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5HT Basics

I have a question. I have taken these meds before and have been a little confused about what they are doing with the serotonin level.
No Prob. *Taz clears her throat and begins the chemistry lecture* (Yes, I've got the diplomas to qualify for this)

When one nerve needs to pass a signal to the next nerve, it has to do so by getting the message across the gap between the two known as the synapse. The way this happens is that an electrical pulse travels along nerveA until it hits the end where it wacks into these pockets of stuff called neurotransmitters. These neurotransmitters float across the gap and fit into triggering receptors on nerveB. This sets off an electrical signal along nerveB.
Ok, one message sent! A success!

So now all of the neurotransmitters are sitting over on nerveB's side of the gap and just like people in an elevator, chemicals like to stay as far away from each other as they can. So the neurotransmitters realize "Hey, there's too many of us on this side and not enough on the A side." and the begin to go back, just to balance it out. Next time you ride in an elevator, watch how people redistribute themselves each time someone gets on or off. That's what chemicals try to do all the time. It's called diffusion.

When the neurotransmitters get back to nerveA, they are sucked back up by nerveA at reuptake sites and put back into the pockets they came from in the first place. So as far as the neurotransmitters sitting on nerveB can see, there's always too many of them on the B side and not enough on the A side, cause they "disappear" when they get to the A side. This goes on until all of the neurotransmitters are back in their pockets.
OK, ready and waiting for next message! That's how it works normally.

Now, the stuff about meds and depression. It seems that with depression, nerveA just doesn't fire a signal to nerveB very often. Not as often as it should. So the idea is to send more signals to nerveB than nerve A actually sends. One of the common neurotransmitters is serotonin, though there are many others. And it seems that it is a lack of serotonin type transmissions that cause the depression. Though that's not always the case. Sometimes it's one of the other neurotransmitters that isn't getting sent to nerveB enough. 

Ah HAA! So you just take some serotonin. There's more neurotransmitters, so nerveB gets hit by them more often and you get more signals. Yes, but there's lots of complications about how to do this. You can't just take serotonin. There's lots of reasons why that I won't get into. SSRI's accomplish this by fitting into the reuptake sites on nerveA, like plugging up the end of a vacuum with a big cork. So the next time nerveA *does* fire, the serotonin goes flying into the synapse and hits nerveB. Then just like before, the neurotransmitters want to get away from each other, but now that the reuptake sites are corked, the folks who get back to nerveA don't disappear. So, they all stay around in the gap just swimming around. And every once in a while one will bounce back to nerveB and send an extra signal that wasn't sent directly by A. So nerveB gets closer to the amount of signal that it needs to make you not feel depressed. Now, the next time nerveA fires (it can make it's own serotonin if it needs, it just is lazy and would rather reuse what it's already made), all the serotonin goes flying into the synapse that the rest of them are still swimming around in. NerveB gets hit again and now there's twice as many folks just swimming around in the gap bumping into nerveB and sending little extra signals.

Over time, nerveA fires off enough that it's pretty crowded in the gap and nerveB is getting hit plenty enough to make you feel better. This is why it takes time for the ssri's to work. Just putting the cork in doesn't fix it right away. It takes time for the serotonin levels to build up in the synapse to a point where it helps enough.

Oh, and one last point. When there's so many neurotransmitters swimming around, every once in a while they knock into a cork and pop it out and it gets lost and the reuptake site starts sucking in the serotonin again happy that it won't have to make any new ones this time. This is why you have to keep taking the antidepressants everyday. To replace those corks that have gotten displaced somehow.
That's it!
Well, one last thing. SSRI stands for Selective Serotonin Reuptake Inhibitor.
I think the Serotonin Reuptake Inhibitor part is pretty clear now, but why are they called selective?

Remember I said there's lots of different kinds of neurotransmitters. Well, the reuptake sites for them can't be stopped up with these corks. Wrong size. So all the other neurotransmitters act just like normal going back and forth between nerveA and nerveB. Only the serotonins hang out in the synapse. Therefore, the corks are selective and only fit into THOSE reuptake sites that suck up serotonin. Sometimes they sorta fit into one of the other reuptake site and that's why there's differences among the ssri's available. The game is to make the perfect cork for a hole that you don't really know what it looks like. Exercise can help out the situation because it is one of many factors that helps nerveA make more serotonin to send into the gap. Lots of things act this way.

