This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Major depressive disorder (MDD) is a common, severe, chronic and often life-threatening illness that contributes to significant morbidity and mortality. Although there is a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]), despite adequate dosage, duration, and compliance. Current pathophysiological theories regarding the neurobiology of depression include alterations in intracellular signaling cascades, and impairments of cellular plasticity and resilience. There is recent evidence suggesting that promoting growth factors, such as brain derived neurotrophic factor (BDNF), may provide a mechanism for the treatment of depression. New information indicating modulation of glutamate receptors in the actions of antidepressant treatments suggests a novel approach to develop a new class of antidepressants. Studies have shown that the biarylpropylsulfonamide AMPA receptor potentiators (LY392098 and LY451616) have antidepressant effects in animal models of depression. Several studies have demonstrated that AMPA receptor activation can increase expression of BDNF both in vitro and in vivo, thus providing one possible new approach for treatment via an AMPA receptor potentiator. In this study we propose to compare the ampa receptor potentiator Org 24448 to placebo for the treatment of MDD. Patients, ages 21 to 55 with a diagnosis of MDD (without psychotic features), will be randomized to double-blind treatment with either Org 24448 or placebo for an 8-week period. Acute efficacy will be determined by demonstrating a greater response rate vs. placebo using specified criteria.Primary Specific AimTo assess the efficacy of acute therapy with an AMPA receptor potentiator compared to placebo in patients with major depression without psychotic features according to the DSM-IV criteria, in improving overall depressive symptomatology. This will be achieved by measuring the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline score to the score at the end of 8 weeks of therapy between the 2 groups.Hypothesis: Subjects randomized to acute therapy with Org 24448 will have greater response rates compared to subjects randomized to placebo.Secondary Specific Aims [exploratory (anticipate low power)]:1. To explore whether subjects with major depression randomized to acute therapy with Org 24448 will manifest improved cognitive function, especially memory, as measured by neuropsychological testing compared to subjects randomized to placebo. This will be measured by statistical evidence in change in neuropsychological function from baseline to the end of treatment. 2. To explore whether the subjects who are administered Org 24448 compared to those who receive placebo will have in an increase in BDNF as measured in the CSF.
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