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.
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.
[10] A 2024 systematic review and meta-analysis assessed the beneficial and harmful effects of TCAs in the treatment of major depressive disorder in adults.
[11] TCAs had a higher rate of serious adverse effects than placebo, but this did not reach statistical significance (ORTooltip odds ratio = 2.78; 95% CI: 2.18–3.55; k = 35).
[11] The TCAs were used in the past in the clinical treatment of ADHD,[13] though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Attentin, Dexedrine, Vyvanse).
[15] 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.
[17][18] 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.
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.
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.
New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia.
[28] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, cholinergic rebound, headache, nausea, malaise, or motor disturbance.
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.
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] 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).
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.
[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.
[34] 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.
[53][54] Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine).
[57] 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.
[64] 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.