Intranasal Ketamine in Ultra-REsistant Depression (SURE-ECT Non Responders)
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional

Summary: 
      Despite the known efficacy of pharmacotherapy (i.e. antidepressants) and psychotherapeutic
      interventions in treating depressive disorders, research evidence suggests that 20% to 40% of
      patients with major depressive disorder (MDD) do not respond adequately to such treatments.
      These patients are diagnosed with Treatment-Resistant Depression (TRD), and are sometimes
      treated with convulsive therapy. However, about 10-30% of TRD patients do not respond to
      convulsive therapy, and are thus diagnosed with Ultra-Resistant Depression (URD). Using an
      open label pilot study involving subjects, this trial aims to assess the safety,
      tolerability, and clinical effects of intranasal ketamine (IN) treatment in patients who do
      not respond to convulsive therapy. Intranasal ketamine (IN) treatment approach has shown
      promising therapeutic outcomes for patients with TRD, but has not yet been studied on
      patients with URD.
    

Detailed description: 
      Ketamine is a fast-acting anesthetic that can have stimulant effects when taken at low doses.
      It acts as a non-competitive high-affinity N-methyl-d-aspartate (NMDA) receptor antagonist
      that stimulates synaptic glutamate release and blocks extra-synaptic NMDA receptors. This
      mechanism of action mediates excitatory synaptic transmission through the central nervous
      system and therefore results in robust antidepressant effects. Administering intravenous (IV)
      ketamine to patients with TRD has shown to produce rapid antidepressant effects.
      Nevertheless, delivering IV ketamine to patients can be challenging since it requires
      specialized expertise and equipment. A promising alternative that preserves IV ketamine's
      rapid onset of therapeutic action while minimizing inconvenience and discomfort is intranasal
      drug delivery (IN). This current proof-of-concept clinical trial is an open label pilot study
      on patients with treatment-resistant unipolar depression who did not respond to, or did not
      tolerate, an acute course of convulsive therapy. Using a combination of Transcranial Magnetic
      Stimulation (TMS) neurophysiological tools with electromyography (EMG) and
      electroencephalography (EEG), this trial also aims to explore biomarkers of ketamine's
      antidepressant effect by examining ketamine's action on NMDA neurotransmission. Investigating
      the impact of ketamine on cortical excitation and inhibition could provide insight into the
      role of NMDA receptors in cortical physiology, and therefore determine potential predictors
      of clinical response for depression.

      Objective 1: To test the safety and tolerability of IN ketamine in patients with URD who did
      not respond to/tolerate an acute course of convulsive therapy

      Hypothesis 1: IN ketamine will be safe and well tolerated in patients with URD

      Objective 2: To test the clinical effects of IN ketamine patients with URD who did not
      respond to/tolerate an acute course of convulsive therapy

      Hypothesis 2: IN ketamine will result in improvement in depressive symptoms, suicidal
      ideation, and quality of life measures (compared to scores from baseline)

      Objective 3: To investigate the impact of ketamine on cortical excitation via intracortical
      facilitation (ICF) and cortical inhibition via short-interval cortical inhibition (SICI)
      paradigms

      Hypothesis 3: IN ketamine will result in neurophysiological changes as measured by TMS-EMG
      and EEG
    

Intervention name(s): Intranasal Ketamine (IN)
Intervention type(s): Drug
Intervention description(s): A sterile form of ketamine will be administered intranasally twice weekly for four weeks. Dosing schedule will be determined based on patient's weight using a specialized formula. Patients will be started at the lowest dose during the first treatment session. Dose will be titrated further to therapeutic dose in the following sessions. The dose will be adjusted if patients do not tolerate full therapeutic doses. After receiving the second treatment of each week, participants will be seen by a study physician to determine dosing for the following week. Patients will be monitored by trained personnel for the full duration of the 2 hour supervision period. Vital signs and physical symptoms will be monitored consistently and measurements taken every 30 minutes. Appropriate medications will be provided to manage treatment-related side effects and any adverse events. Labetalol will be used in the management of treatment-related transient hypertension as needed.
Intervention MeSH terms: Ketamine
Intervention model: Single Group Assignment
Intervention model description: Open label pilot study
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Convulsive therapy; Open-label trial; Pilot study; Treatment-resistant depression (TRD); Ketamine; Intranasal drug delivery (IN); N-methyl-d-aspartate (NMDA); Receptor antagonist; Transcranial magnetic stimulation (TMS); Electromyography (EMG); Electroencephalography (EEG); Intracortical facilitation (ICF); Short-interval cortical inhibition (SICI); Electroconvulsive Therapy (ECT)