Effect of Ketamine vs. Active Placebo on Suicidal Ideation in Depressed Inpatients With Major Depressive Disorder or Bipolar Depression.
Condition: Major Depressive Disorder; Bipolar I Disorder; Bipolar II Disorder; Bipolar Depression; Suicidal Ideation
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Bipolar Disorder; Suicidal Ideation
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Depression and suicidal ideation/attempt/death are major causes of morbidity and mortality
      from psychiatric illnesses. In 2009, the World Health Organization listed depression as the
      leading cause of years lost due to disability worldwide. Suicide is the 9th most common cause
      of death in Canada with 1.6% of Canadians ultimately dying from suicide (Statistics Canada,
      2012) and the 2nd most common cause of death in young people after accidental deaths. This
      information highlights the importance of finding treatments to prevent suicidal deaths.

      Ketamine has been shown to provide rapid treatment response for major depressive episodes
      both in major depressive disorder (MDD) and bipolar disorder (BD), via a single intravenous
      infusion which persists for at least 72 hours.

      The purpose of this study is to conduct a pilot trial of IV ketamine + treatment as usual
      (TAU) vs. midazolam (an active placebo) + TAU to estimate sample size for a full-scale RCT
      examining these treatments for decreasing suicidal ideation among depressed inpatients with
      major depressive disorder and bipolar depression.

      A total of 52 patients will be recruited for this trial. All subjects will be inpatients at
      Sunnybrook Health Sciences Centre with a diagnosis of either major depressive disorder or
      bipolar disorder type I or II currently depressed. Suicidal ideation must be present at
      baseline assessment in order to be included in the study. Thirteen subjects will be
      randomized to each treatment arm in each treatment stream - that is, 13 will be recruited to
      ketamine + TAU in the major depressive disorder stream, and 13 will be recruited to the
      midazolam + TAU in the major depressive stream. Likewise, 26 subjects with bipolar depression
      will be randomized to these two treatments.
    

Detailed description: 
      Depression and suicidal ideation/attempt/death are major causes of morbidity and mortality
      from psychiatric illness. The World Health Organization (2009) lists depression as the
      leading cause of years lost due to disability worldwide. Suicide is the 9th most common cause
      of death in Canada with 1.6% of Canadians ultimately dying from suicide (Statistics Canada,
      2012) and the 2nd most common cause of death in young people after accidental deaths. The
      investigators' data show that at least 50% of people dying from suicide in Toronto suffer
      from depression with a small proportion ~12% suffering from BD. These data underscore the
      urgency of developing new treatments for both MDD and BD but also the suicidality that is
      often associated with them.

      Ketamine treatment represents a potentially viable, safe and effective treatment for
      MDD/bipolar depression + SI. The Investigators therefore propose to conduct a pilot trial in
      preparation for a full- scale randomized controlled trial (RCT) which would aim to determine
      the efficacy of IV ketamine + a standard medication treatment (Treatment As Usual; TAU) vs.
      midazolam, an "active" placebo + TAU in treating SI among inpatients with MDD and in
      inpatients with bipolar depression. If the full-scale RCT demonstrates ketamine's efficacy,
      it would have important implications for both future research as well as inpatient treatment.

      The primary objective is to conduct a pilot trial of IV ketamine + TAU vs. midazolam + TAU to
      estimate sample size for a full-scale RCT examining these treatments for decreasing SI among
      depressed inpatients with MDD and bipolar depression.

      The primary hypothesis is that the effect size for reducing SI in the ketamine group vs. the
      midazolam group will be in the moderate range or above (d > 0.5 at 14 and 42 days) in terms
      of reduction in scores on the Scale of Suicidal Ideation (SSI) and the Columbia-Suicide
      Severity Rating Scale (CSSRS) for both subjects with MDD and subjects with bipolar
      depression.

      Further, there are secondary objectives and secondary hypotheses. The secondary objectives
      are:

        1. To estimate effect size for producing clinical response (≥50% reduction in
           Montgomery-Asberg Depression Rating Scale (MADRS) scores) and remission (MADRS<12) in
           the ketamine group vs. the midazolam group at 14 and 42 days in both MDD and bipolar
           depression.

        2. To determine whether the ketamine group produces a more rapid reduction in SSI, CSSRS
           and MADRS scores compared to the midazolam group in both MDD and bipolar depression.

        3. [bipolar depression stream only] To determine whether ketamine or midazolam induces
           manic symptoms in any subjects and, if so, whether ketamine produces manic symptoms in
           more subjects than midazolam.

