One of the mysteries about depression is that it's not that tractable to pharmacological therapy. So if you look at people who suffer with depression, about a third of people see significant benefit from modern SSRI and related antidepressant drugs. About a third see very tiny benefit and about a third see no benefit at all.

And part of the reason is because maybe our term depression is too big a bucket. Depression is actually many different biological disorders and only a subset of those are helped by SSRIs and will need different therapies for the other ones. That's certainly part of it. But part of it might actually have to do with inflammation.

So if you think that inflammation is a risk factor in depression, well, you could do something very simple, right? You could gobble an ibuprofen, right? There's a whole bunch of anti-inflammatory drugs that are very well understood. And so, well, what if you just say, all right, you know, let's have a study where we have a bunch of depressed people and we have them all eat anti-inflammatory drugs for a few weeks and we see if this relieves their depression.

And the answer seems to be no, it doesn't. Well, and that's a little bit hard to understand because there are definitely links between inflammation and depression. So for example, one of the early treatments for hepatitis C that's since been superseded by more modern drugs was a pro-inflammatory cytokine molecule.

And when you gave it to people to treat their hepatitis C, almost everyone became depressed on this drug. So you say, oh, well, this really seems like a link. Likewise, there are certain neurological diseases like multiple sclerosis. It turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous.

And you might think, well, there's a trivial reason for that. If you're paralyzed from MS, you're bummed out about life. And that's the reason. But if you look at people who have spinal cord injuries from accidents, they actually have major depression at a rate from people who are uninjured.

So that doesn't seem to be it. It's not just that you're bummed out from being paralyzed, although of course it's reasonable to be bummed out about being paralyzed. But that's not it. So what happens in MS? Well, there's a bunch of cytokines, including one called interleukin-6, IL-6. That's elevated massively if you take a spinal tap and you look at cerebral spinal fluid.

And so that could be causative for depression. So all these real reasons to think that inflammation is involved. But yet the idea is still a little messy. So now what if instead of looking at the general population of depressed people, you look at the subset of people that don't respond to SSRI antidepressants?

Are they helped by anti-inflammatories? And there's a bit of a hint that maybe they are. It's not definitive yet. There are a couple of studies. It's right on the edge. But I think this is a really good example of how we are going to see progress very soon in the body-to-mind part of mind-body medicine that is going to be of enormous benefit to people.

So interesting. Could I get your thoughts on one candidate hypothesis that I've been thinking about? I've covered depression on a few episodes. And I've had Robin Carter-Harris from UCSF and Dr. Matthew Johnson from your very own Johns Hopkins University, both of whom run laboratories studying psychedelics for the treatment of depression.

The clinical trials on psilocybin. And to be clear, psilocybin is still illegal. It's been decriminalized a few places. But we're not talking about recreational use. We're talking about several therapy sessions without psilocybin, then 2.5 gram approximately dosages of psilocybin given separately, again, with therapists present, and then follow-up therapy sessions seem to lead to relief of depression in approximately somewhere between 65% and 80% of people, in some cases total remission, in some cases some relief without remission.

OK. So we can set that result on the shelf. It's been repeated a number of different times. Compare that to the results of SSRIs, which seem to help a third of people, a third minimally, and a third not at all. And of course, there's the side effect profiles of the SSRIs and associated drugs, not just the SSRIs, but buprenorphine and the other antidepressants that are taken in prescription drug form.

And then there's this inflammation piece. So could we hypothesize that relief from depression has something to do with neuroplasticity, rewiring of neural circuits, and that psilocybin, we know, can encourage neuroplasticity, and that perhaps SSRIs can encourage neuroplasticity in some people, not all, and that inflammation is a barrier to neuroplasticity?

To me, this is the only thing that can reconcile the current status of the results. And then there's ketamine-based therapies, and so we have to also kind of set that on the shelf. But let's set that aside on the shelf for now to keep it simple. It seems to me that based on the time course over which SSRIs work, the fact that they increase serotonin very quickly, but the relief from depression comes much later, the fact that neuromodulators like serotonin are intimately involved in neuroplasticity, they can in some cases gate neuroplasticity, that it all centers back to changing neural circuits.

