The primary purpose of this study is to see if it is safe to give patients with cancer a low dose of the FDA approved anesthetic drug ketamine at the same time they receive radiation, chemotherapy, and/or surgery for their cancer treatment to treat depression and its effects. Researchers would also like to see if giving ketamine at the same time as cancer treatment is practical and reasonably acceptable to the patient.

Depression has many negative consequences for outcomes in those with cancer. It causes delayed treatments, increases in hospital lengths of stay, decreases in treatment adherence, poorer self-care, and decreased quality of life, even at 3 years post treatment. The presence of depression is the number one predictor of incomplete treatment and difficulty with rehabilitation. Therefore, investigators would also like to see if it is feasible to give patients ketamine during their routine cancer treatment treat depression and its negative effects on cancer treatment outcomes, and also help with anxiety, pain, and quality of life. The study will also use a placebo to compare to the good and/or bad effects of ketamine. A placebo is not an active drug and it will be look the same as ketamine, as a liquid to be taken by mouth.

Ketamine is approved by the U.S. Food and Drug Administration (FDA) as a general anesthetic by itself for some diagnostic and surgical procedures or combined with other general anesthetic agents. It has also been shown to reduce cancer pain. Ketamine is considered experimental in this study because it is not approved by the FDA for the treatment of depression.

This is a prospective, single center, double blind, randomized, two-arm feasibility study of oral ketamine versus placebo for the treatment of depression in depressed patients with cancer undergoing curative intent cancer therapy. Approximately 20 patients with cancer about to undergo cancer therapy will be randomized 1:1 to receive study treatment with one of the following regimens:

Arm A: nightly oral administration of 1.0 mg/kg ketamine Arm B: nightly oral administration of placebo (after completion of Arm B, patients will have the option to receive a nightly oral administration of 1.0 mg/kg ketamine and follow study procedures over again)

Consenting patients will undergo screening procedures, and if eligible, a baseline interview and brief questionnaires regarding depression, mental and emotional health, and quality of life assessments.

Study treatment will be administered for 12 weeks unless the patient experiences unacceptable toxicities, exhibits moderate to severe depressive symptoms, or withdraws consent. Patients on the placebo treatment arm will have the option to receive ketamine and follow all study procedures over again with the ketamine drug after completion of the placebo treatment.

Patients will be asked to complete psychosocial measurements every two weeks while on study treatment and monthly during a five-month follow-up period.

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent.
• Subject receiving or within twelve weeks of having received curative intent cancer treatment with radiation and/or chemotherapy
• Age ≥ 18 years.
• Has moderate to severe depression according to Quick Inventory of Depressive Symptomatology-Self Rated 16 (QIDS-SR-16) scores of ≥ 11 AND a Hospital Anxiety and Depression Scale (HADS) Depression subscale score of ≥ 8.
• Documented adequate liver function within the screening period as defined by:
• ALT < 5 X institutional upper limit of normal (ULN)
• AST < 5 X institutional ULN
• Total bilirubin < 5 X institutional ULN
• Both men and women of all races and ethnic groups are eligible for this trial.
• Use of other antidepressants is permitted if dose has been the same for at least 12 weeks prior to study entry and still meet inclusion #4.
• Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating and the study physician immediately. Urine pregnancy testing will be done throughout the trial for women of childbearing potential.
• Must read and understand English fluently.

Exclusion Criteria:

• Receiving another investigational agent on a clinical trial that prohibits participation in other studies of investigational agents.
• Meets MINI International Neuropsychiatric Interview (MINI Plus), criteria for diagnoses of schizophrenia, bipolar illness, delirium or psychosis.
• Has high Suicidal Risk Assessment (SRA) scores ≥ 10.
• Use of monoamine oxidase inhibitors within 14 days of study entry.
• History of allergic reactions or hypersensitivity to ketamine.
• Documented history of severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease.
• Documented history of significant tachyarrhythmia, severe angina, or myocardial ischemia
• Documented history of poorly controlled hypertension (Systolic Blood Pressure > 180 mmHG or Diastolic Blood Pressure > 100 mmHG), with or without antihypertensives.
• If a woman is or becomes pregnant or is nursing at any time before or during the treatment period, she will be excluded from the study.
• Score of ≥ 8 on the WHO Alcohol Use Disorders Identification Test (AUDIT)