> Thanks for the lecture Taz. Nicely illustrative. 'Course, it opens a whole host of new question, but then good information >always does.
> One question (or set of questions) - just let me know if I've got this right: When you talk about Nerve A and Nerve B, you're >actually talking about nerve cells, right? Also known as neurons? Now, each neuron can take the role of either A or B, and in >fact does so during the transmission of impulses, which occurs along a chain of neurons, like a bucket brigade transferring >water. And the long arms of the neurons along which the signals travel are called dendrites, are they not? Or something like >that. So rather than talking about Nerve (or neuron) A and B, maybe we're talking about dendrites A and B, and each neuron >has one of each kind of dendrite, a receiving one and a transmitting one. Is this true?

Exactly right. I was just talking on a more general level and not actually getting down to the specific anatomy. I was looking at it more conceptually at this particular time. But you are exactly right. The first draft said neuron A and neuron B. But I felt it would be more clear to a wider audience to just call them nerves. Well actually, a nerve cell is more than just a cord with a receiving end and a sending end. Each cell has a nucleus that is located in a region of the cell called the body of the neuron. Then there are several dendrites attached to the body, some sending some receiving. As far as I understand, it's a networking, a web like structure.

> If so, this would suggest that transmissions go across each synapse in only one direction.

I believe this is true. Someone correct me if I am wrong. There is a fundamental difference physiologically between a sending dendrite and a receiving dendrite. The sending dendrite contains the vesicles that contain the neurotransmitters, whereas, these vesicles are not found at the end of a dendrite that receives.

> If not, and transmissions can go either way, then each dendrite can play the role of A or B, i.e. transmitter or receiver. .Which is true?

I think it's defined whether a specific synapse conducts messages one way or the other. It's possible for two neurons to be a two way path by connecting two one way synapses. Kinda like a BLVD:
a sending den. A a receiving den. B

/|---------------> forward synapse >----------------|\

body |                                                              | body

     of |                                                             | of

     A |                                                              | B

\|---------------< return synapse <----------------|/

a receiving den.A a sending den. B



(Hope that picture comes out right) and then there could be any number of other dendrites off of A or B connecting them to other neurons. It's even probable, especially when you're talking about the brain, that both A and B would be connected to say neuron C that is nearby and connected to D and .....

It's all quite a mess, actually. I think that's why we can't simulate the brain with a computer very well. Similar concepts really, but... the brain is just a mess. It's a wonder it works so well. Perhaps that's why it works so well. But enough on the philosophical side...

> Also, does each neuron have only two dendrites? Or can one have several?

Uh, I think I already covered that. :\

> Fascinating stuff. I hope my questions make some sense.

Yup. Good questions. Forced me to clarify the situation more.

> Another more pragmatic question also suggests itself. If SSRIs increase synaptic activity, why do they make so many people >drowsy (myself included)? I'm sure the answer to that one is not so simple, but I'd sure like to know.

I don't have an answer for you but I can take a stab at a guess if you don't mind. The way I think about it is that everybody's brain is networked differently. I mean there are some patterns, but the actually cell to cell networking varies from individual to individual. It seems that the amounts of neurotransmitters used and which types are used for each synapse also vary. All of these synapses are part of pathways that carry out particular functions for us and who knows what neurotransmitters are being used to do what in the brain of any on particular person. It's impossible to say. There's too many possibilities. My guess is that the side effects that a particular person experiences because of an ssri, which by definition increases only serotonin levels, tell us what pathways that serve which functions *that* particular person's brain uses serotonin in. Boy, that's confusing. Let me try again. When you increase the serotonin to bring the pathways involved in depression up to snuff, you can hyperactivate other pathways that serve other functions just sorta by accident. And the other pathways that get hyperactivates vary from person to person giving a wide range of side effects that appear. There. I think that's better. So to answer you're question about yourself directly. I'd say that you happen to be wired in such a way that the pathways involved in controlling your sleep use a lot of serotonin to communicate. So when you enhance the activity of this pathway, you want to sleep more. I think the same kind of reasoning can be used to explain why any side effect occurs and why the side effects that do occur vary so dramatically and also why some meds work for some people and not for others.

But take all of this last stuff with a grain of salt. This is just the way I think about it. I don't know what the real answer to your question is but I'm comfortable with this explanation until I learn more.

