Action of Ketamine in Treatment-Resistant Depression
Condition: Treatment-resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Depression carries the largest burden of all medical disorders in middle to high income
      countries, as determined by the World Health Organization. Despite many antidepressant
      strategies, only a third of patients get well after their first treatment and a third remain
      ill after several treatments. Moreover, antidepressant treatments all have a delayed action
      ranging up to several weeks.

      Ketamine (KET) has been used for decades as a sedative and anesthetic. In treatment-resistant
      depressed patients(TRD), an intravenous dose much lower than necessary for anesthesia may
      produce a robust antidepressant effect and may even abolish suicidal thoughts within hours,
      peaking within 24 hours. But, its antidepressant effect generally lasts only days.Previous
      studies examining KET in TRD have been critiqued for lack of an effective placebo measure due
      to brief perceptual experiences associated with KET. Thus, the current study compares KET
      against a short-acting sedative. The phases of this study compare response to a single KET
      injection to 6 injections over 2 weeks. Next, KET responders are given 1 injection a week for
      3 weeks of either KET or the sedative agent to determine if beneficial effects of KET are
      maintained, and to assess duration of its benefits after repeated administration. The genetic
      profile of patients for a substance promoting contacts between cells and brain will be
      determined to investigate if response to KET could be predicted with that blood test. This
      substance, as well as several chemicals that produce inflammation, will also be measured in
      the blood to investigate their role in the effect of KET. Patients will receive, in total, no
      more than the equivalent of two to three anesthetic dose of KET. Results from this study will
      help establish the beneficial effects of a single KET injection as a rapid intervention for
      major depression, and to investigate the possibility of obtaining a prolonged antidepressant
      effect with repeated injections.
    

Detailed description: 
      Major depressive disorder (MDD) carries worldwide the largest burden of diseases among
      mental, neurological, and substance-use disorders measured in Disability Adjusted Life Years
      (DALYs), according to the World Health Organization (WHO).1 In turn, MDD has the highest
      DALYs in middle to high income countries, with ischemic cardiac diseases being second.2
      Although there are effective treatments for MDD, a large proportion of patients do not
      achieve remission even after several attempts, and any significant response, when it
      manifests itself, takes place a delay of a few weeks.3,4 There is always urgency to treat MDD
      because although patients may have been ill for several weeks, months, and sometimes years,
      they are often in a crisis situation when they consult. The nature of the crisis may be
      familial, financial/professional, or the consultation may take place because of intense
      personal suffering, possibly involving suicidal ideation. Consequently, rapid therapeutic
      action and high remission rates represent the two major unmet needs for MDD.

      In the last few years, considerable attention has been dedicated to the glutamate system as a
      possible contributor of the antidepressant response. The most striking breakthrough has been
      the rapid antidepressant response of intravenous ketamine using doses that are about a
      quarter of the routinely utilized anesthetic dose in children and adults.5,6 Unlike many
      anesthetic agents, ketamine does not depress cardiovascular and respiratory parameters.7 The
      primary action of ketamine is to block N-Methyl-D-Aspartate (NMDA) receptors. The
      antidepressant response to ketamine often manifests itself within a few hours, but is
      generally maximal after 24 hours.8 Importantly, a single infusion produces in the most
      subjects a robust decrease of suicidal ideation.9,10 The drawback of this approach is,
      however, that its benefits generally disappear within a week.6 Consequently, much clinical
      work remains to be carried out in order to better understand and maintain the antidepressant
      response of ketamine.

      Specific aim #1: The first aim of this proposal is to characterize the antidepressant action
      of a single dose of ketamine in a truly double-blind paradigm. Indeed, even the low doses of
      ketamine (0.2-0.5 mg/kg)8,11 produce mild derealization and therefore the use a mere saline
      solution in prior studies has been inadequate as a control.

        1. To show that the infusion of a low dose of the short-acting benzodiazepine midazolam
           will serve as an adequate active control for ketamine. It is hypothesized that because
           midazolam produces marked sedation, it will serve as an adequate control.

        2. To determine if the brain-derived neutrophic factor (BDNF) mediates the antidepressant
           response. In mice, a VAL/MET polymorphism for the BDNF gene, ketamine is devoid of
           effects. The influence of this polymorphism will be evaluated in patients.

      Specific aim #2: The second goal of this proposal is to attempt enhancing and prolonging the
      antidepressant effect of ketamine by giving it repeatedly at a rate of three infusions per
      week for two consecutive weeks.

        1. To assess whether ketamine responders will improve further after a six infusions over
           two weeks. It is hypothesized that ketamine non-responders following a single infusion
           will not show a significant improvement with repeated infusions of ketamine at a dose of
           0.5 mg/kg given three times a week for two weeks, but that in responders repeated
           ketamine will produce a more robust and sustained antidepressant action than a single
           infusion.

        2. To assess whether the inflammatory status of the depressed patients is altered by the
           response to ketamine. Pro-inflammatory mediators and cortisol are generally elevated in
           depression while melatonin is decreased. These anomalies are typically restored with
           effective treatments. This will be investigated in the light of the rapid antidepressant
           effect of ketamine.

      Specific aim #3: The third goal of this proposal is to prolong the antidepressant effect of
      ketamine. In this third consecutive phase of the project, ketamine-responsive patients will
      receive ketamine on a once weekly basis.

      1)To demonstrate that the antidepressant effect of ketamine will be sustained over four weeks
      using a single infusion per week. The antidepressant response to a single infusion of
      ketamine disappears within 7 days. It is hypothesized that repeated infusions of ketamine, at
      an interval of one week for four weeks, will maintain the antidepressant effect.

