Ketamine as an Alternative Treatment to ECT in Major Depressive Disorder
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Developing more effective and faster acting antidepressant is of outmost clinical importance.
      Available antidepressant therapies have a delayed therapeutic effect. It typically takes
      several weeks before symptom relief is evident. Furthermore, antidepressants are relatively
      ineffective - as many as 30% of patients do not respond to any medication at all. In this
      study the investigators evaluate the NMDA-receptor antagonist ketamine as a potentially new
      antidepressant treatment for severely depressed patients and compare its effectiveness with
      that of electroconvulsive therapy (ECT).
    

Detailed description: 
      In line with the PICO model, patient selection and procedures for experimental and control
      treatments and outcome measures are rigorously defined. Inpatients, aged 18-85, diagnosed
      with major depressive disorder (MDD, according to DSM-IV), that have been offered and have
      accepted ECT, are eligible to participate. Patients must be proficient in spoken and written
      Swedish, and score ≥ 20 points on the Montgomery Åsberg Depression Rating Scale (MADRS).
      Exclusion criteria are known allergy to the active substance; co-morbid conditions that could
      interfere with the treatment (e.g. primary psychosis); habitual difficulties to speak, hear,
      remember or reason; on-going or recent (6 months) drug abuse; treatment according to LPT
      (Lagen om psykiatrisk tvångsvård; Compulsory Psychiatric Care Act); and a number of
      cardiovascular conditions.

      Patients randomized to the experimental treatment receive intravenous infusions of racemic
      ketamine (0.5 mg/kg), delivered over a period of forty minutes thrice weekly (Monday,
      Wednesday, Friday). Patients in the control group receive ECT in line with standard
      procedures (including anesthesia, muscle relaxation and oxygenation) thrice weekly. ECT was
      chosen as the reference treatment as it is the most effective treatment for patients
      suffering from moderate to severe depression.

      Primary outcome is the proportion of patients in remission after 4 weeks of treatment in each
      arm. Remission is defined as a MADRS ≤ 10.

      The study uses a non-inferiority design. Demonstrating superiority of ketamine was not an
      option based on the number of patients needed to gain sufficient power with such a design.
      Also, the investigators do not believe that ketamine treatment needs to be more effective, at
      least not in terms of the primary outcome. ECT is associated with side effects (in particular
      amnesia during the treatment period, but some patients also report persistent memory
      problems) and patients need to be anaesthetised under the supervision of a anaesthesiologist.
      The treatment is thus fairly demanding and expensive. A significant amount of patients are
      also unwilling to undergo ECT. Given non- inferiority of ketamine regarding the primary
      outcome, and given that it is associated with fewer side effects or shorter time to remission
      and does not involve the need for anaesthesia, in a risk-benefit analysis the scale might be
      tipped in favour of ketamine, even if it is not superior per se.

      Secondary outcomes include proportion of patients in re mission and /or response and
      symptomatic relief at follow-up time points (3, 6 and 12 months after treatment cessation).
      Also addressed is how the two treatments affect cognition. A computerized test battery, the
      Cambridge Automated Neuropsychological Test Automated Battery (CANTAB) is administered prior
      to the first treatment, after two weeks, shortly after remission and at three additional time
      points (3, 6 and 12 months) after conclusion of the treatment. See figure for specification
      and description of cognitive tests.

      Blood samples are drawn before the first treatment and 2-3 months after finishing treatment.
      Apart from plasma and serum samples (which will be used for later analysis of potential
      biomarkers such as IL 6 and D-serine), additional blood is collected for genomic DNA
      analysis. A total of 4 x 6 mL are taken at each occasion. Blood samples are stored at the
      regional biobank.

      Time to response will be analysed with parametric survival analysis (for changes in MADRS
      score) or with non-parametric analysis of two-way ordinal data with repeated measurements34
      (for ordinal data). Cognitive data and biological samples will be analysed with t-tests
      (paired or unpaired as appropriate) or with analysis of variance ANOVA.

      Study sample size was calculated based on actual or assumed remission rates, the primary
      outcome parameter of the study. A remission rate of 60% was set for the reference treatment
      (ECT). A non-inferiority limit of 40% was set for the experimental intervention (ketamine).
      This is an arbitrary level, based on an assumption of fewer and milder side effects, faster
      antidepressant effect and the fact that the patients do not need to be anaesthetized and
      given muscle relaxants. With the above limits, a power of 80% and a significance level of 5%,
      97 patients are required in each arm, according to: n = (2 * 8,4 * p(1-p) / difference2),
      where "2" and "8,4" are derived from significance and power levels, p are the (actual and
      assumed) levels for the proportion of patients reaching remission for ECT and ketamine (60%
      and 40% respectively). The size of the cohort is calculated to be sufficiently large to
      detect ECT-associated cognitive side effects.
    

Intervention name(s): Ketamine IV Infusion; ECT
Intervention type(s): Drug; Procedure
Intervention description(s): Patients randomized to the experimental treatment receive intravenous infusions of racemic ketamine (0.5 mg/kg), delivered over a period of forty minutes thrice weekly (Monday, Wednesday, Friday) under supervision.; ECT given in line with standard procedures (including anesthesia, muscle relaxation and oxygenation) thrice weekly.
Other intervention name(s): Ketamine
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Depressive Disorder, Major; Antidepressive Agents/adverse effects; Depressive Disorder, Major/drug therapy; Infusions, Intravenous; Ketamine/administration & dosage*; Ketamine/adverse effects; Treatment Outcome; Electroconvulsive therapy