Tricyclic Antidepressants (TCAs): Difference between revisions

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~~This category groups~~ medicines ~~belonging~~ to the [[~~Classes~~|Tricyclic ~~Antidepressants~~ (~~TCAs~~)]] class. ~~See~~ [[~~Classes~~]] for the full taxonomy.

The '''tricyclic antidepressants''', or '''TCAs''', were the first medicines found to lift depression, and they were found by a clinician who was looking for something else. In 1955 the Swiss psychiatrist Roland Kuhn, working at the cantonal asylum at Münsterlingen on the shore of Lake Constance, was given a compound by the Geigy company, coded G 22355, in the hope that it might be a new sedative in the manner of the recently introduced chlorpromazine.<ref name="kuhn1958">Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). ''American Journal of Psychiatry''. 1958 Nov;115(5):459–464. PMID: 13583250.</ref> As a calmative it disappointed; the agitated and psychotic patients it was tried on did not improve and some grew worse. Kuhn noticed instead that a few withdrawn, melancholic patients brightened, and he turned the trial toward depression. The compound was imipramine, and his 1958 report of its effect in depressive states announced the first antidepressant.<ref name="kuhn1958"/> The medicines that followed shared imipramine's three-ringed chemical skeleton, and the name tricyclic records that shape rather than any action.<ref name="gillman2007">Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. ''British Journal of Pharmacology''. 2007 Jul;151(6):737–748. PMID: 17471183.</ref>

What the three rings do was worked out afterward. The tricyclics block the reuptake of two monoamines, serotonin and norepinephrine, leaving more of each in the synapse, and it is this dual reuptake blockade that is thought to carry the antidepressant effect.<ref name="frazer1997">Frazer A. Pharmacology of antidepressants. ''Journal of Clinical Psychopharmacology''. 1997 Apr;17 Suppl 1:2S–18S. PMID: 9090571.</ref> The difficulty is that the same molecules also block histamine H1 receptors, muscarinic acetylcholine receptors, and alpha-1 adrenergic receptors, and it is this receptor promiscuity, not the reuptake action, that produces the class's burdens: sedation and weight gain from the antihistamine effect, dry mouth, constipation, blurred vision, and urinary hesitancy from the antimuscarinic effect, and dizziness on standing from the alpha-adrenergic effect.<ref name="gillman2007"/> The later antidepressants designed to keep the dual reuptake blockade while dropping this receptor binding, the [[:Category:Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)|SNRIs]], were in effect an attempt to build a cleaner tricyclic.<ref name="frazer1997"/>

The tricyclics divide along a chemical line that also predicts how they behave. The tertiary amines, among them imipramine, amitriptyline, clomipramine, doxepin, and trimipramine, favor serotonin reuptake inhibition and carry more of the sedating and anticholinergic load; the body demethylates several of them into secondary amines, which favor norepinephrine and are somewhat better tolerated.<ref name="gillman2007"/> Two of those secondary-amine metabolites are themselves marketed medicines: desipramine is the demethylated metabolite of imipramine, and nortriptyline the demethylated metabolite of amitriptyline, each more noradrenergic than its parent.<ref name="gillman2007"/> Clomipramine stands somewhat apart as the most serotonergic of the group,<ref name="gillman2007"/> and it is the one tricyclic with an established place in obsessive-compulsive disorder, a use that foreshadowed the serotonergic antidepressants to come.<ref name="clomipramine1991">Clomipramine Collaborative Study Group. Clomipramine in the treatment of patients with obsessive-compulsive disorder. ''Archives of General Psychiatry''. 1991 Aug;48(8):730–738. PMID: 1883256.</ref>

The gravest property of the tricyclics is their danger in overdose, and it is a danger separate from anything they do to mood. In high doses the tricyclics block cardiac sodium channels, slowing conduction through the heart; the electrocardiogram shows a widening QRS complex, and the result can be ventricular arrhythmia, seizures, coma, and death.<ref name="kerr2001">Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. ''Emergency Medicine Journal''. 2001 Jul;18(4):236–241. PMID: 11435353.</ref> Because a depressed patient is by definition at some risk of self-harm, prescribing a medicine that is lethal in a week's supply is a hazard built into the indication itself, and it is the single most important reason the safer SSRIs and SNRIs displaced the tricyclics as first-line treatment for depression even though they did not clearly surpass them in efficacy.<ref name="cipriani2018">Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. ''The Lancet''. 2018;391(10128):1357–1366. PMID: 29477251.</ref> That 2018 network meta-analysis of 21 antidepressants in fact ranked amitriptyline among the most effective of all the medicines compared, a reminder that the tricyclics were retired for their safety, not their power.<ref name="cipriani2018"/>

