Optimization of IV Ketamine for Treatment Resistant Depression
Condition: Major Depressive Disorder (MDD); Treatment Resistant Depression (TRD)
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Intervention: Ketamine; Midazolam
Intervention description: Single dose .5 mg/kg IV (in the vein) infused over 40 minutes; single dose 0.045 mg/kg IV infused over 40 minutes
Intervention MeSH terms: Midazolam; Ketamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 73.0
Sex: All
Minimum age: 21 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      Existing treatments for major depressive disorder (MDD) generally take weeks to months to
      exert their maximal benefit. There is an urgent need to develop rapid-acting treatments for
      MDD. Ketamine, a high-affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has
      been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric
      and adult patients. Beyond its well-established role in anesthesia and pain management, there
      is emerging evidence that ketamine may have rapid antidepressant properties for patients with
      severe mood disorders.

      In this study we are investigating whether ketamine can have an antidepressant effect
      compared to midazolam. Midazolam has similar anesthetic effects compared to ketamine but has
      not been shown to be an antidepressant, and is therefore acting as an active control in this
      study.

      The study period can last up to 8 weeks, depending on your response to the study medication.
      There are two required overnight stays in our Research Commons as part of this study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients, 21-80 years of age;

          2. 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 serum beta-human growth hormone at screening and at pre-infusion;

          3. Participants must fulfill DSM-IV criteria for Major Depression without psychotic
             features, based on clinical assessment by a study psychiatrist and confirmed by a
             structured diagnostic interview, the Structured Clinical Interview for DSM-IV TR Axis
             I Disorders, Patient Edition (SCID-P);

          4. 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);

          5. Participants have not responded to three or more adequate trials of an antidepressant
             as determined by Antidepressant Treatment History Form (ATHF) criteria (score >=3);

          6. Participant scores on the IDS-C30 must be greater than or equal to 32 at both
             Screening and within 24 hours prior to Visit 1a (Phase 1);

          7. Current major depressive episode is of at least 4 weeks duration.

          8. 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;

          9. Each participant must be able to identify a family member, physician, or friend who
             will participate in the Treatment Contract.

        Exclusion Criteria:

          1. Lifetime history of psychotic features, diagnosis of schizophrenia or any other
             psychotic disorder, or diagnosis of bipolar disorder

          2. Lifetime histories of autism, mental retardation, pervasive developmental disorders,
             or Tourette's syndrome;

          3. Current diagnosis of Obsessive Compulsive Disorder or eating disorder (bulimia nervosa
             or anorexia nervosa);

          4. Subjects with DSM-IV drug or alcohol abuse/dependence within the preceding 2 years;

          5. 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;

          6. Patients judged clinically to be at serious and imminent suicidal or homicidal risk;

          7. Women who are either pregnant or nursing;

          8. Serious, unstable medical illnesses including hepatic, renal, gastroenterologic
             (including gastroesophageal reflux disease), respiratory (including obstructive sleep
             apnea, or history of difficulty with airway management during previous anesthetics),
             cardiovascular (including ischemic heart disease and uncontrolled hypertension),
             endocrinologic, neurologic (including history of severe head injury), immunologic, or
             hematologic disease;

          9. Clinically significant abnormal findings of laboratory parameters, physical
             examination, or ECG;

         10. Patients with one or more seizures without a clear and resolved etiology;

         11. Patients starting hormonal treatment (e.g., estrogen) in the last 3 months prior to
             Visit 1a;

         12. Treatment with an irreversible MAOI or any other FDA approved Anti depressant
             medication within one week prior to Visit 1a (with the exception of a stable dose of
             non-benzodiazepines hypnotics i.e. zolpidem, eszopiclone, etc for at least 3 months);

         13. Treatment with fluoxetine within 4 weeks prior to Visit 1a;

         14. Evidence-based individual psychotherapy (e.g. CBT or IPT) and other
             non-pharmacological antidepressant treatments (e.g. light therapy) will not be
             permitted during the acute study period (7 day);

         15. Previous recreational use of PCP or Ketamine.

         16. Past intolerance or hypersensitivity to midazolam

         17. Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg) not controlled by
             diuretic or beta-blocker therapy alone or in combination.

         18. Evidence of age-related cognitive decline or mild dementia suggested by a score of <
             27 on the Mini-Mental State Examination (MMSE) at Screening