View source for Tricyclic antidepressant

{{Short description|Class of medications}}
{{Use dmy dates|date=September 2024}}
{{cs1 config|name-list-style=vanc|mode=cs1}}
{{Infobox drug class
| Image               = File:Imipramine.svg
| ImageClass          = skin-invert-image
| Alt                 =
| Caption             = [[Chemical structure]] of the prototypical and first marketed tricyclic antidepressant [[imipramine]] showing its three [[functional group|rings]].
| Width               = 200px
| Pronounce           =
| Synonyms            =
<!-- Class identifiers -->
| Use                 =
| ATC_prefix          =
| Mode_of_action      =
| Mechanism_of_action =
| Biological_target   =
| Chemical_class      = [[Tricyclic]]
<!-- Clinical data -->
| Drugs.com           = <!-- {{Drugs.com|drug-class|?}} -->
| Consumer_Reports    =
| medicinenet         =
| rxlist              =
<!-- External links -->
| MeshID              = D000929
}}

'''Tricyclic antidepressants''' ('''TCAs''') are a class of medications that are used primarily as [[antidepressant]]s. TCAs were discovered in the early 1950s and were marketed later in the decade.<ref>Carson VB (2000). [https://books.google.com/books?id=QM5rAAAAMAAJ Mental health nursing: the nurse-patient journey] W.B. Saunders. {{ISBN|978-0-7216-8053-8}}. pp. 423</ref> They are named after their [[chemical structure]], which contains three [[cyclic compound|rings of atoms]]. [[Tetracyclic antidepressant]]s (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

Although TCAs are sometimes [[medical prescription|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 inhibitor]]s (SSRIs), [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs) and [[norepinephrine reuptake inhibitor]]s (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.<ref>{{cite journal | vauthors=Trindade E, Menon D, Topfer LA, Coloma C | title=Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis | journal=CMAJ | volume=159 | issue=10 | pages=1245–1252 | date=November 1998 | pmid=9861221 | pmc=1229819 | url=http://www.cmaj.ca/content/159/10/1245.reprint}}</ref>

== Medical uses ==
The TCAs are used primarily in the [[therapy|clinical treatment]] of [[mood disorder]]s such as [[major depressive disorder]] (MDD), [[dysthymia]], and [[treatment-resistant depression|treatment-resistant]] variants. They are also used in the treatment of a number of other [[disorder (medicine)|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]] [[premature ejaculation]] (clomipramine) and [[panic disorder]] (PD), [[post-traumatic stress disorder]] (PTSD), [[body dysmorphic disorder]] (BDD), [[eating disorder]]s like [[anorexia nervosa]] and [[bulimia nervosa]], certain [[personality disorder]]s such as [[borderline personality disorder]] (BPD), [[neurological disorders]] such as [[attention-deficit hyperactivity disorder]] (ADHD),<ref>{{cite web | url=http://www.medicinenet.com/script/main/art.asp?articlekey=41885 | editor-last=Shiel | editor-first=William C. | date=n.d. | title=Attention-Deficit/Hyperactivity Disorder: Nonstimulant Therapy (Strattera) and Other ADHD Drugs | type=Web page | work=MedicineNet | archive-date=2005-03-23 | archive-url=https://web.archive.org/web/20050323134329/http://www.medicinenet.com/script/main/art.asp?articlekey=41885 | url-status=dead}}</ref> [[Parkinson's disease]]<ref>{{cite journal | vauthors=Paumier KL, Siderowf AD, Auinger P, Oakes D, Madhavan L, Espay AJ, Revilla FJ, Collier TJ | display-authors=6 | title=Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson's disease | journal=Movement Disorders | volume=27 | issue=7 | pages=880–887 | date=June 2012 | pmid=22555881 | doi=10.1002/mds.24978 | author9=Parkinson Study Group Genetics Epidemiology Working Group | url=https://www.movementdisorders.org/MDS-Files1/Resources/PDFs/md_article2.pdf}}</ref> as well as [[chronic pain]], [[neuralgia]] or [[neuropathic pain]], and [[fibromyalgia]], [[headache]], or [[migraine]], [[smoking cessation]], [[tourette syndrome]], [[trichotillomania]], [[irritable bowel syndrome]] (IBS), [[interstitial cystitis]] (IC), [[nocturnal enuresis]] (NE),<ref name="pmid12917922">{{cite journal | vauthors=Caldwell PH, Sureshkumar P, Wong WC | title=Tricyclic and related drugs for nocturnal enuresis in children | journal=The Cochrane Database of Systematic Reviews | volume=2016 | issue=1 | pages=CD002117 | date=January 2016 | pmid=26789925 | pmc=8741207 | doi=10.1002/14651858.CD002117.pub2 | editor1-last=Glazener | editor1-first=Cathryn MA}}</ref> [[narcolepsy]], [[insomnia]], [[emotional lability|pathological crying and/or laughing]], [[Chronic (medicine)|chronic]] [[hiccup]]s, [[ciguatera poisoning]], and as an [[augmentation (psychiatry)|adjunct]] in [[schizophrenia]].

