Ketamine Infusions May Help in Suicidal Emergencies
Intravenous ketamine has consistently been found to bring about almost immediate antidepressant effects (usually within two or three hours), which can last three to five days in duration. Typical doses are 0.5 mg/kg IV infusion over 40 minutes. A new abstract presented at the meeting of the American College of Emergency Physicians in 2010 indicated that when patients received 0.2 mg/kg ketamine infused over a period of 1-2 minutes, suicidal ideation decreased within 40 minutes. Fourteen of 15 subjects were no longer suicidal after the infusion, and in 13 of those 14 the improvement was sustained at follow-up ten days later.
Editor’s note: Such rapidly occurring, robust antidepressant/antisuicidal effects from IV ketamine continue to suggest that it is useful for emergency room therapeutic maneuvers.
An article by L.I. Lee et al. published in Science in 2010 suggested that an intracellular pathway involving the enzyme mTOR is critical to the acute antidepressant actions of ketamine in animal system models. If this pathway is blocked with drugs acting at ERK, PI3K or AKT (enzymes and kinases that form part of a signal transduction pathway leading from neurotrophic receptors to the nucleus), the effects of ketamine do not occur (L.I. Lee et al., Science, 2010).
In an animal model of chronic unpredictable stress, a variety of biochemical and micro-anatomical changes are observed when animals demonstrate depressive-like behavior. Chronic unpredictable stress is associated with reductions in all of the following: numbers of synapses, amounts of post-synaptic density 95 protein, gluR1 subunits in the glutamate receptor, and dendritic spine density in glutamate-containing pyramidal cells. This atrophy could result in decreased synaptic function and could also affect memory and behavior. Ketamine not only reverses these deficits in pyramidal cell dendritic spine density (particularly in layer 1 of the cortex), but it also increases synthesis of brain-derived neurotrophic factor (BDNF).
The data by Lee et al. are particularly remarkable because they demonstrate that an acute ketamine infusion can actually reverse some of the micro-structural changes associated with an animal model of depression (i.e. chronic unpredictable stress). It is not known whether the same positive effects on dendritic spines occur in humans, but it is likely given the remarkable acute onset of antidepressant and antisuicidal effects when people receive ketamine infusions. Now a key objective is to determine the best methods for sustaining the acute onset effects achieved with IV ketamine for a longer term.
Ketamine blocks the glutamate N-methyl-D-aspartate (NMDA) receptor, through which calcium flows, and which is necessary for many different types of long-term synaptic plasticity, including long-term potentiation, a molecular model of long-term memory. Ketamine’s ability to block NMDA receptors is probably at least partially responsible for its acute onset antidepressant effects, because two pharmaceutical companies have found that compounds that block the NR2B subunit of the NMDA receptor are also associated with acute onset antidepressant effects. In addition, the anti-Alzheimer’s drug memantine (Namenda), which blocks the NMDA receptor, has been reported to augment and accelerate the acute antidepressant effects of lamotrigine. It appears that blocking the NMDA receptor is a new target of therapeutics that may yield new antidepressant treatments with rapid onset of action.
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