Last Updated on April 3, 2023 by Mike Robinson
Tricyclic antidepressants (ADT) were one of the first antidepressant drugs discovered. Its name is due to its chemical structure, which is composed of three rings.
As the name suggests, they are effective in treating depression. However, it is also used for other conditions such as bipolar disorder, panic disorder, obsessive-compulsive disorder, migraine, or chronic pain.
The antidepressant effects of these drugs were discovered by accident since, previously, only their antihistaminic and sedative properties were known.
Tricyclic Antidepressants
Tricyclic Antidepressants: Effects and Mechanism of ActionSince this discovery, they have been the pharmacological treatment par excellence for more than 30 years. It began to be commercialized at the end of the 1950s, and in the 1980s, its use was reduced with the “boom” of selective serotonin reuptake inhibitors ( SSRIs ).
They are prescribed less frequently since they are 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 deficit of one of the three monoamines: noradrenaline 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 get levels of noradrenaline, dopamine, or serotonin available to increase to a safe point. This would result in the interruption of depressive symptoms.
Actually, tricyclic antidepressants have five drugs in one: a serotonin reuptake inhibitor, noradrenaline, an anticholinergic and antimuscarinic drug, an alpha-1 adrenergic antagonist, and an antihistamine.
Serotonin and norepinephrine reuptake inhibitors
The main mechanism of action of tricyclic antidepressants is the inhibition or blocking of the so-called “monoamine reuptake pump.” Within the monoamines, in this case, we talk about serotonin and noradrenaline.
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 noradrenaline previously released for further degradation. Under normal conditions, it helps to control the amount of monoamines that are acting in our brain.
In the case of depression, as there is a small amount of these substances, it is not convenient for the reuptake pump to act. This is because it would decrease that amount even more. That is why the mission of tricyclic antidepressants is to block this reuptake pump. Thus, it acts by increasing the levels of the mentioned neurotransmitters.
However, what ensures that the effects achieved with the antidepressant are maintained over time (although this is stopped) is that this block produces changes in the brain.
When there is a greater quantity of serotonin or noradrenaline in the synaptic space (that space existing between two connecting neurons exchanging information), the receptors in charge of capturing these substances are regulated.
In depression, the brain changes, developing many receptors for monoamines.
In contrast, tricyclic antidepressants increase the levels of monoamines in the synapse. The receptor neuron captures this increase and decreases its number of receptors little by little since it no longer needs them.
Side effects of tricyclic antidepressants
As mentioned in the previous section, tricyclic antidepressants are considered five drugs in one. However, three of them are the ones that cause the dreaded adverse effects for which the use of these types of antidepressants is being abandoned.
Alpha-1 adrenergic antagonist
One of the side effects of tricyclic antidepressants is the blocking of so-called alpha-1 adrenergic receptors. Causing a decrease in blood pressure, dizziness, and drowsiness.
Anticholinergic and antimuscarinic
Tricyclic antidepressants, on the other hand, block acetylcholine receptors (M1). This results in side effects such as blurred vision, constipation, dry mouth, and drowsiness.
Antihistamine
Another effect of tricyclic antidepressants is the blockage of histamine H1 receptors in the brain.
This results in an antihistamine effect, i.e., drowsiness and weight gain (due to an increased appetite).
Other side effects are urinary retention, sedation, excessive sweating, tremors, sexual dysfunctions, confusion (mainly in the elderly), and overdose toxicity.
Under what conditions are tricyclic antidepressants recommended?
Despite everything, tricyclic antidepressants seem to be very effective for the treatment of:
– Fibromyalgia.
– Pain.
– Migraines.
Severe depression. The greater the depression, the more effective this treatment is. In addition, it is more advisable for those whose depression is endogenous and has genetic components.
– Sedative or hypnotic (to sleep).
When are tricyclic antidepressants not recommended?
By logic, this type of drug is discouraged in the following cases:
Patients who have little tolerance to urinary retention, constipation, and diurnal sedation.
people with any heart disease.
Overweight patients
Those who have a high risk of suicide Since tricyclic antidepressants are toxic in overdose, these patients can use them for that purpose.
Patients who take several drugs at the same time should be aware that unwanted drug interactions may occur.
people with some dementia.
– Epileptic people, since it increases the frequency of seizures.
On the other hand, these drugs are usually not recommended for children under 18. They can be dangerous during pregnancy, breastfeeding (since they pass into breast milk), or if alcohol, other drugs, or supplements are consumed.
Absorption, distribution, and elimination
Tricyclic antidepressants are administered orally and are rapidly absorbed through the gastrointestinal tract.
They are very soluble in lipids, which results in a broad and rapid distribution throughout the body. However, before this distribution, the drugs go through a first metabolism in the liver. Some studies indicate that the intestinal tract reabsorbs approximately 30% of the lost substances through the bile.
Once reabsorbed, tricyclic antidepressants cross the blood-brain barrier. These antidepressants possess a strong affinity with the brain and the myocardium. Tricyclic antidepressants have 40 times more association with the brain and five times more with the myocardium than other body tissues.
