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.