The study will evaluate the safety and efficacy of AV-101.

Inclusion Criteria:

• Diagnosed with MDD, single or recurrent, and currently experiencing a MDE of at least 8 weeks in duration.
• Has a history of inadequate response to at least 1 approved antidepressant including at least 1 and no more than 3 during the current depressive episode.
• Meet the threshold on the total HAMD-17 score of > 20
• If female, a status of nonchildbearing potential or use of an acceptable form of birth control.
• Body mass index between 18 to 40 kg/m2.
• Other criteria may apply

Exclusion Criteria:

• History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes.
• Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within 6 months prior to screening.
• Women who are pregnant or breastfeeding or a positive pregnancy test at screening or baseline.
• Currently taking a prohibited adjunct therapy. Such drugs must be washed out for at least 4 weeks prior to baseline.
• Current diagnosis of moderate or severe substance use (including alcohol) disorder (abuse or dependence, as defined by DSM-5), with the exception of nicotine dependence, at screening or within 6 months prior to screening.
• In the opinion of the investigator, the subject has a significant risk for suicidal behavior
• Has received electroconvulsive therapy, or had repetitive transcranial magnetic stimulation in the current episode.
• Has received vagus nerve stimulation at any time prior to screening.
• Any current or past history of any physical condition, which in the investigator's opinion might put the subject at risk or interfere with study results interpretation.