Tricyclic antidepressant

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Tricyclic antidepressant
Chemical class
Tricyclic
External links
MeSHD000929
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Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade.[1] They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[2]

History

The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of

antihistamines developed by Rhône-Poulenc in the 1940s.[3] 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.[4]
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.[3] Some testing of Geigy's imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[4] Geigy later became Ciba-Geigy and eventually Novartis.

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.[4] This compound has a different three-ring structure than imipramine.

Medical uses

The TCAs are used primarily in the

adjunct in schizophrenia
.

Nortriptyline and desipramine may be preferred medications over other TCAs among older adults due to their reduced anticholinergic effects, diminished cardiac toxicity, and more linear pharmacokinetics.[8][9]

Clinical depression

For many years the TCAs were the first choice for

overdose (see therapeutic index) are far wider in comparison. A 2024 systematic review concluded that, in the treatment of depression, "[t]he long-term effects of tricyclic antidepressants and the effects on quality of life are unknown. Short-term results suggest that tricyclic antidepressants may reduce depressive symptoms while also increasing the risks of serious adverse events," but cautioned that "results were based on low and very low certainty evidence," owing to the poor quality of the clinical trials reviewed.[11]

Nonetheless, the TCAs are commonly prescribed for

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.[13]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,

hyperactivity and impulsivity, but have little to no benefits on attention.[17]

Chronic pain

The TCAs show efficacy in the clinical treatment of a number of different types of

prophylaxis
, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Side effects

Many

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/

irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.[23] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[24]

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.

New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia.[25] Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.[26] Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.

Discontinuation

Antidepressants in general may produce withdrawal. However, 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."[27] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[28] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[29]

Overdose

Main article: Tricyclic antidepressant overdose

TCA overdose is a significant cause of fatal drug

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. 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 it is rapidly absorbed from the 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:[31]

  1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis, blurred vision, fever
  2. Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including
    ECG
    changes (prolonged QRS, QT, and PR intervals)
  3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia, convulsions, drowsiness
  4. Pulmonary effects: hypoventilation resulting from CNS depression[32]
  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

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).

Interactions

The TCAs are highly metabolised by the

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.[33] 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.

Pharmacology

The majority of the TCAs act primarily as SNRIs by blocking the

anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[36]

In addition to their

5-HT7,[40] α1-adrenergic,[37] and NMDA receptors,[41] and as agonists at the sigma receptors[42] (σ1[42] and σ2[43]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[44] The TCAs also have varying but typically high affinity for antagonising the H1[37] and H2[45][46] histamine receptors, as well as the muscarinic acetylcholine receptors.[37] As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.[47]

Most, if not all, of the TCAs also

overdose seen with the TCAs via cardiotoxicity.[50] It may also be involved in their efficacy as analgesics, however.[51]

In summary, tricyclic antidepressants can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors.  Thus their dangerous side effect profile limits their use in daily practice.

Binding profiles

See also: Tetracyclic antidepressant § Binding profiles

The binding profiles of various TCAs and some

affinities (Ki, nM) for various receptors and transporters are as follows:[52]

Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7 α1 α2
D2
H1
H2
 mAChTooltip Muscarinic acetylcholine receptor σ1 σ2
Amineptine >100,000 10,000 1,000–1,400 >100,000 74,000 ND ND ND >100,000 >100,000 >100,000 ≥13,000 ND >100,000 ND ND
Amitriptyline 2.8–4.3 19–35 3,250 ≥450 18–23 4.0 65–141 93–123 4.4–24 114–690 196–1,460 0.5–1.1 66 9.6 300 ND
Amoxapine 58 16 4,310 ND 0.5 2.0 6.0–50 41 50 2,600 3.6–160 7.9–25 ND 1,000 ND ND
Butriptyline ≥1,360 5,100 3,940 7,000 380 ND ND ND 570 4,800 ND 1.1 ND 35 ND ND
Clomipramine 0.14–0.28 38–54 ≥2,190 ≥7,000 27–36 65 54 127 3.2–38 ≥535 78–190 13–31 209 37 546 ND
Desipramine 18–163 0.63–3.5 3,190 ≥6,400 115–350 244–748 ND >1,000 23–130 ≥1,379 3,400 60–110 1,550 66–198 ≥1,990 ≥1,610
Dibenzepin ND ND >10,000 >10,000 ≥1,500 ND ND ND >10,000 >10,000 >10,000 23 1,950 1,750 ND ND
Dosulepin 8.6–78 46–70 5,310 4,000 152 ND ND ND 419 2,400 ND 3.6–4.0 ND 25–26 ND ND
Doxepin 68–210 13–58 ≥4,600 276 11–27 8.8–200 136 ND 24 28–1,270 360 0.09–1.23 174 23–80 ND ND
Imipramine 1.3–1.4 20–37 8,500 ≥5,800 80–150 120 190–209 >1,000 32 3,100 620–726 7.6–37 550 46 332–520 327–2,100
Iprindole ≥1,620 1,260 6,530 2,800 217–280 206 ND ND 2,300 8,600 6,300 100–130 200–8,300 2,100 >10,000 ND
Lofepramine 70 5.4 >10,000 4,600 200 ND ND ND 100 2,700 2,000 245–360 4,270 67 2,520 ND
Maprotiline 5,800 11–12 1,000 ND 51 122 ND 50 90 9,400 350–665 0.79–2.0 776 570 ND ND
Norclomipramine 40 0.45 2,100 19,000 130 ND ND ND 190 1,800 1,200 450 ND 92 ND ND
Northiaden 192 25 2,539 2,623 141 ND ND ND 950 ND ND 25 ND 110 ND ND
Nortriptyline 15–18 1.8–4.4 1,140 294 5.0–41 8.5 148 ND 55 2,030 2,570 3.0–15 646 37 2,000 ND
Opipramol ≥2,200 ≥700 ≥3,000 >10,000 120 ND ND ND 200 6,100 120–300 6.0 4,470 3,300 0.2–50 110
Protriptyline 19.6 1.41 2,100 3,800 70 ND ND ND 130 6,600 2,300 7.2–25 398 25 ND ND
Tianeptine >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000
Trimipramine 149–2,110 ≥2,450 ≥3,780 8,000 32 537 ND ND 24 680 143–210 0.27–1.5 41 58 ND ND
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

With the exception of the

inhibitors
of the transporters. Tianeptine is included in this list due to it technically being a TCA, but with a vastly different pharmacology.

Therapeutic levels of TCAs are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM.[53] Plasma protein binding is generally 90% or greater.[53]

Chemistry

There are two major groups of TCAs in terms of

dibenzoxazepines (amoxapine).[54][55]

In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of

secondary amines (desipramine, nortriptyline, protriptyline).[56][57] Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.[57] Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.[58] In 2021, a new method was developed at the Institute for Bioengineering of Catalonia for designing photochromic analogs of tricyclic drugs via (1) isosteric replacement of the two-atom bridge between the aromatic systems with an azo group and (2) opening of the central ring. The authors named the strategy "crypto-azologization".[59]

Society and culture

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[60] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[61] and generally have low misuse potential.[62] Nonetheless, due to their atypical mechanism of action, amineptine and tianeptine (dopamine reuptake inhibition and μ-opioid receptor agonism, respectively) are the two TCAs with the highest addiction and misuse potential. Several cases of the misuse[63] of amitriptyline alone[64][65] or together with methadone[63][66] or in other drug dependent patients[67][68] and of dosulepin with alcohol[69] or in methadone patients[70] have been reported.

List of TCAs

Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:

Legend:

  • † indicates products which have been withdrawn from the market worldwide.
  • ‡ indicates products which are not available in any country in which English is an official language.
  • § indicates products which are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
  • Bolded names indicates products which are available in at least three countries in which English is an official language.

See also

References

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Further reading

External links