> Teacher! Teacher! (waving hand in air) My understanding is that usually after being on an SSRI for a while, the brain >becomes adjusted to take care of itself and you don't need the SSRI anymore. Would you please explain? Have the corks >become permanent? Or are the neuron A's now overproducing serotonin so it doesn't matter that the corks are gone and the >stuff is being sucked up again back into neuron A?

Gee! I didn't know the classroom was full. I would have gotten nervous! :\ I think I can answer this one. But please someone correct me if I'm wrong. Quick answer, no the corks aren't permanent. They get flushed from your body when you stop taking the SSRI. Usually completely in about a month. The latter case is the correct one.

Why? The nitty gritty: There's two types of clinical depression. Those caused by predominantly genetic factors and those caused by predominantly situational factors. The resulting physiological condition is the same regardless of the cause, though. And the treatment is the same. But recovery differs. In the case of situational depression, I believe that the general idea is that once you get the brain chemistry functioning properly, the individual can live their life the way they want and eliminate the stressors that triggered the depression in the first place. This is why therapy is SO important as a counterpart to the treatment of depression with meds. As the causes of the depression are dealt with, the need for external help to keep the brain chemistry in balance theoretically should disappear. If you don't change the situation that caused the depression, when you get off the antidepressant, the depression will probably return. (Statement of the obvious?)

In the case of a "genetic" depression, it seems that the body's chemistry just has a natural tendency to be out of balance some. And even AFTER dealing with situational causes, the depression will still need to be treated with meds. This is important to emphasize: Those individuals who are dealing with depression and also have a family history of mental illness are probably predisposed towards depression just naturally. However, this does NOT exclude the influence of situational causes, nor the responsibility of these individuals to address the additional situational factors. A point that is too often over looked, IMHO. So therapy is EQUALLY important to the management of depression for folks in this group. So all in all, the treatment is the same regardless of the cause. You take whatever meds work for you and you get therapy to decipher why you are depressed. You take steps to change your life in significant ways, which theoretically you can now do because the depression is being treated. Then you try to wean yourself off of the meds. If you can get off of them great! You've won the battle and are healthy again.

If you slip back, you repeat the cycle and then try to get off of them again. Maybe you have to make three or four significant changes in your life before you are able to come off the meds and feel just as good without them as with them. Sometimes, you won't ever be able to get off of them completely, no matter what you do to change your life for the better. Then you just have to accept that you need this medication to stay healthy. You just have to keep hanging in there and trying to get it right for yourself.

To answer your question directly, it's the positive changes that you make in your life that change how much serotonin the brain produces naturally. So yes the brain can return to the normal functioning situation and the corks just get flushed from your system. Most CAN recover from this illness and DO in time. There are a few of us though who can never *really* recover and have to be on low levels of medication for very long periods of time. Perhaps a lifetime, in order to manage the illness and maintain a healthy mind and body and lifestyle.

> Thanks for the lesson. While I'm not disagreeing with what you are saying about the chemistry of nerve transmissions, etc., I >do have a question. In the package insert for Zoloft, in the pharmacodynamics section, it says something to the effect of >"Zoloft appears to act by inhibiting uptake of serotonin by human platelets." Could you explain what role platelets could be >playing in all this?

> P.S. I didn't have the package insert with me when I wrote this, so the quote may not be exact.

> Thanks, Jim

Hmmmm. Don't know what to say to this one. "human platelets" to me refers to the particulates in the blood that are responsible for the clotting mechanism. I am not aware of any involvement of these particles in the cause or treatment of depression.

This question further intrigues me because there is no direct interaction between the constituents of the blood and the neurons of the brain. There exists a membrane called, oddly enough (*giggle*) the blood-brain barrier, and only certain types of small molecules can pass thought this barrier, oxygen and carbon dioxide being the most important to pass back and forth. I don't think serotonin can even cross the barrier. So I don't see how it could interact with platelets at all. Let alone how Zoloft can at by interfering in this interaction.

New stuff: I asked my doctor about it and learned that there is actually much more serotonin in the blood platelets than in the neurons. It serves a purpose in both places. The name serotonin actually refers to the role that the molecule plays with respect to the blood platelets. The reason your insert references the platelets and not the neurons is because it is easy to study the reuptake of serotonin by the platelets and it is assumed that the same mechanism is operating within the neural synapse. Although, once again, we really don't know what it going on. But it is the effect that Zoloft has within the neural setting that is the reason for the alleviation of the depression. (Dr. Ivan posted that information but I didn't save it.)