This project is designed to examine the role of the subgenual anterior cingulate cortex (sgACC) in anhedonia and anxiety in humans with depression, as well as the acute and sustained effects of ketamine on agACC activation and depression symptoms.

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.

All of the individual participant data collected during the trial, after deidentification.

Immediately following publication. No end date.

Investigators whose proposed use of the data has been approved by an independent review committee ('learned intermediary') identified for this purpose.

Any purpose. Specify Other Mechanism Data from this study will be submitted to the National Institute of Mental Health Data Archive (NDA). The NDA is a data repository run by the National Institute of Mental Health (NIMH) that facilitates data sharing across mental health and other research communities. Periodically during and after study completion, the researchers will upload deidentified data information to the NDA. Other researchers nationwide can then file an application to obtain access to deidentified study data for research purposes.

Double blind