[[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.<ref>{{cite web | last1=Moraczewski | first1=Jordan | title=Tricyclic antidepressants | date=17 August 2023 | url=http://www.ncbi.nlm.nih.gov/books/NBK557791/ | website=StatPearls | access-date=2023-10-08 | place=Treasure Island, Florida | publisher=StatPearls Publishing | pmid=32491723 | last2=Awosika | first2=Ayoola O. | last3=Aedma | first3=Kapil K.}}</ref><ref>{{cite journal | vauthors=Gillman PK | title=Tricyclic antidepressant pharmacology and therapeutic drug interactions updated | journal=British Journal of Pharmacology | volume=151 | issue=6 | pages=737–748 | date=July 2007 | pmid=17471183 | pmc=2014120 | doi=10.1038/sj.bjp.0707253}}</ref>

=== Clinical depression ===
For many years the TCAs were the first choice for [[pharmacological]] [[therapy|treatment]] of [[major depressive disorder|major depression]]. Although they are still considered to be [[efficacy#Medicine|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.<ref name="pmid7980178">{{cite journal | vauthors=Mitchell PB, Mitchell MS | title=The management of depression. Part 2. The place of the new antidepressants | journal=Australian Family Physician | volume=23 | issue=9 | pages=1771–3, 1776–1781 | date=September 1994 | pmid=7980178}}</ref> Newer antidepressants are thought to have fewer and less severe [[adverse effect|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 dose|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.<ref name="pmid10498158">{{cite journal | vauthors=Broquet KE | title=Status of treatment of depression | journal=Southern Medical Journal | volume=92 | issue=9 | pages=846–856 | date=September 1999 | pmid=10498158 | doi=10.1097/00007611-199909000-00001}}</ref> They are not considered [[drug addiction|addictive]] and are somewhat preferable to the [[monoamine oxidase inhibitor]]s (MAOIs). The side effects of the TCAs usually come to prominence before the [[therapeutic effect|therapeutic benefits]] against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as [[volition (psychology)|volition]] can be increased, possibly giving the [[patient]] a greater desire to attempt or commit [[suicide]].<ref name="pmid8452661">{{cite journal | vauthors=Teicher MH, Glod CA, Cole JO | title=Antidepressant drugs and the emergence of suicidal tendencies | journal=Drug Safety | volume=8 | issue=3 | pages=186–212 | date=March 1993 | pmid=8452661 | doi=10.2165/00002018-199308030-00002 | s2cid=36366654}}</ref>

