The OBSERVE Protocol

Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet the following criteria: 1. Recently started treatment (within 75 days of screening visit) with IV ketamine or Spravato® as prescribed by a clinician for the treatment of moderate to severe (based on an initial MADRS score ≥ 25) TRD (refractory to two or more antidepressant trials) without psychotic features and having appropriate baseline measures collected before starting treatment. These patients are referred to as treatment-continuing subjects. OR 2. Scheduled to receive standard clinical treatment with IV ketamine or Spravato® as prescribed by a clinician for the treatment of moderate to severe (based on an initial MADRS score ≥ 25) TRD (refractory to two or more antidepressant trials) without psychotic features. These patients are referred to as treatment-initiating subjects. In addition, in order to be eligible, an individual must meet all of the following additional criteria: 3. Adult ages 18 or older 4. Provision of signed and dated informed consent form prior to any study procedures 5. Stated willingness to comply with all study procedures and availability for the duration of the study Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: 1. Diagnosis of bipolar disorder or psychotic disorder (i.e., schizophrenia, schizoaffective disorder) 2. Other psychiatric comorbidities are permitted so long as depression is the predominant diagnosis 3. Active or recent (within 12 months) substance use disorder (other than nicotine)