Wednesday, August 3, 2016

Neurochemical in Focus - Serotonin




In a previous Neurochemical in Focus piece we looked a bit at dopamine, its pathways and its affects on our moods and behaviours. Today we're going to look at another very long overdue neurochemical and topic - serotonin.

Neurochemicals and their roles in brain functions are the very foundation and core of pharma-psychiatry's "chemical imbalance" theory for "mental illnesses" and are the basis for every prescription written to treat depression, bipolar, schizophrenia, anxiety disorders, OCD and ADHD.

The initial focus of this blog was to take apart and demolish the chemical imbalance theories of mood and psychiatric disorders but I don't want to get into that too much here today. My aim for this piece today is to build towards a better understanding of serotonin and its roles in brain behaviours (and thus our moods and behaviours) and look into how popular drugs for depression are alleged to work. 

While I've since done a good deal of my own reading and study into our topic today, I owe a great debt of gratitude to Robert Whitaker and his landmark book Anatomy of an Epidemic for not only spurring and inspiring my interest in neuroscience, but for introducing me to the understanding of attempting to treat psychiatric and mood disorders at the synapses of the brain with the use of drugs. 

I'd come across his book early in 2013 and then had the great fortune to attend a lecture he was giving in Vancouver where I was able to meet and talk with him at some length. It was that talk and that meeting which led to a great deal of what Taming the Polar Bears would eventually become. Robert's high integrity methods to his research and writing and his early encouragement of my efforts were very instrumental in my approach to understanding and writing about science and the brain as well as my research methods. He very patiently read and critiqued some of my early efforts (along with the famed (and somewhat rebel) psychologist Bruce E. Levine) which greatly aided in steering me in the right direction. 



As with all neurochemicals, the roles of serotonin in the brain and body are greatly more complex than that presented by the pharmaceutical industry in their ads and narratives for the antidepressants they market.

Let's have a bit of a look. 


Serotonin or 5-hydroxytryptamine (5-HT) is biochemically derived from tryptophan. Serotonin is a monoamine neurotransmitter primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness
Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The serotonin is secreted luminally and basolaterally which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. 
- Wikipedia (with some editing for clarity and brevity)

That's a very basic introduction into serotonin. Now, let's unpack that a bit and look more into what's relevant to us mental health peeps. 

The discovery and genesis of the understanding of neurochemicals' roles in brain function took place in the mid-fifties. Synapses and their basic functions had just been discovered yet it remained unknown how exactly information was "handed off" between communicating neurons at the synaptic level. Some argued for an electrical basis (which is partially correct as we'll see) while others proposed that chemicals were involved. As noted science historian Elliot Valenstein characterized it, it was "a war between the sparks and the soups". 

Further experiments were conducted which discovered that synaptic communication was indeed carried out by chemical messengers and subsequently a number of them were identified and further experiments showed that the "moods" and behaviours of animals could be altered or affected by introducing drugs that in some way modulated the levels of these neurotransmitters (as they would come to be known). 

And it was from these seeds that the "chemical imbalance" theories for mood and psychiatric disorders began to emerge with dopamine, monoamines (including serotonin) along with a third major neurotransmitter called norapinephrine being identified as the lead "culprits".

As noted in that Wikipedia excerpt, serotonin is part of a group of neurotransmitters in the class of monoamine. Some of the earliest pharmaceutical produced antidepressants were based on attempting to modulate monoamine and were called monoamine oxidase inhibitors or MAOIs and new variations on those are still prescribed and used today. 

Later research, primarily carried out or was funded by the pharmaceutical industry, isolated serotonin as having more specific effects on our moods and with great fanfare, SSRI antidepressants were introduced to the world with the release of Prozac by the pharmaceutical giant Eli Lilly in 1986.

If you walk into a doctor's office today complaining of depression or are admitted to a psychiatric facility to be "treated" for depression (a word I use very loosely), there is a very good chance you will be prescribed an SSRI antidepressant. 

SSRI stands for selective serotonin reuptake inhibitor. As our goal in this blog is to better understand our mental states, the reasons behind them and how they can be treated, a better understanding of this is going to be very pertinent to us. 

First of all, let's take a closer look at serotonin pathways in the brain and a little bit about what those are all about. 



