The Complexities of Treating Depression | Dr. David Linden & Dr. Andrew Huberman

00:00:00.000 | One of the mysteries about depression is that it's not that tractable to pharmacological

00:00:11.900 | therapy.

00:00:12.900 | So if you look at people who suffer with depression, about a third of people see significant benefit

00:00:19.180 | from modern SSRI and related antidepressant drugs.

00:00:26.860 | About a third see very tiny benefit and about a third see no benefit at all.

00:00:32.900 | And part of the reason is because maybe our term depression is too big a bucket.

00:00:37.860 | Depression is actually many different biological disorders and only a subset of those are helped

00:00:44.220 | by SSRIs and will need different therapies for the other ones.

00:00:47.700 | That's certainly part of it.

00:00:49.560 | But part of it might actually have to do with inflammation.

00:00:53.020 | So if you think that inflammation is a risk factor in depression, well, you could do something

00:00:59.460 | very simple, right?

00:01:01.140 | You could gobble an ibuprofen, right?

00:01:04.140 | There's a whole bunch of anti-inflammatory drugs that are very well understood.

00:01:08.980 | And so, well, what if you just say, all right, you know, let's have a study where we have

00:01:13.340 | a bunch of depressed people and we have them all eat anti-inflammatory drugs for a few

00:01:17.580 | weeks and we see if this relieves their depression.

00:01:20.060 | And the answer seems to be no, it doesn't.

00:01:25.140 | Well, and that's a little bit hard to understand because there are definitely links between

00:01:32.220 | inflammation and depression.

00:01:33.620 | So for example, one of the early treatments for hepatitis C that's since been superseded

00:01:40.940 | by more modern drugs was a pro-inflammatory cytokine molecule.

00:01:46.980 | And when you gave it to people to treat their hepatitis C, almost everyone became depressed

00:01:51.620 | on this drug.

00:01:52.620 | So you say, oh, well, this really seems like a link.

00:01:57.860 | Likewise, there are certain neurological diseases like multiple sclerosis.

00:02:03.340 | It turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous.

00:02:10.220 | And you might think, well, there's a trivial reason for that.

00:02:12.780 | If you're paralyzed from MS, you're bummed out about life.

00:02:16.420 | And that's the reason.

00:02:17.420 | But if you look at people who have spinal cord injuries from accidents, they actually

00:02:21.620 | have major depression at a rate from people who are uninjured.

00:02:26.060 | So that doesn't seem to be it.

00:02:27.140 | It's not just that you're bummed out from being paralyzed, although of course it's reasonable

00:02:30.860 | to be bummed out about being paralyzed.

00:02:32.840 | But that's not it.

00:02:34.060 | So what happens in MS?

00:02:35.940 | Well, there's a bunch of cytokines, including one called interleukin-6, IL-6.

00:02:40.960 | That's elevated massively if you take a spinal tap and you look at cerebral spinal fluid.

00:02:46.840 | And so that could be causative for depression.

00:02:49.800 | So all these real reasons to think that inflammation is involved.

00:02:54.440 | But yet the idea is still a little messy.

00:02:56.440 | So now what if instead of looking at the general population of depressed people, you look at

00:03:01.240 | the subset of people that don't respond to SSRI antidepressants?

00:03:07.660 | Are they helped by anti-inflammatories?

00:03:11.260 | And there's a bit of a hint that maybe they are.

00:03:15.000 | It's not definitive yet.

00:03:16.000 | There are a couple of studies.

00:03:18.800 | It's right on the edge.

00:03:20.440 | But I think this is a really good example of how we are going to see progress very soon

00:03:28.840 | in the body-to-mind part of mind-body medicine that is going to be of enormous benefit to

00:03:39.080 | people.

00:03:40.760 | So interesting.

00:03:41.840 | Could I get your thoughts on one candidate hypothesis that I've been thinking about?

00:03:46.680 | I've covered depression on a few episodes.

