Novel Pharmacology

Intravenous Ketamine (IVK) Studies

Our program offers an intravenous ketamine intervention for individuals with treatment resistant depression. Ketamine has long been used as an anesthetic medication. Recent evidence shows that subanesthetic doses of ketamine have rapid and robust antidepressant and anti-suicidal effects, which can have potentially life-saving relief for many individuals. Ketamine appears to work by changing the levels of glutamate, the most abundant neurotransmitter in the brain, which leads to changes in how brain cells communicate with each other and resulting in changes in emotions and thinking. 

Click here for more information on IV Ketamine

 

Deciphering Metacognition and Treatment Response in Depression with a Novel Digital Paradigm (Auditory MMN EEG)

Study’s Overview:

The purpose of this observational study is to assess how brain function and biological signals change in response to ketamine treatment that is given to patients with treatment-resistant depression (TRD). This data will be used to develop a computational model to represent the underlying biological and physiological activities that occur in response to ketamine treatment. This model will be developed using Electroencephalography (EEG). During the EEG, the auditory mismatch negativity (MMN) task will be done, which consists of listening to a series of alternating tones.

Eligibility:

Inclusion Criteria

  1. Aged 18 to 65 years
  2. Diagnosis of Major Depressive Disorder
  3. Failure of at least two trials of antidepressant therapy during the current depressive episode (treatment-resistant depression) and receiving ketamine treatment clinically as administered by their clinician

Exclusion Criteria

  1. History of bipolar disorder or psychosis
  2. Current substance use or history of substance use during the past year (excluding nicotine and caffeine use disorder)

Treatment Description:

  • Participation in the study will last a total of 3 weeks
  • As part of this study, you will go through 3 EEG recording visits before your clinical ketamine infusions at Visits 1, 2, and 4
  • Depressive symptoms will be assessed 5 times over the phone (after each of 4 ketamine infusions and one week after the last ketamine infusion)

If you would like to know more information about this study, please access our Informed Consent for the Auditory MMN EEG Study.docx

Nitrous Oxide (N2O) Studies

Nitrous oxide (N2O), also known as laughing gas, is an anesthetic gas that is frequently encountered in dental offices. However, it is also used in a variety of settings including labour and delivery units, as well as operating rooms. It is inexpensive and is on the World Health Organization’s list of Essential Drugs. Nitrous oxide is believed to work as an NMDA receptor antagonist, a mechanism shared with ketamine. However, unlike ketamine, it has minimal side effects. Current evidence has demonstrated that a single administration of nitrous oxide has been shown to decrease depressive symptoms, and there is ongoing research examining the effects of nitrous oxide in depression. Thus, we intend to carry out a research study to explore the clinical efficacy and functional outcomes of repeated nitrous oxide administrations.

 

Eligibility: 

  • Diagnosis of Major Depressive Disorder 
  • Have not seen results following a previous course of treatment for the Major Depressive Disorder such as pharmaceuticals, psychotherapy, or rTMS
  • Male or Female, aged 18-65 years old

Treatment description

  • This is a pilot study that will utilize repeated administrations of nitrous oxide gas.
  • Participants will be randomized to receive either inhaled nitrous oxide gas plus infused saline solution, or placebo (inhaled oxygen gas with infused midazolam–a different sedative agent).
  • Participants will be given 50% mg/mL of nitrous oxide to inhale plus a saline solution delivered intravenously, or 50% oxygen gas to inhale plus 1 mg/mL of midazolam delivered intravenously.  Both interventions will last one hour, and will be administered once a week for four weeks.
  • Participants will be followed for 90 days after completion of treatment.

Overview:

Bipolar disorder (BD) is a severe and persistent mental illness that is characterized by alternative periods of sustained elevation in mood (manic episodes) and decreased mood (depressive episodes), intermixed with euthymia (having no mood disturbances). Depressive symptoms predominate over the course of BD and are responsible for greater psychosocial and functional impairment. Unfortunately, treatment outcomes remain poor.

Within the last 10 years, several small studies have shown that giving nitrous oxide can provide immediate relief of depression symptoms in depressed patients who had not responded to prior antidepressant medications. Our objective is to explore if repeated use of nitrous oxide has beneficial effects on depression symptoms in people who suffer from BD.

While nitrous oxide is extensively used as an anesthetic treatment for pain relief in dentistry and surgery, the use of nitrous oxide in this study is considered investigational because it has not been approved by Health Canada to treat the symptoms of depression.

Eligibility:

  • Male or female, aged 18-65 years old
  • Currently experiencing a major depressive episode (MDE)
  • Meet the diagnostic criteria for bipolar disorder I or II
  • Have not noticed any symptom improvements from at least 2 antidepressant trials during current major depressive episode

Treatment description:

  • Participation in the study will last 5-10 weeks.
  • Participants will be asked to come to St. Michael’s Hospital once per study procedure and once per MRI visit (up to 4 visits in total). The other study assessments will be completed on the phone. Patients will continue taking their current medications during this study. It is important that the antidepressant drugs participants normally use remain unchanged during the participation in the study.
  • Participants will be randomly assigned (i.e., flipping a coin) to one of two groups: The N2O group (inhaled nitrous oxide plus intravenous saline solution) or (2) The placebo group (inhaled O2 plus intravenous midazolam, a different sedative agent). 
  • Participants in the nitrous group will be given 50% mg/mL of nitrous oxide to inhale through a face mask or mouthpiece for one hour.
  • Participants in the placebo group will be given a single dose of O2 to inhale (50% concentration) along with a single infusion of midazolam (0.02 mg/kg in 100 mL) over 60 minutes.
  • Regardless of the group that participants are in, they  will feel similar side effects such as sleepiness and relaxation.
  • The study doctor administering the medication will know which group participants are in to ensure their safety.

