My Issue With The Monoamine Hypothesis And The Potential For Better Treatments

As a general disclaimer, I’m not like… Actually a degreed learner of this… So this is based on my current level of understanding from my own research and my own opinions.

First off, what the heck is that? Well, WAYYY back, in my post on Biological Causes of Depression, I talked about it, but let’s refresh.

In the short version, the Monoamine Hypothesis states that depleted levels of a class of neurotransmitters called Monoamines are the root cause of mood disorders. This is the idea that lies behind pharmaceutical interventions like SSRIs, Benzodiazepines, and MAOIs to name a few, to treat depression and anxiety.

And… well. It’s not wrong. Many, many, many people take pharmaceutical drugs and their symptoms are alleviated. And many of those people spend their life on those drugs. Either through the fear of letting go of them or because they actually can’t. If they go off, their depression comes back to kick them in the face.

But, it’s also wrong.

I think it’s a wrong way of looking at it.

It looks to me more accurate to say that depleted levels of Monoamines aren’t “The Cause” of depression/ anxiety, but a symptom. It seems to happen as a part of the disorder.

You see, these things don’t exist in a vacuum the way that presentation implies. Something, be it environment, genetics, lifestyle, are the force that influences the levels to be abnormal. It’s not your production line that’s the cause. It’s that you have a problem in your life affecting your ability to produce in the first place. And yeah, it’s complicated. There is an interplay. It’s not just that you have a crappy diet. It’s not just that you got the short stick with genetics. It’s not just that you don’t exercise, or your work/home environment is toxic, or you had a trauma in your life.

A lot of things likely happened to get you to any given situation.

So let’s say you have a crappy diet. Well, your parent’s very likely taught you how to eat. (That’s their job. Teaching you. Even if they didn’t actively teach you, you modeled your behavior after theirs.) And in teaching you how to eat, they probably also passed on a lot of other behaviors, either consciously, unconsciously, or genetically! Maybe you eat to cope with emotions, and mom did too. Well, that correlates with having poor emotional management skills as well. It correlates with higher levels of stress. It correlates with higher levels of Trait Neuroticism. That all correlates with higher levels of stress hormones. That correlates with higher levels of inflammatory biomarkers. That correlates with less cellular recovery- including in the brain. That correlates with higher risk of depression, anxiety, Alzheimer’s, general Dementia, Parkinson’s, Crohn’s, IBS, Diabetes, M.S., Lupis, Arthritic Conditions… Etc…

Notice I say “correlates”. Not, “causes”. This list of correlations can go back and forth and in circles. What came first? The family history of poor eating habits, or a disease? The disease, or the inflammation? Christ. It really depends. And it takes a lot of untangling to figure out just that one situation.

Sometimes it’s clear cut. You suffer a trauma. You get depressed. Problem obvious. How to deal with it, is not so obvious. Some professionals (and patients) want to just push a medication at it. But that doesn’t solve your problem. It’s putting a towel over spilled milk and hoping nobody notices. And soon, that milk is going to go rancid.

The biggest problem I have with medications for disorders is that so often people only take the medication. They don’t analyze why their Monoamine levels are low, to begin with. And then they don’t fix the thing damaging or diverting their production line. (This excludes the situations of low receptor responsiveness/ synaptic excitability.) And so, the problem, if a solvable one, never gets fixed.

I’ll give you an example. Serotonin is synthesized in the body from the amino acid Tryptophan. Tryptophan, however, doesn’t just turn into Serotonin in the human body. It has other functions. It looks like this:


