It can be really useful to understand how medications work, as it can make both the therapeutic effects and side effects make more sense. As a mental health nurse, former pharmacist, and psych med-taker, this is a major area of interest for me. This is the first of a series of psych meds 101 posts that will break down different classes of medications; this post is on antidepressants.
How Antidepressants Work
Most antidepressants affect the three major neurotransmitters implicated in depression: serotonin, norepinephrine, and dopamine. Nerve cells (neurons) communicate with other neurons via connections known as synapses. The neuron sending the signal is presynaptic, and the receiving neuron is postsynaptic. The presynaptic neuron releases neurotransmitter molecules in the synaptic cleft (the space between the two neurons), and the neurotransmitters act at specific receptors on the postsynaptic neuron.
Why does that matter? Many antidepressants are reuptake inhibitors. That means that they block recycling pumps on the presynaptic side that would normally take up and recycle some of the neurotransmitter molecules that were released. This means there’s more neurotransmitter floating around the synaptic cleft that’s available to act at receptors on the postsynaptic neuron. Over time, this actually changes the number of receptors that the postsynaptic neuron produces, which may explain the delayed onset of action for antidepressants.
Other antidepressants may block certain types of receptors on either pre- or post-synaptic neurons, and this may influence the release of one or more types of neurotransmitters.
A lot of medications are messy, in the sense that they don’t only do what we want them to do. Some antidepressants affect histamine receptors, and this can cause side effects such as sedation and weight gain. Activity at muscarinic receptors can cause sedation, dry mouth, and constipation.
There are multiple different kinds of serotonin and norepinephrine receptors, and they impact various processes in the body. When serotonin gets busy at certain types of receptors it can produce unwanted effects, like insomnia, weight gain, or sexual dysfunction. Norepinephrine can act at certain receptors to affect things like blood pressure, causing lightheadedness.
The fact that these side effects are possible doesn’t predict which ones, if any, you will experience. For some people, experiencing some degree of side effects will be an acceptable price to pay for the benefit of the medication; that will depend on how tolerable the side effects are for you, how well the medication works, and how hard it’s been to find a medication that works as well as this one does. What’s key is open communication with your prescriber around what’s working and what’s not.
Antidepressant discontinuation syndrome
Antidepressants aren’t addictive, but people can have negative effects when coming off of them too quickly. This antidepressant discontinuation syndrome, and can include things like dizziness, gastrointestinal upset, anxiety, sleep problems, headache, and a sensation of brain zaps. It’s a major problem for some people, but by no means everyone; I’ve never had any problems coming off of antidepressants. There’s no way to predict what your individual experience will be.
Classes of Antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
These inhibit the activity of the presynaptic serotonin recycling pumps. Escitalopram is the most “clean,” in the sense that it does what it’s supposed to and not much else. Other medications in this class include citalopram, sertraline, fluoxetine, and paroxetine.
Serotonin and norepinephrine reuptake inhibitors (SNRIs)
These inhibit the presynaptic recycling pumps for both serotonin and norepinephrine. Some people are less responsive to meds that act on serotonin alone, and do better when norepinephrine gets involved too. Drugs in this class include venlafaxine, desvenlafaxine, and duloxetine.
Norepinephrine and dopamine reuptake inhibitors (NDRIs)
Bupropion inhibits the presynaptic recycling pumps for norepinephrine and dopamine. Because of the different mechanism of action, it can be combined with an SSRI for a triple-whammy effect.
Tricyclic antidepressants (TCAs)
These inhibit the recycling pumps for serotonin and norepinephrine. However, they are quite “messy” and affect a number of different receptors, meaning they tend to cause more side effects. They are dangerous in overdose because they can potentially disrupt the heart rhythm.
Several years ago, a psychiatrist wanted to put me on nortriptyline. While I reluctantly agreed, I soon stopped it because I didn’t think it was a safe medication to have at home, given that I do get suicidal thoughts in the context of depression. Other examples of TCAs include amitriptyline and imipramine. This class of medications is also used to manage nerve pain.
Monoamine oxidase inhibitors (MAOIs)
These inhibit the monoamine oxidase (MAO) enzyme, which acts inside neuronal cells to break down serotonin, norepinephrine, and dopamine. They’re an older class of medications, and despite being very effective, they’re seldom used because of the need to restrict dietary intake of tyramine.
Tyramine is an amino acid that’s normally broken down in the gut by MAO, but if MAO is blocked by medication, tyramine is absorbed into the bloodstream. This sends blood pressure through the roof, a condition referred to as hypertensive crisis. Tyramine is found in a number of different foods, including aged cheeses and fermented foods.
Tranylcypromine is the most common MAOI. Moclobemide is a variation of an MAOI called a RIMA (reversible inhibitor of monoamine oxidase). It acts reversibly on the MAO enzyme, so that tyramine is still able to get broken down safely by MAO in the gut.
Various other medications, such as mirtazapine and vortioxetine, work in novel ways, which I won’t get into the specifics of here. The combination of mirtazapine and venlafaxine is sometimes referred to as “California rocket fuel”; this is part of my current treatment plan, and while I’m not getting a rocket fuel effect it has helped.
Other medications can be used to augment antidepressant therapy, including lithium, atypical antipsychotic medications, and liothyronine (a form of thyroid hormone).
There are also new outside-of-the-box treatments being studied such as ketamine, which affects a different neurotransmitter system. You can read more about ketamine here.
If you’ve made it this far, good for you! I hope you’ve found some of this useful, and maybe it’s even given you some added insight into medications you have taken or are taking.
There’s more on psych meds on the Psych Meds Made Simple book page. The rest of the Psych Meds 101 series covers:
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Ashley L. Peterson
BScPharm BSN MPN
Ashley is a former mental health nurse and pharmacist and the author of four books.