SSRIs: Talkin’ ’bout Prozac

I’m sure many of you have seen some of my posts on depression pharmacotherapies, the serotonin theory, and the serotonin system. But I’m still getting a lot of questions, and a lot of misconceptions about how the various drugs work. So I’m going to provide a little more information on the types of pharmacotherapies. And this time, you’re also getting PICTURES!
SSRI diagram1.png
Yup. We’ve been here before.


For further stuff on neurotransmission, take a look at this post. This one isn’t going to cover vesicles or stuff like that. Just get down and dirty with the serotonin.
So as you probably know, neurotransmitters, like serotonin, are released into the synapse. Like this:
SSRI diagram2.png
Now here is where people get mixed up. A neurotransmitter, in itself, is just a chemical. It doesn’t MEAN anything on its own. It’s just a chemical, and could be anything, really. No, what’s important about transmitter is the effects it has on a receptor.. So it doesn’t matter how much or how little transmitter you have anywhere, if there is no receptor to interact with it. Like this:
SSRI diagram3.png
Now, that neurotransmitter can’t hang around forever, it needs to be broken down or taken away, or it will keep stimulating the receptors. You don’t want that, normally, you want a reaction to be short and sweet and done. So you have transporters:
SSRI diagram4.png
Those little blue things. Those suck up the serotonin back into the presynaptic neuron to be used again, or broken down.
SSRI diagram5.png
So now let’s talk about SSRIs, Selective Serotonin Reuptake Inhibitors. These drugs, including things like Prozac, Celexa, Lexapro, Zoloft, and Paxil, just to name some big ones, all have their primary mode of action by BLOCKING the serotonin transporter. When I said this before, I had some people thinking that this would LOWER the levels of serotonin in the synapse. Quite the reverse:
SSRI diagram6.png
The serotonin transporter can’t bring up serotonin anymore. This means that, as more serotonin is released through natural cell firing, serotonin is going to build UP in the synapse:
SSRI diagram7.png
And with all that serotonin around, the receptors on the postsynaptic neuron are going to be stimulated a lot more than they would be normally. So this means that they effects of serotonin become a lot BIGGER than they might be otherwise. And this can help some of the symptoms associated with depression. We used to think that this was because depression was caused by low levels of serotonin. But we now think that, if there ARE low levels of serotonin associated with depression, these might be part of the symptoms rather than the source of the problem. Thus, treating some of the neurochemical symtoms can still help the symptoms that a person with depression might experience, but they don’t necessarily SOLVE the problem of depression. For that, we’re still doing research.

13 Responses

  1. Nice post – and thankfully, reuptake inhibitors like SSRIs and SNRIs don’t only help against depression, they are used for treatment of social phobia and panic disorders etc… quite effectively. The SNRI Venlafaxine has even been shown to reduce the probability for recurrent episodes of depression.
    I have a few questions though – regarding the mechanisms involved:
    1. Could give a little more detail on the reuptake itself? I know the vesicles get to the presynaptic cell-wall in the first place by being tagged with synaptotagmin through influx of calcium-ions and are then transported to the cell-wall through motor-proteins (kinesin)… but how do they get taken up? Are those gates that ‘just’ let the surrounding transmitter-molecules through or are they somehow transported?
    2. Shouldn’t nearby glial-cells clear out the neurotransmitters after a while?
    3. How come the post-synaptic neuron doesn’t adapt to the constantly higher levels of transmitters by reducing the number of receptors? Or does this in fact happen? I can’t imagine that it does so to a greater extent, as that would probably mean a worsening of the symptoms after the treatment ends…
    I couldn’t find anything on this in either the latest edition of Kandel or Dale Purves’s ‘Neuroscience’ – and a search on the net wasn’t too helpful either.

  2. Oops – I meant to say I couldn’t find anything on that third question… just found the relevant articles on the first one.
    My bad. Guess I didn’t look hard enough.

  3. “We used to think that this was because depression was caused by low levels of serotonin. But we now think that, if there ARE low levels of serotonin associated with depression, these might be part of the symptoms rather than the source of the problem.”
    I’m curious — did this shift happen because of any new evidence, or was it just that new hypotheses were proposed?

  4. Heya Sci, can you talk about the difference in time scales between SSRIs being active in the synapse, and patients with depression actually feeling better? My understanding is that the first of these is more or less instant, and the second takes a couple weeks. What’s the current thinking on that?

