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. 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).
Medical uses 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 cyclic vomiting syndrome (CVS) and anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder (SAD), obsessive-compulsive disorder, panic disorder (PD), Adjustment disorder, post-traumatic stress disorder (PTSD), and body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD) and Avoidant personality disorder (AvPD), neurological disorders such as attention-deficit hyperactivity disorder (ADHD), Parkinson's disease and Autism Spectrum Disorder (ASD), 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 (IBS), interstitial cystitis (IC), nocturnal enuresis (NE), 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 (see therapeutic index) 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 (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. 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 (amitriptyline and clomipramine) and only 36 trials. A total of 103 short-term clinical trials with 10,590 participants employing 12 different TCAs (and TeCAs) were included. TCAs showed a small benefit on depression over that of placebo in terms of reduction in Hamilton Depression Rating Scale-17 (HDRS-17) scores (mean difference: –3.77 points; or with removal of an outlier study: –3.16 points). 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 (ORTooltip odds ratio = 2.78; 95% CI: 2.18–3.55; k = 35). 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 (Strattera, Tomoxetin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Attentin, 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. 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.
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