Tricyclic antidepressants

Definitions & Key takeaways

Tricyclic antidepressants (TCAs) are a class of medications used to treat depression, anxiety disorders, migraine, and chronic pain. They are named for their chemical structure, which includes three rings of atoms.

TCAs work by preventing serotonin and norepinephrine reuptake from the synaptic cleft, thus enhancing the effect of both neurotransmitters on postsynaptic neurons. Some common TCAs include amitriptyline, imipramine, and nortriptyline.

Common side effects include dry mouth, blurred vision, constipation, dizziness, and drowsiness. TCAs can also cause more serious side effects, such as heart rhythm disturbances, seizures, and an increased risk of suicide, particularly in younger individuals.

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Introduction0:00–0:32

Tricyclic antidepressants, or TCAs, 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.
Tricyclic antidepressants work by increasing the levels of serotonin and norepinephrine to alleviate the symptoms of depression.

Physiology0:32–1:56

Alright, now within the brain, there are many different types of neurons, but we’re just going to focus on two: serotonergic neurons which produce serotonin, and noradrenergic neurons which produces norepinephrine.
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. 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, while noradrenergic neurons have norepinephrine transporters or NET.
These membrane proteins transport the serotonin and norepinephrine in the synaptic cleft back into presynaptic neurons. This leads to decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing.

Mechanism of Action1:56–2:59

So, in conditions such as major depressive disorder, tricyclic antidepressants can be used to increase the levels of serotonin and norepinephrine.
Tricyclic antidepressants are subdivided into 2 main groups: tertiary TCAs, which include amitriptyline, imipramine, and clomipramine; and secondary TCAs, which include desipramine and nortriptyline.
Tertiary TCAs are also known as non-selective tricyclic antidepressants and they inhibit both serotonin transporters and norepinephrine transporters, while secondary TCAs, which are also known as selective tricyclic antidepressants, inhibit only norepinephrine transporters.
This way, tricyclic antidepressants are increasing levels of serotonin and norepinephrine or just norepinephrine within the synaptic cleft, thus increasing the activity of postsynaptic neurons.
It's important to note that these medications are slow-acting because it takes time for serotonin and norepinephrine to accumulate within the synaptic cleft.
Because of this, it usually takes 2-4 weeks before improvements can be seen. Even though they’re very effective in the treatment of depression, tricyclic antidepressants are not considered as the first line therapy due to their severe side effects.

Indications2:59–3:42

They’re typically reserved for when there is no response to other antidepressants, such as selective serotonin reuptake inhibitors, or SSRIs.
Other indications for TCAs include phobic disorders, chronic neuropathic pain, like peripheral neuropathy, and as migraine prophylaxis.
Now, for medication specific indications, clomipramine can be used in the treatment of obsessive-compulsive disorder, or OCD, while imipramine is used in the treatment of nocturnal enuresis, which is involuntary urination while asleep.

Side effects3:42–5:40

Besides serotonin and norepinephrine transporters, TCAs also block histamine H1 receptors, causing sedation; alpha 1 receptors, causing orthostatic hypotension; and muscarinic receptors, causing atropine-like side effects.
Atropine-like side effects occur more commonly with tertiary TCAs and they include dry mouth, tachycardia, urinary retention, confusion, and hallucinations.
TCAs 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 TCAs and other antidepressants that increase serotonin level, such as selective serotonin reuptake inhibitors.
Treatment of serotonin syndrome consists of administration of cyproheptadine, which is a serotonin antagonist that blocks 5HT2 receptors.
TCAs are also cardiotoxic and can lead to arrhythmias and prolong the QT interval. Treatment of cardiotoxicity consists of administration of sodium bicarbonate in order to prevent arrhythmias.
It’s important to remember the most common causes of death when using TCAs are the 3 C’s: convulsion, coma, and cardiotoxicity.
Finally, most tricyclic antidepressants are inhibitors of cytochrome P450 enzymes. These liver enzymes are responsible for the metabolism of a variety of drugs and toxins in our body.
So, when combined with other drugs that are metabolized by cytochrome P450 enzymes, such as benzodiazepines, TCAs will reduce their rate of elimination and cause them to build up in the body.
In addition, if taken with ethanol or sedative hypnotics, TCAs can cause severe respiratory depression and death. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!

Memory Palace5:40–7:42

Let’s start with this old triplane from WWI for the suffix -triptyline, as in amitriptyline and nortriptyline. Next for the drugs ending in “pramine”: we will use an opulent and imperial emperor for imipramine.
His sentencing a prisoner to work in the coal mine for clomipramine. The prisoner’s wife is in despair for desipramine.
Now, for the indications, let’s have a previous worker from the mines in a wheelchair with a big frown for depression. His arms and legs are bandaged up to represent peripheral neuropathy and his head is also bandaged up representing migraines.
Since he’s immobile, a terrifying giant spider is building a web on him, which represents arachno- and other phobias. For medication specific indications, the coal miner, is obsessively going through his keepsakes, looking for the love letter from his wife, representing OCD, while the emperor, is holding a sleeping puppy that’s peeing on himer, representing nocturnal enuresis.
For side effects, let’s have a tropical palm tree for the atropine-like side effects. Under the tree are two army men taking a nap, for sedation.
One of them stood up too quickly and got lightheaded, representing orthostatic hypotension. Serotonin syndrome 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.
For the 3 C’s that represent the most common cause of death, let’s have a seriously ill person who’s comatose. His arms are trembling, representing convulsions, and he’s hooked up to a heart monitor that’s going crazy, representing arrhythmia.
On top of the heart monitor, there’s a long-tailed squirrel who’s a real cutie, because TCAs can cause long Q-T intervals.
Finally, to represent cytochrome P450 inhibition, let’s have the triplane shoot at a giant chrome colored cell. All right, as a quick recap.

Review7:42–8:22

Tricyclic antidepressants, or TCAs, are antidepressant medications that prevent serotonin and norepinephrine reuptake from the synaptic cleft, thus enhancing the effect of both neurotransmitters on postsynaptic neurons.
Aside from major depressive disorder, TCAs can also treat OCD, chronic pain, nocturnal enuresis, peripheral neuropathy, and it can be used for migraine prophylaxis.
Lastly, these medications are not considered as the first line therapy due to their severe side effects, such as convulsions, coma, cardiotoxicity, and serotonin syndrome.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map8:22–8:41

Stay tuned for the answers after the credits.