About one-third of depressed patients will not get better after multiple antidepressant treatments. This situation put a high burden on patients with depression due to worsening quality of life and increasing health care costs. Difficult-to-treat depression might be even worse among Veterans given that the frequency of depressive symptoms is 2 to 5 times higher than among the general US population. A breakthrough discovery happened in recent years when investigators found that one infusion from an old anesthetic named ketamine showed high efficacy and rapid antidepressant effect (sometimes within hours) but lasted only up to a week. The investigators propose to study if multiple infusions of ketamine can provide greater and longer antidepressant effects than one infusion. If that is the case, multiple infusions could be an alternative to relieve depressive symptoms that do not response to multiple antidepressant drugs.

Recent studies have found rapid and highly efficacious antidepressant effects of a single ketamine infusion in treatment-resistant depression (TRD). However, a single infusion appears insufficient to maintain response as most patients return to previous depressive state within a week. The strategy of multiple infusions to increase efficacy and sustain antidepressant effects has not yet been systematically evaluated in an randomized control trial (RCT). The proposed study is a one-center, interventional, efficacy study designed to determine antidepressant outcomes of serial ketamine infusions compared to a single ketamine infusion among Veterans with TRD. The investigators have hypothesized that six infusions will be superior to a single infusion of ketamine in both decreasing severity of depressive symptoms and maintaining response. Participants will be male/female Veterans (18 to 75 years old) of any era or military background who suffer from TRD defined as failure to achieve remission from at least 2 antidepressant trials of different pharmacological classes. Potential participants will be recruited from Mental Health clinics and screened for eligibility using a two stage process (phone/chart review, followed by interview). Exclusion criteria includes post-traumatic stress disorder, psychosis-related disorder, bipolar disorder, alcohol/substance use disorder 6 months prior to screening; unstable medical illness; serious/imminent suicidal/homicidal risk; Parkinson's disease, dementia, seizures; traumatic brain injury; contraindicated medications (e.g., MAO inhibitors, barbiturates); received electroconvulsive therapy (ECT) during current episode; pregnancy/nursing. Baseline assessments will be completed 1-2 weeks prior to starting treatment. Participants will be randomly assigned to one of two parallel treatment conditions: 1) six ketamine infusions at 0.5 mg/kg or 2) single ketamine infusion at 0.5 mg/kg preceded by five midazolam infusions at 0.045 mg/kg. Midazolam was chosen as an active placebo given similar pharmacokinetics and dissociative effect profile to ketamine. Each intervention will be provided for a total of 12-day infusion-phase on a Monday-Wednesday-Friday schedule. The, follow-up visits will occur at weekly intervals for the first 4 weeks, at 2-week intervals for the next 8 weeks, and at 4-week intervals for the remaining 12 weeks or until relapse. The primary end point is the Montgomery- sberg Depression Rating Scale (MADRS) score 24 hours following the last infusion where the peak antidepressant effects of ketamine occur. Secondary outcomes for the treatment phase include remission defined by MADRS<10, and response defined as a reduction in the baseline MADRS score 50%. For the follow-up period, durability of antidepressant response will be defined by "time to relapse" to a MADRS score <50% of baseline at that visit. Independent evaluation of depressive symptom severity and potential covariates of antidepressant effect (e.g., pain intensity, level of anxiety) will be ascertained at baseline, at several time points during infusion period, and at follow-up. On the day of infusion, subjects will arrive in the morning after an overnight fast. Hemodynamic measures will be recorded every 10 min for 1 hour beginning 10 min before infusion. Subjects will then receive IV infusion over 40 minutes. Severity of depressive symptoms, pain intensity, level of anxiety will be obtained before and 24 hours after infusion. Acute dissociative effects, manic/hypomanic symptoms, and psychotomimetic effects will be measured 30 minutes before the start of each infusion and at the end of infusion (t0+40 mins) and again at t0+120mins and t0+180mins. The infusion will be discontinued in the event of significant adverse events. Procedures for the subsequent infusions at days 3, 5, 8, 10, and 12 will be identical to those of the first infusion.

Inclusion Criteria:

• Male or female Veterans aged 18 to 75 years.
• Have a telephone in their home and able to hear telephone conversations.
• Must meet current DSM-IV criteria for major depressive disorder (MDD), single or recurrent, without psychotic features confirmed by depression subset of the Structured Clinical Interview-Clinical Trial for DSM-IV (SCID).
• Have score 32 on the Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30)for severity of major depressive episode (MDE) at screening.
• Current major depressive episode resistant to treatment defined as failure to achieve improvement from at least 2 antidepressant trials of different pharmacological classes. Systematic evaluation of previous antidepressant trials will be assessed by the Antidepressant Treatment History Form (ATHF) .
• If applicable, current antidepressant dosages including augmenting agents and/or frequency and duration of psychotherapy sessions must remain stable for at least 6 weeks prior to beginning of the study.

Exclusion Criteria:

• Inability to speak English.
• Inability or unwillingness to provide written informed consent.
• Moderate/severe cognitive impairment by Mini Mental State Examination (MMSE) scores 27.
• Current or lifetime DSM-V criteria for post-traumatic stress disorder (PTSD), acute stress disorder, psychosis-related disorder, bipolar disorder I or II disorder, substance-induced mood disorder, any mood disorder due to a general medical condition or any Axis I disorder other than MDD as the primary presenting problem.
• History of moderate or severe traumatic brain injury, Parkinson's disease, dementia of any type, multiple sclerosis, seizures or other central nervous system (CNS) related disorders.
• History of comorbid substance disorder within 6 months of assessment plus positive urine toxicology screen test during baseline assessments.
• Clinically unstable medical illness that could compromise the patient's ability to tolerate or likely interfere with the study procedures (e.g., history of or current myocardial ischemia or arrhythmias, congestive heart failure, severe pulmonary, renal, or hepatic disease, uncontrolled hypertension).
• Current or within less than 14 days use of barbiturates or monoamine oxidase inhibitors (MAOi).
• For women: pregnancy (confirmed by lab test), initiation of female hormonal treatments within 3 months of screening, or inability/ unwillingness to use a medically accepted contraceptive method during the study.
• Imminent risk of suicidal/homicidal ideation and/or behavior with intent and/or plan.

The time frame of data collection was 3 years and 8 months (from April 2015 through December 2018). Each participant was assessed for up to 28 weeks.