The purpose of this study is to test the effects of the medication ketamine and the medication called nitroprusside in patients with major depression. Ketamine has both good and bad effects. Some studies have shown that ketamine improves depression. However, studies have also shown that it causes strange and sometimes unpleasant sensations referred to "psychotic" or "dissociative" symptoms. An example of a psychotic symptom would be hearing or seeing something that in reality is not there. The study team would like to see if nitroprusside can prevent the reported bad effects of ketamine without blocking the reported good effects. This might make ketamine a better treatment for depression.

Ketamine is an effective fast-acting therapeutic intervention for patients with treatment refractory depression that is known to have the unwanted effect of inducing temporary psychotomimetic symptoms (i.e., delusions, hallucinations and thought disorganization) in some patients. The precise mechanisms of these psychotropic effects remain to be elucidated, but for several decades the NMDA-type glutamate receptor has been hypothesized to be of central importance. In this vain, recent studies of the antihypertensive agent nitroprusside - which increases the availability of the molecular nitric oxide, a known by-product of NMDA activity - have found evidence for antipsychotic properties both in humans with psychotic illness and healthy subjects given ketamine. Here, the clinical team proposes a study that will build on this work by evaluate the effects of nitroprusside on both the antidepressant and psychotomimetic effects of ketamine given to patients to treat refractory depression. In addition, as an exploratory aim, by collecting serial blood samples from the subjects, as the subjects are administered ketamine and nitroprusside, the clinical team will seek to determine functional markers of therapeutic effect and the mechanisms by which ketamine modulates both mood and psychotic states Research Question: The clinical team will test whether the effects of ketamine (KET) on mood and psychotic states is modified by co-administration with sodium nitroprusside (NP) in patients with depression. Furthermore, the clinical team will evaluate the extent to which the underlying biology of disease states and drug mechanisms can be inferred through analysis of brain-derived molecular material isolated from the peripheral circulation.

Specific Aims:

Aim I. To test whether co-administration with NP has any impact on the efficacy of KET as an antidepressant.

Aim II: To test the ability of NP to prevent the psychotomimetic effects of KET in patients with depression.

Research Hypotheses:

Research Hypothesis I. Patients pre-treated with NP will experience attenuated antidepressant effects (measured by MADRS score) following KET compared to pre-treatment with placebo.

Research Hypothesis II: Patients pre-treated with NP will experience attenuated psychotomimetic effects (e.g., CADSS score) immediately following KET compared to pre-treatment with placebo.

Inclusion Criteria:

• Male or female patients, 21-65 years of age;
• Female individuals who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative pregnancy test at screening and at pre-infusion;
• Participants must fulfill current DSM-5 criteria for Major Depression without psychotic features or Persistent Depressive Disorder with specifier of "with persistent major depressive episode";
• Depression is at least moderate severity, defined as a CGI-S score of ≥ 4;
• Current major depressive episode is of at least 4 weeks duration
• Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document
• Each participant must be able to identify a family member, physician, or friend who will act as an emergency contact

Exclusion Criteria:

• Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder;
• Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;
• Current diagnosis of obsessive compulsive disorder (OCD) or eating disorder (bulimia nervosa or anorexia nervosa);
• Subjects with DSM-V drug or alcohol abuse/dependence within the preceding 2 years;
• Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation;
• Patients judged clinically to be at serious and imminent suicidal or homicidal risk;
• Women who are either pregnant or nursing;
• Any serious, unstable medical illnesses including hepatic, renal impairment, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease;
• History of congestive heart failure or established coronary artery disease;
• History of cerebrovascular insufficiency
• History of intrapulmonary arteriovenous shunts, co-arctation of the aorta or other conditions where cardiac outflow tract is obstructed;
• Vitamin B12 deficiency;
• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;
• Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinin clearance of >1.3 mg/dL;
• Thyroid impairment, as reflected by a thyroid-stimulating hormone (TSH) > 4.2 mU/L;
• Hepatic injury, as reflected by AST or ALT greater than twice the upper limit of the reference range (AST: >80; ALT >110)
• Patients who have a positive urine toxicology for illicit substances at screening and within 24 hours of the infusion;
• Treatment with an irreversible MAOI within 2 weeks prior to randomization or fluoxetine within 4 weeks prior to randomization;
• Treatment with other antidepressants (classified as SSRIs, SNRIs, Atypical Antidepressants, MAOIs, TCAs) within one week of randomization.
• Previous recreational use of phencyclidine (PCP) or KET;
• Hypertension with systolic BP >160 mm Hg or diastolic BP >90 mm Hg at screening, systolic BP > 165 mm Hg or diastolic BP > 95 mm Hg immediately prior to treatment with study drug or hypotension with systolic BP < 90 or diastolic < 60 at screening or immediately prior to treatment with study drug; heart rate >110 or <60 at either of these time points;
• Treatment with sildenafil (Viagra), tadalafil (Cialis), Avanafil (Stendra), Vardenafil (Levitra) or other drugs in the same category of phosphodiesterase-5 enzyme inhibitors within 2 weeks of infusion.

24 hours after infusion

Both participants and research staff (aside from pharmacy) will be blinded