Bipolar Depression
Conditions
Keywords
Bipolar disorder, Bipolar depression, Natural substances, Depression
Brief summary
The primary objective of this 15-week clinical trial is to test the hypothesis that treatment with two proven mitochondrial enhancers, acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA), has significantly greater efficacy than placebo as an augmentation treatment in bipolar depressed patients who display an incomplete response to conventional treatments.
Detailed description
The primary objective of this proposed clinical trial is to test the hypothesis that treatment with two proven mitochondrial enhancers, acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA), has significantly greater efficacy than placebo as an augmentation treatment in bipolar depressed patients who display an incomplete response to conventional treatments. We propose to test this hypothesis by performing a 15-week placebo-controlled, double-blind, parallel group, flexible-dose study investigating the use of ALCAR and ALA as an augmentation to treatment as usual in depressed bipolar patients. We will compare the efficacy of acetyl-l-carnitine (ALCAR) at doses of 1000-3000mg/day and alpha-lipoic acid (ALA) at doses of 600-1800mg/day with placebo on symptom improvement in individuals diagnosed with bipolar disorder type I, current episode depressed. Improvement will be assessed using the 21-Item Hamilton Depression Rating Scale (HAM-D), the Montgomery Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Clinical Global Impression-Severity and Improvement Scales (CGI-S and CGI-I). Furthermore, we hypothesize that improvement in depression symptoms following treatment with ALCAR and ALA will be associated with increases in phosphocreatine (PCr), beta-nucleoside triphosphate (β-NTP), and intracellular pH in the anterior cingulate cortex (ACC) both at week 1 and week 12 of treatment.
Interventions
DRUGacetyl-l-carnitine PLUS alpha-lipoic acide
1000-3000 mg/day of acetyl-l-carnitine in addition to 600-1800 mg/day of alpha-lipoic acid.
DRUGPlacebo
Placebo
Sponsors
Stanley Medical Research Institute
Mclean Hospital
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female age 18-65 years. * Meets DSM-IV criteria for Bipolar Disorder, type I with current episode depressed. * Current score of greater than or equal to 18 on the 21-Item Hamilton Depression Rating Scale at Visits 1 and 2. * Maintained on a stable treatment regimen with no changes in medication dosages for at least two weeks prior to study entry.
Exclusion criteria
* Unwilling or unable to provide informed consent * Score of greater than or equal to 12 on the Young Mania Rating Scale at Visit 1 or 2. * Current suicidal or homicidal ideation. * Active psychotic symptoms. * Lifetime history of schizophrenia or obsessive-compulsive disorder. * DSM-IV diagnosis of alcohol or substance dependence in the 3 months prior to screening. * Clinically significant medical condition that would interfere with study participation. * History of hypersensitivity to ACLCAR or ALA. * Pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The 25-Item Hamilton Depression Rating Scale. | Baseline to 15 Weeks | Scores could range from 0 - 72 units on a scale, with 0 representing the least number of depressive symptoms and 72 representing the most number of depressive symptoms. |
| The Montgomery-Asberg Depression Rating Scale | Baseline to 15 weeks | Scores could range from 0 - 60 units on a scale with 0 representing the least number of depressive symptoms and 60 representing the most number of depressive symptoms. |
| The Young Mania Rating Scale | Baseline to 15 weeks | The scores could range from 0 - 60 units on a scale with 0 representing the least number of manic symptoms and 60 representing the most number of manic symptoms. |
| Clinical Global Impression-Severity | Baseline to 15 weeks | Scores could range from 0 - 7 units on a scale, with 0 representing the least severe (Normal, not at all ill) and 7 representing the most severe (Among the most extremely ill patients). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phosphorus MRS Scans on 4T Scanner | Baseline to 12 weeks | Whole brain total NTP levels as measured by a phosphorus MRS scan on the 4T scanner. The data could range from 0 - 1, with 0 representing the lowest NTP level and 1 representing the highest NTP level. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in August 2008 and ended in May 2011 and took place at a research lab within McLean hospital.
Pre-assignment details
To limit heterogeneity in the imaging sample, we accepted only type I bipolar disorder participants for the imaging component of the study.
Participants by arm
| Arm | Count |
|---|---|
| ALCAR/ALA Participants taking 1000-3000mg/day of acetyl-l-carnitine PLUS 600-1800mg/day of alpha-lipoic acid. | 20 |
| Placebo Participants taking placebo. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 |
| Overall Study | Protocol Violation | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | ALCAR/ALA | 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 | 20 Participants | 20 Participants | 40 Participants |
| Age Continuous | 44.9 years STANDARD_DEVIATION 11.9 | 46 years STANDARD_DEVIATION 10.3 | 45.45 years STANDARD_DEVIATION 11.1 |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 19 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Clinical Global Impression-Severity
Scores could range from 0 - 7 units on a scale, with 0 representing the least severe (Normal, not at all ill) and 7 representing the most severe (Among the most extremely ill patients).
