Neural Circuit Effects of Ketamine in Depression

Inclusion Criteria: 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; Exclusion Criteria: 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.