  5. Such excellent questions, peeps! Sci is more than a bit ill today, but will try to answer with clarity.
    MPhil:
    1) Yes, I think it’s active transport, but I see you found some articles. The vesicles TO the membrane we believe are currently doing the “kiss and run” thing, releasing some serotonin into the synapse, but not merging entirely with the cell membrane to dump their entire contents. As for the reuptake, active transport, sodium- and potassium-dependent. So for every serotonin that goes IN, sodium and potassium (I think it’s 2 Na and 1K, but I’d have to look that up) go out, providing the energy for the transporter to function.
    2) Nearby glial cells DO help clear neurotransmitter out of the synapse, but that’s an effect that is still being studied, and which Sci will admit she doesn’t know a lot about. There is also passive diffusion of serotonin out of the synapse, but most of the serotonin will be taken up by transporters, which work very quickly, and so are responsible for rapid termination of the signal.
    3) YES! The post-synaptic neuron’s receptors DO adapt after a while. Most serotonin receptors are G-protein coupled (which I can write a post about later if I have the energy) and it’s known that chronic stimulation will cause those receptors to become less sensitive. So they will adapt. Not only do we think this is responsible for some of the withdrawal effects of going off SSRIs (which can include refractory depression), we also think that the desensitization of the receptors may be partially responsible for the EFFECTS of SSRIs, that this adaptation may be required for them to have their anti-depressive effects.
    Zachary: Both. New evidence AND new hypotheses. It turns out that lowering global levels of serotonin can make you a bit pissy, but doesn’t actually appear to CAUSE depression. Also, SSRIs don’t work for everyone, implying that there is more than serotonin in the root cause of depression (or that there are several kinds of depression, also a very strong possibility). Finally, other drugs, such as the SNRIs (selective norepinephrine reuptake inhibitors) work for depression as well, and may not hit serotonin at all, not to mention the work being done right now with drugs hitting brain-derived neurotrophic factor. Yeah, a lot of new stuff…
    Abby N: Excellent point. Yes, most SSRIs and antidepressants in general take several weeks to hit (this means that some doctors will also prescribe a stimulant such as Ritalin to try and cover the interval), and this has been a source of hair-pulling among depression scientists for years. Just an increase in serotonin doesn’t appear to do it. This makes us think that long-term treatment might be required because the adaptations in the system (produced by chronic high levels of serotonin) could be what help the depressive symptoms. Other hypotheses include the BDNF theory, which says that SSRIs cause changes in neuronal growth and connections, which take some time, and contribute to the anti-depressant effects. So the short answer is that yes, these drugs take some time to work, and no, we don’t know why. But we’re working on it.

  6. I read somewhere that serotonin is somehow related to headaches or migrains. Can you explain, if it is true. thanks. I am a disabled veteran with chronic PTSD, and one of my symptoms is terribly painful headaches.
    I take Zolmitriptan for them, and it stops them in an hour completely.
    The VA will not give me enough though. They say it is a dangerous drug.

  7. Sort of related to #6, why is it that Lexapro drastically reduces my need for NSAIDS for pain?

  8. I can’t believe I didn’t think of sci…I adore sci and therefor feel compelled to tag her!!!!!
    And I love the pictures!!! They make me very happy – happier than the prozac…If I were taking prozac…

  9. Good explanation of this topic – although as always in the brain there is more than meets the eye…
    Animal experiments show that acute doses of SSRIs actually reduce the firing rate of 5HT neurones. This is thought to be because there are 5HT receptors on these neurones, which act to inhibit their own firing – basically, it’s a simple system for keeping 5HT levels from getting too high, when they do, 5HT release is reduced.
    eventually the presynaptic receptors are thought to get downregulated. this is one explanation for the delay in antidepressant onset.
    blocking these “presynaptic” inhibitory receptors with various drugs increases cortex 5HT levels – in animals. whether this happens in humans and if so whether it could speed up the antidepressant response is controversial. there have been some trials of a drug called pindolol which have given promising results that it does accelerate the response although a lot of people are still skeptical (I think because it sounds a bit too good to be true, also the trials were small).

  10. Indeed, Neuroskeptic, indeed. I love me some 5-HT1A receptors (those are the ones on 5-HT cells bodies which, when stimulated, decrease 5-HT cell firing). I don’t know that just the presynaptic receptors being downregulated would account for all effects of SSRIs, though, because one would imagine that post-synaptic receptors are getting downregulated to a similar extent (though not all go in the same direction, if you see the effects of knocking out the serotonin transporter in mice).
    And yeah, in my opinion pindolol is probably too good to be true. It’s a weak/partial 5-HT1A agonist, but it’s also got non-selective beta-blocking activity. Could make for some un-fun side effects. OTOH, have you seen the effects of Buspar?
    Re: Migraines. Honestly, I’d have to do some research. There is a known role for serotonin in migraine, but I don’t know the details. As for Zolmitriptan, it’s possible you need some lower doses (or fewer doses) because of the risk of heart attack in susceptible individuals. It can also cause some sedative effects.
    Additionally, there is a role for 5-HT in pain, but I think it’s pretty poorly understood. Donna, I’d have to look that up.

  11. So does Prozac help with anxiety? i need to know..and if it does how long does it take to help for it?

  12. […] and treatment for depression, which we’ll also be talking about, you can see my tutorials here , here, and […]

  13. […] and treatment for depression, which we’ll also be talking about, you can see my tutorials here , here, and […]

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