Tricyclic antidepressant

Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. They are named after the drugs' molecular structure, which contains three rings of atoms (compare tetracyclic antidepressant). The term 'tricyclic antidepressant' is sometimes abbreviated to TCA.

Mechanism of action

The exact mechanism of action is not well understood, however it is generally thought that tricylic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine, dopamine or serotonin by nerve cells. Although this pharmacologic effect occurs immediately, often the patient's symptoms do not respond for several weeks.

Clinical use: treatment of depression

For many years they were the first choice for pharmacological treatment of depression. Although still considered effective, they have been increasingly replaced by SSRIs and other newer drugs. These newer antidepressants are thought to have fewer side effects and are also thought to be less effective if used in a suicide attempt, as the treatment and lethal doses (see therapeutic index) are farther apart than with the tricyclic antidepressants. Tricyclic antidepressants are sometimes still used to treat refractory depression that has failed to respond to standard SSRI therapy. They are not considered addictive and are preferable to the MAOIs. Side effects usually occur before depression is effectively suppressed; for this reason they can be dangerous, as volition is increased, giving the patient greater ability to attempt suicide.

Clinical use: treatment of ADHD

Tricyclic antidepressants (TCAs) have been shown to be effective in treating attention-deficit hyperactivity disorder. ADHD is thought to be caused by dopamine and norepinephrine shortages in the brain's prefrontal cortex. Tricyclic antidepressants block the reuptake of these neurotransmitters, thus acting as dopamine and norepinephrine agonists. They are commonly used in patients for whom psychostimulants (the primary medication for ADHD) are ineffective. TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits; they help limit hyperactivity and impulsivity but have little effect on attention.

Clinical use: analgesia

Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain (like back pain in radiculitis). A precise mechanism for their analgesic action is unknown, but it is thought that they modulate opioid systems in the CNS via an indirect serotonergic route. Typically pain modification requires lower dosages than for treating depression (e.g. Amitriptyline at 10 to 30 mg rather than 75 to 150mg). They are also effective in migraine prophylaxis, but not in relief of an acute migraine attack. This is also believed to be related to serotonergic effects.

Clinical use: nocturnal enuresis

Tricyclics with greater anti-muscarinic action (i.e. Amitriptyline, Imipramine and Nortriptyline) may prove useful in helping to treat nocturnal enuresis (bedwetting) in children over the age of 7 years. The drug needs to be gradually withdrawn and the total treatment period is advised to be no greater than 3 months at a time.

TCA poisoning

The cyclic antidepressants produce sedation, alpha blocking, anticholinergic, and quinidineliie effects. In the central and peripheral nervous systems, norepinephrine, 5-hydroxytryptamine, and dopamine are blocked. Ingestion of tricyclic antidepressants is a serious problem in the pediatric population because of the availability of these in the home when prescribed for bed wetting and depression. Poisoning in TCA is a leading cause of death. The CNS and heart are the two main systems that are affected. Symptoms include drowsiness, delirium, hallucinations, disorientation, seizures, coma, hypertension followed by hypotension, and arrhythmias. An electrocardiogram should be obtained to check for QRS widening and QT and QTc prolongation. Supportive therapy should be given, including intubation if necessary. Activated charcoal should be given to prevent further absorption. Sodium Bicarbonate should be given to treat and prevent dysrhythmias. Treat arrhythmia not responding to sodium bicarbonate with lidocaine. Hypotension may be treated with fluids and norepinephrine in some cases. Seizures usually resolve without treatment. Symptomatic patients should be monitored in an intensive care unit. Patients who are completely asymptomatic after 6 hours of observation may be discharged. Seizures and arrhythmias are the most important life threatening complications.

Side effects

Many side effects are related to anti-muscarinic properties. These include:

Dry mouth (salivary secretion is affected)
Blurred vision (accommodation in the eye is affected)
Decreased gastro-intestinal motility and secretion. This may lead to constipation.

Partial resistance to these effects develops within about two weeks. They may be beneficial, as they indicate to the patient that the drugs are having an effect. Other side effects may include drowsiness, anxiety, restlessness, urinary retention or difficulty with urination, cognitive and memory difficulties, weight gain, sweating, dizziness, hypotension, akathisia, decrease in sexual ability and desire, muscle twitches, weakness, nausea, increased heart rate and irregular heart rhythms (rare). Some of these side effects relate to their anti-muscarinic properties.

TCAs are highly metabolized by the cytochrome P450 hepatic enzymes. While taking TCA you should avoid taking Cimetidine due to dangerous drug-drug interactions that may lead to death. (Cimetidine, which is an H₂-antihistamine, inhibits the activity of cytochrome P450.)

Example compounds

The first tricyclic antidepressant discovered was imipramine, which was discovered accidentally in a search for a new antipsychotic in the late 1950s.

Antidepressant drugs in the tricyclic drug group include:

amitriptyline (Elavil®, Endep® Tryptanol®))
clomipramine (Anafranil®)
desipramine (Norpramin®, Pertofrane®)
dothiepin hydrochloride (Prothiaden®, Thaden®)
doxepin (Adapin®, Sinequan®)
imipramine (Tofranil®)
lofepramine (Gamanil®, Lomont®)
nortriptyline (Pamelor®)
protriptyline (Vivactil®)
trimipramine (Surmontil®)

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