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.

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

Inclusion Criteria:

1. Individuals with a diagnosis of non-psychotic MDD as confirmed by the Mini-International Neuropsychiatric Interview (MINI)

2. Individuals meeting criteria for Ultra Resistant Major Depressive Disorder (URD) in current episode

   URD is defined as:

   1. those who received at least eight convulsive therapy treatment sessions and did not respond, or
   2. those who were not able to tolerate convulsive therapy

3. Individuals scoring 14 and above on the Hamilton Rating Scale for Depression-24 Items (HRSD-24)

4. Individuals capable to provide consent who are receiving care as outpatients

Exclusion Criteria:

1. Individuals with history of substance use disorder (i.e. dependence or abuse) within the past month; and lifetime history of ketamine substance use disorder as confirmed by the MINI
2. Concomitant major unstable medical illness such as poorly controlled high blood pressure or patients diagnosed with enlarged prostate or reporting any other urinary related issues
3. Pregnancy or the intention to become pregnant and breastfeeding during the study as confirmed by self-report. Female participants of reproductive potential must be willing to use a medically acceptable method of birth control which include highly effective (e.g. approved hormonal contraceptives, intrauterine device, tubal ligation) or double barrier (e.g. male condom with diaphragm, male condom with cervical cap) methods of contraception or abstinence if that is the usual and preferred lifestyle of the participant
4. Presence of cardiac decompensation/heart failure v)
5. Diagnosis of any primary psychotic disorder, bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder (current) as confirmed by the MINI
6. Diagnosis of severe personality disorder as assessed during the initial consultation with a physician at the Temerty Centre prior to study entry
7. Any significant neurological disorder (e.g., a space occupying brain lesion, a history of stroke, a cerebral aneurysm, a seizure disorder, Parkinson's disease, Huntington's chorea, multiple sclerosis) as assessed through medical history review during the initial consultation with a physician at the Temerty Centre prior to study entry
8. Individuals presenting with a medical condition, a medication, or a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator
9. Individuals requiring a benzodiazepine with a dose equivalent to lorazepam 2 mg/day or higher; being on any anticonvulsant(e.g. Lamotrigine) and/or opioid medication due to the potential of these medications to limit the efficacy of ketamine
10. Individuals unable to communicate in spoken and written English fluently enough to complete the required study assessments due to a language barrier or a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete clinical assessments)
11. Individuals with cognitive or physical impairment which may potentially interfere with IN ketamine administration and subject's ability to stay in the same place for a 2-hr monitoring supervision as assessed through medical history review during the initial consultation with a physician at the Temerty Centre prior to study entry
12. Any intracranial implant (e.g., aneurysm clips, shunts, cochlear implants) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed given that we will be using TMS-EMG/EEG
13. Those unable to secure escort to accompany them back home after ketamine sessions will also be excluded from this study
14. Any known allergy to the study medication or any component/ingredient of the ketamine preparation