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?
I'm not saying there isn't a biochemical component to depression (or any other mood disorders). The specific theory that I'm talking about is "low serotonin causes depression" (as in the proximate cause, not the ultimate cause). When SSRIs were first discovered to be useful for treating depression, one of the theories about why they worked was that they boosted levels of serotonin, but we know now that's not true. It doesn't mean it can't be explained in other ways (like the one this article discusses).
Also, if there is a behavioral component to depression as well, then it doesn't necessarily mean someone is to blame for their disorder. You don't control the environment you grow up in, which has an enormous impact even on traits that are highly heritable (the whole subject of heritability is very misunderstood anyway).
So basically if I were going to describe depression's cause, I'd say it's a mixture of biochemical reactions, behavioural traits, and environmental stresses that cause it.
A behavioral component manifests itself as a chemical process within the brain. So it may be used to explain the cause of certain chemical processes, but it's still the chemical processes that have to be dealt with. Though it doesn't necessarily follow that a chemical intervention is necessary: If the cause of the chemical change was behavioral, the solution might be as well, such in the form of various type of therapy.
In the article they discuss that known SSRIs weakly bind a different receptor which may be why they have an antidepressant effect. It would explain why more specific SSRIs that are thought to target serotonin receptors selectively do not work.
That they see a bunch of them doing the same thing is pretty convincing.
to quote:
"Now to the BDNF hypothesis. I used the phrase “unknown mechanism” above, and that’s exactly what this work may have cleared up. The authors show that when the TrkB protein forms a dimer in the cell membrane, a binding site for small molecules is formed at the interface. A whole list of known antidepressants (fluoxetine, imipramine, venlafaxine, moclobemide, ketamine, esketamine, and R,R-hydroxynorketamine) bind to this site at about 1 micromolar levels (and can displace each other in binding assays(, while a set of control CNS compounds like chlorpromazine, diphenhydramine, and indeed S,S-hydroxynorketamine do not. It will not be lost on those who’ve done research in the field that the antidepressant compounds listed above have been thought to work through completely different mechanisms. "
"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.
It used to be the case that the theory for why people have depression was "people who are depressed don't have enough serotonin" (in very simple terms), and the reason why SSRIs work was supposed to be that they increase levels of serotonin, but scientists have found that boosting levels of serotonin alone does not help with depression.
After a long battle with depression, this is how I interpret the phenomenon that "boosting" serotonin levels does not work.
SSRI's do not increase the pool of available serotonin, they just artificially increase the amount that remains in the synaptic cleft, facilitating additional firing of the neuron (or for a longer duration, I'm not sure which). They do not increase a neuron's ability to synthesize serotonin and release it into the synaptic cleft at the appropriate time. SSRI's cause our neurons to reuse serotonin longer than they normally would, which is not how we evolved to use serotonin.
The way this felt to me as a human interacting with the world around me was artificial happiness and artificial feelings of ease. I felt "better", but it didn't feel like it was grounded in anything real. I felt happy when happy things happened, but I also felt happy when sad things happened. Eventually it wore off and SSRI's no longer had any effect on me.
I eventually tried tryptophan and B vitamins (specifically B6), which our bodies use to synthesize serotonin. I got a similar effect to when I first started SSRI's, but it felt real. I was able to be happy when something happy happened. But when something sad happened I also felt sad. This effect has endured for 4 years now.
I have since found that I had a serious problem with a particular toxin which poisons many of the pathways involved with serotonin synthesis (among many many others including one of the most fundamental, the Citrate Cycle). A way around the poisoning is large doses of the appropriate nutrients. This is because the toxicity causes serious inefficiencies in their use by the body's biochemical pathways.
This was my personal experience. Depression is caused by many factors and I'm sure what works for me would not work for many. It can be genetic issues, other kinds of toxins, and overwhelming amount of trauma, chronic infections, unhealthy relationships, etc. Or a combination of those.
Sure. I usually don't bring it up unless asked because it is very controversial.
Chronic mercury toxicity was the cause. I've confirmed this diagnosis with dramatic improvement to chelation therapy. I've also done some novel testing that indirectly confirms the diagnosis. It's not something you can test for directly unless you start taking biopsies of tissues you wouldn't want to cut out of someone alive. It resides in "deeper" tissues, not in the blood. The effect of mercury on biochemical pathways has been mapped out quite extensively, and we even know what and why certain genes make some people more susceptible than others. Not something you'll find in mainstream medicine, but the research is extensive and still rapidly growing. Particularly in the toxicology and chemistry circles.