Finally, they are metabolized in the liver and pass to the renal system to be excreted. Most of the substance will be expelled within 36 hours under normal conditions. This renal elimination is essential to take into account in overdose cases.
How long before tricyclic antidepressants take effect?
It takes approximately two to four weeks to take effect. For real, lasting changes to occur in the nervous system, they must be taken for at least six months. Although, in cases of recurrent depression, a more extended treatment (two years or more) may be recommended.
After this cycle, the dose gradually decreases until it is completely removed. If it is interrupted earlier than necessary, the symptoms can return quickly. In addition, 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 act in the same way. Each one has slight variations, which allow for adapting to each patient’s situation.
In general, there are two classes of tricyclic antidepressants:
Tertiary amines have a more significant effect on the increase of serotonin than the rise of noradrenaline. However, they cause greater sedation, greater anticholinergic effects (constipation, blurred vision, dry mouth), and hypotension.
This group contains antidepressants such as imipramine (the first to be marketed), amitriptyline, trimipramine, and doxepin.
Doxepin and amitriptyline are the most sedating types of tricyclic antidepressants. Also, along with imipramine, they are the most likely to cause weight gain.
Tertiary amines are more convenient for depressed people with sleep problems, restlessness, and agitation.
Secondary amines are those that increase the levels of noradrenaline more than those of serotonin and cause irritability, overstimulation, and sleep disorders. They are recommended for depressed patients who feel dull, apathetic, and fatigued. An example of this type of tricyclic antidepressant is desipramine.
Some tricyclic antidepressants that should be mentioned are:
Maprotiline belongs to the group of secondary amines and causes increased seizures.
Amoxapine: It works like an antagonist of the serotonin receptors (which increases the serotonin in the synapse). It has neuroleptic properties, so it can be recommended for patients with psychotic symptoms or manic episodes.
Clomipramine is one of the most potent tricyclic antidepressants to block the reuptake of serotonin and norepinephrine. Its effectiveness in treating obsessive-compulsive disorder has been demonstrated, although it increases the risk of seizures at high doses.
– Nortriptyline: Like desipramine, it seems to be one of the tricyclic antidepressants with side effects better tolerated by patients.
– Protriptyline
– Lofepramina
Negative side-effects
Sedative effects that can cause accidents:
As tricyclic antidepressants give rise to sedation symptoms, driving or operating machines is not recommended. Suppose it is under its products; the risk of suffering from 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.
The risk of suicide increases:
It has been found that in some cases of adolescents and young adults, suicidal desires appear after beginning to take tricyclic antidepressants. It is linked to the first few weeks of starting the medication or after increasing the dose.
Researchers do not know precisely whether these ideas are due to depression or the effects of antidepressants.
Some believe that may be because restlessness and agitation are more pronounced at the beginning of the treatment. This can cause the depressive to feel like they have enough energy to commit suicide if there have been previous thoughts of suicide, which is very common in depression.
This risk seems to decrease as the treatment progresses. However, if you notice a sudden change, it is best to go to a professional as soon as possible.
It can lead to intoxication from an overdose, a coma, and even death;
There have been documented cases of tricyclic antidepressant abuse or misuse. For example, in healthy people, the aim is to feel more social and euphoric, followed by symptoms such as confusion, hallucinations, and temporary disorientation.
The intoxication caused by tricyclic antidepressants is not strange. The lethal dose of desipramine, imipramine, or amitriptyline is 15 mg per kg of body weight. Be careful with young children; they could exceed this threshold with only one or two pills.
The abuse of this type of antidepressant can cause, in addition to the potentiation of the secondary symptoms mentioned, tachycardia, fever, altered mental status, intestinal occlusion, stiffness, dry skin, dilated pupils, chest pain, respiratory depression, coma, and even death.
Serotonin syndrome
Sometimes tricyclic antidepressants can cause this syndrome due to the excessive accumulation of serotonin in the nervous system.
However, it often appears when antidepressants are combined with other substances that further increase serotonin levels. For example, other antidepressants, some drugs, analgesics, or nutritional supplements such as St. John’s Wort
The signs and symptoms of this syndrome include anxiety, agitation, sweating, confusion, tremors, fever, loss of coordination, and tachycardia.
Related article: Depressive Neurosis: Symptoms, Causes and Treatment
Withdrawal syndrome:
Tricyclic antidepressants are not considered addictive since they do not produce “cravings” or a desire to retake them.
However, leaving them all at once may cause withdrawal symptoms in some people. These can vary according to the type of drug and do not last more than two weeks.
Anxiety, restlessness, and agitation
Changes in mood and low mood
– Alteration of sleep.
– A sensation of tingling.
– Dizziness and nausea.
– Symptoms similar to the flu, diarrhea, and stomach pains
If antidepressants are gradually reduced until they are stopped, these symptoms do not occur.
