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.

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. Tricyclics may also possess an affinity for muscarinic and histamine H1 receptors to varying degrees. Although the pharmacologic effect occurs immediately, often the patient's symptoms do not respond for 2 to 4 weeks.^[1]

Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, pain, nocturnal enuresis, and ADHD, but they have also been used successfully for headache, bulimia nervosa, interstitial cystitis, irritable bowel syndrome, narcolepsy, insomnia, persistent hiccups, pathological crying or laughing, smoking cessation, as an adjunct in schizophrenia, and in ciguatera poisoning.^[1]

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. 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.^[2] They are not considered addictive and are preferable to the MAOIs. Side effects usually occur before depression is effectively suppressed; for this reason and via other mechanisms they can be dangerous, as volition may be increased, giving the patient greater ability to attempt suicide.^[3]

Tricyclic antidepressants have been shown to be effective in treating attention-deficit hyperactivity disorder.^[4] 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.^[5] 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.^[6]

Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain (like back pain in radiculitis).^[7][8] 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.^[9] Typically pain modification requires lower dosages than for treating depression (e.g. Amitriptyline at 10 to 30 mg rather than 75 to 150 mg). 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. There is, however, little evidence for an analgesic effect in acute pain.^[1]

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. It is thought that the anticholinergic effects of tricyclics may inhibit urination, and/or the CNS stimulant effect may lead to easier arousal when the stimulus of a full bladder occurs.^[10] However, one robust review of tricyclics for the treatment of enuresis found the benefits of tricyclics were relatively small and transient and due to potentially serious adverse effects suggested more research into other methods (bedwetting alarms, behavioural methods, desmopressin) which may be better suited for treatment of this condition.^[11]

Many side effects are related to tricyclics antimuscarinic actions. The antimuscarinic side effects are relatively common and include:

• Dry mouth (salivary secretion is affected)
• Dry nose, nose that accumulates snot and requires manual cleaning
• Blurred vision (accommodation in the eye is affected)
• Decreased gastro-intestinal motility and secretion. This may lead to constipation
• Urinary retention or difficulty with urination
• Hyperthermia

Tolerance to these adverse effects often develops if treatment is continued, side effects may also be less troublesome if treatment is initiated with low dose and then gradually increased, although this may delay the clinical effect.

Other side effects may include drowsiness, anxiety, restlessness, cognitive and memory difficulties, confusion, dizziness, akathisia, hypersensitivity reactions, increased appetite with weight gain, sweating, decrease in sexual ability and desire, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms.^[1]

TCAs are highly metabolized by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, antipsychotics, and calcium channel blockers) may produce decreases in the tricyclic's metabolism leading to increases in tricyclic blood concentrations and accompanying toxicity. Drugs which prolong the QT interval including antiarrythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs which have antimuscarinic properties.^[1]

Tricyclic antidepressant overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented and due to their cardiovascular and neurological toxicity. Additionally, they are a serious problem in the pediatric population due to their inherent toxicity^[12] and the availability of these in the home when prescribed for bed wetting and depression.

The central nervous system and heart are the two main systems that are affected. Initial or mild symptoms include drowsiness, a dry mouth, nausea, and vomiting. More severe complications, include hypotension, cardiac rhythm disturbances, hallucinations, and seizures. Electrocardiogram (ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay (QRS prolongation).^[13] Seizures and cardiac dysrhythmias are the most important life threatening complications.

Tricyclics have a narrow therapeutic index, i.e. the therapeutic dose is close to the toxic dose. In the medical literature the lowest reported toxic dose is 6.7 mg per kg body weight, ingestions of 10 to 20 mg per kilogram of body weight are a risk for moderate to severe poisoning, although doses ranging from 1.5 to 5 mg/kg may even present a risk. Most poison control centers refer any case of TCA poisoning (especially in children) to a hospital for monitoring.^[14] Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs.^[15] Serum drug levels are not useful in tricyclic overdose.^[16]

Most of the toxic effects of TCAs are caused by four major pharmacological effects. TCAs have anticholinergic effects, cause excessive blockade of norepinephrine reuptake at the postganglionic synapse, direct alpha adrenergic blockade, and importantly they block sodium membrane channels with slowing of membrane depolarization, thus having quinidine like effects on the myocardium.^[17]

Initial treatment of an acute overdose includes gastric decontamination of the patient. This is achieved by administering activated charcoal which adsorbs the drug in the gastrointestinal tract either orally or via a nasogastric tube. Other decontamination methods such as stomach pumps, ipecac induced emesis, or whole bowel irrigation are not recommended in TCA poisoning.^[18][19]

Symptomatic patients are usually monitored in an intensive care unit for a minimum of 12 hours, with close attention paid to maintenance of the airways, along with monitoring of blood pressure, arterial pH, and continuous ECG monitoring.^[17] Supportive therapy is given if necessary, including respiratory assistance, maintenance of body temperature, and administration of sodium bicarbonate as an antidote. Sodium bicarbonate is given intravenously and it has been shown to be an effective treatment for resolving the metabolic acidosis and cardiovascular complications of TCA poisoning. If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidyshythmic drugs such as phenytoin and magnesium can be used to reverse any cardiac abnormalities. However, no benefit has been shown from lidocaine or other class 1a and 1c antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning.^[20] Hypotension is initially treated with fluids along with bicarbonate to reverse metabolic acidosis (if present), if the patient remains hypotensive despite fluids then further measures such as the administration of epinephrine, norepinephrine, or dopamine can be used to increase blood pressure.^[20] Another potentially severe symptom is seizures; often seizures resolve without treatment but administration of a benzodiazepine or other anticonvulsive may be required for persistent muscular overactivity. There is no role for physostigmine in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures.^[17]

Tricyclic antidepressants are highly protein bound and have a large volume of distribution; therefore removal of these compounds from the blood with hemodialysis, hemoperfusion or other techniques are unlikely to be of any significant benefit.^[19]

Studies in the 1990s in Australia and the United Kingdom showed that between 8 and 12% of drug overdoses were following TCA ingestion. TCAs may be involved in up to 33% of all fatal poisonings, second only to analgesics.^[21][22]

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

• Antidepressant
• Clinical depression
• Tetracyclic antidepressant