A 2024 [[systematic review]] and [[meta-analysis]] assessed the beneficial and harmful effects of TCAs in the treatment of major depressive disorder in adults.<ref name="KampPetersenFaltermeier2024">{{cite journal | last1=Kamp | first1=Caroline Barkholt | last2=Petersen | first2=Johanne Juul | last3=Faltermeier | first3=Pascal | last4=Juul | first4=Sophie | last5=Siddiqui | first5=Faiza | last6=Barbateskovic | first6=Marija | last7=Kristensen | first7=Andreas Torp | last8=Moncrieff | first8=Joanna | last9=Horowitz | first9=Mark Abie | last10=Hengartner | first10=Michael Pascal | last11=Kirsch | first11=Irving | last12=Gluud | first12=Christian | last13=Jakobsen | first13=Janus Christian | title=Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis | journal=BMJ Mental Health | volume=27 | issue=1 | date=2024 | issn=2755-9734 | pmc=10806869 | doi=10.1136/bmjment-2023-300730 | page=e300730 | pmid=39093721}}</ref> 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{{nbsp}}trials.<ref name="KampPetersenFaltermeier2024" /><ref name="CiprianiFurukawaSalanti2018">{{cite journal | vauthors=Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title=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 | journal=Lancet | volume=391 | issue=10128 | pages=1357–1366 | date=April 2018 | pmid=29477251 | pmc=5889788 | doi=10.1016/S0140-6736(17)32802-7 | url=}}</ref> A total of 103 short-term clinical trials with 10,590 participants employing 12 different TCAs (and TeCAs) were included.<ref name="KampPetersenFaltermeier2024" /> TCAs showed a small benefit on depression over that of [[placebo group|placebo]] in terms of reduction in [[Hamilton Rating Scale for Depression|Hamilton Depression Rating Scale-17]] (HDRS-17) scores (mean difference: –3.77 points; or with removal of an [[statistical outlier|outlier]] study: –3.16 points).<ref name="KampPetersenFaltermeier2024" /> Due to the possibility of [[unblinding]] by [[side effect]]s, it was unclear whether TCAs had a genuine antidepressant effect or whether the benefits were merely due to amplified [[placebo effect]]s.<ref name="KampPetersenFaltermeier2024" /> TCAs had a higher rate of serious [[adverse effect]]s than placebo, but this did not reach statistical significance ({{Abbrlink|OR|odds ratio}} = 2.78; 95% CI: 2.18–3.55; k = 35).<ref name="KampPetersenFaltermeier2024" /> The [[quality of evidence]] was low to very low and the results were at high risk of [[bias]].<ref name="KampPetersenFaltermeier2024" /> Among the collaborators of the systematic review and meta-analysis included [[Irving Kirsch]], [[Joanna Moncrieff]], and [[Michael P. Hengartner]].<ref name="KampPetersenFaltermeier2024" />

=== Attention-deficit hyperactivity disorder ===
The TCAs were used in the past in the clinical treatment of ADHD,<ref name="pmid2676967">{{cite journal | vauthors=Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS | title=A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy | journal=Journal of the American Academy of Child and Adolescent Psychiatry | volume=28 | issue=5 | pages=777–784 | date=September 1989 | pmid=2676967 | doi=10.1097/00004583-198909000-00022}}</ref> though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as [[atomoxetine]] (Strattera, Tomoxetin) and [[stimulant]]s like [[methylphenidate]] (Ritalin, Focalin, Concerta), and [[amphetamine]] (Adderall, Attentin, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of [[dopamine]] and [[norepinephrine]] [[brain activity|activity]] in the [[prefrontal cortex]] of the [[Human brain|brain]].<ref name="pmid19183781">{{cite journal | vauthors=Blum K, Chen AL, Braverman ER, Comings DE, Chen TJ, Arcuri V, Blum SH, Downs BW, Waite RL, Notaro A, Lubar J, Williams L, Prihoda TJ, Palomo T, Oscar-Berman M | display-authors=6 | title=Attention-deficit-hyperactivity disorder and reward deficiency syndrome | journal=Neuropsychiatric Disease and Treatment | volume=4 | issue=5 | pages=893–918 | date=October 2008 | pmid=19183781 | pmc=2626918 | doi=10.2147/NDT.S2627 | doi-access=free}}</ref> Most of the TCAs [[reuptake inhibitor|inhibit]] the [[reuptake]] of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.<ref name="pmid10560028">{{cite journal | vauthors=Biederman J, Spencer T | title=Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder | journal=Biological Psychiatry | volume=46 | issue=9 | pages=1234–1242 | date=November 1999 | pmid=10560028 | doi=10.1016/S0006-3223(99)00192-4 | s2cid=45497168}}</ref> Notably, the TCAs are more effective in treating the [[behavioral]] aspects of ADHD than the [[cognitive deficit]]s, as they help limit [[hyperactivity]] and [[impulsivity]], but have little to no benefits on [[attention]].<ref name="pmid9418743">{{cite journal | vauthors=Popper CW | title=Antidepressants in the treatment of attention-deficit/hyperactivity disorder | journal=The Journal of Clinical Psychiatry | volume=58 | issue=Suppl 14 | pages=14–29; discussion 30–1 | year=1997 | pmid=9418743}}</ref>

