Major Affective Disorders are common and often chronic life threatening illnesses. Furthermore a significant fraction of patients do not respond to treatment with serotonin reuptake inhibitors (SSRI's), have only a partial response with continued significant morbidity and functional impairment, or suffer from drug induced side effects that decrease the individuals' quality of life. Side effects from SSRI's include gastrointestinal symptoms, anxiety, sleep disturbance, and sexual dysfunction. Evidence from recent clinical trials and preclinical studies suggests that blockade of 5-HT2 receptors may have antidepressant effects when combined with reuptake blockade of serotonin at serotonin transporters. In order to better determine whether 5-HT2A receptors are responsible for this effect we propose to study the highly specific and potent 5-HT2A antagonist, M100907, in combination with escitalopram in SSRI resistant major depression.