Efficacy of Repeated Ketamine Infusions for Treatment-resistant Depression
Condition: Treatment-resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 2

Summary: 
      About one-third of depressed patients will not get better after multiple antidepressant
      treatments. This situation put a high burden on patients with depression due to worsening
      quality of life and increasing health care costs. Difficult-to-treat depression might be even
      worse among Veterans given that the frequency of depressive symptoms is 2 to 5 times higher
      than among the general US population. A breakthrough discovery happened in recent years when
      investigators found that one infusion from an old anesthetic named ketamine showed high
      efficacy and rapid antidepressant effect (sometimes within hours) but lasted only up to a
      week. The investigators propose to study if multiple infusions of ketamine can provide
      greater and longer antidepressant effects than one infusion. If that is the case, multiple
      infusions could be an alternative to relieve depressive symptoms that do not response to
      multiple antidepressant drugs.
    

Detailed description: 
      Recent studies have found rapid and highly efficacious antidepressant effects of a single
      ketamine infusion in treatment-resistant depression (TRD). However, a single infusion appears
      insufficient to maintain response as most patients return to previous depressive state within
      a week. The strategy of multiple infusions to increase efficacy and sustain antidepressant
      effects has not yet been systematically evaluated in an randomized control trial (RCT). The
      proposed study is a one-center, interventional, efficacy study designed to determine
      antidepressant outcomes of serial ketamine infusions compared to a single ketamine infusion
      among Veterans with TRD. The investigators have hypothesized that six infusions will be
      superior to a single infusion of ketamine in both decreasing severity of depressive symptoms
      and maintaining response. Participants will be male/female Veterans (18 to 75 years old) of
      any era or military background who suffer from TRD defined as failure to achieve remission
      from at least 2 antidepressant trials of different pharmacological classes. Potential
      participants will be recruited from Mental Health clinics and screened for eligibility using
      a two stage process (phone/chart review, followed by interview). Exclusion criteria includes
      post-traumatic stress disorder, psychosis-related disorder, bipolar disorder,
      alcohol/substance use disorder 6 months prior to screening; unstable medical illness;
      serious/imminent suicidal/homicidal risk; Parkinson's disease, dementia, seizures; traumatic
      brain injury; contraindicated medications (e.g., MAO inhibitors, barbiturates); received
      electroconvulsive therapy (ECT) during current episode; pregnancy/nursing. Baseline
      assessments will be completed 1-2 weeks prior to starting treatment. Participants will be
      randomly assigned to one of two parallel treatment conditions: 1) six ketamine infusions at
      0.5 mg/kg or 2) single ketamine infusion at 0.5 mg/kg preceded by five midazolam infusions at
      0.045 mg/kg. Midazolam was chosen as an active placebo given similar pharmacokinetics and
      dissociative effect profile to ketamine. Each intervention will be provided for a total of
      12-day infusion-phase on a Monday-Wednesday-Friday schedule. The, follow-up visits will occur
      at weekly intervals for the first 4 weeks, at 2-week intervals for the next 8 weeks, and at
      4-week intervals for the remaining 12 weeks or until relapse. The primary end point is the
      Montgomery- sberg Depression Rating Scale (MADRS) score 24 hours following the last infusion
      where the peak antidepressant effects of ketamine occur. Secondary outcomes for the treatment
      phase include remission defined by MADRS<10, and response defined as a reduction in the
      baseline MADRS score 50%. For the follow-up period, durability of antidepressant response
      will be defined by "time to relapse" to a MADRS score <50% of baseline at that visit.
      Independent evaluation of depressive symptom severity and potential covariates of
      antidepressant effect (e.g., pain intensity, level of anxiety) will be ascertained at
      baseline, at several time points during infusion period, and at follow-up. On the day of
      infusion, subjects will arrive in the morning after an overnight fast. Hemodynamic measures
      will be recorded every 10 min for 1 hour beginning 10 min before infusion. Subjects will then
      receive IV infusion over 40 minutes. Severity of depressive symptoms, pain intensity, level
      of anxiety will be obtained before and 24 hours after infusion. Acute dissociative effects,
      manic/hypomanic symptoms, and psychotomimetic effects will be measured 30 minutes before the
      start of each infusion and at the end of infusion (t0+40 mins) and again at t0+120mins and
      t0+180mins. The infusion will be discontinued in the event of significant adverse events.
      Procedures for the subsequent infusions at days 3, 5, 8, 10, and 12 will be identical to
      those of the first infusion.
    

Intervention name(s): ketamine; midazolam
Intervention type(s): Drug; Drug
Intervention description(s): sedative; sedative
Intervention MeSH terms: Midazolam; Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depressive Disorder, Treatment-Resistant