Tricyclic antidepressant

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In medicine and pharmacology, tricyclic antidepressants are antidepressants that are adrenergic uptake inhibitors that "contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system."[1]


Tertiary amine tricyclics

Older tricyclics include amitriptyline, doxepin, and imipramine have a tertiary-amine side chain block both serotonin and norepinephrine and increase anticholinergic drug toxicity.[2]

Secondary amine tricyclics

Secondary amine tricyclics include desipramine, nortriptyline, and others. These medications have less affect on serotonin receptors and more on norepinephrine receptors. These medications have less anticholinergic drug toxicity and less sedation.[3]


Mirtazapine, a tetracyclic compound, is classified as a tricyclic antidepressant by the National Library of Medicine in the United States.[4] However, mirtazapine is also considered a second-generation antidepressant.

Mechanism of action

It is generally accepted that they antagonize catechol-O-methyl transferase in postsynaptic neurons. Blocking this enzyme means that it slows the metabolism of serotonin and norepinephrine in the postsynaptic neuron, keeping a higher concentration in the synapse that continues to affect receptors. In contrast, most second-generation antidepressants operate on the presynaptic neuron to maintain high synaptic levels of these neurotransmitters.

Depression may be due to the monoamine-deficiency hypothesis, which is a "deficiency in serotonin or norepinephrine neurotransmission in the brain."[5]

By blocking the reuptake of norepinephrine and serotonin, tricyclics may overcome the mono-amine deficiency.[6]

Medical uses


For more information, see: Depression.

Irritable bowel

For more information, see: Irritable bowel syndrome.

Tricyclic antidepressants can reduce symptoms of irritable bowel syndrome, perhaps with greatest benefit for diarrhea-predominant irritable bowel syndrome.[7]

Chronic pain

For more information, see: Pain.

Drug toxicity

Second-generation antidepressants are not clearly safer than tricyclic antidepressants.[8]


  1. Anonymous (2024), Tricyclic antidepressant (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. (2006) “Antidepressant Agents”, Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th. New York: McGraw-Hill. ISBN 0-07-142280-3. 
  3. Baldessarini Ross J, "Chapter 17. Drug Therapy of Depression and Anxiety Disorders" (Chapter). Brunton LL, Lazo JS, Parker KL: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11e
  4. Anonymous (2024), Mirtazapine (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. Belmaker RH, Agam G (2008). "Major depressive disorder". N. Engl. J. Med. 358 (1): 55–68. DOI:10.1056/NEJMra073096. PMID 18172175. Research Blogging.
  6. Katzung, Bertram G. (2006). “Antidepressant Agents”, Basic and Clinical Pharmacology, 10th. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. 
  7. (2008-12-18) "An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome". Am J Gastroenterol 104 (S1): S1-S35. ISSN 0002-9270. Retrieved on 2008-12-20.
  8. Coupland CA, Dhiman P, Barton G, Morriss R, Arthur A, Sach T et al. (2011). "A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database.". Health Technol Assess 15 (28): 1-202, iii-iv. DOI:10.3310/hta15280. PMID 21810375. Research Blogging.