There are lots of different models of depression. One of them is sickness behavior, i.e. the way that you act when your immune system is fighting off particularly foul bacteria or viruses. Symptoms of sickness behavior include anhedonia, anorexia, fever, sleep changes, and decreased social interaction. In depression that looks like sickness behavior, presumably, your body's immune response is over-active for some reason to the detriment of other mental and behavioral faculties.
What causes sickness behavior? Dysregulation of inflammatory cytokines maybe.
What's that? Your body produces both inflammatory cytokines and anti-inflammatory cytokines. They fight each other a bit. When there's an infection in your body, inflammatory cytokines cause local inflammation, like swelling and redness, and pain, and elevated temperature of the body part. If a bacterial colony colonizes a person's body, the person can have low-grade peripheral inflammation all the time without obvious redness or swelling. The same immune processes are still going on. in the blood and tissues, involving cytokines and lots of other chemicals that have longs names full of numbers.
People with depression that looks like sickness behavior generally don't have swollen, red, infected body parts, so why are inflammatory cytokines relevant to depression? In addition to peripheral inflammation, there's also central inflammation: neuroinflammation.
Neuroinflammation? Isn't the brain immunologically privileged? Isn't there a barrier of immuno-competent cells (astrocytes and endothelial cells) surrounding the brain and preventing infectious agents from crossing into the cerebrospinal fluid via the blood? Yes, and there are like a hundred guesses about how neuro-inflammation happens despite the blood-brain barrier, and honestly, a bunch of them might be right. The main thing to know is that it's not the infectious agents that are passing over the blood-brain barrier, it's the inflammatory cytokines (and other chemicals that are downstream of cytokines in chemical reaction pathways) that get into the brain. Or they at least trigger the brain to produce its own cytokines.
Why does this matter again? Because acute administration of inflammatory cytokines in healthy people produces sickness behavior: anhedonia, anorexia, fever, sleep changes, and decreased social interaction. Also, cytokines are found at elevated levels in people with some types of depression, like depression with anhedonia, anorexia, fever, sleep changes, and decreased social interaction. There's a consensus that those sickness behaviors are adaptations of the immune system. How they are all individually adaptive, I don't know. The consensus is that jointly they help a sick person to conserve energy and allocate internal resources to either combat infection or to repair tissues that have been damaged by injuries. And maybe they help you to limit contact with other people? I think I've heard that too.
So cytokines = sickness behavior = depression? No, not all depression is thought to involve cytokines: post-partum depression and depression which follows drug withdrawal, for example, are thought not to involve elevated inflammatory cytokines in the brain or the blood. But if you're depressed and your depression doesn't look like those, then yeah, maybe. Maybe the topic of inflammatory cytokines is worth some of your attention.
What does neuroinflammation even mean? Is it redness and swelling in the brain, or is it the low-level kind of inflammation that isn't necessarily visible? As near as I can tell, neuroinflammation does not involve swelling in the brain, at least not in the normal case where infectious agents haven't crossed the blood-brain barrier. The normal non-infectious version of neuroinflammation is just a continuation of the production of chemicals like cytokines and their less easily pronounced relatives, but now in the brain. In the brain, those chemicals do different things than in the rest of the body. Fevers, as a component of sickness behavior, are the result of cytokines acting on the hypothalamus. The other symptoms of sickness behavior (anhedonia, anorexia, sleep changes, and decreased social interaction) aren't as well linked to the action of cytokines on brain regions, so far as I know, but I don't know much. Less behaviorally direct, lots of things are known about how the chronic production of cytokines in the brain messes up other chemical processes, like the production of neurotransmitters and neural growth factors. I keep saying just "cytokines", but it's the inflammatory ones specifically.
So these chemicals are important for immune function, but their chronic production has bad effects, and they're found in elevated levels in people with some kinds of chronic neuropathology: especially depression that looks like being sick, without the swelling, but also other pathologies like multiple sclerosis.
What can be done about it? Probably we first want to figure out why it's there in the first place: why is there is a background level of inflammatory response? That would be the ideal things to treat. I don't know enough about that. We could call it inflammatory cytokine dysregulation for short. Other than figuring out why it's happening, we could also just treat the symptoms: anti-inflammatories are the treatment for inflammation, and these are generally NSAIDs or anti-cytokines.
I don't know much of anything about anti-cytokines, or cytokine inhibitors, except that they increase the risk of infections, which makes sense, given that they're suppressing an immune response.