00:03:49.320 | And I've had Robin Carter-Harris from UCSF and Dr. Matthew Johnson from your very own

00:03:56.240 | Johns Hopkins University, both of whom run laboratories studying psychedelics for the

00:04:00.600 | treatment of depression.

00:04:02.880 | The clinical trials on psilocybin.

00:04:06.920 | And to be clear, psilocybin is still illegal.

00:04:09.160 | It's been decriminalized a few places.

00:04:11.120 | But we're not talking about recreational use.

00:04:12.680 | We're talking about several therapy sessions without psilocybin, then 2.5 gram approximately

00:04:20.800 | dosages of psilocybin given separately, again, with therapists present, and then follow-up

00:04:25.120 | therapy sessions seem to lead to relief of depression in approximately somewhere between

00:04:30.640 | 65% and 80% of people, in some cases total remission, in some cases some relief without

00:04:37.320 | remission.

00:04:38.320 | OK.

00:04:39.320 | So we can set that result on the shelf.

00:04:41.160 | It's been repeated a number of different times.

00:04:44.360 | Compare that to the results of SSRIs, which seem to help a third of people, a third minimally,

00:04:49.800 | and a third not at all.

00:04:51.720 | And of course, there's the side effect profiles of the SSRIs and associated drugs, not just

00:04:55.680 | the SSRIs, but buprenorphine and the other antidepressants that are taken in prescription

00:04:59.680 | drug form.

00:05:00.800 | And then there's this inflammation piece.

00:05:03.780 | So could we hypothesize that relief from depression has something to do with neuroplasticity,

00:05:11.320 | rewiring of neural circuits, and that psilocybin, we know, can encourage neuroplasticity, and

00:05:19.800 | that perhaps SSRIs can encourage neuroplasticity in some people, not all, and that inflammation

00:05:27.320 | is a barrier to neuroplasticity?

00:05:30.780 | To me, this is the only thing that can reconcile the current status of the results.

00:05:35.640 | And then there's ketamine-based therapies, and so we have to also kind of set that on

00:05:38.640 | the shelf.

00:05:39.640 | But let's set that aside on the shelf for now to keep it simple.

00:05:43.280 | It seems to me that based on the time course over which SSRIs work, the fact that they

00:05:48.440 | increase serotonin very quickly, but the relief from depression comes much later, the fact

00:05:53.360 | that neuromodulators like serotonin are intimately involved in neuroplasticity, they can in some

00:05:57.920 | cases gate neuroplasticity, that it all centers back to changing neural circuits.

00:06:02.880 | And so what we're really trying to do, whether or not it's transcranial magnetic stimulation,

00:06:06.040 | or now we can throw ketamine in there, or psilocybin, or SSRIs, that treating depression

00:06:11.000 | is about rewiring the brain.

00:06:13.120 | It's not about chemical A or B per se, although serotonin seems involved.

00:06:18.760 | To me, what I'd love to see are more studies about the interaction between neuroplasticity

00:06:25.860 | and inflammation.

00:06:27.460 | And are we seeing that kind of work out there?

00:06:29.880 | And because these results sort of sit as disparate, somewhat conflicting, but it seems like inflammation

00:06:35.480 | is anti-neuroplasticity, and broadly speaking here.

00:06:39.280 | I realize there are many interleukins, there are many, some of which are inflammatory,

00:06:43.520 | some of which are anti-inflammatory, but is that a meaningful hypothesis?

00:06:48.160 | Do you think there's any hope whatsoever to actually cure depression if we sort of start

00:06:55.240 | to unify the results in these different camps?

00:06:59.760 | Yeah, I think it's a completely reasonable hypothesis, and I would be broader.

00:07:03.680 | And I would say, honestly, the relief of any neuropsychiatric condition ultimately is from

00:07:09.720 | neuroplasticity in some form or another.

00:07:12.400 | And I think it's worthwhile to step back a bit and talk about what neuroplasticity means.

00:07:19.240 | To date, there has been a focus on synapses, on the contacts between neurons as the site

00:07:27.000 | of neuroplasticity, and that's warranted.

