It's a long read, but my short version would be this: "Depression is a mode where the brain underweighs evidence from new experiences in favor of pre-existing negative prior assumptions."
I like to say that the brain is very good at adjusting to adversity, but apparently very bad at adjusting to it's absence. I've heard that people who went through the Great Depression (unrelated :-), tended to spend the rest of their lives hording supplies.
> brain underweighs evidence from new experiences in favor of pre-existing [...] prior assumptions.
Isn't this what brains do typically, outside of depression?
I omitted the word "negative" from the quote as that part I don't think is universal. It still seems a somewhat limited modifier in modelling depression.
The linked article's paragraph on "lumping together depression and trauma" also seems to accidentally expand on this conflation. I understand the causes of depression are likely numerous, so natural tendencies of those not prone to depression can't be ruled out as contributory factors, but I'm not sure I see an argument there for their being significant.
What drugs are best at extinguishing those negative priors? Vorinostat worked for me when a slew of antidepressants did not, but it's hard to find and can have side effects. It was really astounding. I just felt normal, unafraid, but not in a weird amped up way as with Adderall. I could just talk to people fluidly and think normally.
Antidepressants aren't just used for depression, they're also used to treat a spectrum of anxiety disorders like OCD and panic disorder, although the doses used to treat anxiety disorders are much higher than those used for depression. I don't think the BDNF-related hypothesis explains the efficacy of antidepressants in treating anxiety disorders, but I could be wrong.
Under the maladaptive neuroplasticity theory which motivates the BDNF connection, I think anxiety could be taken into account naturally: just as depression is a maladaptive persistent overlearned estimate of the world as threatening, unrewarding, and pointless, which persists despite regular experiences which should falsify those beliefs and lead to learning (but doesn't), anxiety is persistent overestimation of risks which persist despite regular experiences of dangerous risks not happening which should lead to learning (but doesn't). So if boosts to neuroplasticity can help a depressive learn that life doesn't suck, it makes sense if boosts could also help an anxious person learn that life isn't so dangerous.
A perfect show of how little is know about the effect of those drugs:
>they're also used to treat a spectrum of anxiety disorders like OCD and panic disorder
A massive amount of people treated for depression have panic disorder because of these drugs, so they can treat or induce the same thing in different people.
This doesn't really seem to address how they work, in two fundamental ways:
1) We've had a good idea of the pharmacokinetics for a little while. All this research does is enhance that knowledge and take it one level deeper. Essentially, we've just gone one turtle lower in the pile of turtles standing on backs.
2) No theory of how antidepressants work will complete until we also understand why they so often do not work for many people.
Trying to find how ADs work is like injecting a small piece of machine code to a running computer system and trying to find out what changes are produced. Its clinical effects are like the effects on the GUI.
There are many abstraction levels in the process and mostly we have to make large jumps over them.
Discl: I am a doctor specialized, among others, in adult psychiatry
While I appreciate the intention, I think it's a bad analogy.
Can you think of a small piece of machine code that you could inject into arbitrary computers that would produce useful effects in some significant proportion of the computer population? (Don't think so...)
Computers and biological systems are so wildly different. Although perhaps you'd find better analogies comparing brains to machine learning systems. Eg. "Trying to find out how ADs work is like applying some simple numerical transformation on some particular part of a deep neural network and trying to find out what changes are produced".
Oddly enough.. I think ML researchers often do find little "tricks" that improve the performance of neural nets without being able to fully grasp how or why. It's somewhat similar to how we use and understand ADs.
I have a feeling SSRIs work for a reason we would never expect. In fact, I have a feeling nearly all mental disorders work according to rules we do not even imagine now. It seems to me medical psychology has some great analogies to 1320s science, and the only answers that will come will be after my death.
There is an effective, rigorous school of psychology called Neurolinguistic Programming but it's got a bad rep in scientific/academic circles (the Wikipedia entry calls it out as pseudoscience.)
FWIW I was cured of a chronic, crushing depression in a single session that lasted no more than ten minutes or so. (I don't know exactly how long it was because I was in a deep trance. Subjectively it was only a few moments.)
Nuplazid seems to have a pretty clear theory of what it is doing.
It's an anti-psychotic that is currently targeted at Parkinson's disease related psychosis; hallucinations and delusions are fairly common in people with Parkinson's disease.
So cholesterol plays a huge role! The brain is the fattiest organ, so it makes a lot of sense. That we haven't found a correlation between statins and depression is certainly a quandary though.
I wonder if our national obsession with anti-fat dietary advice has had an impact on depression's prevalence in our population. It would seem to make sense that if we depress people with low-fat frankenfoods they naturally react with lower physical activity levels.
I wonder if omega-3 / omega-6 dietary balance changes the structure of the cell membranes to make them less permeable. Greater omega-3 cell membrane composition certainly seems to have a real impact on retina cells and the overall function of the retina[1].
