Bipolar Depression
Conditions
Keywords
Bipolar depression, Elderly, Lamotrigine, Brain energy metabolism
Brief summary
We propose to study the efficacy and tolerability of lamotrigine in the treatment of older adults with bipolar depression and to compare measures of brain energy metabolism between older subjects with bipolar depression and healthy age-matched controls in order to better understand treatment response in geriatric bipolar depression.
Detailed description
We will use MRI techniques and neuropsychological testing to investigate potential markers of treatment response in elderly bipolar depressed patients receiving lamotrigine and age-matched, non-depressed controls. We intend to test these hypotheses: 1. At least 50% of older subjects with bipolar depression will respond treatment with lamotrigine as evidenced by a 50% reduction on the Montgomery Asberg Rating Scale (MADRS). In addition, treatment with lamotrigine will be safe and well tolerated as evidenced by a drop-out rate of less than 10% due to adverse effects. 2. Compared with healthy age-matched, non-demented, non-depressed controls, subjects with geriatric bipolar depression will demonstrate abnormalities in cerebral energy metabolism as assessed by elevated levels of glutamate and lactate, and decreased levels of NAA, using 1H MRS at 4T. 3. Successful treatment with lamotrigine in geriatric bipolar depression will result in decreases in lactate and glutamate, and elevations in NAA. 4. Baseline measures of executive functioning and information processing speed (measured by performance on the Wisconsin Card Sorting Test (WCST), Trails A and B and Stroop tests) will be impaired in subjects with geriatric bipolar depression compared with healthy controls. These measures will improve with successful treatment with lamotrigine and correlate with improvements in markers of cerebral energy metabolism (lactate, glutamate, NAA).
Interventions
DRUGLamotrigine
Lamotrigine with dosage range from 25 mg to 200 mg per day.
Sponsors
Mclean Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
(for Bipolar Subjects): * 60 years or older * Meet DSM-IV diagnostic criteria for Bipolar Disorder, Current Episode Depressed * First episode of mania before the age of 50 (early-onset bipolar disorder) * Montgomery-Asberg Depression Rating Scale (MADRS) Score of greater or equal to 20. * Young Mania Rating Scale (YMRS) of less than or equal to 6. * Able to provide informed consent * Must speak English * Must be able to visit McLean Hospital for the screening visit and six study visits during the 8-week duration of the study. * Subjects may be taking other medications for bipolar depression including antidepressants, mood stabilizers and antipsychotic mediations prior to lamotrigine therapy, but may not have any dosage adjustments of these medications in the week before lamotrigine is added.
Exclusion criteria
(for Bipolar Subjects): * Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease. * History of seizure disorder * History or current diagnosis of the following psychiatric illnesses: any organic mental disorder (including dementia), schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder not otherwise specified, unipolar major depressive disorder, patients with substance dependence disorders, including alcohol, active within the last 12 months. * First episode of mania after the age of 50 (to exclude late-onset bipolar disorder) * History of multiple adverse drug reactions or allergy to the study drugs. * Use of medications that are excluded in this study (benzodiazepines, barbiturates; however, the use of non-benzodiazepine sedative hypnotics (such as zolpidem (Ambien)) may be used as needed except within 48 hours of the MRI scan) * Any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Glutamine to Creatine Ratio by Diagnosis at Baseline | Baseline | — |
| Mean Glutamate to Creatine Ratio by Diagnosis at Baseline | Baseline | — |
| Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline | Baseline | — |
| Associations Between Depression Symptom Severity and Glutamate to Creatine Ratio at Baseline | Baseline | Estimated changes in least squares mean in the metabolite ratio per 10-point increase in MADRS score. The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex. |
| Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up | 8 Weeks | Follow-up Least Squares Mean - Baseline Least Squares Mean |
| Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up | 8 weeks | Follow-up Least Squares Mean - Baseline Least Squares Mean |
| Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up | 8 weeks | Follow-up Least Squares Mean - Baseline Least Squares Mean |
| Association of MADRS Changes With Glutamate to Creatine Ratio Changes From Baseline to Follow-up | 8 Weeks | Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. The MADRS minimum score is 0 and maximum is 60, with 60 being the most depressed score. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex. |
| Associations of MADRS Changes With Glutamine to Creatine Ratio Changes From Baseline to Follow-up | 8 weeks | Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex. |
| Associations of MADRS Changes With NAA to Creatine Ratio Changes From Baseline to Follow-up | 8 weeks | Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex. |
| Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline | Baseline | The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. |
| Means of MADRS Scores at 8 Weeks | 8 Weeks | The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BPD Subjects Open Label Study
Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day. | 23 |
| Control Subjects Age matched controls without BPD | 14 |
| Total | 37 |
Baseline characteristics
