Monoamine oxidase inhibitors

Definitions & Key takeaways

Monoamine oxidase inhibitors (MAOIs) are a class of medications used to treat depression, anxiety, and other mental health disorders. MAOIs work by blocking an enzyme called monoamine oxidase, which breaks down monoamine neurotransmitters, namely serotonin, norepinephrine, and dopamine, so they can be released again into the synapse. By blocking this enzyme, these chemicals are able to remain at higher levels in the brain, providing a beneficial effect on mood and behavior. Common side effects of MAOIs include drowsiness, dizziness, insomnia, dry mouth, and weight gain.

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Introduction0:00–0:40

Monoamine oxidase inhibitors, or MAOIs, are a class of medications used in the treatment of depression, which is a mood disorder that causes a persistent feeling of sadness and loss of interest in everyday activities.
Even though the exact cause of depression is still unknown, there is some evidence that suggests it’s related to low levels of serotonin, norepinephrine, and dopamine, which are also called monoamines because they have only one amine group.
Now, monoamine oxidase inhibitors work by increasing levels of serotonin, norepinephrine, and dopamine, which helps to alleviate the symptoms of depression.

Physiology0:40–2:22

Alright, now within the brain, there are many different types of neurons, but we’re going to focus only on three: serotonergic neurons that release serotonin, noradrenergic neurons that release norepinephrine, and dopaminergic neurons that release dopamine.
Each of these neurons synthesizes and stores neurotransmitters in small vesicles, so when an action potential reaches the presynaptic membrane, these vesicles fuse with the membrane, releasing neurotransmitters in the synaptic cleft.
Serotonergic neurons release serotonin, which then binds to 5-HT2 receptors, thereby increasing neural stimulation and regulating mood, feeding, and reproductive behavior.
On the other hand, noradrenergic neurons release norepinephrine, which hooks up to norepinephrine receptors (NE receptors), boosting alertness and focus.
Lastly, dopaminergic neurons release dopamine, which binds to dopamine receptors, stimulating cognitive functions, motivation, and awakeness.
As long as there’s a high enough concentration of neurotransmitters in the synaptic cleft, the postsynaptic neurons will continue to fire.
Now, each of these presynaptic neurons has small reuptake proteins, which pump the neurotransmitters from the synaptic cleft back into presynaptic neurons.
Once inside the neuron, a class of enzymes called monoamine oxidases will break down some of these neurotransmitters; monoamine oxidase A breaks down serotonin, norepinephrine, and dopamine; and monoamine oxidase B only breaks down dopamine.
The neurotransmitters that are not broken down are packaged into pre-existing vesicles, waiting to be released once more.

Mechanism of action and Indications2:22–4:20

Now, in people with major depressive disorder, MAOIs are used to increase the levels of all the neurotransmitters related to depression.
It’s important to note that MAOI are not the first-line therapy due to their severe side effects. Instead, selective serotonin reuptake inhibitors, or SSRIs, are used as the first-line therapy.
MAOIs can be used as the second or third line therapy, and they are especially effective in treating atypical depression.
In contrast to major depressive disorder, which is characterized by a persistent feeling of sadness, individuals with symptoms associated with atypical depression are able to improve their mood in response to positive events and circumstances.
They also experience increased appetite, weight gain, sleepiness, and fatigue. Now, MAOIs are subdivided into two types: non-selective and selective.
Non-selective MAOIs, such as isocarboxazid, phenelzine, and tranylcypromine inhibit monoamine oxidase A and monoamine oxidase B, so serotonin, norepinephrine, and dopamine levels will increase.
These medications are also called irreversible MAOIs because they bind irreversibly to the enzymes, permanently blocking their function.
Once these enzymes are inhibited, the monoamines neurotransmitters get packed into pre-existing vesicles. So, the next time an action potential reaches the presynaptic membrane, more neurotransmitters are released into the synaptic cleft and thus alleviating the symptoms of depression.
On the other hand, selective MAO-B inhibitor like selegiline and rasagiline will only inhibit MAO B, so they only increase the level of dopamine.
Although they can be used as antidepressants, they are more commonly used to treat Parkinson’s disease, a neurodegenerative disorder that affects the dopaminergic neurons in the substantia nigra region of the brain.

Side effects4:20–6:00

The most dangerous side effects of MAOIs include serotonin syndrome and hypertensive crisis. Serotonin syndrome is a life-threatening condition caused by serotonin accumulation, which over stimulates the nervous system.
This syndrome is characterized by skin flushing, hyperthermia, agitation, muscle rigidity, seizure, and coma. This is very common when other antidepressants that increase serotonin level, such as SSRIs, are combined with MAOIs.
Due to this, it’s recommended that MAOIs be stopped for at least two weeks, which is the time it takes to replace the MAO enzymes, before starting another antidepressant.
Treatment of serotonin syndrome consists of administration of cyproheptadine, which is a serotonin antagonist that blocks 5-HT2 receptors.
On the other hand, hypertensive crisis is a condition characterized by hyperthermia, increased blood pressure, increased heart rate (tachycardia), arrhythmias, and agitation.
It’s commonly seen in individuals that combine MAOIs with tyramine-rich food and drinks, such as cheese, wine, and beer.
Normally, within the cells of the gut wall, both monoamine oxidase A and monoamine oxidase B break down tyramine. But when they’re inhibited, more tyramine is absorbed.
High concentration of tyramine increases norepinephrine release, which leads to hypertensive crisis. Treatment of this condition consists of administration of phentolamine, which is an adrenergic antagonist that blocks norepinephrine receptors.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! So, let’s have a sad, old man representing major depressive disorder, but he’s being cheered up by a little girl with a flower, representing its effectiveness for treating atypical depression.

Memory Palace6:00–7:37

Now, these are treated by the nonselective MAOIs, so let’s use a fiery phoenix, for phenelzine, who’s sitting in a box full of ice for isocarboxazid.
The box is on top of a trampoline for tranylcypromine. The trampoline has the large letters A and B on it to help you remember these medications inhibit both MAO-A and MAO-B.
Next, let’s have an empty parking spot for the MAOIs that can be used to treat Parkinson's disease. A man wearing a ghillie suit is protecting this parking spot, which represents selegiline and rasagiline.
Unfortunately, the ghillie suit doesn’t help him hide, since there’s a big, red letter B on it. But it does help you remember these medications are selective for MAO-B.
Now, for the side effects of MAOIs, let’s use the knight representing serotonin syndrome from our SSRI video. He’s dead, and is about to be cremated.
His body is stiff, so there’s muscle rigidity, the hot fire represents hyperthermia, and the armor is glowing red for flushing.
For hypertensive crisis, let’s set a platter full of cheese and wine, which are both tyramine rich foods, on top of a red garden hose representing a blood vessel.
This crushing weight increases the pressure in the hose, so hypertension! All right, as a quick recap.

Review7:37–8:21

Monoamine oxidase inhibitors, or MAOIs, are antidepressant medications that inhibit monoamine oxidases and prevent the breakdown of serotonin, norepinephrine, and dopamine, so they can be released again into the synapse.
Non-selective MAOIs, which include isocarboxazid, phenelzine, and tranylcypromine, are second or third line antidepressants that are particularly effective against atypical depression.
Selective MAO-B inhibitors, such as selegiline and rasagiline can treat Parkinson’s disease. These medications are not the first-line therapy for depression due to dangerous side effects like serotonin syndrome and hypertensive crisis.
But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map8:21–8:32

Stay tuned for the answers at the end.