Bipolar Disorder
Conditions
Keywords
Bipolar Disorder, Cognition
Brief summary
Converging evidence suggests that patients with bipolar disorder suffer from deficits in neurocognitive functioning that persist, despite remission of acute affective symptoms. These impairments contribute directly to functional disability, highlighting the need for interventions above and beyond standard treatments in order to achieve a full inter-episode recovery. The current study aims to investigate the safety and efficacy of a dopamine agonist (pramipexole), on these persistent cognitive abnormalities in euthymic bipolar patients using a placebo-controlled, adjunctive, 12-week trial design.
Detailed description
All eligible participants will undergo study visits at screening, baseline (week 0), week 1, week 2, week 3, week 4, week 6, week 8, and week 12, (end of study). Randomization will be conducted via a computer generated program and all study staff will be blinded unless un-blinding is required for safety reasons. Subjects will be randomized on a 1:1 ratio with stratification for concomitant antipsychotic status and depression at baseline (HRSD \<8 vs \> 8). Study drug will be blinded and matched to placebo. Adapting from our previous work in BD and according to package labeling, the dosage titration schedule will be slow and flexible. Dosing will be initiated at 0.25 mg QHS on night one, followed by 0.25 mg BID day two onward, and increased every week to a target of 4.5 mg/day. As compared with our previous maximum 1.5 mg/day (Burdick et al. 2012), we opted to allow up to 4.5 mg/day (the maximum approved dosage in Parkinson's disease) to ensure adequate target engagement. We are familiar with this dose range, as 4.5 mg/day was allowed in our study in BD depression (Goldberg et al. 2004). Dosing will be flexible based on side effects; however, if 1.5 mg/day cannot be tolerated, the subject will be discontinued. Titration will occur up to week 6 and then efforts will be made to maintain the same dose until the completion of the trial (week 12).
Interventions
DRUGPramipexole
Up to 4.5mg, PO, (by mouth) per day of the 12-week study.
DRUGPlacebo
placebo match study drug
Sponsors
The Zucker Hillside Hospital
Northwell Health
National Institute of Mental Health (NIMH)
Icahn School of Medicine at Mount Sinai
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-65 * DSM-IV BD I or II diagnosis * Affective stability, defined by a Young Mania Rating Scale (YMRS) rating of \< 8 and a Hamilton Depression Rating Scale (HRSD) rating of \< 16 at screening and baseline. We will further require that any subsyndromal depression has not significantly worsened in the 4 weeks prior to randomization so as to avoid enrolling subjects who are on the verge of a full depressive episode. * Evidence of clinically-significant neurocognitive impairment at screening * Clinically-acceptable, stably-dosed, mood stabilizing medication regimen for \> 1 month prior to enrollment, with no medication changes planned over the 12-week study period.
Exclusion criteria
* History of CNS trauma, neurological disorder, ADHD, or learning disability * Positive urine toxicology or DSM-IV diagnosis of substance abuse/dependence within 3 months * Active, unstable medical problem that may interfere with cognition * Recent history of rapid-cycling * Abnormal lab or ECG result at screen * History of heart failure * Significant suicidal risk (HRSD item 3 \> 2 or by clinical judgment) * Estimated IQ in MR range as per Wide Range Achievement Test (WRAT) standard score of less than 70 * Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (including oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy) * Women who are breastfeeding * Participation in any other investigational cognitive enhancement study within 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MATRICS Consensus Cognitive Battery | Baseline | MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Young Mania Rating Scale (YMRS) | Baseline and week 12 | Mean change of symptoms of mania throughout the study. YMRS contains 7 items rated from 0 (symptom absent) to 4 (severe symptom) and 4 items scored 0 (symptom absent) to 8 (severe symptom), with total range from 0 to 60, where higher score indicates manic symptoms. |
| Hamilton Rating Scale for Depression (HRSD) | Baseline and week 12 | Mean change of symptoms of depression throughout the study. HRSD consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe), with a total score range of 0-56, where higher score indicates more depressive symptoms. |
| Brief Psychiatric Rating Scale (BPRS) | Baseline and week 12 | Mean change for positive symptoms throughout the study. BPRS consists of 18 items, each defined by a series of symptoms. Each item is rated on a 7-point scale, ranging from 1 (not observed) to 7 (very severe), with a total score range from 18-126, where higher scores indicate psychiatric symptoms. |
| Number of Participants With Suicidal Acknowledgements | up to Week 12 | Number of individual participants who acknowledged at least one item on the Columbia Suicide Severity Rating Scale (C-SSRS) over the 12-week study period. Examples of items on the scale are suicidal ideation (having thoughts, planning) and suicidal behavior (preparing, attempting). |
| The Probabilistic Stimulus Selection Task | Baseline | The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups. |
Countries
United States
Participant flow
Pre-assignment details
Protocol enrollment of 103 is the total number of participants who signed a consent form. 63 were randomized to a treatment group. The discrepancy between 103 and 63 is the total number of participants who completed a screen visit but failed to randomize (N=40).
Participants by arm
| Arm | Count |
|---|---|
| Pramipexole Pramipexole, by mouth. Dosing will be initiated at 0.25 mg on night one, followed by 0.25 mg twice-a-day day two onward, and increased every week to a target of 4.5 mg/day for the 12-week duration of the study.
Pramipexole: Up to 4.5mg, PO, (by mouth) per day of the 12-week study. | 33 |
| Placebo Placebo, by mouth. Dosing will be initiated at 0.25 mg on night one, followed by 0.25 mg twice-a-day day two onward, and increased every week to a target of 4.5 mg/day for the 12-week duration of the study.