I’ve always understood the chemical imbalance description of depression (and other mental health conditions) to be a casual way of describing the conditions as being part of the person rather than a choice — and not a way to describe the internal mechanics of the conditions. I’ve found it effective when having conversations about mental health conditions: how would you describe depression without using that phrase, based on what this paper reveals?
"The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma.
In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus."
"Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate
(NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world."
Novel antidepressants now are NMDA receptor antagonists, or take a look at tianeptine which works just as well, yet it only affects your opioid receptors. None of which have to do with the monoamine hypothesis.
Forgive my ignorance, but what alternative is there to a chemical imbalance of some sort? Structural differences? I have schizoaffective bipolar subtype, and wouldn't mind some links to more current literature, I'm obviously very behind.
That theory makes as much sense as the theory that "chemical imbalances" (i.e. low-alcohol) cause social anxiety.
Alcohols are produced in your brain naturally and adding more changes behavior. Clinical trials show that more alcohol increases sociability compared to placebos (but with side effects). There are some concerns about giving alcohol to three year olds, but it is better that they become socialized at a young age than deal with the consequences for life.
I am not a neuro anything, but has that been the a big debate in the antidepressant discussion long? The low level of serotonin? Is that a fallacy or an i missing something?
We have new insight now into how antidepressants interface with specific signaling molecules, making them more effectively permeate the neuron cell membrane.
It's still about chemical balance. It's a highly complex system involving more than serotonin, though.
He mentions serotonin reuptake inhibitors once, but it looks like this finding applies to other substances identified as anti-depressants that aren't necessarily serotonin targeting.
Not really, it’s just proposing a different chemical imbalance than the “monoamine hypothesis” (i.e. serotonin, etc.). That one has already been disfavored for the past few decades, due to a lot of findings that it has trouble explaining. In particular the discovery of effective antidepressants that don’t affect the monoamine receptors enough or in sufficiently similar ways.
To my knowledge the idea that depression is a result of low serotonin has not been accepted by the scientific community at any time; immediately after SSRIs were shown to have an effect lots of people assumed that serotonin was important, but reuptake inhibition wouldn't even treat low levels overall, let alone matching the super weird timing effects.
That associates statin use with depression, not cholesterol. That’s a huge difference. Those results (which are not an RCT) could easily be explained by those that are less depressed are more likely to seek any non-psychiatric outside medical treatment.
First: cholesterols are a family of molecules, like alcohols, not just one thing.
Second: statins inhibit cholesterols so while it is associated, it's good to mention that cholesterols are anti-depressive, which is something anyone with any university bio education will know.
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Sometimes I try to think in more philosophically terms about the word "disease".
It's often said depression is natural, and it only becomes a problem because of sedentary lifestyle.
Diseases are bad, but when you dig, nature doesn't work in term of good or bad. I think it's difficult to really know at what point depression becomes problematic, since doctors have a hard time making a good diagnostic. Brains are complicated.
For the cognitive aspect of depression a nice comprehensive and dense video I found is [0], key factors in slide at 24:10 and the reasons for this approach are at a slide at 23:00 including why a medication only approach is intractable in the long term.
I am not a biologist by any stretch, but I will try.
A common mechanism of action may have been found across antidepressants where none was found before. This common mechanism between both Prozac and Ketamine has some impacts on how cholesterol is used in the brain and BDNF (neuron survival and growth regulator).
[+] [-] mcherm|5 years ago|reply
[+] [-] linsomniac|5 years ago|reply
[+] [-] thinkingkong|5 years ago|reply
[+] [-] hyperpallium2|5 years ago|reply
[+] [-] mahathu|5 years ago|reply
[+] [-] lucideer|5 years ago|reply
Isn't this what brains do typically, outside of depression?
I omitted the word "negative" from the quote as that part I don't think is universal. It still seems a somewhat limited modifier in modelling depression.
The linked article's paragraph on "lumping together depression and trauma" also seems to accidentally expand on this conflation. I understand the causes of depression are likely numerous, so natural tendencies of those not prone to depression can't be ruled out as contributory factors, but I'm not sure I see an argument there for their being significant.
[+] [-] kekebo|5 years ago|reply
[0] https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que...
[1] https://www.youtube.com/watch?v=NOAgplgTxfc
[+] [-] prionassembly|5 years ago|reply
[+] [-] starpilot|5 years ago|reply
[+] [-] heavyset_go|5 years ago|reply
[+] [-] gwern|5 years ago|reply
[+] [-] unknown|5 years ago|reply
[deleted]
[+] [-] Daho0n|5 years ago|reply
>they're also used to treat a spectrum of anxiety disorders like OCD and panic disorder
A massive amount of people treated for depression have panic disorder because of these drugs, so they can treat or induce the same thing in different people.
[+] [-] doggodaddo78|5 years ago|reply
[+] [-] ineedasername|5 years ago|reply
1) We've had a good idea of the pharmacokinetics for a little while. All this research does is enhance that knowledge and take it one level deeper. Essentially, we've just gone one turtle lower in the pile of turtles standing on backs.
