When I first saw Victoria in the clinic waiting room, she struck me as familiar, like one of my friend's mom's from when I was a kid in the suburbs -- slightly distracted-looking, well put-together. Up close, she looked more tired. 

"I've gone to therapists and psychiatrists ever since I was probably 15 years old," she says. "It works maybe when I'm there and they tell me positive things. But after I leave there, it just escapes my mind and it's just like I'm back to square one." 

Victoria has the kind of depression that's often called treatment-resistant. It's gotten so bad she's had to go on disability.  She's been unable to keep up a job.

"I was always a workaholic, always good attendance, always a hard worker," she says. "But mentally, I just went into a bad state."

Victoria's not her real name, we're using it to protect her privacy. She's taking part in a study at the University of Pittsburgh Medical Center with professor of psychiatry Greg Siegle.

"Fifty percent of people respond to therapy, and 50 percent of people respond to medication, they're not necessarily the same 50 percent," Siegle says. He's been working on more focused therapies for people with depression like Victoria's.

"Every other medical specialty, we give you a test," he says, "and based on the test we give you a treatment. In psychiatry we just don't do the tests. Part of the problem has traditionally been that we don't know what to test. We don't know the mechanisms or how disorders work well enough to do a test. We're just starting to learn this."

Matt Rudorfer heads the psychopharmacology and somatics treatment program at the National Institute of Mental Health. He says we're still not even sure what depression is. Being able to diagnose a patient with depression doesn't necessarily bring us any closer to knowing how to treat them.

"It is simply not that kind of one-to-one relationship as, say, taking an antibiotic to attack a specific bacteria which has been identified in the laboratory," he explains.

He says a good treatment would probably only have to act in one particular area of the brain-- "But (A) we don't know what that area is and (B) even if we did, we have no way of directing the medication there."

Helen Mayberg is one of the pioneers of this search for a location. She's a neurologist at Emory University. She says in the past, researchers have gotten too hung up on thinking depression is all about chemical imbalances.

"The brain is not a bowl of soup and you add the chemical and you stir," she says. "Chemicals work within networks, within systems, within pathways. And where in the brain a chemical may be working is as important as knowing what chemical you should use."

She found that the people with really severe depression, the kind that just wouldn't go away after other treatments, seemed to have overactivity in the part of their cingulate cortex called Brodmann Area 25, that's a couple inches behind the bridge of your nose. It's an area of the brain that monitors negative emotion.

And when she did deep brain stimulation of that area, basically turning down its activity, the connected areas seemed to be able to function more normally. Most of her patients who didn't get better from anything else, felt better when they kept doing the deep brain stimulation.

She also uses brain scans to compare depressed people who get better with drugs, and those who got better with therapy.

"People that did or did not get better on drugs looked different from each other," she says. "People who did or did not get better on therapy, look different from each other. And then, the ultimate test is that people who respond to therapy have very different brain scans than people who respond to drugs."

And they looked different, of course, in specific parts of their cingulate cortex.

Greg Siegle, back at University of Pittsburgh Medical Center, has also been focused on Brodmann Area 25. Depressed people who have a hard time in cognitive therapy, they seem to have extra activity there, in that area that monitors negative emotion.

"So if you're sitting around constantly monitoring emotion, you might not be best candidate for intervention that says let's break away from that monitoring and do something about the thought," he says.

He says what he thinks it really comes down to, is an attention issue. These people are too caught up in their own negative thoughts (he calls them ruminations) to pay enough attention to therapy.

During Victoria's test session, he explains to me a possible way around that. His lab was looking for a way that they could still get the attention of someone really caught up in depression.

"And it turns out, just about anybody can get annoyed," he says, so the idea was, "let's capitalize on that."

How they do this is by putting tiny electrodes on the inside of people like Victoria's wrist. And they have her ruminate.

As his lab workers adjust Victoria's electrodes, he explains the trial to me. "So in this intervention, we pass a weak current through the wrist, which kind of itches a little bit; it's a little bit annoying," he says. "And we see if they can pay attention to it. And if they can't, we can turn up the voltage so it's a little more annoying. And then they're good at paying attention.

"We are hacking their attention. And when they can pay attention to the current at that higher voltage, we'll turn it down. We'll keep turning it down till it's a tiny crumb of sensation. And when can pay attention to that, then we've really hacked it, we've rebooted it."

The idea is that after five sessions of this, and five should be enough, they should be better able to pay attention to things in the real world that they want to. Like their therapy sessions.

"Your brain is not a closed immutable system," Siegle says. "Your brain can be changed, and we can hack that."

Other researchers are trying to do this sort of thing by seeing whether we can test genetically what drugs will work for depression patients, or whether a simple questionnaire can tell if you'll be responsive to therapy. And then adjust a person's treatments accordingly.

Victoria met with Greg Siegle in his office after her test session was over.

"How was that?" he asks her.

"It just helps me when I'm ruminating about that thought to realize that there's something going on outside of my thinking," she tells him.

It will take more time, and therapy sessions, to know if Siegle's intervention really improved her receptivity to therapy. But she says that feeling of having control over her ruminations, that's what she needs.

As Victoria was getting ready to leave, I remembered to ask for one more biographical detail.

"Do you mind if I say how old you are?" I ask her.

"No, I don't mind," she says, "I'm 45 years old. Yeah. I still feel like I'm 18, I still feel like I haven't grown up but anyways," she laughs.

I didn't really respond when she said this, I figured she meant she still felt young at heart, it's something a lot of people say. The interview seemed over, and I thanked her.

"Oh no problem," she says. "And I don't know if you want to add this, it's just, because of my negative thinking from when I was so young, I wouldn't try to better myself, and just kept thinking that I'm a bad person. And since I was always running away from feelings, it kind of kept me stuck at mentally being at a younger age than I actually am. So I don't know if that makes sense, but a lot of times I just feel like I'm 18 years old because I'm actually starting to grow as a person."

She says even though her depression's been treatment-resistant, she feels better that she's working at ways to fix that, like being in Greg Siegle's study.

"Because I'm actually, like, dealing with everyday life instead of running away from it," she says.

Siegle says if the intervention with the electrical impulses proves successful, it's something patients with depression could soon be able to do in their own homes. The study has a few more years to go.