TRICYCLIC ANTIDEPRESSANTS: TYPES, EFFECTS, AND HOW THEY WORK - ARTE - 2025

The tricyclic antidepressants (TCAs) are among the first antidepressant drugs discovered. Its name is due to its chemical structure, which is composed of three rings. They are effective in treating depression, although they are also used for other conditions such as bipolar disorder, panic disorder, obsessive-compulsive disorder, migraines, or chronic pain.

The antidepressant effects of these drugs were discovered by accident, as previously only their antihistamine and sedative properties were known. Since this discovery, they have been the pharmacological treatment par excellence for more than 30 years. It began to be commercialized from the end of the 50s; and around the 1980s, its use was reduced with the “boom” of selective serotonin reuptake inhibitors (SSRIs).

Model of the molecule of amitriptyline, a tricyclic antidepressant.

Currently they are prescribed less frequently; since they are being replaced by other antidepressants that cause fewer side effects. However, they can be a good option for some people when other treatments have failed.

How do tricyclic antidepressants work?

It is believed that in individuals with depression there is an imbalance in certain brain chemicals called neurotransmitters. More specifically, it is associated with a deficiency of norepinephrine or serotonin.

There are several complex processes that can cause this decrease in neurotransmitters. Antidepressants act on one or more of them with one goal: to make the levels of available norepinephrine, dopamine or serotonin rise to a safe point. This would result in the interruption of depressive symptoms.

Tricyclic antidepressants actually have five drugs in one: serotonin reuptake inhibitor, norepinephrine, anticholinergic and antimuscarinic drug, alpha 1 adrenergic antagonist, and antihistamine.

Serotonin and norepinephrine reuptake inhibitor

The main mechanism of action of tricyclic antidepressants is the inhibition or blocking of the so-called "monoamine reuptake pump". Within monoamines, in this case we speak of serotonin and norepinephrine.

The reuptake pump is a protein that is located in the membranes of neurons (nerve cells in the brain). Its function is to "absorb" the serotonin and norepinephrine that have previously been released, for their subsequent degradation. Under normal conditions, it serves to control the amount of monoamines that are acting in our brain.

In the case of depression, as there is little quantity of these substances, it is not advisable for the reuptake pump to act. This is because that amount would decrease even more. Therefore, the mission of tricyclic antidepressants is to block this reuptake pump. Thus, it works by increasing the levels of the neurotransmitters mentioned.

However, what guarantees that the effects achieved with the antidepressant are maintained over time (even if it is stopped taking), is that this blockage produces changes in the brain.

When there is more serotonin or norepinephrine in the synaptic space (the one between two neurons that connect, exchanging information), the receptors responsible for capturing these substances are regulated.

In depression, the brain changes, developing many receptors for monoamines. Its objective is to compensate for the lack of these, although it is not very successful.

In contrast, tricyclic antidepressants increase monoamine levels at the synapse. The receptor neuron captures this increase, and its number of receptors decreases little by little; since you stop needing them.

Under what conditions are tricyclic antidepressants recommended?

Regardless, tricyclic antidepressants seem to be very effective for treating:

- Fibromyalgia.

- Pain.

- Migraines.

- Severe depression. It seems that the greater the depression, the more effective this treatment is. In addition, it is more advisable in those people whose depression is endogenous, and with genetic components.

- Sedatives or hypnotics (to sleep).

Under what conditions are they not recommended?

Logically, this type of drug is not recommended for the following cases:

- Patients who have low tolerance to urinary retention, constipation and daytime sedation.

- People with any heart disease.

- Overweight patients.

- Those who have a high risk of suicide. Since tricyclic antidepressants are toxic in overdose, and these patients can use them for this purpose.

- Patients who take several other medications at the same time, as unwanted drug interactions may occur.

- People with some dementia.

- Epileptic people, as it increases the frequency of seizures.

On the other hand, these drugs are usually not recommended for people under 18 years of age and can be dangerous during periods of pregnancy, breastfeeding (since they pass into breast milk), if alcohol or other drugs, drugs or supplements are consumed.

Absorption, distribution and elimination

Tricyclic antidepressants are administered orally and are rapidly absorbed from the gastrointestinal tract. They are very soluble in lipids, which gives rise to a wide and rapid distribution throughout the body.

However, before this distribution they undergo a first metabolism in the liver. Some studies indicate that approximately 30% of the lost substances are reabsorbed by the intestinal tract through the bile.

Once reabsorbed, tricyclic antidepressants cross the blood-brain barrier. In fact, these antidepressants have a strong affinity for the brain and myocardium. Tricyclic antidepressants have 40 times more affinity with the brain and 5 times more with the myocardium than other tissues in the body.

Finally, they are metabolized in the liver and pass to the renal system to be excreted. Most of the substance will be expelled within a maximum of 36 hours under normal conditions. This renal elimination is important to take into account in cases of overdose.

How long does it take to take effect?

They take approximately two to four weeks to take effect. For real lasting changes to occur in the nervous system, they need to be taken for at least six months. Although in cases of recurrent depression, a longer treatment (two years or more) may be recommended.

After this cycle, the dose is gradually reduced until it is completely withdrawn. If it is stopped early, symptoms can return quickly. Also, if the dose is stopped abruptly, withdrawal symptoms may occur.