Image taken from

What the image doesn’t show is that the kynurenine pathway produces quinolinic acid before producing nicotinic acid (vitamin B3). B3 is good. Quinolinic acid is not good. It is what’s known as an excitotoxin. It interacts with neurons in the central nervous system in a destructive way and can lead to neuronal cell death. (it can inhibit glutamate reuptake, inducing glutamate toxicity and increasing the quinolinic toxicity, over exciting certain receptors activating destructive enzymes that lead to cellular death, can become a free radical… Etc…) Researchers have found that when sufficient levels of inflammation are present in the body, the kynurenine pathway hijacks as much tryptophan as possible, and builds up quinolinic acid in the brain, leading to cellular damage, increased quinolinic acid production, and the cycle settles in. Quinolinic acid has been found in high concentrations in patients with (research papers ahead.) Depression, Suicidal patients, Bi-polar, Schizophrenia,(pdf download link) ALS, Alzheimer’s, HIV, Huntington’s, and Parkinson’s. The correlations between cause and effect is still being researched, but the connection is there. (There is some evidence against quinolinic acid in Alzheimer’s and Huntington. Different parts of the brain were looked at. ) So, in an early call nut-shell, there’s a big part of your stress – inflammation – disease triad.

A lot of research is going into looking for ways to dampen the effects of quinolinic acid on the brain and possible ways to prevent its over formation in the first place.

And that’s just one example. Not only are your tryptophan stores being hijacked, but your body might just also be producing its own acidy demise. (Which has led some researchers to believe this is why 5-HTP supplementation might be helpful for depression. It skips the tryptophan stage and therefore can’t be hijacked. My personal experience is that yes it helps, but I am also doing a lot of other things to help my body.)

It sounds so easy. Just decrease your inflammation! Well… That is easier said than done. First, you need to know why your body is producing such a crazy immune response. Then you need to treat that.

Again. Only one example. One root cause. That has another rabbit hole of other roots.

And we’re very rapidly learning so much about the brain and its functions. A lot of stuff is coming to light with research into other ways inflammation affects the body, neurodegeneration/regeneration, how brain mass and injury effect mental health, the role of brain centers like the Default Mode Network in illnesses,[1] [2] and we’re even discovering new types of neurons! We’re discovering new medicines, and discovering new uses for old medicines too[1] [2] [3] [4]. The understanding of neuroscience is rapidly changing and the world of psychiatric medicine needs to do it’s best– sometimes better– to keep up with it.

It’s rapidly becoming clearer that simply throwing one kind of drug at the problem is not the best solution. Sometimes using drugs isn’t even the best solution. Some people need medications. Some people need to get their life in order. Some people are living life not pursuing anything meaningful, and need to find that meaning. (meaning counters suffering.) Some people need to fix their diet. Some people need to process trauma and grief. Some people need to shape up and face what they’ve been avoiding. Some people need to do multiple things.

I’m not saying down with pharmaceuticals, I’m saying, down with the old and not as effective! Down with the band-aid solutions that leave people tied to them for life!

And even with all this new understanding and new therapies, there may still be some people who can never leave their therapy behind. And that’s okay. Absolutely, because they deserve to not live in a living hell. But they also deserve a more effective therapy– especially one with less terrible side effects.

Treating depression is a thorny, twisty problem, and will take a deep level of analysis to uncover your roots.

It’s part of why so many patients find little to no relief from simple SSRIs or other current pharmaceutical interventions.

I’m not saying chuck your anti-depressants out a window and never look back either. (that will fuck you up. If you want to withdraw safely from a drug, work with your doctor.) Your doctor prescribed them for a reason. Maybe a good reason. Maybe a bad one. (if it’s bad, maybe find a better doctor.)

But I also, as just a regular person say, try everything! All the combinations! Find an exercise program that works for you! Eat a diet that your body likes and can derive maximal nutrition from! Sleep well, and regularly! Fix your house and make it beautiful! Fix your family, if you can. (or know when to call it quits, at least.) take up a stoic practice. Grow your brain. Find something deeply meaningful. Find out if you have any allergies or intolerances. Break any bad habits you know don’t help you. Visit a therapist to process shit and learn new skills. If you need supplementation or medication, learn what options you have. Don’t take things at face value. Mental illness rarely has just one source, and so it will rarely have one fix.

Find what works. And never stop doing it. Find what harms you. And stop doing it.

“Know thyself”

The man had come searching for a magical solution to his woes, but he had found an answer much more simple. Pain lost it’s power when other things became more important. Kahar didn’t need a potion or an aon to save him– he just needed something do do.

Brandon Sanderson, Elantris

As always, I’m not a doctor or a professional. Merely someone deeply interested in these things. Any links are used only for the information they contain and are not affiliated.

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