There is mixed-to-positive support in drug trials for the antidepressant effect of non-steroidal anti-inflammatory drugs, NSAIDS, generally usually used in conjunction with regular anti-depressants that directly target neurotransmitter production. NSAIDs are a drug class that includes aspirin and ibuprofen among others. They target chemicals called COX1 or COX2, which I think are like downstream messengers of cytokines, but don't trust me on that. I've heard that selective-COX2 inhibitors do much better as anti-inflammatories and anti-depressants than other NSAIDs. Celebrex is a COX2-selective NSAID. It's mainly advertised and indicated for arthritis. I don't know whether aspirin hits COX1 or COX2 or both, but you shouldn't be taking it in large regular doses for depression, even though it seems like a cheap readily available solution to inflammation. It's got all sorts of terrible side effects, not limited to intestinal bleeding. Also, if taking lots of aspirin could fix a big class of depression, wouldn't people have figured that out by now? They would have. For every analgesic on the market, there are already people taking unsafe amounts, and they would have figured it out.
But it's interesting, right? Inflammatory cytokines: not yet a target of any depression treatment, but maybe one day.
Glucocorticoids and Hippocampal Neurodegeneration
:: Chronic Cortisol Damages The Hippocampus
Stress increases glucocorticoids in the brain (cortisol in humans, corticosterone in rodents). Long exposure neurodegenerative effects include mitochondrial dysfunction, cell atrophy & death, and hyperphosphorylation of cytoskeletal Tau protein (which is important for dendrite remodeling). No, I don't know what those words mean either. So chronic levels of cortisol in the brain can cause cellular damage, and they are known to do particular damage to cells in the hippocampus. Where does cortisol come from? When is it produced?
:: Serotonin Increases Cortisol Via The PVN
When there is an elevated level of serotonin in the cerebrospinal fluid around the hypothalamus (a midbrain structure) and in particular, the paraventricular nucleus of the hypothalamus, somehow that causes the production of glucocorticoids (cortisol) in the adrenal cortex by the kidneys. Weird right? That's super far away from the hypothalamus. But that's the pathway. Where did that elevated serotonin come from? In the brain, serotonin is mostly produced in the Raphe Nuclei in the brain stem, and no one really knows why or when. Maybe serotonin production is increased in response to stress, like threats or physical over-exertion or starvation or I don't know what else. It's as good an answer as any. Regardless of what starts the chain, the rest of the chain goes Serotonin -> PVN of Thalamus -> Adrenal Cortex -> Cortisol. It's a dynamically simple pathway as I've sketched it: more of this, more of that. Let's talk about the root of the pathway - serotonin - and how serotonin-selective reuptake inhibitors (SSRIS) alter serotonin levels.
:: Acute use of SSRIs Increases Serotonin while Chronic use of SSRIs Decreases Serotonin
Elevated serotonin, not underproduction, seems to be the bigger problem of mood disorders, although we're really bad at measuring it in the CNS. Acute (=short term) administration of SSRIs makes serotonin levels higher and worse. If elevated serotonin is associated with mood disorders, and short term administration of antidepressant SSRIs increases serotonin, shouldn't SSRIs make mood disorders worse when you first start taking them? They don't, so far as I know: the usual short-term response to SSRI antidepressants is no change for a few weeks, and then things start to improve. We imagine that after chronic (=long term) administration of SSRIs, some compensatory mechanisms in the brain must reduce serotonin levels. That is the predominant theory. I don't know what compensatory mechanism that might be. I should read up on it. There's another thing that gets worse during short term administration of SSRIs: short term administration of SSRIs interferes with the production of neural growth factors (little hormones which are especially important for healing cell damage in the hippocampus). Let's talk about them.
:: BDNF Counteracts Cortisol's Damage on The Hippocampus
BDNF is a peptide hormone which acts as a growth factor for neurons. Acute (= short term) administration of SSRIs like fluoxetine reduces BDNF. That's bad: it means that the brain can't heal as well when there's cell damage to the hippocampus following sustained exposure to cortisol. And what about long term use of SSRIs? Apparently, based on this, chronic (=long term) SSRI administration increases BDNF transcription. Nice! Biphasic differential transcription, huh? I don't fully know what those words mean in context, but that sounds cool.
:: All Together Now
Supposedly astrocytes synthesize BDNF, GDNF, and NGF. Maybe damage to astrocytes from cortisol is enough to explain the reduction in BDNF following acute administration of SSRIs. So the pathway would be acute (= short term) SSRIs -> higher serotonin -> PVN thalamus activation -> more cortisol production -> cell damage to astrocytes -> less synthesis of BDNF and other growth factors. And how might chronic (= long term) administration of SSRIs counteract hippocampal neurodegeneration? Well, perhaps chronic administration of SSRIs reduces hippocampal neurodegeneration by triggering the mysterious compensatory mechanism that eventually reduces serotonin, which eventually leads to less cortisol, which means astrocytes can produce growth factors and repair cell damage. In this model, it's like there's a threshold concentration of cerebrospinal serotonin required before the compensatory mechanisms trigger, and SSRIs cross that level. It's a guess anyway. Alternatively, that biphasic differential transcription thing in the link. Maybe that's the mechanism. I don't know. I just thought you might like to know what I read about tonight: glucocorticoids and hippocampal neurodegeneration.