I use a newer chelator called emeramide. It's currently in Phase II clinical trials and will probably be approved within 10 years. Although, it can be very dangerous if someone takes a too large of a dose, and the person pushing it through FDA approval does not seem to be fully aware of how bad it can be. Generally, the sicker you are the lower the dose you need to start on. This phenomenon is extensively documented in the Facebook groups where mercury toxic people discuss their experiences and results.
Emeramide binds to mercury the strongest, but also chelates other toxic metals like lead and cadmium, so those could certainly be complicating factors. Especially lead, as I grew up in a home and neighborhood with lots of it.
As for where the mercury came from, the timeline of my symptoms, animal toxicology studies, and it's removal in 2001, and more, all point towards the vax(inations I received as a child. For example, I had random and inexplicable symptoms as a kid like attacks of projectile vomiting without being sick, and bloody noses that would last for hours.
Thanks for the context, very interesting. When did you get those shots as a child (ie what year, if you don't mind), and do you have any sense of which ones might have been the cause?
My parents followed the usual schedule. I was born in 1986. I'm not sure what the schedule was exactly back then, but I had several shots under the age of 5, a few more leading up to age 10, and a few more up until my last shot in 2016. Iirc the majority of them before 2001 included thimerosal as a preservative. I don't think any one shot was a specific cause, and rather it was a cumulative thing. I do know that the MMR shot does not contain thimerosal.
This FDA Q&A is a good read, although obviously biased against my perspective:
The FDA does acknowledge that kids in my generation were exposed to mercury slightly exceeding the established safety limit for oral exposure, but makes no mention as to how it is not appropriate to use an oral limit when the exposure is through injection. Toxicologists know that the exposure route makes all the difference in how toxic a substance is, and it is specifically written into environmental regulations like RCRA. For example, ingested substances are first directed straight to the liver through the portal vein for detoxification before being spread to the rest of the body. Injected substances bypass this defense mechanism. No exposure limits have ever been developed for injection, because the laws are all written for pollution, and people obviously do not inject pollution into themselves. (I was an environmental engineer for several years.)
That FDA Q&A also discusses how there was a lot of concern expressed by healthcare professionals regarding thimerosal, and that's why it was (mostly) removed, but they stress that it was just to be safe, and they have no reason to believe that it's dangerous. To be honest, it sounds like covering-their-ass double-speak to me, and reminds me of how polluting companies handle their coverups. The reality is that these things are so difficult to prove one way or the other, and the liability and denial issues are immense. No one wants to admit to themselves or others that they accidentally poisoned someone. Not just for financial reasons but for their own psychological well-being.
I'm not sure that the reason why some (e.g. official) health information sources keep repeating that isn't just a combination of having an easy explanation and making a (benign) attempt to induce a placebo effect in unknowledgeable patients.
If you either get massively technical about complex things that would make most laymen's heads spin, or shrugged your shoulders and said that we don't really know, you might miss on the potential psychological effects that you can get by projecting some kind of confidence.
"Low serotonin" was never the actual medical position on why antidepressants worked, it was marketing. The medical position is "we don't know why they work"; some antidepressants actually lower serotonin (SNRI) and some increase it (SSRI) and they both seem to help.
Also, they take weeks to take effect which doesn't make sense for a neurotransmitter effect, since Adderall (which raises dopamine) works instantly for ADHD.
I've heard theories that just doing anything to your brain knocks it out of state enough to stop being depressed (eg psychadelics do this), or that antidepressants actually improve your sleep quality and your brain cleans itself up over time.
It's a re-uptake inhibitor for both serotonin and norepinephrine which keeps your body from flushing our those chemicals which raises serotonin levels as long as production is stable.
High doses of SNRI will contribute to Serotonin syndrome, which makes your argument hard to believe.
Oh, I was going from memory, so I guess that part's wrong.
But there are effective antidepressants that aren't strongly based on the serotonin effects SSRIs have, like trazodone (weakly increases it) and especially ketamine (doesn't do it, works better than most antidepressants, works near-instantly instead of taking weeks).
And I would like to add that ketamine has nothing to do with the monoamine hypothesis, it is an NMDA receptor antagonist. It has nothing to do with serotonin, dopamine, and noradrenalin.
See my other comment about the growing interest in the glutamate system instead of serotonin and the like.
Can you please explain what seratonin syndrome is, particularly (like the above hypnosis / nlp split) where the edge of medical literature is? Highly interested, however for some reason was previously inclided to believe the phenomenon did not exist, akin to how adrenal fatigue can't be proven.
