Anxiety & Depression Association of America

MDD Group - Male or female aged 18-65 years; - Ability for participant to comply with the requirements of the study as determined by the PI; - Capacity to provide informed consent; - Meets diagnostic criteria for current MDD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5); - In a current major depressive episode (MDE) of at least moderate severity according to DSM-5; - Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year). - Women of childbearing potential must have a negative pregnancy test at screening and prior to the infusion. HC Group - Male or female aged 18-65 years; - Capacity to provide informed consent; - Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year). - Ability for participant to comply with the requirements of the study as determined by the PI;

MDD Group - Current or history of schizophrenia or other psychotic disorder/episode, bipolar disorder, neurodevelopmental disorder, or neurocognitive disorder; - Current major depressive disorder with psychotic features; - Substance use disorder within the past 2 years*; - Lifetime history of ketamine use disorder; - Antidepressant medication within 2 weeks of Baseline (4 weeks for fluoxetine); - Severe current illness as reflected by a CGI score >5; - Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease; - Clinically significant abnormalities of laboratories, physical examination, or ECG; - Positive urine toxicology screen for drugs of abuse at the time of screening, except cannabis; - Women who plan to become pregnant, are pregnant or are breast-feeding (because the medical risk of using ketamine during pregnancy and breast-feeding is unknown); - Active suicidal intent or plan; CSSRS score >2; - Any contraindications to MRI, including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more; - Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the participant or the quality of the data. HC Group - Current or history of any psychiatric, neurodevelopmental disorder, or neurocognitive disorder; - Substance use disorder within the past 2 years*; - Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease; - Clinically significant abnormalities of laboratories or physical examination; - Positive urine toxicology screen for drugs of abuse at the time of screening, except cannabis; - Current pregnancy; - Women who are breast feeding; - Active suicidal intent or plan; CSSRS score >2; - Any contraindications to MRI, including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more.