Displaced from the front line in depression, the tricyclics did not leave medicine. Their action on the descending noradrenergic pathways that dampen pain makes amitriptyline and nortriptyline mainstays of neuropathic pain.<ref name="moore2015">Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. ''Cochrane Database of Systematic Reviews''. 2015 Jul;(7):CD008242. PMID: 26146793.</ref> Amitriptyline is also a standard preventive for migraine,<ref name="silberstein2012">Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. ''Neurology''. 2012 Apr 24;78(17):1337–1345. PMID: 22529202.</ref> and doxepin's strong antihistamine action is used, at very low dose, as a hypnotic for insomnia.<ref name="krystal2011">Krystal AD, Lankford A, Durrence HH, et al. Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. ''Sleep''. 2011 Oct 1;34(10):1433–1442. PMID: 21966075.</ref> A medicine introduced as the first antidepressant is now as likely to be prescribed for pain or for sleep as for mood.

== Members indexed ==

The tricyclics are listed below, with imipramine first as the founding medicine of the class and the others following alphabetically.

* '''[[imipramine]]''': the first tricyclic and the first antidepressant, introduced by Roland Kuhn's 1958 report. A tertiary amine, demethylated in the body to desipramine.

* '''[[amitriptyline]]''': a tertiary amine, among the most effective antidepressants ever measured, now used as much for neuropathic pain and migraine prevention as for depression. Demethylated to nortriptyline.

* '''[[amoxapine]]''': a tricyclic by structure that also blocks dopamine receptors, and so behaves partly as a neuroleptic; indexed here and, under the wiki's multi-membership convention, among the neuroleptics as well.<ref name="gillman2007"/>

* '''[[clomipramine]]''': the most serotonergic of the tricyclics and the one with an established use in obsessive-compulsive disorder.

* '''[[desipramine]]''': a secondary amine and the active demethylated metabolite of imipramine, favoring norepinephrine reuptake inhibition.

* '''[[doxepin]]''': a tertiary amine whose strong antihistamine action is used, at very low dose, as a hypnotic for insomnia.

* '''[[nortriptyline]]''': a secondary amine and the demethylated metabolite of amitriptyline, more noradrenergic and somewhat better tolerated than its parent.

* '''[[protriptyline]]''': a secondary amine, and like the other secondary amines among the better tolerated of the class.<ref name="gillman2007"/>

* '''[[trimipramine]]''': a tertiary amine, and so among the more sedating of the class.<ref name="gillman2007"/>

== Notes on scope ==

This category indexes the medicines built on the tricyclic three-ring skeleton whose principal action is dual serotonin and norepinephrine reuptake inhibition. The boundary is chemical and pharmacological together: a medicine belongs here if it is a tricyclic by structure and a dual reuptake inhibitor by action.

The line between the tricyclics and their neighbors is one of selectivity. The [[:Category:Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)|SNRIs]] share the tricyclics' dual reuptake action but drop the histamine, muscarinic, and adrenergic binding that makes the tricyclics burdensome and dangerous. [[amoxapine]], a tricyclic by structure, also blocks dopamine receptors and so behaves partly as a neuroleptic; following the wiki's multi-membership convention it may be reachable both here and from the neuroleptic indexes where its pharmacology warrants. Several tricyclics used chiefly in pain or sleep are likewise reachable from the wiki's pain-medicine and hypnotic indexes.

== About these pages ==

Each medicine indexed here has its own page, built on the wiki's standard structure for a medicine: a history-first account, then pharmacology, indications, adverse effects, and interactions. The tricyclics sit within the larger family of antidepressants, and the full taxonomy of antidepressant classes is set out at [[:Category:Antidepressants|Antidepressants]].

This is one of the wiki's MedCategory class-overview pages. It carries the [[:Category:MedCategory|MedCategory]] and [[:Category:MedCategoryFull|MedCategoryFull]] marker tags; the second suppresses the member list that MediaWiki would otherwise generate automatically, so that the curated index above is the only one the reader sees. The category sits beneath [[:Category:Antidepressants|Antidepressants]] and beneath [[:Category:Pharmaceutical|Pharmaceutical]], the origin category for medicines that came into use through scientific discovery rather than traditional practice. The tricyclics, discovered in the laboratories of Geigy and first understood at a Swiss asylum in the 1950s, are pharmaceutical-origin medicines in full.

== References ==

[[Category:MedCategory]]

[[Category:MedCategoryFull]]

[[Category:Antidepressants]]

[[Category:Pharmaceutical]]

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