Stress increases glucocorticoids in the brain (cortisol in humans, corticosterone in rodents). Long exposure neurodegenerative effects include mitochondrial dysfunction, cell atrophy & death, and hyperphosphorylation of cytoskeletal Tau protein (which is important for dendrite remodeling). No, I don't know what those words mean either. So chronic levels of cortisol in the brain can cause cellular damage, and they are known to do particular damage to cells in the hippocampus. Where does cortisol come from? When is it produced?
:: Serotonin Increases Cortisol Via The PVN
When there is an elevated level of serotonin in the cerebrospinal fluid around the hypothalamus (a midbrain structure) and in particular, the paraventricular nucleus of the hypothalamus, somehow that causes the production of glucocorticoids (cortisol) in the adrenal cortex by the kidneys. Weird right? That's super far away from the hypothalamus. But that's the pathway. Where did that elevated serotonin come from? In the brain, serotonin is mostly produced in the Raphe Nuclei in the brain stem, and no one really knows why or when. Maybe serotonin production is increased in response to stress, like threats or physical over-exertion or starvation or I don't know what else. It's as good an answer as any. Regardless of what starts the chain, the rest of the chain goes Serotonin -> PVN of Thalamus -> Adrenal Cortex -> Cortisol. It's a dynamically simple pathway as I've sketched it: more of this, more of that. Let's talk about the root of the pathway - serotonin - and how serotonin-selective reuptake inhibitors (SSRIS) alter serotonin levels.
:: Acute use of SSRIs Increases Serotonin while Chronic use of SSRIs Decreases Serotonin
Elevated serotonin, not underproduction, seems to be the bigger problem of mood disorders, although we're really bad at measuring it in the CNS. Acute (=short term) administration of SSRIs makes serotonin levels higher and worse. If elevated serotonin is associated with mood disorders, and short term administration of antidepressant SSRIs increases serotonin, shouldn't SSRIs make mood disorders worse when you first start taking them? They don't, so far as I know: the usual short-term response to SSRI antidepressants is no change for a few weeks, and then things start to improve. We imagine that after chronic (=long term) administration of SSRIs, some compensatory mechanisms in the brain must reduce serotonin levels. That is the predominant theory. I don't know what compensatory mechanism that might be. I should read up on it. There's another thing that gets worse during short term administration of SSRIs: short term administration of SSRIs interferes with the production of neural growth factors (little hormones which are especially important for healing cell damage in the hippocampus). Let's talk about them.
:: BDNF Counteracts Cortisol's Damage on The Hippocampus
BDNF is a peptide hormone which acts as a growth factor for neurons. Acute (= short term) administration of SSRIs like fluoxetine reduces BDNF. That's bad: it means that the brain can't heal as well when there's cell damage to the hippocampus following sustained exposure to cortisol. And what about long term use of SSRIs? Apparently, based on this, chronic (=long term) SSRI administration increases BDNF transcription. Nice! Biphasic differential transcription, huh? I don't fully know what those words mean in context, but that sounds cool.
:: All Together Now
Supposedly astrocytes synthesize BDNF, GDNF, and NGF. Maybe damage to astrocytes from cortisol is enough to explain the reduction in BDNF following acute administration of SSRIs. So the pathway would be acute (= short term) SSRIs -> higher serotonin -> PVN thalamus activation -> more cortisol production -> cell damage to astrocytes -> less synthesis of BDNF and other growth factors. And how might chronic (= long term) administration of SSRIs counteract hippocampal neurodegeneration? Well, perhaps chronic administration of SSRIs reduces hippocampal neurodegeneration by triggering the mysterious compensatory mechanism that eventually reduces serotonin, which eventually leads to less cortisol, which means astrocytes can produce growth factors and repair cell damage. In this model, it's like there's a threshold concentration of cerebrospinal serotonin required before the compensatory mechanisms trigger, and SSRIs cross that level. It's a guess anyway. Alternatively, that biphasic differential transcription thing in the link. Maybe that's the mechanism. I don't know. I just thought you might like to know what I read about tonight: glucocorticoids and hippocampal neurodegeneration.
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