That gives a pretty decent idea as to where the pathways originate and some of the destinations. I liked this particular illustration because it gives a rough brain view plus that little "flow chart" at the bottom helps give us a better idea. 

As we learned in the post on dopamine pathways, none of this works in isolation. As with dopamine originating in specialized nuclei called the Ventral Tegmental Area (or VTM), serotonin has an originating nuclei (or group of specialized neurons) that is responsible for sending out serotonin related signalling. Serotonin pathways originate in the raphe nuclei. These are located in the brain stem, a very old (and original) part of our brains in evolutionary terms and indeed serotonin plays key roles in many life forms, even the humble round worm (C. Elegans, a favourite of neuroscience types to poke and prod and experiment with). 

As for the destination end of things, we have the thalamus and hypothalumus, two key nodules that we briefly visited in the introduction to the stress response system, then the caudate neucleus which plays key roles in motor and non-motor functions and as such is of keen interest in Parkinson's and Obsessive Compulsive Disorder. The hippocampus is also a destination (this sea horse shaped pair of nodules (one in each hemisphere) plays the role in episodic memory formation) and then we go up into the frontal lobes of our fancy neocortex and other areas of the cortex (the very outer layer of the brain). 

The cerebellum as a destination is quite interesting, I believe. We've touched on the role of this very ancient bit of brain hardware in Neuroanatomy 101, where we saw it was greatly responsible for much of our physical movements and coordination and in An Introduction to Music Therapy where we learned that more recent research shows that it is involved with the coordination of all kinds of higher cognitive functions and is very involved with both the playing and appreciation of music. 

For reasons I could not say, not in that illustration or chart as a destination is the nucleus accumbens, a rather significant region that has much to do with cognitive processing of aversion, pleasure, reward, and reinforcement learning.

Still with me? I hope so! We're getting to the crux of the biscuit soon. 

Okay, so what does serotonin do? What does any neurotransmitter do for that matter? We probably have all heard the narrative that serotonin is responsible for feelings of happiness and well being and that a depletion of serotonin makes us "depressed" and hence the need for pharmacological aids to "increase" levels of serotonin which in theory "treats" our depression. 

Well, I hate to break it to you but serotonin - or any neurochemical for that matter - doesn't really "do" anything, or at least not in the sense of the narrative that we've been told in regards to "moods".

Let's have a look at what I mean by that. 

Once again, let's revisit some basic brain anatomy. We'll call this diagram A.



Look first to the left side of the illustration. If you've been following along (and somehow I suspect nobody really follows along with all of these, but on we forge), you'll see we have some cell bodies (neurons), axons and dendrites. Axons carry signals near and far to other neurons and dendrites that receive incoming signals. This is one way (though only one way, I must emphasize) in which neurons communicate to do all the myriad things our brains do like call up a memory (of how to do something or a face or almost endless so on), feel and process emotions, form the "moving picture show" that is our sight and vast amounts of etcetera.

It is in the neurons that stuff is stored and happens and neurons communicate their little micro bits of stuff with tens of thousands to millions to billions of other neurons to make up bigger bits of mental, cognitive, emotional, etc stuff that makes us what we are or controls what we're doing, thinking or feeling, or initiating and controlling every single physical movement we do. 

So it's the neurons, or more accurately, groups and networks of neurons that do stuff, not neurotransmitters. 

But - but! - the neurons can't do their thing with billions of other networked neuron buddies if neurotransmitters don't do their thing so let's take a closer look at this thing neurotransmitters do.

At the point where axon (sending) meets dendrite (receiving), we have a synapse. I have a better illustration for serotonin related synapses here (diagram B):




We have a transmitting, or sending, neuron represented in yellow above (which is actually the very end tip of an axon) and receiving in green below (which, in this case, is actually the tip of a dendrite). Where it says "synapse" with that large bracket is more often known as the synaptic cleft, a gap that is a mere 20 nanometers across. 

There are some really key bits to that illustration for us to understand here. There's no need to look into those items listed in the sending end of things (unless you're a true neurobiology geek of the chemical bent - but briefly, it's just the process for creating serotonin). What we want to learn here is the vesicles containing serotonin (represented by the little red dots) on the sending side and the receptors on the receiving side. 

