Tricyclic antidepressants

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.

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.

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.

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.

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.