Introducing the brain: cause and treatment of depression (Introduction)

by David Turell , Monday, May 27, 2024, 20:01 (178 days ago) @ David Turell

Interview with a psychiatrist/neuropharmacist:

https://www.quantamagazine.org/what-happens-in-the-brain-to-cause-depression-20240523/

"One of the great misconceptions about brain chemistry is that the brain is dominated by norepinephrine and serotonin. Together, norepinephrine and serotonin account for just a few percentage of the synapses in the brain. And the great majority, the great information highway of the brain, accounting for more than 90% of the synapses of the brain, are nerve cells that use a different chemical called glutamate to communicate.

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"The main neurotransmitter of these glutamate neurons is glutamate, serotonin, serotonin, GABA, GABA. So we’ll use that convention.

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"And the more we learn about brain function, the more the main information highway of the brain, the glutamate system, and the main inhibitory tuning mechanism of the brain for glutamate… Glutamate is excitatory, and its effects are balanced by another chemical called GABA, which is the main inhibitory transmitter of the brain. And so the great balancing act within the brain is usually managed mostly by the interplay of GABA for inhibition and glutamate for excitation.

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"But those neurons, their activity is actually tightly tuned in terms of the magnitude of their activation and the timing of their activation by inhibition. So the brain generates information through excitation, but is tuned and becomes functional through inhibition.

"Without GABA, the brain would be like a noisy TV set or radio, where you would hear all the background noise and it would be hard to figure out what the signal was. But the right balance between excitation and inhibition gives us a nice, clear information signal in the brain.

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"...And it turns out in depression those signal to noise properties become compromised in circuits involved in the regulation of mood, the anticipation of reward, in motivation and attention, and even, memory.

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"But it also happens in other kinds of cells. There are cells called glia that support the nerve functions. Glia mop up the glutamate that’s released and make sure that there’s not so much glutamate floating around that it becomes toxic to the nerve cells.

"There’s another kind of cell involved in the biology of depression, called microglia. Now microglia, that name sounds like they’re just tiny little glia, but that’s not exactly what they are.

"Microglia are the brain’s immune cells. And it turns out that a process in the body called inflammation, which gives you sore joints, which contributes to your asthma, which may increase your blood pressure, in the brain activates the microglia, creates inflammatory processes in the brain, which compromise the structure and function of nerve cells and contribute to depression risk.

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"KRYSTAL: A variety of stress hormones, they activate the microglia, and they in turn release pro-inflammatory substances like cytokines.

"But one of the things that we’ve learned about microglia that make them so interesting to me is they are involved in the cleanup in the brain. They are surrounding the synapses just like the other kinds of glia are. And they can be involved in the protection of synapses, they can release nerve growth factors, or when they’re immunologically activated, they eliminate synapses.

"...And people who have moderate to severe depression show reductions in various parts of the brain in synaptic density, which tells us that these synapses are being eliminated.

"...we now have some very preliminary positron emission tomography data that suggests that single doses of ketamine can regrow these synapses in depressed patients.

"What’s interesting is that a single dose of ketamine in a healthy person does not increase the density of synapses. A single dose of ketamine, though, regrows lost synapses. I like to think of it as a sign that this drug recruits resilience mechanisms intrinsic to the brain to restore normal brain structure and normal brain function as well.

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"You realize, the brain is not static. It’s incredibly, unbelievably plastic. And it raises really fundamental ideas that it’s not just depression that we want to treat by harnessing neuroplasticity, but there are opportunities to treat other disorders that we don’t treat as effectively as we should.

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"...in depression we have evidence of at least three different kinds of pathology related to the glutamate synapse. One, the synaptic elimination that I mentioned earlier. Two, the synapses are not as functional, they’re less effective. And three, the glutamate that’s released is not handled very effectively because of the compromise of the glia and other factors.

"And it seems that ketamine addresses all three of these forms of glutamate pathology: regrowing synapses, restoring synaptic effectiveness, and compensating for glutamate receptor overstimulation.

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"We have effective treatments. We have ketamine, we have S-ketamine, we have electroconvulsive therapy, we have new forms of transcranial magnetic stimulation. We will soon have psilocybin for depression."

Comment: Krystal continues to extoll the drug advances. But we have learned a lot about the brain's neurophysiology involved with specific hormones. Not by chance.