Lecture Four and Why I Like this Course

Just to begin: a serotonin based view on clinical depression is not enough. It sure is simple, beautiful, treatable, but just simply not true.

But before continuing on that, let me just say a thank you. This is truly an interesting course, because it makes me think. Because finally I have a possibility to think on my own and also to bring those thoughts out. Something that the university really doesn’t encourage – weird, because isn’t that exactly what we’re supposed to do here?

But yes. The lecturers balance each other out: it’s good to have a very rational (and sometimes even mechanical, sorry) to tell us how the mechanisms work. But then also to have a humanist psychologist who tells us how these actually manifest in our being. Now this is something truly remarkable, unifying the qualitative experience with the measurable mechanism. A great combination to reach true understanding. Exactly how neuroscientific research should also work.

But yes, back to the depression!

That whole thing leads back to the 60’s, the golden era of chemicals (and not just for hippies). That is when they found out about neurotransmitters and saw the correlations with different moods. Such as the one where serotonin levels seemed to correlate with happiness.

And there is surely some truth to this. We can just look at the raver’s who took serotonin-releasing ecstasy or MDMA in the 90’s. Yup, happiness in there. Just look at the smileys.

Then why SSRI’s don’t work? Elevated serotonin levels, but no response? I liked the idea of “the people needing time to think themselves” and I think this surely true. The psychological component should not and even cannot be removed in this kind of research. But when looking at the mechanisms behind that, I think it gets way more complicated than just increased serotonin levels.

First of all: emotions are a complex phenomena. Second of all: depression is way more than just “a bad mood”. Depression isn’t just sadness or melancholia, it is a persistent feeling of sadness and loss of interest in everything and all the time.

Well, in here lies the first clue – it is “persistent”. If it is persistent, then there is something constantly doing something in your brain, right?

Well, you could say that “it is the low serotonin levels”. Well, no. SSRI’s don’t seem to work very well for minor depression. Well, maybe it’s just not potent enough. But we have drugs that can very selectively release serotonin to your brain, such as MDMA, MDA or MDAI. What they seem to do, is not just increase your mood, but create a very interesting condition in you, referred to as empathogenic or  entactogenic by psychotherapeutists.

What we see, is the suppression of anxiety, disinhibition, empathy towards others, affection and sociality enhancement among other things. A perfect state to work on difficult personal matters, I would say. What a shame, that all these tools have been made impossible to be used because of the current legislation.

So, if this only comes from mostly serotonin, it seems to do a lot more in the brain then thought and should be as a lot more complex transmitter then “the mood transmitter”. Of course the above mentioned state is something we all would want to experience all the time, right? Free of worries and full of love? But it is not possible. Constantly elevated serotonin levels can cause life-threatening symptoms and the positive effects seem to diminish very rapidly after usage. In fact, major depression is a very common side-effect of continuous MDMA-usage.

But if not serotoning levels, then what is persistent in the brain? Well, you said it yourself already. It is the negative thoughts. The constant negative self-referential process that is going in your brain.

And what are brains constantly doing? They like to do this process called default mode network. Constant self-referention.

And this is where we should put our research and our treatments. To the breakage of the negative self-feeding loop and then the recreation of it into a new and healthier sense of self.

How do we do it? Well, therapy of course. That is the only persistent way. But we could use drugs too. But better than SSRIs.

The clinical effect of SSRIs is not due to increased serotonin levels increasing mood, but due to the enhanced plasticity it creates in the plain via glutamate connected process.

The big three of the amines – dopamine, noradrenaline and serotonin – should not be thought as “classical neurotransmitters” but as “neuromodulators”. In addition to many basic physiological fuctions, serotonin participates to higher brain functions, such as cognition and emotional states, by modulating synaptic plasticity via glutamate.

And plasticity equals the brains ability to create new connections. And new connections equal new thoughts. And new thoughts equal braking the viscous cycle of negativity.