=== 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]].<ref name="pmid16762426">{{cite journal | vauthors=Micó JA, Ardid D, Berrocoso E, Eschalier A | title=Antidepressants and pain | journal=Trends in Pharmacological Sciences | volume=27 | issue=7 | pages=348–354 | date=July 2006 | pmid=16762426 | doi=10.1016/j.tips.2006.05.004}}</ref><ref name="pmid9121808">{{cite journal | vauthors=McQuay HJ, Tramèr M, Nye BA, Carroll D, Wiffen PJ, Moore RA | title=A systematic review of antidepressants in neuropathic pain | journal=Pain | volume=68 | issue=2–3 | pages=217–227 | date=December 1996 | pmid=9121808 | doi=10.1016/S0304-3959(96)03140-5 | s2cid=25124663}}</ref> 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 [[Serotonin|serotonergic]] and [[noradrenergic]] [[Neuromodulation (biology)|neuromodulation]], among other properties.<ref name="pmid6219612">{{cite journal | vauthors=Botney M, Fields HL | title=Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system | journal=Annals of Neurology | volume=13 | issue=2 | pages=160–164 | date=February 1983 | pmid=6219612 | doi=10.1002/ana.410130209 | s2cid=40631429}}</ref><ref>{{cite journal | vauthors=Benbouzid M, Gavériaux-Ruff C, Yalcin I, Waltisperger E, Tessier LH, Muller A, Kieffer BL, Freund-Mercier MJ, Barrot M | display-authors=6 | title=Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia | journal=Biological Psychiatry | volume=63 | issue=6 | pages=633–636 | date=March 2008 | pmid=17693391 | doi=10.1016/j.biopsych.2007.06.016 | s2cid=22957748}}</ref><ref>{{cite journal | vauthors=de Gandarias JM, Echevarria E, Acebes I, Silio M, Casis L | title=Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain | journal=Arzneimittel-Forschung | volume=48 | issue=7 | pages=717–719 | date=July 1998 | pmid=9706370}}</ref> They are also effective in [[migraine]] [[prophylaxis]],<ref>{{cite journal | last1=Jackson | first1=J. L. | title=Tricyclic antidepressants and headaches: systematic review and meta-analysis | journal=BMJ | volume=341 | pages=c5222 | year=2010 | pmid=20961988 | pmc=2958257 | doi=10.1136/bmj.c5222 | last2=Shimeall | first2=W. | last3=Sessums | first3=L. | display-authors=3 | last4=Dezee | first4=K. J. | last5=Becher | first5=D. | last6=Diemer | first6=M. | last7=Berbano | first7=E. | last8=O'Malley | first8=P. G.}}</ref> though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

