Edward Kaftarian:
And we might have new markers to show improvement. There's some interesting data on adenylyl cyclase, which is found in platelets. And in depression, the protein that adenylyl cyclase creates gets stuck in some sort of cholesterol matrix. And what happens is... I think I said the opposite way, but the protein that creates the adenylyl cyclase... Sorry, the other way around.

Andrew Penn:
I'm just impressed you can pronounce it.

Edward Kaftarian:
I know. How am I going to pronounce this? Adenylyl cyclase. The protein that creates adenylyl cyclase gets stuck in a cholesterol matrix in depression, and then your level of adenylyl cyclase is low. So, if you have some of these medications, you can potentially check levels of adenylyl cyclase before and after treatment...

Andrew Penn:
To see if they...

Edward Kaftarian:
To see if it's actually working.

Andrew Penn:
... If you're actually getting the desired biological effect.

Edward Kaftarian:
Exactly. And then the amount of that effect. So where

Andrew Penn:
Ah, it's quantifiable.

Edward Kaftarian:
Quantifiable. So, we're entering into really exciting time because we haven't had lab tests. That's the whole thing about psychiatry. We never had lab tests.

Andrew Penn:
Right. Which is what leads some people to erroneously assume we're some kind of fictional profession.
That the things that we treat aren't real because they're not measurable on a serum level, or on an MRI.

Edward Kaftarian: Right.

Andrew Penn:
It's, of course, a specious argument; but really, to be able to have those biological markers... We were talking earlier about CRP as a predictor for antidepressant response. That people with higher CRPs, greater than one, tend to respond better to noradrenergic agents like, bupropion and nortriptyline. Whereas people who are depressed, and not inflamed, often respond better to serotonergic agents. That's a really simple test that I can order along with my TSH and my CBC. And all the things I'm going to get anyways for a patient when I'm starting treatment, and helps me guide treatment, which is really something we haven't had in psychiatry.

Edward Kaftarian:
And again, repurposing what we have for mental health, which is great. And I'm glad that you brought up the
inflammatory mechanisms of depression, because that's really important too. So, we're talking about stress causing an inflammation and that you see react to protein. You also see cytokine problems.

Andrew Penn:
Interleukin 6 and interleukin 1.

Edward Kaftarian:
1 and 6 being the pro-inflammatory interleukins. And then you have interleukin 10, which is an anti inflammatory one. So, it's really that there is a problem with homeostasis of those interleukins. So when people say depression is a brain disease, we ain't lying here.

Andrew Penn:
No, that's true.

Edward Kaftarian:
It's really a brain disease.

Andrew Penn:
I mean, it's a brain disease. It's also a whole person disease too. And it's interesting to me seeing things such as exercise, meditation, social interaction, all having anti-inflammatory effects. And this is something we've seen with our colleagues, Rakesh and Saundra Jain, with their WILD 5 program; that they've seen evidence of anti-inflammatory effects when people are able to do these changes in their behaviors. So it's a both/and, which is really exciting. And we don't need to have this sort of artificial schism between psychotherapy and psychopharmacology because really, we're treating the same person, right?

Edward Kaftarian:
Psychotherapy has a direct impact on all of these cellular and biological mechanisms.

Andrew Penn:
That's right.

Edward Kaftarian:
And you mentioned diet, exercise. I mean, that's huge. We already talked about how BDNF with intermittent fasting can be affected. Also, exercise can induce higher levels of that. And then we have, in people with diabetes, we have higher rates of depression; and there is an insulin mechanism. There's a metabolic... Obviously diabetes is a metabolic disease; and you have higher incidence in bipolar disorder and depression with metabolic disease. And so, what we're seeing is that in this metabolic situation, the brain in depressed people with metabolic disease operates much slower. And the thinking is that these circuits, that are involved in thinking. These circuits, they turn on and off. So it's sort of like when you're in front of a computer and you have all these windows open. You move from one window to another. Your attention is focused on one thing, then the next thing. And people that don't have depression don't have as difficult time trying to go between those things.

Andrew Penn:
That's right.

Edward Kaftarian:
When one circuit turns on it, there's a suppression of another circuit.

Andrew Penn:
Right.

Edward Kaftarian:
But with depression, you have these circuits firing, and then it makes it harder for one circuit to really focus on what you're trying to do. So that affects cognition, that affects emotion. And when you have diet and exercise involved, and you're metabolically sound, you're able to go from one circuit to another without being overwhelmed.

Andrew Penn:
Yeah. And one of the things that we're finding in the psychedelic work is... So I think you're talking about the relationship between the task-positive network and the default mode network.

Edward Kaftarian:
That's it.

Andrew Penn:
And so people with depression often have an overactive default mode network. And it's sort of like two ends of a seesaw. Task-positive network, which you need in order to deal with things that are outside of your head

Edward Kaftarian:
Serial sevens and things like that.

Andrew Penn:
Yeah. Anything that's outside of your head. I mean, even just answering emails requires your task-positive network to come onboard. But that's like the opposite side of a seesaw from your default mode network. So normally in, you were talking about it in a healthy brain, we can switch back and forth between those two networks. But when you have depression, it's like when you're a kid on the playground, and the big kid sat on the bottom of the seesaw and won't let you get down. So, your default mode network is so dominant,
that you can't shift that attention to outside of your own head. And one of the things we're finding with say, psilocybin, is that it turns down all this activity in the brain. And when it comes back online after the drug wears off, that default mode network is less dominant. And so, people have that ability to switch back and forth between those two networks, which is a really intriguing finding. And then the question becomes, well, how do we sustain that? And so, some of the things that you were talking about, perhaps maybe once a person is less depressed and can start to make some of those lifestyle changes, which maybe before they were unable to do, they can then maintain these gains that they've had.

Edward Kaftarian:
When you mention psychedelics, it's just so profound the possibilities. Our brain is about 5% of our matter, of our weight, and it takes about 25% of our energy

Andrew Penn:
And causes about 99% of our problems, right?

Edward Kaftarian:
Exactly. In people with depression, that energy, it consumes so much more energy than average. And so, you feel for people with depression because they're struggling not just about their mood, but their energy level.

Andrew Penn:
Right.