00:07:31.360 | Neurons are plastic, they change as a result of experience, as a result of hormone changes,

00:07:36.800 | as a result of exercise, as a result of lots of things.

00:07:41.000 | But synapses are not the be-all and end-all of neural function.

00:07:45.400 | So, for example, neurons work by sending electrical signals along their lengths and between neurons

00:07:54.240 | and interconverting those with chemical signals.

00:07:57.280 | And the processes of generating those electrical signals, the ion channels that are involved,

00:08:03.660 | that are embedded in membranes, that are involved in that, are also plastic.

00:08:08.040 | They can also change as a result of experience.

00:08:11.480 | That's what we call intrinsic plasticity as opposed to synaptic plasticity.

00:08:17.080 | In addition, there are literal morphological changes.

00:08:20.960 | So when we talk about the wiring of the brain, sometimes we're talking about literal wiring,

00:08:27.120 | like cell A wasn't connected to cell B and now it is, and that changes.

00:08:31.720 | And then sometimes, well, actually cell A was connected to cell B, but cell B wasn't

00:08:36.120 | responsive enough, and now there's a change in cell B, so now cell A can fire cell B.

00:08:41.160 | And that could have been a result of a change in its synapse, making it more receptive to

00:08:45.320 | neurotransmitter release from cell A, or it could be something intrinsic in cell A that

00:08:49.600 | makes it fire its electrical signal, its spike, more easily.

00:08:54.680 | I think that one of the key cell types that's going to be important for your hypothesis

00:09:07.000 | linking inflammation to synaptic plasticity is going to be a cell called a microglial

00:09:13.840 | cell.

00:09:14.840 | And microglial cells are non-neuronal cells in the brain that are motile.

00:09:19.200 | They can crawl around, they have long processes, and they can gobble things up.

00:09:25.640 | They can literally sort of chew away and digest bits of the extracellular scaffolding that

00:09:32.800 | surrounds neurons and synapses and thereby renders them plastic.

00:09:37.880 | They can destroy synapses, and there is a lot of indication that certain disease states

00:09:44.240 | may involve over-exuberant microglia pruning synapses to a degree that they shouldn't.

00:09:52.600 | And we know that microglia are chock full of cytokine receptors, and so are responsive

00:10:01.720 | to inflammatory signals.

00:10:04.560 | When we're talking about inflammation and we're talking about drugs, it's worthwhile

00:10:09.080 | to mention that there are a lot of behavioral things that also can influence the signaling.

00:10:15.080 | So we know, and I know you've discussed on your program, the incredibly salubrious effects

00:10:21.080 | of physical exercise on mental function.

00:10:24.280 | So exercise is about as good an antidepressant as SSRIs are, and the side effects are only

00:10:32.520 | good side effects as opposed to the bad side effects of SSRIs.

00:10:37.560 | And again, this isn't working through some airy, fairy realm.

00:10:41.240 | The reason that exercise works to relieve depression and the reason that exercise works

00:10:46.760 | to maintain your cognitive function as you age is because of biological pathways that

00:10:53.960 | we are now uncovering, some of which will involve microglial cells and neurons and other

00:11:00.560 | types of cells in the brains, some of which will involve not the neurons in the brain

00:11:06.200 | at all, but the brain's vasculature.

00:11:08.760 | So we know that exercise is very salubrious for keeping blood flowing to the brain.

00:11:14.960 | And when you're young, you have a super abundance of blood flowing to your brain.

00:11:18.920 | So it doesn't matter if it's reduced transiently, you're fine.

00:11:23.440 | But as you get older, your blood vessels become more occluded and less elastic, and you're

00:11:30.160 | closer to the trouble spot.

00:11:34.880 | And if you exercise regularly, you can dilate and make your blood vessels, including those

00:11:40.960 | in your brain, more elastic.

00:11:42.880 | And that is almost certainly protective against both depression and cognitive decline as we

00:11:52.000 | age.

00:11:52.440 | [MUSIC PLAYING]

The Complexities of Treating Depression | Dr. David Linden & Dr. Andrew Huberman

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