The overarching goal of the present study is to evaluate the effect of a subanesthetic dose of ketamine 24-hour post-injection on resting state functional connectivity, cognitive control, and reward learning.

Major Depressive Disorder (MDD) participants with treatment-resistant depression (TRD) will be recruited from McLean's Ketamine clinic. Suitability for Ketamine treatment will be determined as typically done by the service - through evaluation by the clinicians on the staff of the Ketamine Service who perform psychiatric consultations and assessments for Ketamine suitability. Potential subjects will be informed about the study only after they have received a positive consultation at the clinic and have already agreed to receive the treatment.

This study consists of a set of questionnaires, urine drug screen, and electroencephalogram (EEG) recordings.

Inclusion Criteria (MDD Subjects):

• All genders, races, and ethnic origins, aged between 18 and 70;
• DSM-5 diagnostic criteria for MDD (diagnosed with the use of the Structured Clinical Interview for DSM-5 (SCID-5));
• A score of ≥32 on the Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30).
• Capable of providing written informed consent, and fluent in English;
• Right-handed;
• Treatment Resistant (as assessed using the MGH Antidepressant Response Questionnaire)
• Have already decided to receive ketamine treatment as part of their standard clinical care

Inclusion Criteria (Control Subjects):

• All genders, races, and ethnic origins, aged between 18 and 70;
• Absence of medical, neurological, and psychiatric illness (including alcohol and substance abuse), as assessed by subject history and a structured clinical interview (SCID-I/NP);
• A baseline Quick Inventory of Depressive Symptomatology (QIDS) score ≤ 5;
• A baseline Hamilton Depression Rating Scale (HDRS) score ≤ 7;
• Capable of providing written informed consent, and fluent in English;
• Right-handed;
• No first-degree relative with mood or psychotic disorder.

Exclusion Criteria (All Subjects):

• Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease;
• History of seizure disorder;
• History or current diagnosis of any of the following DSM-5 psychiatric illnesses: schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, substance abuse disorder;
• Clinical or laboratory evidence of hypothyroidism, hyperthyroidism, or other thyroid disorder that is not controlled by medication;
• Substance use assessed by physician as dangerous for ketamine treatment;
• Untreated glaucoma;
• Complex post-traumatic stress disorder (PTSD) with dissociation;
• Patients with a lifetime history of electroconvulsive therapy (ECT).
• Participants with a lifetime history of ketamine use.

We plan to recruit 30 TRD individuals with current MDD without psychotic features and 30 demographically matched healthy controls. All participants will be ketamine-naïve.