Overview:

The purpose of this clinical trial is to assess the tolerability and effect of two commonly used anesthetic agents, nitrous oxide (laughing gas) and ketamine, that are given to patients with treatment-resistant depression who have current suicidal thinking. Both nitrous oxide and ketamine have been used as anesthetics for >50 years, and are on the World Health Organization’s list of Essential Drugs. Research shows that both medicines are highly effective at rapidly alleviating suicidal thinking and behaviour in patients with treatment-resistant depression, but one might be better and more preferred by patients than the other. 

Eligibility:

Inclusion Criteria

  • Any sex or gender, aged 18 to 65 years
  • Diagnosis of Major Depressive Disorder
  • Have not seen results following a previous course of antidepressant treatment 
  • Have active suicidal thoughts 
  • Able to speak and understand English

Exclusion Criteria

  • History of bipolar disorder or psychosis
  • Current substance use or history of substance use during the past year (excluding nicotine and caffeine use disorder)
  • Certain medical illnesses and blood test results 
  • Recent change in treatment regimen for depression than happened less than 1 month ago

Treatment description:

  • Participation in the study will last a total of 8 weeks: 4 weeks of treatment and 4 weeks of after-treatment monitoring 
  • Participants will be asked to come to the St Michael’s Hospital to receive treatment 
  • You will be randomly assigned to receive either nitrous oxide once a week, or intravenous ketamine twice a week. The total duration for both treatments is 4 weeks. You and the clinical will know which treatment you will be receiving
  • Nitrous oxide, or laughing gas, is an anesthetic agent that is commonly used in dental procedures and child delivery. If assigned to nitrous oxide, you will receive it by inhalation for 60 minutes once a week, for 4 weeks. If you receive this treatment and it does not work for you, you will be offered ketamine treatment free of charge after the trial.
  • Ketamine is an anesthetic agent that will be given intravenously, as this is the most widely studied and effective form of ketamine. If assigned to ketamine, you will receive it for 40 minutes twice a week, for 4 weeks. Please review details of our ketamine clinical program here. 
  • As a part of this study, you will undergo two magnetic resonance imaging scans before and after your treatment
  • You will be monitored for 4 weeks after completing treatment 

Past Studies

Overview:
The stellate ganglion is a part of the cervical sympathetic chain, and it provides sympathetic input to the ipsilateral upper extremity, chest, head, and neck. Using ultrasound guidance, an anesthetic block of the stellate ganglion can affect changes to neural processes which are known to be implicated in depression. Currently, an antidepressant-like effect has been demonstrated in animal models using a stellate ganglion block. This program aims to investigate whether this effect can be replicated in humans.

Eligibility:

  • Diagnosis of Major Depressive Disorder
  • Have not adequately responded to a previous course of treatment for the Major Depressive Disorder such as pharmaceuticals, psychotherapy, or rTMS
  • Male or Female, aged 18-65 years old

Intervention Protocol:

This is a pilot study investigating a Stellate Ganglion Block, a new intervention for major depressive disorders. The first step of the procedure involves the infusion of a sedative agent (midazolam) to induce sleep if necessary. The second step will involve the injection of Lidocaine (a local anaesthetic) into the neck to reduce pain in the region.

The third step will involve the injection of an investigational anaesthetic medication called SENSORCAINE® (5 mg/mL) using ultrasound guidance.

This procedure will take less than 30 minutes, plus 60 minutes of recovery time.

Associated Publications:

Local Injection for Treating Mood Disorders (LIFT-MOOD): A Pilot Feasiblity RCT of Stellate Ganglion Block for Treatment Resistant Depression

Sustained Mood Improvement with Laughing gas Exposure: A Randomized Controlled Pilot Trial. (SMILE Trial) – Sub-Study Protocol to include Neuroimaging

Overview:

The purpose of this sub-study is to provide a better understanding of the changes in the brain’s activity in response to nitrous oxide (N2O), also known as laughing gas, in patients with Major Depressive Disorder (MDD). Brain Scans, known as Magnetic Resonance Imaging (MRI), of patients with MDD have revealed changes in the structure and function of the brain compared to that of healthy people. While many studies commonly include MRI scans alongside interventions proposed to reduce depression symptoms, the imaging performed in this sub-study will specifically allow for the identification of changes in the brain’s structure and blood flow linked to N2O intervention.

Eligibility

Inclusion Criteria: 

  • Eligible for main nitrous oxide (SMILE) study: 
    • Diagnosis of Major Depressive Disorder 
    • Have not seen results following a previous course of treatment for the Major Depressive Disorder such as pharmaceuticals, psychotherapy, or rTMS
    • Male or Female, aged 18-65 years old

 Exclusion criteria:

  • Ineligible for main nitrous oxide study:
    • Contraindication for undergoing MRI scans (e.g., hip circumference larger than 180 cm or metal in the body)

Treatment description (ClinicalTrials.gov Identifier: NCT05528718):

  • Participation in the sub-study will last a total of 4 weeks.  
  • As a part of this sub-study, you will receive 2 fMRI scans in addition to your nitrous oxide or placebo intervention visits, one before the first visit and another after the last.  
  • Participants will be asked to come to the St Michael’s Hospital for the MRI scans twice in total. The other study assessments will be completed on the phone.