== Side effects ==
Many [[adverse effect|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 (apathy/[[anhedonia]]), confusion, restlessness, dizziness, [[akathisia]], [[hypersensitivity]], changes in appetite and weight, sweating, muscle twitches, weakness, nausea and vomiting, [[hypotension]], [[tachycardia]], and rarely, [[arrythmia|irregular heart rhythms]]. Twitching, hallucinations, [[delirium]] and coma are also some of the toxic effects caused by overdose.<ref>{{cite book | last=Gelder | first=Michael G. | last2=Mayou | first2=Richard | last3=Geddes | first3=John | date=2005 | title=Psychiatry | edition=3rd | publisher=Oxford University Press | isbn=978-0-19-852863-0 | page=243}}</ref> [[Rhabdomyolysis]] or muscle breakdown has been rarely reported with this class of drugs as well.<ref>{{cite journal | vauthors=Chabria SB | title=Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity | journal=Journal of Occupational Medicine and Toxicology | volume=1 | pages=16 | date=July 2006 | pmid=16846511 | pmc=1540431 | doi=10.1186/1745-6673-1-16 | doi-access=free}}</ref>

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 [[Antiarrhythmic agent|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]].<ref>{{cite journal | vauthors=Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors=6 | title=Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal=JAMA Internal Medicine | volume=175 | issue=3 | pages=401–407 | date=March 2015 | pmid=25621434 | pmc=4358759 | doi=10.1001/jamainternmed.2014.7663 | author5-link=Rebecca Hubbard}}</ref> Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.<ref>{{cite magazine | last=Fox | first=Cynthia | date=30 April 2015 | title=Strong Link Found Between Dementia, Common Anticholinergic Drugs | magazine=Drug Discovery & Development | publication-place=Rockaway, New Jersey | publisher=Advantage Business Media | issn=1524-783X | oclc=60617296 | url=http://www.dddmag.com/articles/2015/04/strong-link-found-between-dementia-common-anticholinergic-drugs | url-status=dead | archive-url=https://web.archive.org/web/20150502182409/http://www.dddmag.com/articles/2015/04/strong-link-found-between-dementia-common-anticholinergic-drugs | archive-date=2015-05-02}} summarizing {{cite journal | last=Gray | first=Shelly L. | last2=Anderson | first2=Melissa L. | last3=Dublin | first3=Sascha | last4=Hanlon | first4=Joseph T. | last5=Hubbard | first5=Rebecca | last6=Walker | first6=Rod | last7=Yu | first7=Onchee | last8=Crane | first8=Paul K. | last9=Larson | first9=Eric B. | title=Cumulative use of strong anticholinergics and incident dementia | journal=JAMA Internal Medicine | publisher=American Medical Association | volume=175 | issue=3 | date=1 March 2015 | issn=2168-6106 | doi=10.1001/jamainternmed.2014.7663 | doi-access=free | pages=401-407| pmc=4358759 }}</ref> 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 [[Drug withdrawal|withdrawal]]. However, since the term "withdrawal" has been linked to addiction to recreational drugs like [[opioid]]s, the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."<ref>{{cite journal | vauthors=Shelton RC | title=The nature of the discontinuation syndrome associated with antidepressant drugs | journal=The Journal of Clinical Psychiatry | volume=67 | issue=Suppl 4 | pages=3–7 | year=2006 | pmid=16683856 | url=https://www.psychiatrist.com/read-pdf/12515/}}</ref> Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.<ref>{{cite journal | vauthors=van Broekhoven F, Kan CC, Zitman FG | title=Dependence potential of antidepressants compared to benzodiazepines | journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume=26 | issue=5 | pages=939–943 | date=June 2002 | pmid=12369270 | doi=10.1016/S0278-5846(02)00209-9 | s2cid=14286356}}</ref>
In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, cholinergic rebound, headache, nausea, malaise, or motor disturbance.<ref>{{cite web | first=Kent | last=Kunze | title=Somatic therapies in psychiatry | url=https://angel.dmu.edu/section/default.asp?id=0921%5FPSYC%5F2107%5F01 | publisher=Des Moines University Psychiatry Class}}{{dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}{{better source needed|date=September 2024}}</ref>

