Tricyclic antidepressant


Tricyclic antidepressants 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. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants, 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, serotonin–norepinephrine reuptake inhibitors and norepinephrine reuptake inhibitors. Adverse effects have been found to be of a similar level between TCAs and SSRIs.

Medical uses

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder, dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including cyclic vomiting syndrome and anxiety disorders such as generalized anxiety disorder, social phobia also known as social anxiety disorder, obsessive-compulsive disorder, premature ejaculation and panic disorder, post-traumatic stress disorder, body dysmorphic disorder, eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder and Avoidant personality disorder, neurological disorders such as attention-deficit hyperactivity disorder, Parkinson's disease and Autism Spectrum Disorder, as well as chronic pain, neuralgia or neuropathic pain, Complex regional pain syndrome and fibromyalgia, headache, or migraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome, interstitial cystitis, nocturnal enuresis, narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia and certain psychotic disorders.
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.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of major depression. Although they are still considered to be 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, TCAs have been claimed to possibly be more effective in treating melancholic depression than other antidepressant drug classes. 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 are far wider in comparison.
Nonetheless, the TCAs are commonly prescribed for treatment-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. They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors. 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.
A 2024 systematic review and meta-analysis assessed the beneficial and harmful effects of TCAs in the treatment of major depressive disorder in adults. Previous systematic reviews and meta-analyses had not comprehensively assessed TCAs in the same fashion, with the largest including only two TCAs and only 36trials. A total of 103 short-term clinical trials with 10,590 participants employing 12 different TCAs were included. TCAs showed a small benefit on depression over that of placebo in terms of reduction in Hamilton Depression Rating Scale-17 scores. Due to the possibility of unblinding by side effects, it was unclear whether TCAs had a genuine antidepressant effect or whether the benefits were merely due to amplified placebo effects. TCAs had a higher rate of serious adverse effects than placebo, and this did reach statistical significance. However, trial sequential analysis indicated that the required information size had not been reached to conclusively confirm this effect. The quality of evidence was low to very low and the results were at high risk of bias. Among the collaborators of the systematic review and meta-analysis included Irving Kirsch, Joanna Moncrieff, and Michael P. Hengartner.

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD, though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine and stimulants like methylphenidate, and amphetamine. 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. 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.

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. 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. 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. 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. The ability of tricyclic antidepressants that have mast-cell stabilizing effects 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.

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, 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. Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.
Delayed ejaculation may be experienced by some tricyclic antidepressants such as clomipramine.
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. Although many studies have investigated this link, this was the first study to use a long-term approach to find that dementias associated with anticholinergics may not be reversible even years after drug use stops. 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." Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.
In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, cholinergic rebound, headache, nausea, malaise, or motor disturbance.

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 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. Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:
  1. Anticholinergic effects: altered mental status, resting sinus tachycardia, dry mouth, mydriasis, blurred vision, fever
  2. Cardiac effects: hypertension, tachycardia, orthostasis and hypotension, arrhythmias, ECG changes
  3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia, convulsions, drowsiness
  4. Pulmonary effects: hypoventilation resulting from CNS depression
  5. 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 a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract. Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or 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.