Will this make the "chemical imbalance" (i.e. low-serotonin) theory of depression obsolete once and for all?
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.
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. "
"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.
Here's a good journal article on the subject https://sci-hub.st/https://www.sciencedirect.com/science/art...
NHS current website "This type of medication [SSRIs] works by increasing the level of a chemical called serotonin in your brain." https://www.nhs.uk/conditions/generalised-anxiety-disorder/t...
Wikipedia "It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain." https://en.wikipedia.org/wiki/Paroxetine
etc.
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.
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.
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.
This FDA Q&A is a good read, although obviously biased against my perspective:
https://www.fda.gov/vaccines-blood-biologics/vaccines/thimer...
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.
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.
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).
See my other comment about the growing interest in the glutamate system instead of serotonin and the like.
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.
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.
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.
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)
https://sci-hub.st/https://www.sciencedirect.com/science/art...
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).