A given neurochemical (serotonin in this case, or dopamine, or any of a hundred or more other neurotransmitting chemicals) is like a key and the receptor is like a lock. The lock won't receive if the key isn't right and the key won't fit if the lock isn't right. (Very important for understanding not only neurotransmitting chemicals, but also how both many prescription drugs and pain killers and so called street drugs work.) The neurotransmitters crossing the synaptic cleft and fitting into the receptors is what completes the communication between neurons. 

So while they don't actually "do" anything in themselves, neurotransmitters are obviously an essential part of the process of coordinated neuronal activity of all kinds.

Let's quickly review what's involved with inter-neuron communication. (diagram C)



So we have some neurons with some exciting info they want to spread around. If the info is exciting enough the neurons doing the sending will reach a level of excitement called action potential which will then send a series of electrical pulses down the axon. It is these electrical pulses which stimulate those little balloon like sacks (the vesicles) of neurotransmitter chemicals so they travel across the synaptic cleft to fit into the "locks" or receptors in the dendrite, or receiving, end and thus the "info packet" will get handed off to other neurons (and hence the electrical theory of synaptic function (of the "sparks vs soup" battle we looked at above) proving partially correct). 

To give an idea of the scale of these bursts of nano-activity, recall that we have somewhere in the neighbourhood of two hundred and fifty trillion synapses performing these infinitesimally intricate transactions the firing of each of which is measured in hundreds of a second. With every thought, with every move, with every sense processed, with every action your brain must perform, billions upon billions upon billions of these synaptic functions must go smoothly in order that billions of neurons at any given mili-second can do their jobs smoothly. 

In the case of serotonin, again it doesn't "do" anything in creating mental states or mental processes. what it does do is play a critical role in the firing of key brain regions in coordinated ways so that they can do things. If we look back at the brain regions in the serotonin pathways, it's the functioning of those regions that are critical for creating mental states and processes and not only the individual regions, but that they are working properly within larger brain-wide networks. 

I think it's not hard to imagine that such fine transactions that need to take place trillions of times per mili-second may not always go all that smoothly, thus networked brain regions and nodules may not go smoothly and thus we will not always go that smoothly. 

Now we get to the crux of the biscuit regarding serotonin, moods and SSRI antidepressants. ::reaches out to gently nudge readers awake from their slumber:: (I've ten years experience in the classroom, I know how this works)

If you go back and look at Diagram B, you will see in the sending side of synaptic cleft what are labeled serotonin reuptake transporters. (There are reuptake transporters for all the various neurotransmitters in the synapses of their relative pathways.) 

These are one of the "recyclers" of the brain. You see, not every little molecule of serotonin (or other neurotransmitters) in every burst of communication gets used - it doesn't all fit into the receptors - so some will always be left floating around in the synaptic cleft. So what the repuptake transporters do is sort of "vacuum" up the excess neurotransmitter molecules for future use. Very clever, what?! (Though other excess neurotransmitter material will get gobbled up by special waste disposal enzymes)

This is all an almost unfathomably complex set of transactions that evolved over literally billions of years. But for reasons that I will have to leave to explain elsewhere, modern researchers and scientists figured they could be more clever than the brain itself. 

Because it was proposed that serotonin was "responsible" for feelings of pleasure and well being (and presumably thus "happiness") it was further proposed that a depletion of serotonin was responsible for "depression" - you know, being unable to experience pleasure, well being (and presumably "happiness"). So researchers and scientists (who just so happened to be in the employ of multi-billion dollar transnational pharmaceutical companies whose shareholders were giving them grief about their bottom lines) got to doing some tinkering around. What they came up with was the idea that "hey, maybe the problem with "low moods" is that there isn't enough serotonin in the synaptic cleft to create pleasurable and happy feelings". From there they looked into the reuptake transporters and thought, "hey, what if we blocked these reuptake transporters so that there'd be more serotonin in the synaptic cleft and this will make people happier and less depressed?". (Yes, I know I am being breathtakingly and somewhat dismissively brief but it really did go something along those lines.)