Time frame: Baseline to 15 weeks
Population: At baseline, the number of participants analyzed was the number randomized into the study. At endpoint, the number or participants analyzed is the last observation carried forward of the original 20 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALCAR/ALA | Clinical Global Impression-Severity | Baseline Data | 4.6 units on a scale | Standard Deviation 0.5 |
| ALCAR/ALA | Clinical Global Impression-Severity | Endpoint Data | 4 units on a scale | Standard Deviation 0.9 |
| Placebo | Clinical Global Impression-Severity | Baseline Data | 4.6 units on a scale | Standard Deviation 0.51 |
| Placebo | Clinical Global Impression-Severity | Endpoint Data | 4.2 units on a scale | Standard Deviation 0.7 |
Primary
The 25-Item Hamilton Depression Rating Scale.
Scores could range from 0 - 72 units on a scale, with 0 representing the least number of depressive symptoms and 72 representing the most number of depressive symptoms.
Time frame: Baseline to 15 Weeks
Population: At baseline, the number of participants analyzed was the number randomized into the study. At endpoint, the number or participants analyzed is the last observation carried forward of the original 20 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALCAR/ALA | The 25-Item Hamilton Depression Rating Scale. | Baseline Data | 23.3 units on a scale | Standard Deviation 3.5 |
| ALCAR/ALA | The 25-Item Hamilton Depression Rating Scale. | Endpoint Data | 17.5 units on a scale | Standard Deviation 6.4 |
| Placebo | The 25-Item Hamilton Depression Rating Scale. | Baseline Data | 22.1 units on a scale | Standard Deviation 3.2 |
| Placebo | The 25-Item Hamilton Depression Rating Scale. | Endpoint Data | 18.5 units on a scale | Standard Deviation 6.2 |
Primary
The Montgomery-Asberg Depression Rating Scale
Scores could range from 0 - 60 units on a scale with 0 representing the least number of depressive symptoms and 60 representing the most number of depressive symptoms.
Time frame: Baseline to 15 weeks
Population: At baseline, the number of participants analyzed was the number randomized into the study. At endpoint, the number or participants analyzed is the last observation carried forward of the original 20 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALCAR/ALA | The Montgomery-Asberg Depression Rating Scale | Baseline Data | 26.9 units on a scale | Standard Deviation 3.1 |
| ALCAR/ALA | The Montgomery-Asberg Depression Rating Scale | Endpoint Data | 19.6 units on a scale | Standard Deviation 7.9 |
| Placebo | The Montgomery-Asberg Depression Rating Scale | Baseline Data | 25.9 units on a scale | Standard Deviation 3 |
| Placebo | The Montgomery-Asberg Depression Rating Scale | Endpoint Data | 21.7 units on a scale | Standard Deviation 6.3 |
Primary
The Young Mania Rating Scale
The scores could range from 0 - 60 units on a scale with 0 representing the least number of manic symptoms and 60 representing the most number of manic symptoms.
Time frame: Baseline to 15 weeks
Population: At baseline, the number of participants analyzed was the number randomized into the study. At endpoint, the number or participants analyzed is the last observation carried forward of the original 20 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALCAR/ALA | The Young Mania Rating Scale | Baseline Data | 2 units on a scale | Standard Deviation 2.1 |
| ALCAR/ALA | The Young Mania Rating Scale | Endpoint Data | 1.7 units on a scale | Standard Deviation 2.2 |
| Placebo | The Young Mania Rating Scale | Endpoint Data | 2.1 units on a scale | Standard Deviation 1.8 |
| Placebo | The Young Mania Rating Scale | Baseline Data | 2.4 units on a scale | Standard Deviation 2.1 |
Secondary
Phosphorus MRS Scans on 4T Scanner
Whole brain total NTP levels as measured by a phosphorus MRS scan on the 4T scanner. The data could range from 0 - 1, with 0 representing the lowest NTP level and 1 representing the highest NTP level.
Time frame: Baseline to 12 weeks
Population: At baseline, the number of participants analyzed was the number entered into the imaging portion of the study. At endpoint, the number or participants analyzed is the last observation carried forward of the original 10 participants in each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALCAR/ALA | Phosphorus MRS Scans on 4T Scanner | Baseline Data | .230 units on a scale | Standard Deviation 0.009 |
| ALCAR/ALA | Phosphorus MRS Scans on 4T Scanner | Week 1 Data | .229 units on a scale | Standard Deviation 0.011 |
| ALCAR/ALA | Phosphorus MRS Scans on 4T Scanner | Endpoint Data | .229 units on a scale | Standard Deviation 0.006 |
| Placebo | Phosphorus MRS Scans on 4T Scanner | Baseline Data | .233 units on a scale | Standard Deviation 0.009 |
| Placebo | Phosphorus MRS Scans on 4T Scanner | Week 1 Data | .225 units on a scale | Standard Deviation 0.008 |
| Placebo | Phosphorus MRS Scans on 4T Scanner | Endpoint Data | .232 units on a scale | Standard Deviation 0.005 |