Depressive disorders represent a substantial disability burden to patients and to healthcare systems. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are employed as first-line treatments. However, a significant proportion of patients show a suboptimal response to treatment, with continued psychosocial and occupational impairment, further healthcare utilization, and relapse. Small clinical trials have demonstrated improved responses after augmentation of SSRI or SNRI therapies with norepinephrine transporter (NET)�dopamine transporter (DAT) inhibitors, suggesting a benefit for combined inhibition of serotonin transporter (SERT), NET, and DAT. Therefore, a series of 4-aryltetrahydroisoquinoline SERT�NET�DAT inhibitors (triple reuptake inhibitors) has been designed. Optimization has led to BMS-820836, which is currently in Phase II clinical development for patients who have a suboptimal response to current antidepressant treatments. The design, monoamine reuptake profile, and efficacy of BMS-820836 in a preclinical model of depression will be described.

Optimizing triple monoamine reuptake inhibition for depression: The discovery of BMS-820836

243rd National Meeting (2012)

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