And so what we're really trying to do, whether or not it's transcranial magnetic stimulation, or now we can throw ketamine in there, or psilocybin, or SSRIs, that treating depression is about rewiring the brain. It's not about chemical A or B per se, although serotonin seems involved. To me, what I'd love to see are more studies about the interaction between neuroplasticity and inflammation.

And are we seeing that kind of work out there? And because these results sort of sit as disparate, somewhat conflicting, but it seems like inflammation is anti-neuroplasticity, and broadly speaking here. I realize there are many interleukins, there are many, some of which are inflammatory, some of which are anti-inflammatory, but is that a meaningful hypothesis?

Do you think there's any hope whatsoever to actually cure depression if we sort of start to unify the results in these different camps? Yeah, I think it's a completely reasonable hypothesis, and I would be broader. And I would say, honestly, the relief of any neuropsychiatric condition ultimately is from neuroplasticity in some form or another.

And I think it's worthwhile to step back a bit and talk about what neuroplasticity means. To date, there has been a focus on synapses, on the contacts between neurons as the site of neuroplasticity, and that's warranted. Neurons are plastic, they change as a result of experience, as a result of hormone changes, as a result of exercise, as a result of lots of things.

But synapses are not the be-all and end-all of neural function. So, for example, neurons work by sending electrical signals along their lengths and between neurons and interconverting those with chemical signals. And the processes of generating those electrical signals, the ion channels that are involved, that are embedded in membranes, that are involved in that, are also plastic.

They can also change as a result of experience. That's what we call intrinsic plasticity as opposed to synaptic plasticity. In addition, there are literal morphological changes. So when we talk about the wiring of the brain, sometimes we're talking about literal wiring, like cell A wasn't connected to cell B and now it is, and that changes.

And then sometimes, well, actually cell A was connected to cell B, but cell B wasn't responsive enough, and now there's a change in cell B, so now cell A can fire cell B. And that could have been a result of a change in its synapse, making it more receptive to neurotransmitter release from cell A, or it could be something intrinsic in cell A that makes it fire its electrical signal, its spike, more easily.

I think that one of the key cell types that's going to be important for your hypothesis linking inflammation to synaptic plasticity is going to be a cell called a microglial cell. And microglial cells are non-neuronal cells in the brain that are motile. They can crawl around, they have long processes, and they can gobble things up.

They can literally sort of chew away and digest bits of the extracellular scaffolding that surrounds neurons and synapses and thereby renders them plastic. They can destroy synapses, and there is a lot of indication that certain disease states may involve over-exuberant microglia pruning synapses to a degree that they shouldn't.

And we know that microglia are chock full of cytokine receptors, and so are responsive to inflammatory signals. When we're talking about inflammation and we're talking about drugs, it's worthwhile to mention that there are a lot of behavioral things that also can influence the signaling. So we know, and I know you've discussed on your program, the incredibly salubrious effects of physical exercise on mental function.

So exercise is about as good an antidepressant as SSRIs are, and the side effects are only good side effects as opposed to the bad side effects of SSRIs. And again, this isn't working through some airy, fairy realm. The reason that exercise works to relieve depression and the reason that exercise works to maintain your cognitive function as you age is because of biological pathways that we are now uncovering, some of which will involve microglial cells and neurons and other types of cells in the brains, some of which will involve not the neurons in the brain at all, but the brain's vasculature.

So we know that exercise is very salubrious for keeping blood flowing to the brain. And when you're young, you have a super abundance of blood flowing to your brain. So it doesn't matter if it's reduced transiently, you're fine. But as you get older, your blood vessels become more occluded and less elastic, and you're closer to the trouble spot.

And if you exercise regularly, you can dilate and make your blood vessels, including those in your brain, more elastic. And that is almost certainly protective against both depression and cognitive decline as we age.