Systematic studies of adverse cognitive and neurobiological changes subsequent to chemotherapy for lymphoma, breast, and other cancers have attracted substantial interest in the past decade. Little is known, however, concerning the feasibility and effects of potentially protective therapies on cerebral function in patients undergoing chemotherapy. Animal models have recently proved useful in examining some of the toxic effects of chemotherapy agents on working memory and other abilities, as well as on biological properties such as proliferation and survival of neuronal precursors involved in hippocampal neurogenesis. Such models have also proved useful for testing potential neuroprotective properties of agents given before, during and/or after chemotherapy. For example, impairment in spatial working memory and decreased hippocampal neurogenesis is induced in rats by the chemotherapy agent methotrexate, but co-administration of the (FDA-cleared and commercially available) drug fluoxetine has been shown to counteract the negative long-term effects on memory and hippocampal neurogenesis otherwise occurring after methotrexate administration. To determine whether such a strategy could be effective in counteracting effects that chemotherapy may have on cerebral function in humans, well-controlled experimental data obtained with cancer patients is needed.

This investigation will employ a prospective, randomized, double-blinded, placebo-controlled design, to provide a rigorous test of whether fluoxetine, a drug with a long-standing excellent safety profile in humans most commonly marketed as an antidepressant, can offer protection to breast cancer or lymphoma patients against changes in cerebral function occurring after chemotherapy (Specific Aim 1). It will further provide a test of the durability of any protective effects beyond the period during which fluoxetine is used, by re-assessing function approximately 6 months after completion of the regimen (Specific Aim 2). Cerebral function will be assessed by determining distributions of regional cerebral metabolism, previously demonstrated to sensitively detect functional alterations and closely reflect diminished cognitive abilities with high statistical power, using positron emission tomography with the glucose analog radiotracer \[F-18\]fluorodeoxyglucose. Neuropsychologic testing will be conducted in parallel with neuroimaging studies and, as a step towards understanding mechanisms underlying neurotoxic effects of chemotherapy and potentially related to protective effects of fluoxetine, peripheral markers of inflammatory cytokines will be measured in blood samples drawn at the time of neuroimaging (Specific Aim 3). If use of fluoxetine in cancer patients can be validated in this manner and lead to its adoption in the clinical setting, it will constitute the first drug with demonstrated utility for the prevention of cerebral dysfunction associated with exposure to chemotherapy. Moreover, as this involves an agent that is already FDA-cleared for other indications, widely commercially available throughout the U.S. and other parts of the world, and relatively inexpensive since it is obtainable in generic formulations, it would represent a pharmacologic approach that is amenable to rapid translation to the clinical setting.