E. Sherwood Brown, Ph.D., M.D.
Assistant Professor
Department of Psychiatry

Project 1: Hippocampal Changes During Chronic Corticosteroid Exposure
Project 2: Memantine for corticosteroid-induced mood and declarative memory changes

Animal data suggest that stress and corticosterone elevations produce reversible and eventually irreversible changes in memory and the hippocampus. Based on these data, the suggestion has been made that cognitive impairment and hippocampal volume reductions in humans with mood disorders are secondary to cortisol elevations. Our work uses persons receiving prescription corticosteroids as a model system to examine the effects of stress and cortisol on the human hippocampus. Animal data suggest that histiological changes in the hippocampus secondary to corticosteroids can be prevented or reversed by using agents that enhance serotonin reuptake or modulate glutamate (e.g. phenytoin, NMDA receptor antagonists). We completed an open-label pilot study of lamotrigine, an anticonvulsant that inhibits glutamate release, using neurocognitive tests sensitive to hippocampal function to explore the question of reversibility in humans. The results suggest improvement in declarative memory following lamotrigine therapy. We have a double-blind, placebo-controlled trial of lamotrigine, as part of the above grant, looking at cognition, and hippocampal chemistry and activation before at after lamotrigine therapy (Project 1). In another study, we are examining whether the NMDA-receptor antagonist memantine, approved for Alzheimer's disease, reverses declarative memory with corticosteroids (Project 2). In this study we treat patients receiving long-term prednisone and examine declarative memory before and after. In future studies we plan to expand this line of investigation into the effects of stress on the hippocampus by examining agents that might function as protective factors in patients with hypercortisolemia secondary to major depressive and bipolar disorders, as well as in persons receiving prescription corticosteroids.

Project 3: Caregiver Psychiatric Symptomatology and its Relationship to Service Utilization by Children with Asthma

Caregivers of children with asthma appear to have very high rates of psychiatric symptoms. In this study we quantify psychiatric symptoms and disorders in caregivers of children with asthma and examine the relationship between psychiatric symptoms in the caregiver and asthma service utilization by the child. Depressed caregivers are offered antidepressant treatment to determine if effective treatment for depression changes service utilization patterns.

Project 4: Naltrexone for Bipolar Disorder and Alcohol Dependence
Persons with bipolar disorder have higher rates of substance abuse than any other major mental illness. When present substance abuse appears to be associated with treatment non-adherence, higher rates of hospitalization, and less likelihood of remission during hospitalization. However, minimal research has been conducted on the treatment of patients with bipolar disorder and substance abuse. In this project we examine naltrexone versus placebo in patients with bipolar disorder and alcohol dependence. Outcome measures include scales assessing alcohol use, and manic and depressive symptoms.