(Note: This article is from the archive, written when exploring the history of psychopharmaceuticals.)
This hypothesis has its origins with some of the old SSRIs, and tries to explain:
- Why it takes time for antidepressants to work
- How side effects come before the antidepressant works
- How the side effects go away over time
Here is a sketch of a serotonergic neuron:
On the left side are dendrites. Think of these as arms that receive input. On the right is the axon. This is the output arm. The end of the axon is called the presynapse, and the half circle to the right of that is the postsynapse. The little yellow bars are serotonin hormones. The blue blocks on the dendrites and the postsynapse are serotonin receptors.
What we don’t see is the neuron getting the message to release serotonin. You might be thinking the receptors on the dendrites are for that since they’re input, but they’re actually autoreceptors. Their job is to apply brakes to the serotonin release.
When the neuron gets a message from another neuron or neurons to release serotonin, it becomes an electrical message that shoots down the neuron and releases serotonin at the presynaptic site. The serotonin then diffuses over to the postsynaptic receptors and BAM! That serotonin makes something happen. Maybe you get happier. But then maybe you get anxious. Weird, right?
Those serotonin receptors are called 5-HT receptors (5-hydroxytryptamine, the “other” name of serotonin*). There are many 5-HT receptors, involved in mood, blood pressure, sexual activity, headaches, anxiety, memory, nausea, sleep… the list goes on and on.
So this monoamine hypothesis states that depression is in part cause by that serotonergic neuron not releasing very much serotonin from its axon anymore. When that happens, the postsynaptic neuron wonders what’s going on, why it’s not getting much serotonin anymore, and it up-regulates, it creates more serotonin receptors. These new receptors will be many kinds of receptors, not just the ones that help you feel better. So now it’s not just that there is less serotonin, but there are a greater spread of receptor types to be triggered by what little serotonin there is.
Enter an SSRI. This person starts taking an SSRI, a selective serotonin reuptake inhibitor. Look again at the picture above and you’ll see five “Do Not Enter” type circles. These are all on reuptake pumps. While the neuron releases serotonin, it also has reuptake pumps to try to get the serotonin back after it does its job of triggering a receptor. Well, the SSRI interferes with these pumps working. So where we had very little serotonin, now we have more serotonin hanging around these neurons.
Remember the arms on the left, the dendrites, get input. When the uptake pumps shut down over there, the autoreceptors start getting really busy. They become too active, too sensitive. When this happens, the dendrites begin to downregulate the receptors there.
Now, here’s one of the odd things. Those autoreceptors are supposed to help the neuron understand how much serotonin to release. Of course, we have a dysfunctional neuron here, and we’re trying to get it to change, literally trying to change you on a cellular level. When these autoreceptors downregulate due to being over stimulated, there are now fewer receptors receiving serotonergic messages. The result is that the neuron will begin to create more serotonin, and release more from the axon.
Those postsynaptic receptors also have been being flooded with serotonin, and so they too are going to downregulate. Ultimately, this should be the natural state of the neurons: the presynaptic neuron releasing a healthy flow of serotonin when needed (not stunted, not too little), and the postsynaptic neuron having the right amount of proper receptors to receive the serotonin stimuli.
Let’s go back to our original questions:
- Why it takes time for antidepressants to work
- How side effects come before the antidepressant works
- How the side effects go away over time
Why does it take time for the antidepressant to work?
Because that up and downregulation of the receptors takes time, and that’s a big part of the neuronal change we’re looking for the medication to make.
How come there are side effects before the antidepressant even helps?
Because the synaptic zone gets flooded with serotonin while all those extra receptors are there. Many of the receptors do things we don’t want them to do like cause anxiety, give stomachaches, cause sexual issues. For this reason, it is recommended that SSRIs be started at a low dose and increased gradually, as the neurons begin to change.
How do the side effects go away over time?
I think you can answer this one by now. As the postsynaptic zone downregulates, removes, 5-HT receptors over time, less side effects will be felt.
So that is a nutshell summary of the monoamine hypothesis of antidepressants. Obviously, things are more complicated than this. Serotonin, as mentioned before, has many receptors all over the place and a very wide range of capabilities. There are many questions not answered, such as the function of antidepressants in OCD and eating disorders. Personally, I think the hypothesis is a little rough, but it helps us start forming an idea of functions.
This hypothesis grew over time and was dominant, but largely has become superseded by other things such as research on brain-derived neurotropic factors. Regardless, it’s good information to be aware of.
