Atypical antidepressants

Definitions & Key takeaways

Atypical antidepressants are a class of antidepressant drugs that are distinguished from traditional, older antidepressant medications by their unique mechanism of action. They are generally reserved for cases that do not respond to other antidepressants. The atypical antidepressants include drugs like agomelatine, mirtazapine, and bupropion.

Atypical antidepressants are generally better tolerated than older drugs, and they are often just as effective. They are not without their side effects, however. The most common side effects of atypical antidepressants include nausea, headaches, anxiety, insomnia, and sexual dysfunction.

Chapters:

Watch video only

Introduction0:00–0:42

Atypical antidepressants are mainly used to treat major depressive disorder. This disorder causes a persistent feeling of sadness and loss of interest in everyday activities.
Even though the exact cause of depression is still unknown, there's some evidence that suggests it’s related to low levels of neurotransmitters like serotonin, norepinephrine, and dopamine.
Typical antidepressants like selective serotonin reuptake inhibitors or tricyclic antidepressants work by increasing the levels of serotonin and norepinephrine, while atypical antidepressants often have multiple mechanisms of action.
All right, now within the brain, there are many different types of neurons, but we’re going to focus only on three: serotonergic neurons, which produce serotonin; noradrenergic neurons, which produce norepinephrine; and dopaminergic neurons, which produce dopamine.

Physiology0:42–2:39

Each of these neurons synthesizes and stores their neurotransmitters in small vesicles. So, when an action potential reaches the presynaptic membrane, these vesicles fuse with the membrane, releasing neurotransmitters into the synaptic cleft.
Once released, serotonin (or 5-HT) binds to 5-HT2 receptors on the postsynaptic membrane, thereby increasing neural stimulation, and regulating mood, feeding, and reproductive behavior.
On the other hand, norepinephrine binds to norepinephrine receptors on the postsynaptic membrane, boosting alertness. And finally, dopamine binds to dopamine receptors, thereby 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, serotonergic neurons on their presynaptic membrane have serotonin transporters (or SERT); noradrenergic neurons have norepinephrine transporters (or NET); while dopaminergic neurons have dopamine transporters (or DAT).
These membrane proteins transport neurotransmitters from the synaptic cleft back into presynaptic neurons. This leads to a decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing.
Noradrenergic and serotonergic neurons are also rich in alpha 2 receptors. When stimulated, alpha 2 receptors inhibit the activity of the presynaptic neurons and decrease the release of norepinephrine or serotonin.Now, in conditions such as major depressive disorder, atypical antidepressants are typically reserved for individuals that don’t respond to other antidepressants.

Indications2:39–2:59

Common medications in this group include mirtazapine, trazodone, nefazodone, vilazodone, vortioxetine, and bupropion. All right, first let’s start with mirtazapine.

Mirtazapine2:59–4:14

Mirtazapine binds and inhibits several receptors including alpha 2 receptors, 5-HT2A receptors, 5-HT3A receptors, and histamine H1 receptors.
Its main antidepressant effect comes from the inhibition of alpha 2 receptors, which reduces the inhibition of the presynaptic neuron, leading to increased norepinephrine and serotonin release.
Now mirtazapine is actually a serotonin antagonist, which might seem counterintuitive. But there are different types of 5-HT2 receptors; mirtazapine selectively blocks 5-HT2A and 5-HT3A receptors, so more serotonin can bind to 5-HT1A receptors; which have a stronger link to depression.
Inhibition of 5-HT3A receptors also reduces nausea and vomiting. Lastly, inhibition of histamine H1 receptors leads to sedation, which could be desirable in depressed individuals with insomnia.
Other common side effects include dry mouth, increased appetite, and weight gain, which may be helpful for anorexic individuals.
Next we have trazodone and nefazodone. These medications’ main antidepressant effect comes from their ability to bind 5-HT2A receptors, so more serotonin binds to 5-HT1A receptors.

Trazodone and Nefazodone4:14–4:59

They are also weak inhibitors of serotonin reuptake transporters on the presynaptic neuron, thereby increasing the levels of serotonin within the synaptic cleft.
They are strong H1 receptor inhibitors and are commonly used to treat insomnia. Finally they are also alpha 1 receptor inhibitors, which may cause orthostatic hypotension and priapism, which is a prolonged, unwanted erection of the penis.
Nefazodone is also known to cause severe liver damage in rare cases. Next we have vilazodone and vortioxetine, which are strong inhibitors of serotonin reuptake transporters on the presynaptic neuron just like SSRIs.

Vilazodone and Vortioxetine4:59–6:21

However, these medications can also directly bind to and stimulate 5-HT1A receptors; vilazodone is a partial agonist, while vortioxetine is a full agonist.
Since they enhance the effect of serotonin through 2 separate mechanisms, they can also cause serotonin syndrome, which is a life-threatening condition caused by serotonin accumulation and over stimulation of the nervous system.
This syndrome is characterized by skin flushing, hyperthermia, agitation, muscle rigidity, seizure, and coma. It usually occurs in individuals treated with a combination of these medications and other antidepressants that increase serotonin levels, such as selective serotonin reuptake inhibitors.
Treatment of serotonin syndrome consists of administration of cyproheptadine, which is a serotonin antagonist that blocks 5-HT2 receptors.
These medications are anticholinergics and can cause atropine-like side effects such as sedation, blurred vision, orthostatic hypotension, urinary retention, and tachycardia.
Vilazodone can also cause weight gain, while vortioxetine can cause abnormal dreams. The final medication is bupropion, which, unlike most antidepressants, does not have a serotonergic effect.
Instead, bupropion binds to norepinephrine and dopamine reuptake transporters and inhibits them, leading to increased levels of these neurotransmitters within their synaptic clefts.

