JMIR Publications

ABSTRACT

Background:

Major Depressive Disorder is among the four most disabling illnesses worldwide with a lifetime prevalence estimated at 16.2%. Research suggests 20-40% of patients with depression do not respond to pharmacotherapy developing treatment resistant depression (TRD) [2]. Electroconvulsive therapy (ECT) is the gold standard therapeutic approach for ECT, and ECT-non responders represent a rising public health concern with an urgent need to develop effective treatment interventions. Ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert rapid antidepressant effects in patients with TRD when administered in sub-anesthetic doses through 40-min intravenous (IV) infusions. Recently, a ketamine compound, esketamine (Spravato®), administered through intranasal (IN) route received regulatory approval by FDA and Health Canada in treatment of depression. However, esketamine is difficult to access for most patients with severe depression due to significant costs and limited availability. IN racemic ketamine (rketamine) is cheap and easy to access; however, the effects in ECT-non responders have yet to be evaluated.

Objective:

This open label clinical trial aims to test the safety, clinical and neurophysiological effects of IN rketamine in patients with major depressive disorder who did not respond to ECT.

Methods:

Eight sessions of IN rketamine will be administered twice per week to participants enrolled in the trial will (1) result in a change in depressive symptoms; (2) will be safe and well tolerated; (3) result in neurophysiological changes which may indicate biomarkers of response. We will recruit 25 adults (18-65 yr) with TRD over the period of two years from an academic psychiatric hospital in Toronto, ON, Canada. All enrolled will be treated with sub-anesthetic (0.5-0.8 mg/kg) dose of IN rketamine twice per week for eight sessions with close monitoring on-site for 2-hr post-administration.

Results:

A protocol for IN rketamine use in ECT-non responders has been developed and piloted by this group of investigators in three patients, where intervention was well tolerated and patients adhered to the protocol. This study has been approved by the research ethics board (REB), received funding, and approved by the Health Canada. Study initiation is scheduled for Sep 2021, with recruitment to commence October 2021. The first results are expected to be submitted for publication in mid-2022.

Conclusions:

This is the first study to test repeated doses of IN rketamine in patients with major depressive disorder who failed a course of ECT. Findings of this study may provide an alternative option for individuals not responding to ECT where limited choices are available; as well as determine potential neurophysiological markers of clinical response, and provide preliminary data for larger well-controlled randomized clinical trial. Clinical Trial: Trial will be registered in an appropriate registry before participant enrollment.