Tricyclic antidepressant

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Chemical structure of the tricyclic antidepressant amitriptyline.

Tricyclic antidepressants (TCAs) are a class of psychoactive drugs that are used as antidepressants which were first introduced in the early 1950s. They are named after their chemical structure, which contains three rings of atoms. The TCAs are closely related to the tetracyclic antidepressants (TeCAs).

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), though they are still sometimes prescribed.

Besides clinical depression, the TCAs have also been used for the treatment of a number of other disorders, including anxiety disorders, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), nocturnal enuresis, insomnia, and pain, especially neuropathic pain.

[edit] List of TCAs

Drugs in this class include (trade names in parentheses):

• Tertiary Amines
  • Amitriptyline (Elavil, Endep, Vanatrip)
  • Butriptyline (Evadene, Evadyne)
  • Clomipramine (Anafranil)
  • Dosulepin (Prothiade)
  • Doxepin (Adapin)
  • Imipramine (Tofranil)
  • Lofepramine (Feprapax, Gamanil, Lomont)
  • Trimipramine (Surmontil)
• Secondary Amines
  • Desipramine (Norpramin, Pertofrane)
  • Nortriptyline (Aventyl, Nortrilen, Pamelor)
  • Protriptyline (Vivactil)
• Miscellaneous TCAs
  • Dibenzepin (Noveril)
  • Iprindole (Prondol, Prondole)
  • Melitracen (Deanxit)
  • Nitroxazepine (Sintamil)
• Atypical TCAs
  • Amineptine (Survector, Maneon, Directin)
  • Opipramol (Insidon, Pramolan)
  • Tianeptine (Stablon, Coaxil, Tatinol)
• Research Chemicals
  • Cianopramine (Ro11-2465)

[edit] Indications

The TCAs 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, Tourette syndrome, bulimia nervosa, irritable bowel syndrome, narcolepsy, pathological crying or laughing, persistent hiccups, interstitial cystitis, and ciguatera poisoning, and as an adjunct in schizophrenia.

[edit] 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. A recent Cochrane review of their effectiveness concluded that they were only slightly more effective than active placebos.^[1] Newer antidepressants are thought to have fewer side effects and are also thought to be less likely to result in death or serious injury if used in a suicide attempt, as the treatment and lethal doses (see therapeutic index) are farther apart than with the TCAs. The TCAs are sometimes still used to treat treatment-resistant 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]

[edit] Attention-Deficit Hyperactivity Disorder (ADHD)

The TCAs 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^{[citation needed]}. The TCAs block the reuptake of these neurotransmitters.^[5] 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.^[6]

[edit] Pain

The TCAs are also known as effective analgesics for different types of pain, especially neuropathic.^[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] 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.

[edit] Nocturnal Enuresis

The antimuscarinic actions of the TCAs 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 the TCAs 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 the TCAs for the treatment of enuresis found their benefits 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]

[edit] Pharmacology

The vast majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.^[12][13] Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs), and hence, do not elevate dopamine levels.^[12] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.^[14]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT₂^[15] (5-HT_2A^[16] and 5-HT_2C^[16]), 5-HT₆,^[17] 5-HT₇,^[18] α₁-adrenergic,^[15] and NMDA receptors,^[19] and as agonists at the sigma receptors^[20] (σ₁^[20] and σ₂^[21]), some of which may contribute to their therapeutic efficacy, as well as their side effects.^[22] The TCAs also have varying but typically high affinity for antagonizing the H₁^[15] and H₂^[23][24] histamine receptors, as well as the muscarinic acetylcholine receptors.^[15] As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.^[22]

[edit] Binding Profiles

A number of TCAs have been compared below:^{[12][25][15][26]}

The values above are expressed as equilibrium dissociation constants. It should be noted that less is more. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors. The TCAs act as antagonists at all listed receptors.

[edit] Side Effects

Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.

Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, 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 as well.^[27]

Tolerance to these adverse effects of these drugs often develops if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

[edit] Discontinuation

Antidepressants in general may produce a discontinuation syndrome. This is not the same as a withdrawal syndrome.^[28] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.^[29]

[edit] Interactions

The 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 TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity. Drugs that 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 that have antimuscarinic properties.

[edit] Overdose

TCA 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, it is a serious problem in the pediatric population due to their inherent toxicity^[30] and the availability of these in the home when prescribed for bed wetting and depression.

A number of treatments are effective in a TCA overdose.

An overdose on TCA is especially fatal as they are rapidly absorbed from GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose.

Many of the inital signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred Vision, urinary retention, constipation, dizziness and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose^[31]:

1. Anticholinergic effects: Altered mental status (agitation, confusion, lethargy), Resting sinus tachycardia, Dry mucous membranes, Mydriasis (pupil dilation), Fever
2. Cardiac effects: Hypertension (early and transient, should not be treated), Tachycardia, Orthostasis and hypotension, Arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence)/ECG changes (prolonged QRS, QT and PR intervals)
3. Central nervous system effects: Coma, Seizure, Myoclonic twitches/tremor, Hyperreflexia
4. Pulmonary effects: Hypoventilation resulting from CNS depression
5. Gastrointestinal tract effects - Decreased or absent bowel sounds

Due to no specified TCA antagonist, treatment for an overdose consists of a gastric lavage or activated charcoal, depending on how the overdose has progressed. If the overdose is with an especially high concentration of TCAs, then haemodialysis may be required.

[edit] Abuse

A very small number of antidepressant abuse cases have been reported over the past 30 years.^[32]According to the US government classification of psychiatric medications, TCAs are "non-abusable"^[33] and generally have low abuse potential.^[34] Several cases of abuse ^[35] of amitriptyline alone^[36][37] or together with methadone ^[35][38] or in other drug dependent patients ^[39][40] and of dothiepin with alcohol ^[41] or in methadone patients ^[42] have been reported.

[edit] History

The TCAs 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.^[43] 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.^[44] Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, a dibenzazepine 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.^[45] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.^[44] Geigy later became Ciba-Geigy and eventually Novartis.

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 different from the backbone of the TCA amitriptyline.

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.^[44] This compound has a different three-ring structure than imipramine.

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

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.

[edit] See Also

• Antidepressant
• Clinical depression
• Tetracyclic antidepressant

[edit] References

[edit] External Links

• MeSH Tricyclic+Antidepressive+Agents