Placebo: placebo match study drug | 30 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Pramipexole | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 30 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 26 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 14 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 19 Participants | 14 Participants | 33 Participants |
| Region of Enrollment United States | 33 Participants | 30 Participants | 63 Participants |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 37 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 30 |
| other Total, other adverse events | 18 / 33 | 5 / 30 |
| serious Total, serious adverse events | 0 / 33 | 0 / 30 |
Outcome results
Primary
MATRICS Consensus Cognitive Battery
MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | MATRICS Consensus Cognitive Battery | 35.45 T-score | Standard Deviation 12.33 |
| Placebo | MATRICS Consensus Cognitive Battery | 38.07 T-score | Standard Deviation 10.45 |
p-value: 0.38t-test, 2 sided
Primary
MATRICS Consensus Cognitive Battery
MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance.
Time frame: Week 6
Population: The discrepancy in participants analyzed here compared to baseline is due to an early termination from study of 5 participants in pramipexole group and 4 participants in placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | MATRICS Consensus Cognitive Battery | 35.57 T-score | Standard Deviation 13.87 |
| Placebo | MATRICS Consensus Cognitive Battery | 39.81 T-score | Standard Deviation 11.01 |
p-value: 0.22t-test, 2 sided
Primary
MATRICS Consensus Cognitive Battery
MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance.
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | MATRICS Consensus Cognitive Battery | 36.46 T-score | Standard Deviation 13.61 |
| Placebo | MATRICS Consensus Cognitive Battery | 41.50 T-score | Standard Deviation 11.47 |
p-value: 0.17t-test, 2 sided
Secondary
Brief Psychiatric Rating Scale (BPRS)
Mean change for positive symptoms throughout the study. BPRS consists of 18 items, each defined by a series of symptoms. Each item is rated on a 7-point scale, ranging from 1 (not observed) to 7 (very severe), with a total score range from 18-126, where higher scores indicate psychiatric symptoms.
Time frame: Baseline and week 12
Population: Average change in BPRS based on baseline and week 12 score.The discrepancy in participants analyzed here compared to participant flow is due to available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | Brief Psychiatric Rating Scale (BPRS) | -0.63 score on a scale | Standard Deviation 3.53 |
| Placebo | Brief Psychiatric Rating Scale (BPRS) | -0.61 score on a scale | Standard Deviation 3.7 |
p-value: 0.98t-test, 2 sided
Secondary
Hamilton Rating Scale for Depression (HRSD)
Mean change of symptoms of depression throughout the study. HRSD consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe), with a total score range of 0-56, where higher score indicates more depressive symptoms.
Time frame: Baseline and week 12
Population: Average change in HRSD based on baseline and week 12 score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | Hamilton Rating Scale for Depression (HRSD) | -0.24 score on a scale | Standard Deviation 3.78 |
| Placebo | Hamilton Rating Scale for Depression (HRSD) | -.22 score on a scale | Standard Deviation 3.66 |
p-value: 0.99t-test, 2 sided
Secondary
Number of Participants With Suicidal Acknowledgements
Number of individual participants who acknowledged at least one item on the Columbia Suicide Severity Rating Scale (C-SSRS) over the 12-week study period. Examples of items on the scale are suicidal ideation (having thoughts, planning) and suicidal behavior (preparing, attempting).
Time frame: up to Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pramipexole | Number of Participants With Suicidal Acknowledgements | 0 Participants |
| Placebo | Number of Participants With Suicidal Acknowledgements | 5 Participants |
Secondary
The Probabilistic Stimulus Selection Task
The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups.
Time frame: Baseline
Population: The discrepancy in participants analyzed from participants in Participant Flow is due to availability of data because of software issues in running task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | The Probabilistic Stimulus Selection Task | 56.94 percentage of accuracy | Standard Deviation 17 |
| Placebo | The Probabilistic Stimulus Selection Task | 67.56 percentage of accuracy | Standard Deviation 20.12 |
p-value: 0.09t-test, 2 sided
Secondary
The Probabilistic Stimulus Selection Task
The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups.
Time frame: Week 6
Population: The discrepancy in participants analyzed from participants in Participant Flow is due to availability of data because of software issues in running task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | The Probabilistic Stimulus Selection Task | 56.91 percentage of accuracy | Standard Deviation 22.6 |
| Placebo | The Probabilistic Stimulus Selection Task | 56.94 percentage of accuracy | Standard Deviation 22.67 |
p-value: 1t-test, 2 sided
Secondary
The Probabilistic Stimulus Selection Task
The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups.
Time frame: Week 12
Population: The discrepancy in participants analyzed from participants in Participant Flow is due to availability of data because of software issues in running task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | The Probabilistic Stimulus Selection Task | 59.54 percentage of accuracy | Standard Deviation 21.59 |
| Placebo | The Probabilistic Stimulus Selection Task | 50.99 percentage of accuracy | Standard Deviation 16.04 |
p-value: 0.17t-test, 2 sided
Secondary
Young Mania Rating Scale (YMRS)
Mean change of symptoms of mania throughout the study. YMRS contains 7 items rated from 0 (symptom absent) to 4 (severe symptom) and 4 items scored 0 (symptom absent) to 8 (severe symptom), with total range from 0 to 60, where higher score indicates manic symptoms.
Time frame: Baseline and week 12
Population: Average change in YMRS based on baseline and week 12 score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pramipexole | Young Mania Rating Scale (YMRS) | -0.92 score on a scale | Standard Deviation 2.21 |
| Placebo | Young Mania Rating Scale (YMRS) | -0.57 score on a scale | Standard Deviation 1.88 |
p-value: 0.55t-test, 2 sided