Bupropion6:21–7:09

Besides norepinephrine and dopamine transporters, bupropion also blocks nicotinic (Ach) receptors, which makes it useful in smoking cessation.
Another benefit of bupropion is that it has the least sexual side effects out of all the antidepressants. Due to its excitatory effects, bupropion has a potential to cause tachycardia, insomnia, and even a lower seizure threshold, which is particularly important in people with a history of seizures or eating disorders.
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 set up a closed subway station with 3 areas to represent the 3 main types of mechanisms for these drugs.

Memory Palace7:09–11:23

On the left is the entrance gate, and this area is where we’ll put alpha 2 antagonists that cause neurotransmitter release.
Next to it are the train tracks which represent serotonin receptors in the synaptic cleft. The left track has a red light for receptor antagonists and the right track has a green light for agonists.
The final area is a subway tunnel representing the drugs that affect reuptake transport channels. So, the first drug is Mirtazapine which is a magical mirror that zaps people with lightning.
Mirtazapine, mirror, zaps, you get it. Now its main mechanism is blocking alpha 2 receptors, which causes the release of serotonin and norepinephrine so let’s put this mirror in the entrance area.
However, since its secondary effect is to act in the synaptic cleft as a 5-HT2A antagonist, so we want it close to the edge of the antagonist track.
Next on the tracks are trazodone and nefazodone represented by two bowls of thick udon noodles. These are some dangerous noodles since one is topped by a bear trap for trazodone and the other contains a knife for nefazodone.
Since their main mechanism is 5-HT2A antagonism we’ll put them directly on the track, on the antagonist side. Their secondary mechanism is weak inhibition of serotonin reuptake transporters, so you can imagine them moving into the tunnel.
Now we have vilazodone, which is udon noodles topped with a scoop of vanilla ice cream, and vortioxetine, which is an ox caught in the vortex of a tornado.
Since these drugs mainly inhibit serotonin reuptake transporters, we’ll put them by the tunnel. Now, they are also 5-HT1A agonists, so they’ll be on the right track.
Finally, off to the side of the tunnel is bupropion, represented by a cool dude in a leather jacket who’s burping loudly.
He prevents the reuptake of norepinephrine and dopamine but doesn’t affect serotonin like the other medications, so he’s off on his own.
It’s also used for smoking cessation so let’s have a discarded, bent cigarette by his feet. Now for side effects, the main one is that it lowers the seizure threshold, so let’s have him burp out a large cloud of gas that left a passerby passed out and twitching on the ground.
Next, let’s have some girls swooning over him, since it doesn’t have sexual side effects. Serotonin reuptake inhibitors like Vilazodone and vortioxetine have atropine-like side effects, so let’s put a tropical palm tree for atropine between them.
The ox is shouting, “this is a nightmare,” since vortioxetine causes abnormal dreams, and an overweight kid is eyeing the ice cream udon, which causes weight gain.
These drugs also cause serotonin syndrome, which will be represented by a dead knight who’s about to be cremated. He’s stiff, so there’s muscle rigidity, the hot fire represents hyperthermia, and the armor is glowing red for flushing.
The knight was only faking his death, so he starts squirming from the heat to represent agitation and seizure. Trazodone and nefazodone cause sedation via histamine H1 receptor inhibition so let’s have a sleepy snake going hizzzz for histamine.
They also cause priapism, so let’s put a hot dog in each bowl. Nefazodone causes liver toxicity, so there’s also a big liver in that bowl.
Finally we have mirtazapine, which also inhibits H1 receptors, so it gets a sleepy snake too. This medication increases appetite and causes weight gain, so let’s have an overweight man standing in front of the mirror.
He’s got a big wad of cotton in his mouth to represent dry mouth, which also prevents him from vomiting. All right, as a quick recap.
Atypical antidepressants are medications that are used to treat depression when the person does not respond to typical antidepressants.
Mirtazapine increases the release of norepinephrine and serotonin, but also acts as a serotonin antagonist. Trazodone and nefazodone are more potent serotonin antagonists, but also act as weak inhibitors of serotonin reuptake transporters.

Review11:23–12:09

Vilazodone and vortioxetine are strong serotonin reuptake inhibitors and also function as serotonin agonists. Bupropion blocks the reuptake transporters of norepinephrine and dopamine, but doesn’t affect serotonin.
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.
Stay tuned for the answers at the end. Bupropion blocks the reuptake Transporters of narva NASA Mendota mean, but does not affect serotonin.
But wait, there's more here than mine map with all the mnemonics from the video. Go ahead and pause the video.

Mind Map12:09–12:22

So you can test yourself to see what your Amber, Stacy and answers after the credits.