Neural Correlates of Ketamine's Anti-suicidal Effects in Bipolar Depression

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. Sub-anesthetic doses of ketamine administered intravenously (IV) have shown to produce rapid antidepressant and ant-suicidal effects. Despite this important clinical finding, our understanding of ketamine's neurophysiological mechanism of action for suicidality remains limited. This clinical trial is an open label pilot study that aims to address this limitation by studying the effects of IV ketamine on patients with bipolar depression who are currently experiencing suicidal thoughts. Using a combination of Transcranial Magnetic Stimulation (TMS) neurophysiological tools with electromyography (EMG) and electroencephalography (EEG), this trial aims to explore ketamine's action on NMDA neurotransmission to understand ketamine's anti-suicidal effects. Investigating the impact of ketamine on cortical excitation, cortical inhibition, and resting-state cortical oscillation could provide insight into the role of NMDA receptors in cortical physiology and determine potential predictors of clinical response for suicidality in bipolar depression. Objective 1: To examine the effect of a series of therapeutic IV ketamine 40-min infusions on neurophysiological markers linked with cortical excitation and inhibition (as indexed via TMS-EMG and TMS-EEG, as a proxy of NMDA-receptor activity in the cortex) Hypothesis 1: Ketamine will increase intracortical facilitation - a neurophysiological measure of NMDA neurotransmission Objective 2: To examine the effect of ketamine IV 40-min infusions in sub-anesthetic doses on acute suicidality in patients with BD Hypothesis 2: Ketamine infusions will result in improvement of suicidality in BD Objective 3: To examine the safety and tolerability of ketamine IV 40-min infusions in sub-anesthetic doses and its effect on depressive symptoms in patients with BD Hypothesis 3: 1. Ketamine infusions will be safe and well tolerated 2. Ketamine infusions will result in improvement of depressive mood symptoms in BD Objective 4: To examine the effect of ketamine IV 40-min infusions in sub-anesthetic on additional neurophysiological measures and on changes in quality of life measures Hypothesis 4: 1. Ketamine will decrease cortical inhibitory measures as indexed by (SICI) paradigms 2. Ketamine will increase cortical excitation measures as indexed by TMS-evoked potential waveform amplitude 3. Ketamine infusions will result in improvement in quality of life measures