Cognitive Enhancement in Bipolar Disorder

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.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: pramipexole

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • Glen Oaks, New York, United States, 11004
      • North Shore - Long Island Jewish Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active pramipexole; 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; po pramipexole versus matching placebo minimum 0.125 mg bid and maximum 0.75 mg bid; Other Names: Mirapex
Placebo Comparator: Placebo pramipexole; 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; po pramipexole versus matching placebo minimum 0.125 mg bid and maximum 0.75 mg bid; Other Names: Mirapex

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Northwell Health
• Collaborators: Stanley Medical Research Institute
• Investigators: Principal Investigator: Anil K. Malhotra, MD, Northwell Health; Principal Investigator: Katherine Burdick, PhD, Northwell Health

Publications and helpful links

General Publications

• Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK. Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction. J Clin Psychiatry. 2012 Jan;73(1):103-12. doi: 10.4088/JCP.11m07299. Epub 2011 Nov 29.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: January 8, 2008
• First Submitted That Met QC Criteria: January 17, 2008
• First Posted (Estimate): January 18, 2008

Study Record Updates

• Last Update Posted (Estimate): June 12, 2015
• Last Update Submitted That Met QC Criteria: June 10, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Dopamine Agonists; Dopamine Agents; Antioxidants; Antiparkinson Agents; Anti-Dyskinesia Agents; Pramipexole
• Other Study ID Numbers: 05-069; 05T-670 (Other Grant/Funding Number: Stanley Medical Research Institute)