      Secondary hypotheses are:

        1. Effect sizes for achieving clinical response and remission in the ketamine group vs. the
           midazolam group will be in the moderate range or above (d > 0.5 at 14 and 42 days).

        2. There will be a significantly more rapid reduction in SSI, CSSRS and MADRS scores in the
           ketamine group than in the midazolam group.

        3. [bipolar depression stream only] Manic symptoms will occur in <10% of all subjects and
           there will be no differences between the two groups.

      Finally, the exploratory objectives are:

        1. To determine whether mean time to discharge differs between the ketamine and midazolam
           groups in both MDD and bipolar depression.

        2. To determine whether subject satisfaction is differs between the ketamine group and in
           the midazolam group.

      And exploratory hypotheses:

        1. Mean time to discharge from hospital will be faster in the ketamine than in the
           midazolam group in both MDD and bipolar depression.

        2. Subject satisfaction will be higher in the ketamine than in the midazolam group in both
           MDD and bipolar depression.

      Subjects will be inpatients at Sunnybrook Health Sciences Centre with a diagnosis of either
      MDD or BD type I or II currently depressed. To be included in the study, SI must be present
      at the time of baseline assessment. Subjects will be recruited on the first regular week day
      (non-weekend/holiday) after their admission. This is the day on which a comprehensive
      inpatient treatment plan is typically developed. Subjects will be randomized in a 1:1
      double-blind fashion to two groups in both a MDD and a BD stream. That is, 13 subjects will
      be randomized to ketamine + TAU and 13 subjects will be randomized to midazolam + TAU in the
      stream for subjects with MDD. Likewise 26 subjects with bipolar depression will be randomized
      to these two treatments.

      Subjects in the ketamine IV groups will receive infusions 3 times weekly for two weeks (0.5
      mg/kg infused over 40 minutes on approximately days 1, 3, 5, 8, 10 and 12 of admission). The
      exact schedule of dates is referred to as approximate since it may need to be adjusted
      slightly depending on the timing of admission/weekends etc. Subjects in the midazolam group
      will have the same dosing schedule but will instead receive midazolam 0.045 mg/kg IV infused
      over 40 minutes. A sub-anesthetic dose of midazolam was chosen as an active placebo because
      it has CNS effects including sedation and amnestic effects, thus making it more difficult for
      subjects to guess which group they are in. Vital signs including pulse, respiratory rate and
      arterial oxygen saturation will be monitored throughout the ketamine/midazolam infusion and
      for one hour post-infusion as has been the standard in the published literature. If the
      subject experiences side effects, the protocol will allow for the infusion to be slowed to up
      to 90 minutes.

      Subjects will also receive TAU during the course of the study in addition to IV ketamine or
      midazolam treatment. In the MDD group, TAU may include a newly initiated or longstanding
      antidepressant. In the BD group, TAU may include a mood stabilizer such as lithium or
      valproate that is a first or second line agent as per Canadian Network for Mood and Anxiety
      Treatments (CANMAT) guidelines (Yatham et al., 2013). This is done in an attempt to mitigate
      the risks of relapse after cessation of ketamine therapy and also makes the use of midazolam
      treatment ethically justifiable. The duration of the study is two weeks. All subjects will
      receive all 6 treatments, regardless of whether their symptoms have remitted, given recent
      evidence that 6 IV ketamine treatments led to a more robust and lasting response compared to
      only 1-3 treatments (Aan Het Rot et al., 2012). If subjects are discharged before 2 weeks,
      they will be asked to return to hospital as outpatients for any remaining ketamine treatments
      as well as for outcome measures at 2-weeks and 42 days. TAU will be maintained after
      discharge.

      Depression, suicidal ideation measures (MADRS, SSI, CSSRS) and, in the BD stream, mania
      measures (Young Mania Rating Scale; YMRS) will be administered on admission, on treatment
      days in the morning prior to ketamine/midazolam administration and on days 14 and 42. At both
      days 14 and 42, subjects will also be asked to rate their satisfaction with the study.
    

Intervention name(s): Ketamine; Midazolam; Treatment as usual (TAU)
Intervention type(s): Drug; Drug; Other
Intervention description(s): TAU includes any current treatment a patient is receiving from their primary care practitioner. In the major depressive disorder (MDD) group, TAU may include a newly initiated or longstanding antidepressant. In the bipolar depression (BD) group, TAU may include a mood stabilizer such as lithium or valproate that is a first or second line agent as per Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines (Yatham et al., 2013).
Intervention MeSH terms: Midazolam; Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Major Depressive Disorder; Bipolar Disorder; Depression; Suicide; Suicidal Ideation; Ketamine; Midazolam; Inpatients