Of course, mediating glutamate directly is a bad idea. It is toxic as hell. But there are better options.

I think this is why ketamine and other glutamate antidepressants show us promising results. It is due to antagonist effect on the NMDA receptors glutamate will release onto AMPA and other metabotropic receptors. This is effect is much more direct than the SSRI-directed and will thus be a lot faster.

In very treatment resistent depression, such as with terminal cancer patients another possibility would be to use the classical psychedelics, such as LSD or psilocybin, which seem to work directly on the 5HT2A-receptor.

The 5HT2A-receptor is interesting, because depressed people seem to have them a lot more than average person. SSRI’s seem to downregulate them too.

But these psychedelics seem to work immediately, and downregulation of synapses does not happend that fast. What is more interesting, is that even one session can provide long-lasting positive effects.

They seem to produce a very interesting state, with very deep and spiritual feelings of connectedness, which science still doesn’t know much about. The therapeutic effect could be mediated through the direct “breakage” of the brain’s rest state networks. Or something else – there is a lot to learn!

But back to the SSRIs again. They are not good for you. The constant exposure to high serotonin levels will cause “desensitisation” of those receptors, i.e. they don’t respond to stimuli that well or as fast. I think this is the mechanism behind the “blunting of feelings” that can too often be seen in depressed patients taking SSRIs.

Surely, you might not feel that down all the time anymore. But sure as hell you won’t feel the highs anymore either. And if you don’t have those ups and downs, you’re missing on life and it’s wonderful plethora of experiences.

For example, when falling in love, your serotonin levels will go up and then crash down, to create that craving of your loved one. Now if your serotonin levels are constantly high, your brain can’t create this experience.

You can’t fall in love.

And I think falling in love would be the best cure for depression.

P.S. I can gladly give you an presentation what serotonin (and other neuromodulators as well) does in your brain, but I think that is a time for a whole new blog post or a lecture. 🙂

[EDIT] Just researched more on the 5HT1A-autoreceptors and their effect on brain serotonin levels.

So it seems that SSRI’s in the beginning actually activate also a lot of these receptors, which are inhibitory for the neuron itself. I.e. by releasing more serotonin, the activated 5HT1A-receptor acts as a ultra-short negative feedback loop thus making the neuron release less serotonin. So the brain’s serotonin levels actually drop after taking the SSRIs. Only continuous exposure to SSRI’s will downregulate these autoreceptors and thus making more serotonin available in the synapse.

Which could explain the therapeutic lag. Which would actually mean that more serotonin in the brain equals better mood.

Fuck. Hypothesis is wrong!

Back to the drawing board…

Or maybe the situations is more complex? Or maybe there could be different kinds of depression mechanisms in the brain…?

Posted by Niklas Strengell

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One Response to Lecture Four and Why I Like this Course

  1. Mikko Luukinen says:

    I was about to start writing my own blog post about depression and SSRI:s, when I found this one. So, I’ll comment a bit.

    First, these are complicated things. Different kinds of medication affect different people in different ways. Science is always about generalizing. Second, I don’t know if you have personal experience of depression. In case you do, then your comments are a bit more acceptable. (Still, don’t think everyone elses experiences are same as yours.)

    But seriously, it’s pretty hard for me right now to avoid going into personal insults. You talk about experiencing full range of human emotions. Well, let me tell you, if one is too damn depressed to get up from bed until in late afternoon after hours of wallowing in self-pity and self-hatred, one is sure as hell not going to feel those great highs of life. Personally, after getting my medication to suitable kind and level (after long testing and adjusting), I have got energy to study, to have different kind of projects and to love life again. I am not happy all the time, some days are pretty bad. But Not as bad as they were half a year ago. And there sure as hell are highs, when I can do something I love and am interested in, and actually have energy to do it.

    Yeah, medication doesn’t cure depression. And nobody thinks it does. But it gives you some strength so that you can handle your life while therapy and self-care slowly raise you out of your pit.

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