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.

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