This entire process must be properly supervised by a qualified health professional.

Types of tricyclic antidepressants

Not all tricyclic antidepressants work in exactly the same way. Each one has small variations, which allows it to be adapted to the individual situation of each patient.

Generally, there are two classes of tricyclic antidepressants:

Tertiary amines

Structure of tertiary amines. Source: Kes47 (?)

They have a greater effect on increasing serotonin than on norepinephrine. However, they cause greater sedation, greater anticholinergic effects (constipation, blurred vision, dry mouth) and hypotension.

Within this group, there are antidepressants such as imipramine (the first to be marketed), amitriptyline, trimipramine and doxepin.

Doxepin and amitriptyline appear to be the most sedating types of tricyclic antidepressants. Also, along with imipramine, they are the most likely to cause weight gain.

Tertiary amines are more suitable for depressed people with sleep problems, restlessness, and agitation.

Secondary amines

Structure of secondary amines. Source: Kes47 (?)

They are the ones that increase the levels of norepinephrine more than those of serotonin, and cause irritability, over-stimulation and sleep disorders. They are recommended for depressed patients who feel dull, listless, and fatigued. An example of this type of tricyclic antidepressant is desipramine.

Some tricyclic antidepressants to mention are:

- Maprotiline: belongs to the group of secondary amines, and causes an increase in seizures.

- Amoxapine: works as a serotonin receptor antagonist (which increases the amount of serotonin in the synapse). It has neuroleptic properties, so it can be recommended for those patients who have psychotic symptoms, or manic episodes.

- Clomipramine: it is one of the most powerful tricyclic antidepressants in terms of blocking the reuptake of serotonin, as well as norepinephrine. It has been shown to be effective in obsessive-compulsive disorder, although at high doses it increases the risk of seizures.

- Nortriptyline: like desipramine, it seems to be one of the tricyclic antidepressants with side effects that are better tolerated by patients.

- Protriptyline

- Lofepramine

Negative side effects

Dizziness and somnolence

One of the side effects of tricyclic antidepressants is the blockage of so-called alpha 1 adrenergic receptors. Causing a drop in blood pressure, dizziness and drowsiness.

Blurred vision, dry mouth, or constipation

Tricyclic antidepressants, on the other hand, block acetylcholine (M1) receptors. This results in side effects like blurred vision, constipation, dry mouth, and drowsiness.

Weight gain

Another effect of tricyclic antidepressants is the blockage of histamine H1 receptors in the brain. This results in an antihistamine effect, that is, drowsiness and weight gain (due to increased appetite).

Other associated side effects that have been observed are urinary retention, sedation, excessive sweating, tremors, sexual dysfunctions, confusion (mainly in the elderly), and toxicity from overdose.

Sedative effects that can cause accidents

Since tricyclic antidepressants cause sedation symptoms, driving or operating machines is not recommended. Since, if you are under its influence, the risk of suffering or causing accidents increases.

To reduce these problems and avoid daytime sleepiness, the doctor may advise that these drugs be taken at night; before sleep.

Increase the risk of suicide

Suicidal wishes have been found in some adolescents and young adults after starting to take tricyclic antidepressants. Apparently, it is something that is linked to the first weeks of starting the medication or after increasing the dose.

Researchers don't know exactly if these ideas are due to depression itself or to the effect of antidepressants.

Some believe it may be because, early in treatment, restlessness and agitation are more pronounced. This can cause that, if there are some previous ideas of suicide (very common in depression), the depressive feel with enough energy to commit it.

This risk appears to decrease as treatment progresses. However, if you notice a sudden change it is best to go to the professional as soon as possible.

Can lead to overdose poisoning, coma, and even death

Cases of abuse of tricyclic antidepressants or their misuse have been documented. For example, in healthy people with the goal of feeling more sociable and euphoric, followed by symptoms such as confusion, hallucinations, and temporary disorientation.

Tricyclic antidepressant poisoning is not uncommon. The lethal dose of desipramine, imipramine or amitriptyline is 15 mg per kg body weight. Be careful with young children, as they could exceed this threshold with just one or two pills.

The abuse of this type of antidepressant can cause, in addition to the enhancement of the named secondary symptoms: tachycardia, fever, altered mental state, intestinal obstruction, stiffness, dry skin, dilated pupils, chest pain, respiratory depression, coma, and even death.

Serotonin syndrome

Tricyclic antidepressants can sometimes cause this syndrome, due to the excessive accumulation of serotonin in the nervous system.

However, most of the time it appears when antidepressants are combined with other substances that further increase serotonin levels. For example, other antidepressants, some drugs, pain relievers, or nutritional supplements like St. John's wort.

The signs and symptoms of this syndrome include: anxiety, agitation, sweating, confusion, tremors, fever, loss of coordination, and rapid heartbeat.

Abstinence syndrome

Tricyclic antidepressants are not considered addictive as they do not produce "craving" or desire to take them again. However, stopping them suddenly can cause withdrawal symptoms in some people. These can vary depending on the type of drug and do not last more than two weeks:

- Anxiety, restlessness and agitation.

- Changes in mood and low mood.

- Sleep disturbance.

- Tingling sensation.

- Dizziness and nausea.

- Flu-like symptoms.

- Diarrhea and stomach pain.

If antidepressants are gradually reduced to stop, these symptoms do not occur.

References

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