> "Low serotonin" was never the actual medical position on why antidepressants worked, it was marketing. The medical position is "we don't know why they work"; some antidepressants actually lower serotonin (SNRI) and some increase it (SSRI) and they both seem to help.
This just isn't the case. Maybe the more accurate thing to say is that there have been a few "medical positions" on this issue in the past six to eight decades, and "low serotonin" as well as "we don't know how they work" were both out there in the ether. But even that's not fully accurate, because you'd have to be pretty bold to argue that there wasn't a dominant "medical position" on the matter since biological psychiatry finished supplanting the Freudians for control of the field in the 1970s. The dominant position was the chemical imbalance theory, of which "low serotonin" was one of several variations trotted out over the years to both the public and the medical community.
Psychiatry is one of the medical specialties most profoundly co-opted by pharmaceutical industry interests, and both research and clinical practice have been rife with the effects of this influence. You don't even have to appeal to systematic analyses of how profoundly poor the quality of psychiatric research is, or how much pharma ghostwrites those studies, or anything of the kind. You can just ask a researcher in cancer or in neurology; they'll happily tell you.
To cleave the "medical position" from "marketing", as in your comment, elides what really happened: marketing decided what the medical position would be, and both doctors and the public mostly bought it.
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?
It's been a persistent myth perpetuated in the media/journalism/society/etc for a few decades, but there is a lot of scientific evidence showing that it doesn't really explain how depression works, and the fact that SSRIs boost serotonin doesn't explain why they work as a treatment. See https://sci-hub.st/https://www.sciencedirect.com/science/art... for example.
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.
I linked to a paper published and written by several psychiatrists and psychologists that explains the history of the monoamine hypothesis, and why it's not a good theory. Why would they spend so much time debunking a theory nobody believes?
Quoting directly from the article
> Despite decades of research, the role serotonin plays in depressive phenotypes has not been conclusively determined. The original clue that monoamines (serotonin, norepinephrine, and dopamine) were involved in depression came from two serendipitous discoveries (Baumeister et al., 2003; Valenstein, 1998). First, during the investigations of iproniazid as a treatment for tuberculosis and imipramine as a treatment for schizophrenia, clinicians reported that these drugs could reduce depressive symptoms. An effort was then made to find a common pharmacological property that could explain their antidepressant effect. Eventually, researchers found that iproniazid inhibits the enzymes that break down the monoamines, while imipramine blocks the serotonin transporter (SERT) and the norepinephrine transporter (NET). Second, clinical observations suggested that reserpine, a drug known to deplete monoamines, increased depressive symptoms. These findings appeared to solve the puzzle. By preventing the breakdown of norepinephrine and serotonin, or preventing their clearance from the synapse, iproniazid and imipramine appeared to increase forebrain monoamine levels.
> The monoamine-enhancing effect of antidepressant medications (ADMs), coupled with the depression-inducing effects of reserpine, suggested that depression was caused by reduced monoamine neurotransmission (Everett and Toman, 1959; Jacobsen, 1964; Schildkraut, 1965)
Additionaly, this is something that lots of undergraduate psychology textbooks still mention as a potential explanation (one of mine did ~6 or 7 years ago, although at least they said that it was an implausible theory).
Arguably it's life experiences and environmental stimuli that actually play a role in depression et al - it's just these neurotransmitters you speak of are the communicators. E.g. Self-protective mechanism from trauma (physical and/or emotional) to "close ones heart" or develop defensive behaviours - and then being locked into that state, indoctrinated into it - without the ability to disconnect from that pattern until say dramatically changing the chemical supply of transmitters - say either MDMA flooding the brain with serotonin, more than the brain naturally can at once, or say through ketamine or Ayahuasca or other psychedelics that give the opportunity for a perception change outside of the indoctrinated state(s) and behaviours.
I imagine the vast majority of people who's circumstances aren't due to a chemical issue, more so the lack of adequate support for them and/or any element of Maslow's Hierarchy of Needs not being met during rapid and crucial childhood development.
Mood disorders found to be are significantly heritable in twin studies so I don’t think one can say the “vast majority” aren’t due to a chemical issue here. It’s also worth noting that BDNF is not a neurotransmitter, and so having a direct connection with thoughts and personality seems unlikely, though there is reason to believe it may be downstream of long term psychological stresses.
Fair enough, however I'd want to review those studies to see what similarities do exist - even if in different households/environments. Studies that aren't taking into account the relative general lack of health of people in many parts of the world needs to be addressed, accounted for, in research as well.
I do understand how some makeups could allow a large amount of people to certainly to be prone to environmental stresses, have a more fragile-sensitive system - and if those factors are allowed to continue say for decades, there will be a hardening.
