Revised inclusion criteria to 1. specify that the criteria for non-response to oral antidepressant treatments in current episode of depression was less than or equal to (=<)25% improvement; specify that at the start of the screening/prospective observational phase, non-response to oral antidepressant treatment was to be documented on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) (oral antidepressant must have been taken for at least 6 weeks at the minimum therapeutic dose with a lack of clinically meaningful improvement), 2. indicate that the severity of a subject’s depressive symptoms in the current major depressive episode was to be confirmed using a Site Independent Qualification Assessment to ensure enrollment of subjects who have symptoms that reflect the current state of illness, 3. include a lab test which measures levels of free thyroxine if thyroid-stimulating hormone values are out of range, 4. clarify the criteria for assessing pregnancy in women of childbearing potential, and 5. update criteria for methods of birth control. Revised exclusion criteria to 1. exclude subjects with at least 7 bilateral electroconvulsive therapy treatments, 2. exclude subjects who received vagal nerve stimulation in the current depressive episode, 3. exclude subjects with autism spectrum disorder 4. clarify that subjects with major depressive disorder (MDD) with psychotic features are excluded 5. update the list of cardiovascular conditions for exclusion of subjects with coronary artery disease, 6. clarify the definition of clinically significant ECG abnormalities, 7. permit use of concomitant medications that prolong the QT interval/corrected QT interval, 8. include a repeat screening test for abnormal alanine aminotransferase and aspartate aminotransferase values, 9. clarify a positive test for cannabinoids at screening is not exclusionary 10. clarify that uncontrolled diabetes is exclusionary.

Revised inclusion criteria to update minimum antidepressant treatment requirements at study entry to non-response to greater than equal to (=>)1 oral antidepressant treatments (from non-response to ≥2 oral antidepressant treatments) and to update the minimum amount of time the current oral antidepressant treatment must have been taken to at least 2 weeks (from at least 6 weeks); these changes allowed subjects to document non-response to a second oral antidepressant treatment for a minimum of 6 weeks and meet the criteria for Treatment-Resistant Depression (TRD) during the 4-week screening/prospective observational phase. The inclusion criteria were also revised to update the definition of non-response at the end of the screening/prospective observational phase to ≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4 (from ≤25% improvement in the MADRS total score for 2 consecutive visits and a MADRS total score of ≥28 for 2 consecutive visits), to specify the same requirements for contraception for female partners of male subjects as specified for female subjects, and to clarify inclusion of subjects who have thyroid-stimulating hormone outside the normal ranges was permitted. Revised exclusion criteria to delete the exclusion for first degree atrioventricular (AV) block, allow prescription use of psychostimulants with dosing restrictions on intranasal treatment session days, and clarified exclusion of subjects based on obstructive sleep apnea. Reordered the list of key secondary objectives, evaluations, and endpoints to correspond to the revised order of the planned analysis. Deleted the interim analysis for sample size re-estimation. Revised the analysis of onset of clinical response to indicate that subjects were allowed one excursion.