Antidepressant Side Effects & Delayed Therapeutic Effect

Have you ever wondered why antidepressant side effects seem to be worse at the beginning, or why it takes so long for them to actually start doing what you expect of them? There is actually some rhyme and reason for it, so let’s talk about it.

Let’s talk serotonin

People with depression don’t have enough serotonin, and that’s why they call it a chemical imbalance, right? Well, no, actually. The serotonin hypothesis first came about because certain drugs that were known to increase serotonin in the spaces between nerves were helping people with depression. It seemed logical that this would mean that depression involved a serotonin deficit, so scientists came up with this hypothesis, but didn’t have the capacity at the time to properly test it. As the science has advanced, that hypothesis has not been supported; there’s an absolute deficit in serotonin or other neurotransmitters, but the age of Prozac had already pushed the notion of a chemical imbalance out into the world at large.

That being said, having the right amount of something doesn’t mean the whole system is working properly. It’s kind of like having enough gas in the tank doesn’t mean all the gas-utilizing parts of the car are working. So, we start to look at serotonin receptors, i.e. receptors on neurons that serotonin binds at to produce a particular effect.

Serotonin receptors

There isn’t just one kind of serotonin receptor. There’s a bunch of them, in a bunch of different places, and they do a bunch of different things. They’re named starting with 5HT, which is an abbreviation for the chemical name of serotonin. 5HT2a and 5HT7 are both involved in sleep. Several serotonin receptor types influence dopamine activity, which can affect libido and sexual functioning, among assorted other things. 5HT2c is involved in metabolism and obesity. 5HT3 is involved in vomiting. All of this matters for antidepressant side effects, so we’ll come back to it.

Serotonin isn’t the only neurotransmitter in town, but we’ll just stick to that for the sake of this post, as it’s the same general idea for all antidepressants.

Let’s talk synapses

Nerves talk to each other via connections called synapses. The nerve that’s sending the signal is called the presynaptic neuron (i.e. before the synapse), and the nerve that’s receiving the signal is the postsynaptic neuron (i.e. after the synapse). After the presynaptic nerve has received a signal from another nerve, that signal travels down to the opposite end of the neuron, shown in the top part of the diagram above. There are little sacs of serotonin living there that get released out into the synaptic cleft (the space between the two neurons). It’s then free to attach to serotonin receptors on the postsynaptic neuron, which can then do their thing.

The serotonin reuptake pump is the presynaptic nerve’s clean-up crew, sucking back up any leftover serotonin from the synaptic cleft so that it can be recycled.

Antidepressants

SSRIs act on the serotonin reuptake pumps and tell them to stop doing their thing. This means more serotonin is left kicking around in the synaptic cleft. It’s not specific to certain serotonin circuits; if it finds a serotonin reuptake pump, the drug will act on it. That extra available serotonin in going to act on all of your serotonin receptor types, wherever they happen to live.

That’s where we come to side effects. The serotonin receptors, no matter what type, are saying hey, WTF, we’re not used to all this serotonin. Feeling nauseated? That’s probably your 5HT3 receptors saying “me no like!” It’s not that your body is all of a sudden making a bunch of extra serotonin; it’s just shifting where the serotonin hangs out.

Yet the therapeutic effect doesn’t kick in for 4-6 weeks. Why is that?

Me no like

According to psychopharmacology guru Stephen Stahl, an explanation that fits the observed pattern of side effects early on and therapeutic effect later is that therapeutic effect comes about because of changes in the number of serotonin receptors in the synaptic spaces, as well as their sensitivity. These changes likely come as a result of changes in gene expression, which takes a while (about a month).

Once your receptors have sorted themselves out, they’re no longer having that same “me no like” reaction to having more serotonin kicking around in the synaptic clefts. They’re also better adjusted to support your mood. You may still have ongoing side effects, but it’s unlikely to be as bad as the first month. Depending on the specific circuits involved, some side effects (like nausea) are more likely to resolve than others (like sexual dysfunction).

Also, anxiety can be worsened in the receptor “me no like” stage. It takes even longer for the receptors to get properly sorted out in out-of-whack anxiety and OCD circuits; this can be up to 8 weeks.

One possible explanation for antidepressant discontinuation effects is pretty much the same process in reverse. With the reuptake pump able to do its thing again, there’s less serotonin in the spaces between synapses, and receptors start saying “me no like” until genetic expression can be modified to reset the receptors to match with the new serotonin environment.

What does this mean?

If you give up on an antidepressant within the first month, you’ve essentially wasted your time without gaining much information about whether or not it might have worked for you. If the side effects are intolerable, then no question, that’s not a good fit. But if they’re just kind of annoying, sticking it out for at least that first month will give you a clearer picture of what it will be like (both good and bad) for you to be on that medication.

Have you ever had problems with antidepressant side effects when starting out?