I can be a bit (okay more than just a bit) of a geek, and one of my big interests is how medications work. Throw in the fact that I’m a mental health nurse, former pharmacist, and person who has tried piles of different psychiatric medication, and you get someone who will quite happily watch hours of continuing education webinars on the topic.
It can be really useful to understand how medications work, because it can make both the therapeutic effects and side effects make more sense. This is the first of a series of psych meds 101 posts I’m going to write that will break down different classes of medications. I’ll also address antipsychotics, mood stabilizers, anti-anxiety meds, and sleep meds.
Mechanism of Action
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 referred to as presynaptic, and the neuron receiving the signal is referred to as 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, meaning they block recycling pumps on the presynaptic side that would normally take up and recycle some of the neurotransmitter that had been released. This means there is more neurotransmitter floating around the synaptic cleft, 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 want them to. 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 do things that we don’t want it to, causing things like insomnia, weight gain, or sexual dysfunction. Norepinephrine can act at certain receptors to affect things like blood pressure, causing lightheadedness.
Classes of Antidepressants
Selective serotonin reuptake inhibitors (SSRIs):
These inhibit the activity of the presynaptic serotonin recycling pumps. Escitalopram is the most “clean” in 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 not as responsive to meds that act on serotonin alone, and respond better when there is action on norepinephrine. 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 used in combination with SSRI for a triple-whammy sort of 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, and 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 and is involved in breaking down serotonin, norepinephrine, and dopamine. They are an older class of medications and despite being very effective antidepressants they are seldom used because of the need to restrict dietary intake of tyramine. Tyramine is normally broken down in the gut by MAO, but if MAO is blocked by medication, tyramine is absorbed into the bloodstream and sends blood pressure through the roof. This condition is referred to as hypertensive crisis. Tyramine is found in a number of different foods, including aged cheeses and fermented foods.
Tranylcypromine is the most commonly used MAOI. Moclobemide is a variation of an MAOI called a RIMA (reversible inhibitor of monoamine oxidase) that acts reversibly on the MAO enzyme, so that tyramine is still able to get broken down safely by MAO in the gut.
There are a variety of other medications such as mirtazapine and vortioxetine that work in novel ways, which I won’t get into 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. There are also other medications that 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 the action of the neurotransmitter glutamate. I am really excited about this, and will write more about it in future posts.
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. In the upcoming post Psych Meds 101: Mood Stabilizers, I’ll talk about the treatment of bipolar depression, and why antidepressants have a limited role to play.
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