system
Given the following post, respond as if you're commenting on Reddit:
human
ELI5 How does depression become treatment resistant?

I've been diagnosed for a while now with treatment resistant depression because various medications and treatments have had limited to no effect on my symptoms.

I'm curious to know how that occurs and why some instances of depression become more difficult to treat than others.
gpt
To start, we don't *truly* understand what causes depression. We have really good theories that are working a lot better than what we knew even a decade ago, but this is still a thing we're learning a lot about. So part of it is the best doctors will admit our treatments are probably primitive and bad compared to what we'll have 50 years from now.

But we do know that sometimes depression is a chemical imbalance. And often, that's caused by physiological problems. Hormones and other chemicals have a big impact on your mood and behavior, that's part of nature's design. For early man and even most animals, the process of finding food and eating it releases "good" chemicals and part of why we're motivated to bother is to get those chemicals. Modern people don't hunt like that, but still we get releases of "good" chemicals when we do well at our jobs or accomplish other things.

For some people, the parts of the body that produce those chemicals don't work right. Or, the mechanisms in the brain that are supposed to signal their release don't work right. Or, the receptors in the brain that are supposed to feel happy when the chemical is present don't work right. So those people do the thing that's supposed to make them happy and... get nothing. Over time, that makes it harder to decide to do the thing. That's one kind of depression.

Sometimes we can correct that with medicine. The medicine might stimulate the things that make the chemical, or simulate the chemical, or correct the receptors that don't notice the chemical. The goal is to get the person's "do thing, get reward" system working like normal so they feel like doing things and living their life. 

But the brain's tricky. It doesn't want you to get SO HAPPY about one thing that you never do anything else. So if it feels like it's in a state where there's too much "happy chemical" around, it starts to adjust itself to either produce less or ignore some of the receptors. Its goal is to motivate you to go find different things to do (probably "hunt a different animal so you don't overhunt"), so it tries to make it harder to get a thrill from whatever the thing you overindulged in was.

But what if THAT is the system that's broken? What if any time you start feeling normally happy about your accomplishments, your brain overreacts and makes it harder to get happy? Then you'd maybe see some small benefits from medicines, but you'd quickly fall back into depression. That's "treatment-resistant" depression. Or at least what we understand about it. 

Fixing that's tough. It's probably something wrong with the brain, but that's not something we've learned how to really "repair" with that level of detail yet. So the best we can do is offer counseling and hope you have a support network of friends. :(