2) No theory of how antidepressants work will complete until we also understand why they so often do not work for many people.
[+] [-] tsoukase|5 years ago|reply
There are many abstraction levels in the process and mostly we have to make large jumps over them.
Discl: I am a doctor specialized, among others, in adult psychiatry
[+] [-] Xenograph|5 years ago|reply
Can you think of a small piece of machine code that you could inject into arbitrary computers that would produce useful effects in some significant proportion of the computer population? (Don't think so...)
Computers and biological systems are so wildly different. Although perhaps you'd find better analogies comparing brains to machine learning systems. Eg. "Trying to find out how ADs work is like applying some simple numerical transformation on some particular part of a deep neural network and trying to find out what changes are produced".
Oddly enough.. I think ML researchers often do find little "tricks" that improve the performance of neural nets without being able to fully grasp how or why. It's somewhat similar to how we use and understand ADs.
[+] [-] dj_mc_merlin|5 years ago|reply
[+] [-] carapace|5 years ago|reply
FWIW I was cured of a chronic, crushing depression in a single session that lasted no more than ten minutes or so. (I don't know exactly how long it was because I was in a deep trance. Subjectively it was only a few moments.)
[+] [-] spurgu|5 years ago|reply
[+] [-] maxerickson|5 years ago|reply
It's an anti-psychotic that is currently targeted at Parkinson's disease related psychosis; hallucinations and delusions are fairly common in people with Parkinson's disease.
[+] [-] omegaworks|5 years ago|reply
I wonder if our national obsession with anti-fat dietary advice has had an impact on depression's prevalence in our population. It would seem to make sense that if we depress people with low-fat frankenfoods they naturally react with lower physical activity levels.
I wonder if omega-3 / omega-6 dietary balance changes the structure of the cell membranes to make them less permeable. Greater omega-3 cell membrane composition certainly seems to have a real impact on retina cells and the overall function of the retina[1].
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174995/
[+] [-] mckirk|5 years ago|reply
[+] [-] refurb|5 years ago|reply
[+] [-] m00x|5 years ago|reply
[+] [-] anaphor|5 years ago|reply
[+] [-] vegannet|5 years ago|reply
[+] [-] hammock|5 years ago|reply
[+] [-] johnisgood|5 years ago|reply
"Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world."
Novel antidepressants now are NMDA receptor antagonists, or take a look at tianeptine which works just as well, yet it only affects your opioid receptors. None of which have to do with the monoamine hypothesis.
[+] [-] sekh60|5 years ago|reply
[+] [-] konjin|5 years ago|reply
Alcohols are produced in your brain naturally and adding more changes behavior. Clinical trials show that more alcohol increases sociability compared to placebos (but with side effects). There are some concerns about giving alcohol to three year olds, but it is better that they become socialized at a young age than deal with the consequences for life.
In short: science + tons of money = not science.
[+] [-] danielovichdk|5 years ago|reply
[+] [-] omegaworks|5 years ago|reply
It's still about chemical balance. It's a highly complex system involving more than serotonin, though.
He mentions serotonin reuptake inhibitors once, but it looks like this finding applies to other substances identified as anti-depressants that aren't necessarily serotonin targeting.
[+] [-] johncolanduoni|5 years ago|reply
[+] [-] ravi-delia|5 years ago|reply
[+] [-] meowface|5 years ago|reply
[+] [-] sjg007|5 years ago|reply
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606915/
[+] [-] momszack|5 years ago|reply
[+] [-] m00x|5 years ago|reply
Second: statins inhibit cholesterols so while it is associated, it's good to mention that cholesterols are anti-depressive, which is something anyone with any university bio education will know.
[+] [-] doggodaddo78|5 years ago|reply
[+] [-] Estheryacine|5 years ago|reply
[+] [-] hexxiiiz|5 years ago|reply
While this primarily has to do with psychedelics, they address depression as well in the above.
[+] [-] jokoon|5 years ago|reply
It's often said depression is natural, and it only becomes a problem because of sedentary lifestyle.
Diseases are bad, but when you dig, nature doesn't work in term of good or bad. I think it's difficult to really know at what point depression becomes problematic, since doctors have a hard time making a good diagnostic. Brains are complicated.
[+] [-] antman|5 years ago|reply
[0]: https://youtu.be/TVgQ_tgWMyU
[+] [-] justinboogaard|5 years ago|reply
[+] [-] hinkley|5 years ago|reply
Sorry what was that? You're breaking up. I'm off to the store, ttyl.
[+] [-] mastrsushi|5 years ago|reply
[deleted]
[+] [-] loceng|5 years ago|reply
[+] [-] Nbox9|5 years ago|reply
A common mechanism of action may have been found across antidepressants where none was found before. This common mechanism between both Prozac and Ketamine has some impacts on how cholesterol is used in the brain and BDNF (neuron survival and growth regulator).
[+] [-] andrewflnr|5 years ago|reply