These lines of thought, and others, were part of the reasoning that went into "chemical imbalance" theories for mood and psychiatric disorders. The "imbalance" proposed here was that serotonin was in short supply (and thus out of balance), these imbalances were creating mood disturbances, and if we (psychiatrists and medical doctors) could just restore this balance, normal (whatever "normal" is) moods would return. In the case of serotonin, the process of blocking the reuptake transporters would restore the balance by leaving more serotonin in the synaptic cleft to do its thing. 

And thus Selective Serotonin Reuptake Inhibitors were born.

What all antidepressants in the SSRI class do is in some way hinder the reuptake pumps or transporters from doing their jobs. This is the entire premise of these class of antidepressants. 

Which sounded pretty good in theory, I guess (you might sense my skepticism ringing through). 

The idea of the "selective" part is that SSRI drugs would only target a certain type of receptor in serotonin pathways (the 5-HT system). 

But there have always been a great number of problems with both this theory for depression and the process of tinkering with something so highly evolved and as complex as neurotransmitter activity that takes place trillions of times per mili-second for every second you draw breath. 

Let me outline a few.

Firstly, in Anatomy of an Epidemic (pages 79-81)Whitaker describes in great deal how investigators found that drugs like fluoxetine (Prozac, Sarafem, etc) designed to block reuptake pumps (or SERTS - Serotonin Reuptake Transports) greatly altered both pre and post synaptic function and their very structures with profound - and unintended - affects resulting in abnormal functioning.

Furthermore, neurotransmitters are but one aspect of synaptic function. If you look back up at Diagram C, you will see mitochondria represented there. As I outlined in part three of "Bipolar, the Brain and Energy", mitochondria plays extremely critical roles in axon and synaptic signaling functions. If mitochondria is damaged and cannot function, which we also established in that series as a possible result of chronic stress, then inter-neuronal communication is going to be impacted all along the axons and at the synapses themselves thus affecting inter-neuronal communication brain-wide. So what could be happening with poor synaptic functioning is that it is a result of mitochondrial dysfunction. 

Grossly overlooked is synaptic pruning and growth that we first looked at in An Introduction to Neuroplasticity. As we learned there, synapses are in constant flux for both good and bad. It is blazingly obvious to point out that no communication between neurons can take place if synapses for some reason are not there. If we look at what's related to mood in relation to synaptic functioning within specific brain regions and we view this with the understanding of the basic neuroplasticity principle of "use it or lose it", then we might well propose that regions of the brain related to mood are not functioning properly because synapses have been pruned back and thus these regions are not communicating strongly within other brain networks contributing to our moods.

As well, not all brain activity and coordination is conducted through axons, dendrites and synapses. Neurons and groups of neurons also use brain waves to communicate and coordinate activity. Neuroscience is just scratching the surface for understanding this critical form of brain activity and how, for example, the hippocampus uses specific brain waves  to transmit memory information to different regions of the brain. 

Aside from this is the fact that of the total amount of serotonin in the brain and body, only a small percentage (less than 5%) is involved in the brain's serotonin pathways involved in "mood" as well as what we looked at above - that serotonin destinations involve many critical and widespread functions aside from "mood".

But perhaps more importantly, is what we first looked at in the piece on dopamine pathways. Like dopamine pathways origins in the Ventral Tegmental Area, serotonin originates in the raphe nuclei. And like the VTM, the raphe nuclei are part of vastly complex feedback networks. If there is a serotonin depletion (never conclusively proven) and this depletion is affecting mood (definitely never conclusively proven), then we should also consider that this depletion is happening at the nuclei of origin and not at the end synapses. Perhaps it's a question of what's happening in feedback networks to the raphe nuclei and that this nuclei are receiving insufficient stimulation and thus under performing serotonin pathyways.  

Looking into these questions and problems in more detail will have to wait until we begin to investigate the disaster that became vastly widespread SSRI use, a good deal of it "off label". These problems include long term inefficacy, extremely dangerous side effects not the least of which was greatly increased suicide risk and completed suicides and wildly changing behaviour. 

All this being besides the fact that there are numerous, numerous and enormously complicated processes in the brain that affect our moods, mental states, and behaviours besides neurotransmitters alone (which I have touched on in numerous posts in this blog). 

Today, however, I just wanted to give a brief and simple introduction into what all this business about the now famed serotonin is all about. 




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