| Characteristic | Control Subjects | BPD Subjects | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 17 Participants | 24 Participants |
| Age, Continuous | 67.5 years STANDARD_DEVIATION 8.8 | 62.0 years STANDARD_DEVIATION 5.9 | 64.6 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment United States | 14 participants | 23 participants | 37 participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 14 / 45 |
| serious Total, serious adverse events | 0 / 24 | 2 / 45 |
Outcome results
Primary
Association of MADRS Changes With Glutamate to Creatine Ratio Changes From Baseline to Follow-up
Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. The MADRS minimum score is 0 and maximum is 60, with 60 being the most depressed score. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time frame: 8 Weeks
Population: Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Association of MADRS Changes With Glutamate to Creatine Ratio Changes From Baseline to Follow-up | -.007 Glu:Cr/-10 MADRS |
Primary
Associations Between Depression Symptom Severity and Glutamate to Creatine Ratio at Baseline
Estimated changes in least squares mean in the metabolite ratio per 10-point increase in MADRS score. The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time frame: Baseline
Population: Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Associations Between Depression Symptom Severity and Glutamate to Creatine Ratio at Baseline | 0.18 Glu:Cr/+10 MADRS |
Primary
Associations of MADRS Changes With Glutamine to Creatine Ratio Changes From Baseline to Follow-up
Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time frame: 8 weeks
Population: Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Associations of MADRS Changes With Glutamine to Creatine Ratio Changes From Baseline to Follow-up | 0.04 Gln:Cr/-10 MADRS Score |
Primary
Associations of MADRS Changes With NAA to Creatine Ratio Changes From Baseline to Follow-up
Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time frame: 8 weeks
Population: Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Associations of MADRS Changes With NAA to Creatine Ratio Changes From Baseline to Follow-up | 0.05 NAA:Cr/-10 MADRS |
Primary
Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up
Follow-up Least Squares Mean - Baseline Least Squares Mean
Time frame: 8 Weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up | 0.00 serum Glutamate to Creatine ratio |
| Control Subjects | Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up | -0.12 serum Glutamate to Creatine ratio |
Primary
Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up
Follow-up Least Squares Mean - Baseline Least Squares Mean
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up | 0.02 serum Glutamine to Creatine ratio |
| Control Subjects | Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up | 0.08 serum Glutamine to Creatine ratio |
Primary
Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up
Follow-up Least Squares Mean - Baseline Least Squares Mean
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BPD Subjects | Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up | 0.06 NAA to creatine ratio |
| Control Subjects | Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up | -0.03 NAA to creatine ratio |
Primary
Mean Glutamate to Creatine Ratio by Diagnosis at Baseline
Time frame: Baseline
Population: Baseline scans were available for 37 participants. One participant was missing scan data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPD Subjects | Mean Glutamate to Creatine Ratio by Diagnosis at Baseline | .96 mean serum Glutamate to Creatine ratio | Standard Deviation 0.29 |
| Control Subjects | Mean Glutamate to Creatine Ratio by Diagnosis at Baseline | .85 mean serum Glutamate to Creatine ratio | Standard Deviation 0.25 |
Primary
Mean Glutamine to Creatine Ratio by Diagnosis at Baseline
Time frame: Baseline
Population: Baseline scans were available for 37 participants. One participant was missing scan data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPD Subjects | Mean Glutamine to Creatine Ratio by Diagnosis at Baseline | .34 mean serum Glutamine to Creatine ratio | Standard Deviation 0.12 |
| Control Subjects | Mean Glutamine to Creatine Ratio by Diagnosis at Baseline | .36 mean serum Glutamine to Creatine ratio | Standard Deviation 0.18 |
Primary
Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline
The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.
Time frame: Baseline
Population: MADRS scores were available for 27 eligible bipolar subjects and 14 eligible controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPD Subjects | Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline | 24.78 units on a scale | Standard Deviation 6.65 |
| Control Subjects | Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline | 1.03 units on a scale | Standard Deviation 1.55 |
Primary
Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline
Time frame: Baseline
Population: Baseline scans were available for 37 participants. One participant was missing scan data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPD Subjects | Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline | 0.97 Mean NAA to creatine ratio | Standard Deviation 0.14 |
| Control Subjects | Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline | 0.84 Mean NAA to creatine ratio | Standard Deviation 0.22 |
Primary
Means of MADRS Scores at 8 Weeks
The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.
Time frame: 8 Weeks
Population: MADRS scores were available for 16 bipolar subjects who completed the protocol and 8 healthy controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPD Subjects | Means of MADRS Scores at 8 Weeks | 18.31 units on a scale | Standard Deviation 9.41 |
| Control Subjects | Means of MADRS Scores at 8 Weeks | 1.38 units on a scale | Standard Deviation 1.51 |