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Tricyclic antidepressants

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Tricyclic antidepressants


Tricyclic antidepressants (TCAs) are chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade;[1] they are named after their chemical structure, which contains three rings of atoms. The tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants which typically have more favorable side-effects profiles such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and the norepinephrine reuptake inhibitors (NRIs) like reboxetine, though they are still sometimes prescribed for certain indications.

List of TCAs

The TCAs include the following agents which are predominantly serotonin and/or norepinephrine reuptake inhibitors:

and

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.[2] 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.[3] 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 led 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 Roland Kuhn in 1957.[2] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[3] 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.[3] This compound has a different three-ring structure from 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.

Indications

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder, obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), attention-deficit hyperactivity disorder (ADHD), as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, or migraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE),[4] narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI moclobemide. However, tricyclic antidepressants still are probably more successful in treating melancholic depression than other antidepressant drug classes.[5] Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose (see therapeutic index) are far wider in comparison.

Nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants.[6] They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.[7]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,[8] though they are not typically used anymore on account of being replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin, Attentin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[9] Notably, the TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.[10]

Chronic pain

The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia.[11][12] The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties.[13][14][15] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Pharmacology

The 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 synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[16][17] Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[16] 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.[18]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[19] (5-HT2A[20] and 5-HT2C[20]), 5-HT6,[21] 5-HT7,[22] α1-adrenergic,[19] and NMDA receptors,[23] and as agonists at the sigma receptors[24] (σ1[24] and σ2[25]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[26] The TCAs also have varying but typically high affinity for antagonising the H1[19] and H2[27][28] histamine receptors, as well as the muscarinic acetylcholine receptors.[19] 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.[26]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[29][30] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[31]

Binding profiles

The affinities (Kd (nM)) of a selection of TCAs have been compared below at an assortment of binding sites:[16][19][32][33]

Compound SERT NET DAT 5-HT1A 5-HT2A α1 α2 D2 H1 mACh
Amitriptyline 4.3 35 3,250 320 24 26 815 1,230 1.03 13.8
Butriptyline 1,360 5,100 3,940 7,000 380 570 4,800  ? 1.1 35
Clomipramine 0.28 38 2,190 7,000 27 38 3,200 190 31 37
Desipramine 17.6 0.83 3,190 6,700 315 115 6,350 3,400 85 132
Dosulepin 8.6 46 5,310 2,300 258 470 2,400  ? 3.6 25
Doxepin 68 29.5 12,100 283 26 24 1,185 1,380 0.21 52
Imipramine 1.4 37 8,500 7,650 115 61 3,150 1,310 24 68
Iprindole 1,620 1,262 6,530 2,800 280 2,300 8,600  ? 130 2,100
Lofepramine 70 5.4 18,000 4,600 200 100 2,700 2,000 360 67
Nortriptyline 18 4.37 1,140 302 43 58 2,265 1,885 8.2 94
Protriptyline 19.6 1.41 2,100 3,800 70 130 6,600 2,300 25 25
Trimipramine 149 2,450 3,780 8,000 32 24 680 180 0.27 58

The selected ligands act as antagonists (or inverse agonists depending on the site in question) at all receptors listed and as inhibitors of all transporters listed.[16][19][32][33]

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. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.[34] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[35]

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.

TCAs can behave like class 1A Antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle. Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

Discontinuation

Antidepressants in general may produce a discontinuation syndrome. Since the term "withdrawal" has been linked to addiction to recreational drugs like opioids the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[36] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[37] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[38]

Interactions

The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.[39] 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.

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[40] and the availability of these in the home when prescribed for bed wetting and depression. In the event of a known or suspected overdose medical assistance should be sought immediately.

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. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying

Many of the initial 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:[41]

  1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, 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. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
  4. Pulmonary effects: hypoventilation resulting from CNS depression
  5. Gastrointestinal effects: decreased or absent bowel sounds

Treatment of TCA overdose depends on severity of symptoms:
Initially, gastric decontamination of the patient is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not  recommended in TCA poisoning.
If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases - the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).
Treatment is otherwise supportive.

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[42] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[43] and generally have low abuse potential.[44] Several cases of the misuse[45] of amitriptyline alone[46][47] or together with methadone[45][48] or in other drug dependent patients[49][50] and of dothiepin with alcohol[51] or in methadone patients[52] have been reported.

References

External links

  • Medical Subject Headings (MeSH)
  • More information on TCAs
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