Tricyclic antidepressants (TCAs) are a class of medications that are used primarily asantidepressants.[1] TCAs were discovered in the early 1950s and were marketed later in the decade.[2] They are named after theirchemical structure, which contains threerings of atoms.Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
Nortriptyline anddesipramine may be preferred medications over other TCAs among older adults due to their reducedanticholinergic effects, diminished cardiac toxicity, and more linear pharmacokinetics.[7][8]
For many years the TCAs were the first choice forpharmacologicaltreatment ofmajor depression. Although they are still considered to beeffective, 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 MAOImoclobemide. However, TCAs have been claimed to possibly be more effective in treatingmelancholic depression than other antidepressant drug classes.[9] Newer antidepressants are thought to have fewer and less severeside effects and are also thought to be less likely to result in injury or death if used in asuicide attempt, as the doses required for clinical treatment and potentiallylethaloverdose (seetherapeutic index) are far wider in comparison.
Nonetheless, the TCAs are commonly prescribed fortreatment-resistant depression that has failed to respond to therapy with newer antidepressants, they also tend to have fewer emotional blunting and sexual side effects than SSRI antidepressants.[10] They are not consideredaddictive and are somewhat preferable to themonoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before thetherapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, asvolition can be increased, possibly giving thepatient a greater desire to attempt or commitsuicide.[11]
A 2024systematic review andmeta-analysis assessed the beneficial and harmful effects of TCAs in the treatment of major depressive disorder in adults.[12] Previous systematic reviews and meta-analyses had not comprehensively assessed TCAs in the same fashion, with the largest including only two TCAs (amitriptyline andclomipramine) and only 36trials.[12][13] A total of 103 short-term clinical trials with 10,590 participants employing 12 different TCAs (and TeCAs) were included.[12] TCAs showed a small benefit on depression over that ofplacebo in terms of reduction inHamilton Depression Rating Scale-17 (HDRS-17) scores (mean difference: –3.77 points; or with removal of anoutlier study: –3.16 points).[12] Due to the possibility ofunblinding byside effects, it was unclear whether TCAs had a genuine antidepressant effect or whether the benefits were merely due to amplifiedplacebo effects.[12] TCAs had a higher rate of seriousadverse effects than placebo, but this did not reach statistical significance (ORTooltip odds ratio = 2.78; 95% CI: 2.18–3.55; k = 35).[12] Thequality of evidence was low to very low and the results were at high risk ofbias.[12] Among the collaborators of the systematic review and meta-analysis includedIrving Kirsch,Joanna Moncrieff, andMichael P. Hengartner.[12]
The TCAs were used in the past in the clinical treatment of ADHD,[14] though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such asatomoxetine (Strattera, Tomoxetin) andstimulants likemethylphenidate (Ritalin, Focalin, Concerta), andamphetamine (Adderall, Attentin, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency ofdopamine andnorepinephrineactivity in theprefrontal cortex of thebrain.[15] Most of the TCAsinhibit thereuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[16] Notably, the TCAs are more effective in treating thebehavioral aspects of ADHD than thecognitive deficits, as they help limithyperactivity andimpulsivity, but have little to no benefits onattention.[17]
The TCAs show efficacy in the clinical treatment of a number of different types ofchronic pain, notably neuralgia orneuropathic pain andfibromyalgia.[18][19] The precisemechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate theopioid system in the brain downstream viaserotonergic andnoradrenergicneuromodulation, among other properties.[20][21][22] They are also effective inmigraineprophylaxis,[23] though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.[medical citation needed] Tricyclic antidepressant are supposed to have effect on reducing mast cell degranulation, thus reducing pain and the symptoms associated with mast cell activation, such as IBS pain; people with IBS exhibit increased mucosal mast cells, elevated tryptase/histamine, and enhanced proximity of degranulating mast cells to enteric nerves, each correlating with subjective pain scores.[24][25] The ability of tricyclic antidepressants that have mast-cell stabilizing effects (such as amitriptyline) to reduce subjective pain score are believed to help not simply by altering mood, but by reducing visceral afferent firing, possibly through attenuation of nerve-mast cell crosstalk.[24][25][26]
Manyside effects may be related to theantimuscarinic 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, 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.[27]Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[28]
Delayed ejaculation may be experienced by some tricyclic antidepressants such asclomipramine.
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 class1A 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 anddementia.[29] 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.[30] Anticholinergic drugs block the action ofacetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.
Antidepressants in general may producewithdrawal. However, since the term "withdrawal" has been linked to addiction to recreational drugs likeopioids, the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[31] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[32]In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, cholinergic rebound, headache, nausea, malaise, or motor disturbance.[33]
TCA overdose is a significant cause of fatal drugpoisoning. The severemorbidity and mortality associated with these drugs is well documented due to theircardiovascular andneurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[34] 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:[35]
Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (includingventricular tachycardia and ventricular fibrillation, most serious consequence),ECG changes (prolonged QRS, QT, and PR intervals)
Pulmonary effects: hypoventilation resulting from CNS depression[36]
Gastrointestinal effects: decreased or absent bowel sounds, constipation
Treatment of TCA overdose depends on severity of symptoms:
Initially, gastric decontamination of the patient is achieved by administering, either orally or via anasogastric tube,activated charcoal pre-mixed with water, whichadsorbs the drug in thegastrointestinal 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, arenot recommended in TCA poisoning.
If there is metabolic acidosis,intravenous infusion ofsodium 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 andbioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).
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.
With the exception of thesigma receptors, the TCAs act asantagonists orinverse agonists of the receptors and asinhibitors 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.[56]Plasma protein binding is generally 90% or greater.[56]
In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number ofsubstitutions of theside chainamine.[59][60] These groups include thetertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and thesecondary amines (desipramine, nortriptyline, protriptyline).[59][60] Lofepramine is technically a tertiary amine, but acts largely as aprodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.[60] 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.[61] In 2021, a new method was developed at theInstitute for Bioengineering of Catalonia for designingphotochromic 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".[62]
The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis ofchlorpromazine in December 1950 byRhône-Poulenc's chief chemist, Paul Charpentier, from syntheticantihistamines developed by Rhône-Poulenc in the 1940s.[63] 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 anantipsychotic.[64] Research chemists quickly began to explore other derivatives of chlorpromazine.
The first TCA reported for the treatment of depression wasimipramine, 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 asedative 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 psychiatristRoland Kuhn in 1957.[65] Some testing of Geigy's imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[64] Geigy later became Ciba-Geigy and eventuallyNovartis.
Dibenzazepine derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment toSmith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCAamitriptyline.
Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.[64] This compound has a different three-ring structure than imipramine.
A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[66] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[67] and generally have low misuse potential.[68] 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[69] of amitriptyline alone[70][71] or together with methadone[69][72] or in other drug dependent patients[73][74] and of dosulepin with alcohol[75] or in methadone patients[76] have been reported.
TCAs are also used inveterinary medicine for anxiolytic, anticompulsive, and antiaggressive purposes. Most use is off-label, with the exception ofclomipramine (Clomicalm chewable tablet), which is FDA-approved forseparation anxiety in dogs when paired withbehavior modification.[77] Psychotrophic medication is generallynot the first-line treatment for behavior problems. For example, although the American Association of Feline Practitioners (AAFP) and the International Society of Feline Medicine (ISFM) mention TCAs in their guide for the treatment of house-soiling in cats, they are to be attempted only for severe, recurrant cases, after all other methods have failed.[78]
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Bolded names indicates products which are available in at least three countries in which English is an official language.
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