A Safety, Efficacy and Tolerability Study of SEP-225289

Inclusion Criteria: * The duration of the current episode must be at least 1 month but not longer than 12 months. * Subjects must have a primary diagnosis of Major Depressive Disorder. * Subjects must have had at least one previous, diagnosed episode of MDD in the past 5 years. * MDD must be the condition that was chiefly responsible for motivating the subject to seek treatment. * Subject is in general good health. Exclusion Criteria: * Subject is participating in, has participated in, or plans to participate in any investigational drug study. * Subject who has donated blood within the last 30 days or plans to donate blood during and 30 days following participation. * Known failure to respond (in the past 5 years) to two adequate (dose and duration) antidepressant medications with distance mechanisms of action including tricyclics. * Subjects who have undergone Electroconvulsive Therapy treatment. * Treatment with fluoxetine, in the 6 weeks before baseline. * Subject with psychotic disorders, anorexia nervosa, bulimia or post-traumatic stress disorder. * Subject with a history or presence of bipolar disorder (i.e., current or past history of manic episode). * Subjects with Obsessive Compulsive Disorder. * Subjects with a lifetime diagnosis of Panic Disorder. * Subject received treatment with antidepressants within 2 weeks. * Subject with lifetime history of suicidal attempts, alcohol dependence or abuse, drug(s) dependence or abuse (excluding nicotine and caffeine) or has a positive urine drug screen. * Subject has a history of significant risk of suicide or homicide. * Bereavement - Defined as death of a loved one within 3 months. * Subject has a documented history of HIV, hepatitis B or hepatitis C.