Herein is a summary of the major changes made to the original protocol dated 07 March 2008 and reflected in Amendment 1 dated 03 June 2008. Deleted text is struck through and additional text is underlined. 1. More specific and robust language added to exclude subjects with suicidal ideologies and/or tendencies. 2. Change from the Quick Inventory of Depressive Symptomatology – Clinician (QIDS-C) rated scale to the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR). At the completion of the Pretreatment visit, subjects will be given a login ID and password to complete computerized assessment on Day 4 and Weeks 2, 4, 6, 8, 12, 16, 24 and 52 post treatment initiation. A member of the research staff will contact the subjects to confirm current medication use and to record adverse events. During this call, the subjects will be reminded to login to the internet system to complete the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) as well as the Self-Rated Global Measure of the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER). 3. The specific use of a “saliva” drug screen for illicit drug has been removed as none of the commercially available saliva drug kits have been neither FDA approved nor CLIA-waived for use. 4. Typographical error in exclusion number 4 has been corrected to exclude subjects with a known contra-indication to the use of any of the intended medications.

Herein is a summary of the major changes made to the first amended protocol dated 12 June 2008 and reflected in Amendment 2 dated 19 January 2009. 1. The intent of Section 1.2 Objective 3B is to identify markers that predict a “potential placebo response” based on subject reported early symptom reduction. The current analysis includes use of the HAM-D results however the HAM-D is a clinician rated severity of depression and not done at Day 4. Therefore, the HAM-D results have been removed as an indicator for “potential placebo response” at Day 4. 2. In an effort to clarify the prohibited psychological co-morbid conditions, a list of Axis II disorders has been added to the exclusion criteria for both Depressed and Control Subjects. 3. Ongoing discussions with general practitioners and other treating physicians indicate that thyroid stimulating hormone (TSH) assays are not routinely ordered or reviewed in the initial work-up for depression. Therefore, in an effort to follow standard of care practices, the presence of known hyper- or hypothyroidism as an exclusionary criteria has been removed for both study groups. 4. Reference to the Australian Bureau of Statistics for alcohol consumption has been removed in the exclusion criteria for both study groups. 5. More robust and specific language has been added to Section 4 of the protocol in an effort to better clarify the methods (clinician interview versus on-line self reported questionnaire) used to capture psychological and cognitive data. In addition, to lesson the burden and time required by the subject during the Pretreatment and Week 8 clinic visits, a number of questionnaires and interviews have been deleted, combined, reorganized or shortened. Specifically, all interviews and scales completed by a clinician have been grouped as “Psychological and clinical work-up” and all subject completed questionnaires and scales have been grouped and are now in the “BRC Web Questionnaire”. The follow

Herein is a summary of the major changes made to the second amended protocol dated 19 January 2009 and reflected in Amendment 3 dated 17 May 2011. 1. To ensure that the informed consent is always collected, even in cases where further explorative questions are asked on the telephone screening call, informed consent can be completed any time prior to screening and prior to the baseline directed 48hour window. 2. To reduce potential missing data, saliva may be collected in exceptional cases for DNA analysis where blood cannot be collected. To reduce the likelihood of this method being used as a standard as it is a limited option of DNA collection, sites are directed to only collect saliva instead of blood at a 1:15 ratio and document the reasoning in the source. If it is possible, blood should be collected at the week 8 visit as the optimal form of genetic and Metabolomic variables. 3. More robust and specific language has been used in section 4 of the protocol in an effort to better clarify the study procedures. These include: • Participants must start taking the medication by the Day 4 follow-up call. If they have not started by week 2, they are to be excluded from the study. • During the first 8 weeks, patients are to receive the study medication as their only form of treatment. After Week 8, the patient may receive alternate forms of treatment and these should be recorded under concomitant medications. • Early Termination of Medication Visit is to be conducted when patient stops medication before Week 8. The patient should not be washed out of medication at the time of this visit. 4. The following changes to the exclusion criteria were made for MDD subjects: • In an effort to standardise the data with the Brain Resource Databse (used to confirm data), the head injury item has been altered from 15minutes to 10minutes of “loss of consciousness”. • In enhance the ability to enrolled appropriate participants the presence of suicidal ideations and/or