Tricyclic antidepressant

Overview
Tricyclic antidepressants (abbreviation TCA) 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).

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 (along with their actions as listed in MeSH) include:

Note: Other sources suggest that most of the tricyclics combine adrenergic and serotonergic effects to some degree. This is often reported as selectivity ratios. Some of the above, in order from most selective for nor-epinephrine to most selective for serotonin: lofepramine, nortriptyline, amitriptyline, imipramine, clomipramine.

Amine classification
Tricyclics are sometimes classified as tertiary amines and secondary amines. In general, the tertiary amines boost serotonin as well as nor-epinephrine (adrenergic) and produce more sedation, anticholinergic effects, and orthostatic hypotension. The secondary amines act primarily on nor-epinephrine and tend to have a lower side-effect profile.

Tertiary amines include: amitriptyline, imipramine, trimipramine, doxepin, clomipramine, and lofepramine.

Secondary amines include: nortriptyline, desipramine, protriptyline, and amoxapine.

Mechanism of action
The exact mechanism of action is not well understood, however it is generally thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by neurons. 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. Although norepinephrine and dopamine are generally considered stimulatory neurotransmitters, tricyclic antidepressants also increase the effects H1 histamine, and thus most have sedative effects.

Chemistry of re-uptake inhibitors
The chemical action of re-uptake inhibitors in general was unknown for a long time. In August 2007, two research groups independently reported that the tricyclic molecule docks to the transporter protein in a cavity adjacent to where the neurotransmitter substrate binds, locking the substrate in place and thereby obstructing re-uptake transport.

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

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. 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 and via other mechanisms they can be dangerous, as volition may be increased, giving the patient greater ability to attempt suicide.

ADHD
Tricyclic antidepressants 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. They are commonly used in patients for whom psychostimulants (the primary medication for ADHD) are ineffective or contraindicted. 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.

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 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.

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. 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. 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.

Side effects
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
 * 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. Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs. 

Interactions
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 antiarrhythmics 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.

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

Symptoms
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). Seizures and cardiac dysrhythmias are the most important life threatening complications.

Toxicity
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. Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs. However, serum drug levels are not useful for evaluating risk of arrhythmia or seizure in tricyclic overdose.

Toxic mechanism
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.

Treatment
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.

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. 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 antidysrhythmic 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. 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. 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.

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.

Epidemiology
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.

Development history
Tricyclic antidepressants were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of Chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely-used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, an imino-dibenzyl analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania lead to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Ronald Kuhn in 1957. Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ceiba-Geigy and eventually Novartis.

Many patents were filed in the 1950s and 1960s concerning variations on these three-ring structures with applications to psychiatric conditions.


 * Phenothiazine derivatives are described in U.S. patent 2,591,679 issued 1952-04-08 to John W. Cusic. The compounds described contain a sulfur group on the central carbon ring, and a nitrogen atom in the cental ring to which the side chain attaches, in the manner of chlorpromazine. Most of the illustrated side chains contain an amine group.


 * Dibenzazepine derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone identical to the backbone of the TCA amitriptyline and family of side chains typical of early TCA drugs.

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.

These patents cover the structures of the compounds and their mode of chemical synthesis. Understanding of their mode of action as re-uptake inhibitors and development of the serotonin theory of depression came in the years to follow.