Ketamine for Treatment Resistant Late-Life Depression
Condition: Treatment Resistant Depressive Disorder
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Ketamine; Ketamine; Ketamine; Midazolam
Intervention description: randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg; randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg; randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg; single 40 min infusion of MID 0.03mg/Kg
Intervention MeSH terms: Midazolam; Ketamine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: We use a Bayesian, adaptive, randomized design initially allocating subjects to 2 arms in a 1:3 ratio: ARM 1: MID 0.03 mg/kg (active placebo); ARM 2: four conditions KET 0.1 mg/kg, KET 0.25 mg/kg, KET 0.5 mg/kg or MID 0.03 mg/kg. After 1:1:1:1 allocation of the first 20 subjects to ARM 2, Bayesian adaptive randomization may stop for superiority, change randomization ratios and/or prune arms for futility based on the probability of a day 7 treatment response. ARM 1 remains open for allocation to ensure a placebo group sufficiently large for comparison with best dose KET. For analyses, MID of ARM 1 and ARM 2 will be combined so that there are 4 conditions (or arms) for final statistical analyses. We expected to enroll a maximum 72 patients.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 33.0
Sex: All
Minimum age: 55 Years
Healthy volunteers: No
Keywords: ketamine; depression; treatment resistant; treatment resistant depression; late life depression; depression in the elderly; geriatric depression

Summary:

      The purpose of this study is to examine the effectiveness of a single infusion of ketamine
      (KET), to determine which dose is optimal 7 days after infusion using Bayesian Adaptive
      Randomization, and to learn about how ketamine works in the body and brain in persons with
      late-life treatment resistant depression.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female patients, 55 years of age,

          -  Participants must fulfill DSM 5 criteria for a Major Depressive Episode (Unipolar),
             based on a structured diagnostic interview, the DSM 5 M.I.N.I. 7.0

          -  Participants must have a history of at least one previous episode of depression prior
             to the current episode (recurrent MDD) or have chronic MDD (of at least two years'
             duration),

          -  Participants have not responded to two or more adequate trials of FDA-approved
             antidepressants, determined by Antidepressant Treatment Response Questionnaire (ATRQ)
             criteria.

          -  Participants must score 14 or greater on the Quick Inventory of Depressive
             Symptomatology-Self Report (QIDS-SR), and score 27 on the Montgomery Asberg Depression
             Rating Scale (MADRS),

          -  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.

        Exclusion Criteria:

          -  Patients currently on fluoxetine,

          -  History of schizophrenia, schizoaffective disorder or any psychotic disorder, or
             bipolar disorder,

          -  Documented history of a psychotic disorder in a first-degree relative,

          -  Current diagnosis of obsessive-compulsive disorder (OCD) or eating disorder [bulimia
             nervosa or anorexia nervosa],

          -  Alcohol or substance use [except nicotine] within the preceding 6 months,

          -  Patients with any clinically significant personality disorder that would, in the
             investigator's judgment, preclude safe study participation,

          -  Patients judged to be at serious and imminent suicidal or homicidal risk,

          -  Serious, unstable medical illnesses including respiratory [obstructive sleep apnea, or
             history of difficulty with airway management during previous anesthetics],
             cardiovascular [including ischemic heart disease and uncontrolled hypertension], and
             neurologic [including history of severe head injury],

          -  For study entry, patients must be reasonable medical candidates for ketamine or
             midazolam infusion, as determined by a board-certified physician co-investigator
             during study Screening,

          -  Clinically significant abnormal findings of laboratory parameters [including urine
             toxicology screen for drugs of abuse], physical examination, or ECG,

          -  Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg),

          -  Patients with one or more 11 seizures without a clear and resolved etiology,

          -  Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to
             Screening,

          -  Past intolerance or hypersensitivity to ketamine, or history of recreational use of
             phencyclidine (PCP) or ketamine,

          -  Past intolerance or hypersensitivity to midazolam,

          -  Age-related cognitive decline or mild dementia suggested by a score of < 25 on the
             Mini-Mental State Examination (MMSE) at Screening,

          -  Patients taking medications with known activity at the N-methyl-D-aspartate receptor
             (NMDA) or AMPA glutamate receptor [e.g., riluzole, amantadine, lamotrigine, memantine,
             topiramate, dextromethorphan, D-cycloserine], or the muopioid receptor,

          -  Patients taking any of the following medications: St John's Wort, theophylline,
             tramadol, metrizamide,

          -  Patients who demonstrate > 25% decrease in depressive symptoms as reflected by the
             QIDS-SR score from Screening to Randomization,

          -  Patients who have received electroconvulsive therapy (ECT) in the past 6 months prior
             to Screening,

          -  Patients currently receiving treatment with vagus nerve stimulation (VNS) or
             repetitive transcranial stimulation (rTMS).