Reversing Corticosteroid Induced Memory Impairment

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.

• Drug: Lamotrigine
  Lamotrigine has a complex mechanism of action that appears to involve the inhibition of voltage-sensitive sodium channels resulting in a stabilization of membranes and inhibition of presynaptic glutamate release. Lamotrigine attenuates cerebral release of glutamate associated with cerebral ischemia in vitro and in vivo. Lamotrigine prevents cognitive and histologic changes in the hippocampus in animal models of ischemia. In patients with seizure disorders, decreases in plasma glutamate levels with lamotrigine are associated with a reduction in seizures. Lamotrigine or identical appearing placebo will be initiated at 25 mg/day and upwardly titrated to a dose of 400 mg/day over 10 weeks.
• Drug: Placebo
  Placebo matching active medication in all other physical aspects.

• Active Comparator: Lamotrigine
  Lamotrigine has a complex mechanism of action that appears to involve the inhibition of voltage-sensitive sodium channels resulting in a stabilization of membranes and inhibition of presynaptic glutamate release. Lamotrigine attenuates cerebral release of glutamate associated with cerebral ischemia in vitro and in vivo. Lamotrigine prevents cognitive and histologic changes in the hippocampus in animal models of ischemia. In patients with seizure disorders, decreases in plasma glutamate levels with lamotrigine are associated with a reduction in seizures
  Intervention: Drug: Lamotrigine
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

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