Subjects aged 18-65 will be studied who prospectively are shown to be treatment resistant to the SSRI escitalopram. Subjects will be randomized in a double-blind fashion to receive continued open treatment with escitalopram+M100907 or continued escitalopram+placebo. Subjects will have weekly mood and safety ratings during this randomized period for four weeks. At that time subjects who were initially randomized to placebo (and are non-responders) will be switched to active drug for four weeks of randomized treatment while the active group continues an additional four weeks of combination therapy. Those meeting remission criteria will be eligible to extend therapy in open treatment with the combination therapy for an additional period of up to 6 months.