Glutamate moves like a ship between neurons. The sea it sails is called the synapse, the shore it departs from is the presynaptic neuron, and the destination, on the synapse’s far side, is the postsynaptic neuron. Another component, called a glial cell, works to remove glutamate ships from the synapse and recycle them. The glutamate system is affected at each of these points by stress hormones: They push the first neuron to send more ships, interfere with the glial cell’s recycling, and block the docks on the distant shore. All of these changes increase the number of glutamate ships left in the synapse, flooding the cell with aberrant signals. Indeed, depressed people’s brains, or at least animal models of depression, show all three of these problems, leading to long-lasting excesses of glutamate in key portions of the brain.
This superabundance of glutamate makes a neuron fire sooner than it should and triggers a cascade of signals inside the cell, damaging its structure. Glutamate binds to the neuron and allows in a flood of positively charged particles, including calcium, which are vital to making a neuron fire. But in excess, calcium activates enzymes that break down the neuron. Each neuron has tree-like branches, called dendrites, which are used to communicate with other neurons. When overdosed in glutamate, this canopy of branches shrinks, like a plant doused with herbicide. First the “twigs,” called spines, disappear. After prolonged stress, whole branches recede.
This harmful process, called excitotoxicity, is thought to be involved in bipolar disorder, depression, epilepsy, and neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s. In depressed brains, many areas are shrunken and underactive, including part of the prefrontal cortex and the hippocampus. The brain changes that cause mood disorders, Sanacora and his colleagues believe, come in part from chronic stress overexciting neurons with glutamate
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The mood drugs in wide use now focus on modulatory neurotransmitters like serotonin. Ketamine, however, works directly on glutamate signaling. If ketamine is tapping into the root of the problem, this might explain why it works faster, better, and more often than more popular antidepressants.
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Even so, we do know that ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.
