SPD489 in Combination With an Antidepressant in the Treatment of Adults With Major Depressive Disorder

Inclusion Criteria 1. Subject is able to provide written, personally signed and dated informed consent to participate in the study before completing any study-related procedures. 2. Subject is between 18-65 years of age. 3. Subject has a primary diagnosis of non-psychotic MDD. 4. Subject has a MADRS total score 24 5. Subject is willing and has an understanding and ability to fully comply with study procedures and restrictions defined in this protocol. 6. Subject, who is female, must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test and a negative urine pregnancy test and agrees to comply with any applicable contraceptive requirements. 7. Subject is able to swallow a capsule. Exclusion Criteria 1. Subject whose current episode of MDD has not responded to an adequate treatment regimen. 2. Subject who has a lifetime history of treatment resistant depression, defined as having not responded to adequate treatment with 2 or more treatment regimens. 3. Subject has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms. 4. Subject has been hospitalized (within the last 12 months) for their current MDD episode. 5. Subject has a current or lifetime history of attention-deficit/hyperactivity disorder (ADHD). 6. Subject has a first degree relative that has been diagnosed with bipolar I disorder. 7. Subject has a recent history (within the last 6 months) of suspected substance abuse or dependence disorder. 8. Subject is considered a suicide risk, has previously made a suicide attempt within the past 3 years, or is currently demonstrating active suicidal ideation. 9. Subject has a concurrent chronic or acute illness or unstable medical condition. 10. Subject has a history of seizures (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder, serious neurological disease, history of significant head trauma, dementia, cerebrovascular disease, Parkinson's disease, or intracranial lesions. 11. Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medication. 12. Subject has a history of thyroid disorder that has not been stabilized on thyroid medication or treatment within 3 months prior to the Screening Visit. 13. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 14. Subject has glaucoma. 15. Subject has any clinically significant ECG or clinical laboratory abnormalities at the Screening Visit. 16. Subject has a history of moderate to severe hypertension. 17. Current use of any other medication (including over-the-counter \[OTC\], herbal or homeopathic preparations) that has central nervous system effects. 18. Subject has the potential to need to initiate or modify frequency of psychotherapy or to continue or initiate other treatments for depression, outside of those allowed in this protocol. 19. Subject has had electroconvulsive therapy for the current depressive episode 3 months prior to the Lead-in Baseline Visit. 20. The subject has a known or suspected intolerance or hypersensitivity to the investigational product. 21. The subject has a known or suspected intolerance or hypersensitivity to any of the possible antidepressant treatments (escitalopram oxalate or venlafaxine HCL extended release. 22. Subject has a positive urine drug result. 23. Subject has a body mass index of \<18.5 or \>40. 24. Subject is female and is pregnant or nursing. 25. Subject has participated in another clinical study involving SPD489/NRP104 or has previously used commercial lisdexamfetamine dimesylate.