Schizophrenia
Conditions
Keywords
Schizoaffective Disorder, Acetylcholine, Nicotinic Receptors, Nicotine, Galantamine, negative symptoms
Brief summary
This study will evaluate the effectiveness of galantamine and CDP-choline in improving symptoms associated with schizophrenia.
Detailed description
Schizophrenia is a life-long brain disorder affecting approximately 1 percent of Americans each year. Schizophrenia can be extremely disabling, causing people to hear voices, experience paranoia or hallucinations, believe that others are controlling their thoughts, and even fail at maintaining a job or caring for themselves. Current medications help to relieve most of these negative symptoms, but not all. Many people with schizophrenia still suffer from low energy levels, an inability to concentrate, and memory loss. Galantamine is a medication that is used to improve memory and energy levels in people with Alzheimer's disease, and CDP-choline is a nutritional supplement. The purpose of this study is to evaluate the effectiveness of adding galantamine and CDP-choline to a stable anti-psychotic medication regimen of risperidone as a way of improving symptoms in adults with schizophrenia. Participants in this double-blind study will attend an initial screening during which they will undergo a physical exam, an electrocardiogram, and blood and urine collection. Participants will then be randomly assigned to receive galantamine and CDP-choline or a placebo treatment for 16 weeks. Participants assigned to the treatment group will take 500 mg of CDP-choline daily for the first 3 days, 1,000 mg daily for the next 4 days, and 2,000 mg daily for the following 15 weeks. Participants assigned to the treatment group will also take 8 mg of galantamine daily for the first week, 16 mg daily for the next week, and 24 mg daily for the following 14 weeks. Participants assigned to the control group will take two types of placebo pills every day for 16 weeks. All participants will continue to take their regular regimen of risperidone, olanzapine, quetiapine, ziprasidone, and/or aripiprazole throughout the trial in addition to their assigned treatment. Staff members will meet with participants during the first week of the study and every 4 weeks afterward until study completion. During these meetings, participants will identify any side effects, report nicotine intake, breathe into a machine that measures the amount of nicotine in the body, and complete written and computerized tasks on concentration and memory. Each meeting may last up to 3 hours. On the last week of the study, blood and urine samples will be collected and an electrocardiogram will be administered. Results from this study will be used to evaluate whether CDP-choline and galantamine improve schizophrenia symptoms. CDP-choline and matching placebos were purchased from LifeLink Corporation. Galantamine and matching placebos were prepared and donated by Ortho McNeil Janssen Scientific Affairs LLC.
Interventions
DRUGGalantamine
Galantamine will be titrated to 24 mg/day over 2 weeks. Participants will receive 8 mg/day in two divided doses for 1 week, 16 mg/day in two divided doses for 1 week, and 24 mg/day in two divided doses beginning in Week 3. They will be maintained on 24 mg/day for the remainder of the study.
DRUGCDP-choline
CDP-choline will serve as the dietary source of choline. CDP-choline will be titrated to 2000 mg/day over 1 week. Subjects will receive 500 mg/day for 3 days; Thereafter, the dose of CDP-choline will be increased to 1,000 mg/day in two divided doses for 4 days. At the beginning of Week 2, participants will receive the maximum fixed dose of 2000 mg/day in two divided doses, which will be held constant through the end of Week 16.
DRUGPlacebo
The schedule of dose titration of placebo galantamine and placebo CDP-choline will follow the schedule of active medication condition using matching placebos for each agent.
DRUGrisperidone, olanzapine, quetiapine, ziprasidone, and/or aripiprazole
All participants will continue to take their regular regimen of risperidone, olanzapine, quetiapine, ziprasidone, and/or aripiprazole throughout the trial in addition to their assigned treatment.
Sponsors
National Institute of Mental Health (NIMH)
Washington D.C. Veterans Affairs Medical Center
Georgetown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Meets DSM-IV criteria for schizophrenia or schizoaffective disorder * Eligible for care within the Veterans Affairs Medical system * Taking risperidone, olanzapine, quetiapine, ziprasidone, and/or aripiprazole (oral or injection)
Exclusion criteria
* Significant liver, kidney, lung, endocrine, active peptic ulcer, or cardiovascular disease * Seizure disorder and/or head injury * Substance use or abuse within 3 months of study entry * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Measured at Baseline and Weeks 4, 8, 12, and 16 | The score for each subject was the sum of the ratings for five items on the negative-symptom subscale of the PANSS: 1) blunted affect, 2) emotional withdrawal, 3) poor rapport, 4) passive/apathetic social withdrawal, and 5) lack of spontaneity and flow of conversation. Each item (symptom) is rated on a scale from 1 = absence of negative symptom to 7 = extreme negative symptom. The sum of the ratings for the five items range from 5 to 35, with higher scores indicating more severe symptoms. The primary outcome measure is the mean of the sum of these ratings across subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression | Measured at Baseline and Weeks 4, 8, 12, and 16 | The score for each subject was the mean rating on the severity item. The score of the item ranged from 1 (normal) to 7 (among most severely ill). |
| MATRICS Verbal Learning and Memory | Measured at Baseline and Weeks 8 and 16 | The measure of verbal learning and memory is the Hopkins Verbal Learning Test. The score for each subject is the sum of the total number of words recalled correctly for Trials 1, 2, and 3. The measure is the mean of these scores at baseline, Week 8, and Week 16. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Galantamine/CDP Choline Participants assigned to receive galantamine and CDP-choline | 19 |
| Placebos for Galantamine/CDP Choline Participants assigned to receive placebo | 24 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 3 |
Baseline characteristics
| Characteristic | Placebos for Galantamine/CDP Choline | Galantamine/CDP Choline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 19 Participants | 41 Participants |
| Age, Continuous | 52.38 years STANDARD_DEVIATION 11.04 | 54.37 years STANDARD_DEVIATION 8.5 | 53.28 years STANDARD_DEVIATION 9.94 |
| Region of Enrollment United States | 24 participants | 19 participants | 43 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 22 Participants | 17 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 19 | 14 / 24 |
| serious Total, serious adverse events | 0 / 19 | 1 / 24 |
Outcome results
Primary
Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS)
The score for each subject was the sum of the ratings for five items on the negative-symptom subscale of the PANSS: 1) blunted affect, 2) emotional withdrawal, 3) poor rapport, 4) passive/apathetic social withdrawal, and 5) lack of spontaneity and flow of conversation. Each item (symptom) is rated on a scale from 1 = absence of negative symptom to 7 = extreme negative symptom. The sum of the ratings for the five items range from 5 to 35, with higher scores indicating more severe symptoms. The primary outcome measure is the mean of the sum of these ratings across subjects.
