Edward Kaftarian:
Perhaps we should talk about the hypothalamic-pituitary axis.

Andrew Penn:
Yeah, sure, sure.

Edward Kaftarian:
Again, something hard to say on the spot. But yeah, any thoughts on that? I mean, cortisol and depression are obviously very linked.

Andrew Penn:
Yeah, how do you approach that clinically with your patients? I mean, are you drawing labs? Are you monitoring cortisol?

Edward Kaftarian:
I think a lot of people do. I happen to not do that as much. I should, but cortisol is really important, especially for some variants of depression. When you have an overactivity of cortisol that affects early morning awakening, early morning mood, it really has an effect on anhedonia, psychomotor retardation. It also affects your appetite and causes weight loss, fatigue. So, cortisol is so essential. It's essential, but it's not intended to be in these huge amounts. So, when the adrenal cortex pumps this out in people with depression, it really messes you up. And so, I believe with anhedonia, ketamine is something that really helps with that, doesn't it?

Andrew Penn:
Yes, absolutely. Yeah. Which a lot of our existing monoaminergic antidepressants don't. I mean, one of the complaints we hear a lot from people on SSRIs, for example, is that, "I don't feel depressed, but I don't feel much of anything. I don't feel pleasure."

Edward Kaftarian:
That's a big problem.

Andrew Penn:
Yeah. "I don't feel sexual pleasure. I just don't feel depressed, but I don't feel much of anything."

Edward Kaftarian:
And isn't that something that causes a lack of adherence too. They say, "Well, I don't want to be a zombie."

Andrew Penn: Exactly.

Edward Kaftarian: Right.

Andrew Penn:
Exactly. Yeah. No, I think that's one of the main reasons why people stop taking medications, is because they don't feel like themselves. If the goal is to restore people back to their baseline, to feeling like themselves, then not feeling depressed is great; but you want to have all the other pleasures of life as well.

Edward Kaftarian:
And then it really gives psychiatry a bad name. If people are going around talking about, "Well, yeah, I'm not depressed, but they took away my identity."

Andrew Penn:
Exactly.

Edward Kaftarian:
And that's not what we're trying to do.

Andrew Penn:
No. No, of course not. And I can imagine, I don't know, DSM seven or something like that, looking way down the pipeline here, and imagining that we could have... Because it would be great if we could actually start to describe diseases on more than just a phenotype; because all we do right now is we describe things. And as it's been pointed out, that there's so many different combinations of those nine criteria in the MDD diagnosis alone. There's something like 200 different permutations that you could have just of MDD, and we all call them the same disease. But what if we had a diagnosis that was depressive phenotype with elevated inflammatory markers? Where we actually had some specificity about some of the pathology that's happening with the disease. And it may not necessarily be biological, or maybe major depressive episode with significant life stressors, or something like that. But having more specificity, that maybe then could guide our treatment.

Edward Kaftarian:
So that nosological approach of categorizing things, and diagnosing things based on observing the symptoms, that's helpful; but that's not the whole story, I think what you're saying. And when you're talking about neurotropic mechanisms, inflammatory mechanisms, excitatory mechanisms, on top of the monoamine paradigm too, these are all areas that can be examined on their own to show how those phenotypes are expressed. So, you could have a very different type of depression based on what's going on in your body, and that can have... So those epigenetics of somebody has a really negative experience in life. PTSD, for example, anxiety through the roof, and that expresses the gene differently; and that can cause an inflammation, and then that causes a unique type of depression. So, is that what you're getting at?

Andrew Penn:
Yeah. I mean, just really being able to understand the phenomenology of depression. We can describe it
just fine. The DSM is full of descriptions, but because it stays atheoretical, it doesn't offer any kind of
guidance as far as the ideology of it.

Edward Kaftarian:
It's like a bird manual. You look out there and you see a bird that has blue feathers, and you say, "Oh,
that's a..." I don't know birds. Like warbler or something like that. But-

Andrew Penn:
One thing, if infectious disease was where psychiatry is now, we would've just called that disease from the last two years, a cough and tired disease, and sometimes die disease. Right? Because we could identify the pathogen, and clearly identify the response to that pathogen that we could call it COVID, right? But at this stage, it's sort of calling it a cough. When we see somebody who's tearful and anhedonic, we say that person is depressed. When we see somebody who is feeling really flat and anxious, we say they have depression. Those seem like different diseases to me, just from the outside looking in.

Edward Kaftarian:
And I think, going back to what you were saying about it's not a lack of serotonin, depression, I think
should be really thought of in a different way. So it should be thought of as an expression of genes, epigenetics of genes, development, and also degeneration. So it's how your brain was growing and then
how these brain cells started to degenerate and to have difficulty. You even see it in the cell itself. So in
the cells, you have these telomeres and they're shorter in depression, and so you actually see physical effects of depression. But then these DSM diagnoses, the majority of them, you can see it happening in youth, in adolescence. You can see these signs and symptoms of most of the DSM diagnosis that they're there. So, they're there in the beginning, but then depending on your life experience, they're expressed a certain way. And then as you grow older, you have this degeneration. You have the aging process, and that also has an effect. So, we can really look from the beginning to the end and start to track why these things are happening. It's not just a chemical imbalance.

Andrew Penn:
No, absolutely not. And of course, also layering on socioeconomic determinants of health into that too.
That many of those stressors are external things such as poverty, and racism, and all the things that we've been really starting to grapple with in the last few years. And really appreciating that our mental health does not exist in isolation.

Edward Kaftarian:
In a vacuum.

Andrew Penn:
If anything that we've learned from the last couple of years of isolation in the pandemic, is that we really
are in this together. And what affects me, also affects you. So, these larger issues that exist in our culture, or our society, have an effect on the individual and their mental health.

Edward Kaftarian:
Absolutely.

Andrew Penn:
So, these are bigger public health targets to start to look at, of how do we begin to affect those... Can we
alter those conditions to improve mental health?

Edward Kaftarian:
So, it's a responsibility beyond just the formula of which medications. It's not just a laboratory experiment here of give a little bit of this, and a little bit of that.

Andrew Penn:
Absolutely.

Edward Kaftarian:
It's more a holistic, really got to... And when we say holistic, we really mean it. I mean, it's addressing these social determinants. So, bringing it all home here, where do we go from here? Where should our focus be?

Andrew Penn:
I think it's all the above. In multiple choice tests, I always like that option is the 'all the above.' It kind of
appealed to my indecision.

Edward Kaftarian:
C.

Andrew Penn:
C, all the above, right?

Edward Kaftarian:
C-reactive protein

Andrew Penn:
C-reactive protein. And I don't think we have to choose one, or the other. That we can look at these more subtle manipulations in the biology of depression. And at the same time, we can also look at things like people have to have ready access to housing, and food, and purpose; and to be out of poverty. That those things aren't mutually exclusive. And that really, as a profession, we can be advocating for all those things, knowing that they have significant impact on people's wellbeing and mental health.

Edward Kaftarian:
I agree. Well stated.

Andrew Penn:
Thank you. Thanks, Ed. Really good talking with you.

Edward Kaftarian:
Yeah, very nice to talk to you Andrew.