      2)To assess how long the antidepressant effect of repeated ketamine infusions will last in
      follow up. After the first three phases of this project that will last about eight weeks, the
      average duration of a standard antidepressant medication trial, the responders will be
      monitored to follow their clinical evolution. It is hypothesized that the responders will
      show a longer maintenance of their response than after the first infusion in phase one of the
      project.

        1. Phase I: the double-blind crossover. After patients will have been deemed eligible to
           participate in the study, blood will be drawn for genotyping and various assays (BDNF
           Val/Met, BDNF, morning melatonin and salivary cortisol, C-reactive protein, IL-1β, IL-2,
           IL-6, IL-8, IL-12, IFN-γ, TNF-α, and anti-inflammatory factors IL-4 and IL-10, as
           previously done in our laboratory).101-102 They will be randomized to receive
           intravenously either 0.5 mg/kg of ketamine (the readily available racemic mixture) or 30
           µg/kg of midazolam as a 250 ml infusion (prepared in our unit) over 40 minutes, given by
           a research nurse in the presence of a study physician. Their antidepressant drug regimen
           will not be altered throughout the study. A clinician will evaluate their clinical
           status prior to the infusion, using the Montgomery-Asberg Depression Rating Scale
           (MADRS)103 and the Clinical Global Intensity-Severity (CGI-S)104 and the patients will
           rate themselves using the Quick Inventory Depressive Symptoms-Self-report (QIDS-SR)105
           and a self-report questionnaire rating suicidality. The patients will be assessed using
           the Brief Psychiatric Rating Scale-positive symptom scale106 at baseline (before the
           infusion), time 0 (immediately after infusion is complete), then at 60 and 120 minutes
           post time 0. The CGI-Improvement (CGI-I)104 will be used to obtain a clinical evaluation
           of overall change of their condition after two hours before discharging the patients two
           hours after the infusion. The patients will come in the next day for an evaluation using
           the MADRS, CGIs, and the QIDS-SR and will be asked to guess what drug they received.
           Four days after the infusion, the patients will repeat the QIDS-SR at home, and they
           will come in for an evaluation at day 7. If the patients did not respond, or if they
           returned to 80% of their MADRS score before the infusion, they will receive either
           ketamine or midazolam to complete the crossover protocol. If the patients are
           maintaining more than a 20% improvement of their baseline MADRS score, they will be
           asked to come in on a weekly basis for an assessment, and will be asked to complete a
           QIDS-SR twice a week (at days 10, 14, 18, 21, and so on) in order to assess how long the
           therapeutic effect lasts. Patients who have not response to their second infusion or
           those found to have relapsed during the weekly follow-up visits, will continue into
           phase II. Patients who are unable, ineligible, or unwilling to enter phase II will be
           given a recommended treatment plan and returned to their family physician with a
           consultation plan, or additional/alternative treatment options at the discretion of the
           study physician.

           In order to obtain an objective measure of their activity level and of the pattern of
           their sleep-wake cycle, patients will wear an actimeter watch for several days during
           screening and throughout the protocol. The data will be downloaded weekly during the
           visits.

        2. Phase II: the repeated treatment over two weeks. Once patients are deemed not to have
           responded to the second infusion or have lost their improvement (relapsing to a MADRS
           score over 80% of their baseline score prior to the second infusion), they will receive
           repeated ketamine infusions (0.5 mg/kg). They will be given 3 infusions per week for two
           weeks. On visit 6 of phase 2 the patients will be assessed using the Brief Psychiatric
           Rating Scale-positive symptom scale106 at baseline (before the infusion), time 0
           (immediately after infusion is complete), then at 60 and 120 minutes post time 0. Their
           clinical status will be assessed prior to each infusion using the MADRS, the CGI-S, the
           CGI-I, and they will rate themselves using the QIDS-SR and a self-report questionnaire
           rating suicidality. Patients will be assessed two to three days after the sixth
           infusion. The ratings throughout phase II will help determine whether repeated
           administration produces a greater and sustained improvement than a single infusion.
           Biological assays will be repeated at the end of Phase II.

        3. Phase III: the repeated treatment over four weeks and the naturalistic follow-up.

      Two to three days after the sixth infusion, patients not achieving a 50% improvement of their
      MADRS score, when compared to their baseline score prior to the first of the six infusions,
      will be taken out of the study and offered to be treated in our Research Unit using
      additional pharmacological and/or psychotherapeutic approaches. Patients improving by 50% or
      more on the MADRS scale will receive ketamine once a week for four weeks. They will be
      assessed using the same scales as mentioned above prior to each infusion. Patients will be
      assessed two to three days after the fourth weekly infusion. The ratings throughout phase III
      will help determine whether repeated administration of ketamine is effective to maintain the
      beneficial action of a relatively more intense regimen of ketamine.

      Monitoring of the patients reaching more than 80% or more of their MADRS score, when compared
      to their baseline score prior to the last four infusions, will cease and will be offered to
      be treated in our Research Unit using additional pharmacological and/or psychotherapeutic
      approaches. Patients maintaining more than 20% improvement will be assessed weekly to
      determine how long the therapeutic effects of ketamine last. Biological assays will be
      repeated at the end of Phase III.
    

Intervention name(s): Ketamine; Midazolam
Intervention type(s): Drug; Drug
Intervention description(s): Intravenous Bolus infusion Ketamine Hydrochloride 0.50 mg/mL over 40 minutes; Bolus infusion of Midazolam Hydrochloride 1 mg/mL over 40 minutes
Other intervention name(s): Ketamine Hydrochloride; Kevlar; Midazolam Hydrochloride; Midazolam HCL
Intervention MeSH terms: Midazolam; Ketamine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: depression; treatment; ketamine; ottawa; treatment-resistant; infusion