Time frame: Measured at Baseline and Weeks 4, 8, 12, and 16
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 8 | 13.93 units on a scale | Standard Deviation 5.09 |
| Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 12 | 14.93 units on a scale | Standard Deviation 5.2 |
| Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Baseline | 17.63 units on a scale | Standard Deviation 3.48 |
| Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 4 | 17.06 units on a scale | Standard Deviation 5.6 |
| Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 16 | 13.93 units on a scale | Standard Deviation 5.2 |
| Placebos for Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 16 | 16.05 units on a scale | Standard Deviation 5.97 |
| Placebos for Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 4 | 17.08 units on a scale | Standard Deviation 5.64 |
| Placebos for Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 12 | 17.32 units on a scale | Standard Deviation 5.21 |
| Placebos for Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Week 8 | 17.26 units on a scale | Standard Deviation 5.8 |
| Placebos for Galantamine/CDP Choline | Negative Symptoms Measured on Positive and Negative Syndrome Scale (PANSS) | Baseline | 18.29 units on a scale | Standard Deviation 4.52 |
Secondary
Clinical Global Impression
The score for each subject was the mean rating on the severity item. The score of the item ranged from 1 (normal) to 7 (among most severely ill).
Time frame: Measured at Baseline and Weeks 4, 8, 12, and 16
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Galantamine/CDP Choline | Clinical Global Impression | Week 4 | 4 units on a scale | Standard Deviation 0.49 |
| Galantamine/CDP Choline | Clinical Global Impression | Week 12 | 3.87 units on a scale | Standard Deviation 0.64 |
| Galantamine/CDP Choline | Clinical Global Impression | Week 8 | 3.67 units on a scale | Standard Deviation 0.62 |
| Galantamine/CDP Choline | Clinical Global Impression | Week 16 | 3.8 units on a scale | Standard Deviation 0.68 |
| Galantamine/CDP Choline | Clinical Global Impression | Baseline | 4.32 units on a scale | Standard Deviation 0.48 |
| Placebos for Galantamine/CDP Choline | Clinical Global Impression | Week 16 | 3.68 units on a scale | Standard Deviation 0.67 |
| Placebos for Galantamine/CDP Choline | Clinical Global Impression | Baseline | 4.38 units on a scale | Standard Deviation 0.58 |
| Placebos for Galantamine/CDP Choline | Clinical Global Impression | Week 4 | 3.92 units on a scale | Standard Deviation 0.65 |
| Placebos for Galantamine/CDP Choline | Clinical Global Impression | Week 8 | 4.04 units on a scale | Standard Deviation 0.82 |
| Placebos for Galantamine/CDP Choline | Clinical Global Impression | Week 12 | 4 units on a scale | Standard Deviation 0.82 |
p-value: 0.93Mixed Models Analysis
Secondary
MATRICS Verbal Learning and Memory
The measure of verbal learning and memory is the Hopkins Verbal Learning Test. The score for each subject is the sum of the total number of words recalled correctly for Trials 1, 2, and 3. The measure is the mean of these scores at baseline, Week 8, and Week 16.
Time frame: Measured at Baseline and Weeks 8 and 16
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Baseline | 20.5 raw scores | Standard Deviation 5.1 |
| Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Week 8 | 21.8 raw scores | Standard Deviation 4.6 |
| Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Week 16 | 23.0 raw scores | Standard Deviation 4.7 |
| Placebos for Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Baseline | 20.6 raw scores | Standard Deviation 5.8 |
| Placebos for Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Week 8 | 21.2 raw scores | Standard Deviation 5.9 |
| Placebos for Galantamine/CDP Choline | MATRICS Verbal Learning and Memory | Week 16 | 20.4 raw scores | Standard Deviation 5.4 |
p-value: 0.23Mixed Models Analysis
p-value: 0.23Mixed Models Analysis