mania (CARS-M)Total Score at Endpoint | The CARS-M is a 15-item clinician-rated scale designed to assess severity of both manic and psychotic symptoms. There are 2 subscales: a mania scale and a scale for psychotic symptoms and disorganization. There are a total of 15 items on the CARS-M, each of which is rated on a 6-point Likert scale (0/Absent to 5/Extreme), with the exception of item 15 (Insight) which is rated on a 5-point Likert scale. These items yield two subscale scores-one for Mania (items 1-10) and one for Psychosis (items 11-15). Higher scores indicate worsening. The responses are summed to yield the CARS-M-15 score that ranges from 0-74. | Change from Baseline to Week 8 |