Memory Impairment
Conditions
Brief summary
Medically stable outpatients receiving chronic oral corticosteroid therapy were enrolled in a 48-week randomized, double-blind, placebo-controlled, parallel-group, trial of lamotrigine.
Detailed description
Stress and corticosteroid exposure are associated with changes in both the human and animal hippocampus. An extensive literature suggests that corticosteroid-induced changes in the hippocampus are, in part, mediated through increases in extracellular glutamate. In animals, agents that decrease glutamate release prevent dendritic changes in the hippocampus secondary to stress or corticosterone. We have developed a research program using patients receiving prescription corticosteroids (e.g., prednisone) to explore the effects of corticosteroids on the human hippocampus. Our research program is translational in focus, with a goal of exploring whether the reported effects of corticosteroids on the animal hippocampus are also found in humans. A current focus of our research is examining glutamate release inhibitors in patients taking corticosteroids. We have both open-label and placebo-controlled pilot data suggesting that the glutamate release inhibitor lamotrigine is associated with significant improvement in declarative memory (a measure of hippocampal performance) in this population. A definitive study examining declarative memory in corticosteroid-dependent patients receiving lamotrigine vs. placebo is proposed. Neuroimaging and mood will also be assessed.
Interventions
DRUGLamotrigine
Lamotrigine will be initiated at 25 mg/day and upwardly titrated to a dose of 400 mg/day over 10 weeks.
DRUGPlacebo
Sponsors
National Institute of Mental Health (NIMH)
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 18-70 years old * English-speaking men and women * Physician diagnosis of any chronic medical condition requiring treatment with oral corticosteroids confirmed by chart review and/or patients assessment by the PI or co-I.s. * Receiving prednisone therapy of at least 5 mg of prednisone daily for at least 6 months with anticipated treatment for ≥ 15 additional months.
Exclusion criteria
* Baseline RAVLT total T-Score ≥ 60 * Illnesses associated with CNS involvement (e.g., multiple sclerosis, lupus, seizures, brain tumors, head injury with loss of consciousness of more than 30 minutes) or cognitive impairment (e.g., lifetime drug or alcohol dependence, schizophrenia, and mood disorders - e.g., bipolar disorder, major depressive disorder) that appear to be unrelated to corticosteroid use or history of ventilator use that suggests hypoxia. We will include patients with lupus if they do not appear, based on medical history and discussion with treating physician, have significant CNS involvement. We will include participants with brief loss of consciousness. In prior studies we have found that many otherwise eligible participants were excluded due to very brief LOC in childhood or in a motor vehicle accident. * Mental retardation or other severe cognitive impairment. * Pregnant or nursing women. * Severe or life-threatening medical illness that would make completion of study unlikely or study participation potentially unsafe (e.g., highly unstable asthma requiring frequent hospitalization) * Contraindications to lamotrigine therapy (severe side effects in the past, taking medications such as some anticonvulsants with drug-drug interactions with lamotrigine). * High risk or danger to self or others as defined by \> 1 lifetime suicide attempt or assault, any suicide attempt or assault within the past year, and active suicidal or homicidal ideation that includes a plan and intent * Therapy with medications (valproate, carbamazepine, primidone, phenytoin, rifampin, phenobarbital) that alter the metabolism of lamotrigine * Metal implants, claustrophobia, or other contraindications to MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rey Auditory Verbal Learning Test (RAVLT) | 48 weeks | The Rey Auditory Verbal Learning Test (RAVLT) measures verbal or declarative learning and memory. The test consists of 15 nouns read aloud for five consecutive trials with each trial followed by a free-recall trial. Following the fifth trial, an interference list of 15 different words is presented followed by a free-recall trial of that list. Delayed recall of the first list is tested immediately following the interference list and after a 20-minute delay. A recognition test of 50 words including the 15 original words is presented after the delayed recall. Equivalent, alternative versions (different words) were used to minimize practice or learning effects from repeated administration. The raw scores (number of words correct across trials 1-5) are converted to standardized T-scores (M=50; SD=10). This score is used to determine the participant's performance in relation to norm-referenced expectations based on age and sex. A higher score reflects better performance. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lamotrigine Participants took Lamotrigine beginning at 25mg/day and increased to a dose of 400mg/day over 10 weeks using a fixed scheduled. | 26 |
| Placebo Placebo administered the same as the Lamotrigine. | 28 |
| Total | 54 |
Baseline characteristics
| Characteristic | Total | Lamotrigine | Placebo |
|---|---|---|---|
| Age, Continuous | 44.315 years STANDARD_DEVIATION 10.968 | 42.192 years STANDARD_DEVIATION 11.771 | 46.286 years STANDARD_DEVIATION 9.974 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 19 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 13 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 13 Participants | 12 Participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 14 Participants |
| Sex: Female, Male Male | 26 Participants | 12 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 1 / 28 |
| other Total, other adverse events | 2 / 26 | 3 / 28 |
| serious Total, serious adverse events | 5 / 26 | 6 / 28 |
Outcome results
Primary
The Rey Auditory Verbal Learning Test (RAVLT)
The Rey Auditory Verbal Learning Test (RAVLT) measures verbal or declarative learning and memory. The test consists of 15 nouns read aloud for five consecutive trials with each trial followed by a free-recall trial. Following the fifth trial, an interference list of 15 different words is presented followed by a free-recall trial of that list. Delayed recall of the first list is tested immediately following the interference list and after a 20-minute delay. A recognition test of 50 words including the 15 original words is presented after the delayed recall. Equivalent, alternative versions (different words) were used to minimize practice or learning effects from repeated administration. The raw scores (number of words correct across trials 1-5) are converted to standardized T-scores (M=50; SD=10). This score is used to determine the participant's performance in relation to norm-referenced expectations based on age and sex. A higher score reflects better performance.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | The Rey Auditory Verbal Learning Test (RAVLT) | 45.741 T Score | Standard Deviation 9.63 |
| Placebo | The Rey Auditory Verbal Learning Test (RAVLT) | 43.286 T Score | Standard Deviation 6.57 |