== Overdose ==
{{Main|Tricyclic antidepressant overdose}}

TCA overdose is a significant cause of fatal drug [[poison]]ing. The severe [[morbidity]] and mortality associated with these drugs is well documented due to their [[circulatory system|cardiovascular]] and [[neurology|neurological]] toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity<ref name="JEmergMed2005-Rosenbaum">{{cite journal | vauthors=Rosenbaum TG, Kou M | title=Are one or two dangerous? Tricyclic antidepressant exposure in toddlers | journal=The Journal of Emergency Medicine | volume=28 | issue=2 | pages=169–174 | date=February 2005 | pmid=15707813 | doi=10.1016/j.jemermed.2004.08.018}}</ref> 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 (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:<ref>California Poison Control 1-800-876-4766</ref>

# Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting [[sinus tachycardia]], dry mouth, [[mydriasis]], blurred vision, fever
# Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including [[ventricular tachycardia]] and ventricular fibrillation, most serious consequence), [[ECG]] changes (prolonged QRS, QT, and PR intervals)
# CNS effects: [[Syncope (medicine)|syncope]], seizure, coma, [[myoclonus]], hyperreflexia, convulsions, drowsiness
# Pulmonary effects: hypoventilation resulting from CNS depression<ref>{{cite journal | last=Crome | first=Peter | title=Poisoning due to tricyclic antidepressant overdosage: Clinical presentation and treatment | journal=Medical Toxicology | volume=1 | issue=4 | pages=261–285 | date=1 August 1986 | pmid=3537621 | doi=10.1007/BF03259843}}</ref>
# 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 carbon|activated charcoal]] pre-mixed with water, which [[Adsorption|adsorbs]] the drug in the [[Human gastrointestinal tract|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''&nbsp; recommended in TCA poisoning.

If there is metabolic acidosis, [[Intravenous therapy|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).

== Interactions ==

The TCAs are highly metabolised by the [[Cytochrome P450 oxidase|cytochrome P450]] (CYP) hepatic enzymes. Drugs that inhibit [[Cytochrome P450 oxidase|cytochrome P450]] (for example [[cimetidine]], [[methylphenidate]], [[fluoxetine]], [[antipsychotic]]s, and [[calcium channel blocker]]s) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.<ref>{{cite book | last=Preskorn | first=Sheldon H. | date=1996 | chapter=Why Are CYP Enzymes Important When Considering SSRIs? | chapter-url=http://www.preskorn.com/books/ssri_s7.html | title=Clinical pharmacology of serotonin selective reuptake inhibitors | publication-place=Caddo, Oklahoma | publisher=Professional Communications | isbn=978-1-884735-08-0 | oclc=41113507 | url=https://www.preskorn.com/books/ssri_open.html}}</ref> Drugs that prolong the [[QT interval]] including antiarrhythmics such as [[quinidine]], the antihistamines [[astemizole]] and [[terfenadine]], and some [[antipsychotic]]s may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to [[alcohol (drug)|alcohol]] and the effects of [[barbiturate]]s and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

== Pharmacology ==
The majority of the TCAs act primarily as SNRIs by blocking the [[serotonin transporter]] (SERT) and the [[norepinephrine transporter]] (NET), which results in an elevation of the [[Synapse|synaptic]] concentrations of these [[neurotransmitter]]s, and therefore an enhancement of [[neurotransmission]].<ref name="pmid9537821">{{cite journal | vauthors=Tatsumi M, Groshan K, Blakely RD, Richelson E | title=Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal=European Journal of Pharmacology | volume=340 | issue=2–3 | pages=249–258 | date=December 1997 | pmid=9537821 | doi=10.1016/S0014-2999(97)01393-9}}</ref><ref name="pmid17471183">{{cite journal | vauthors=Gillman PK | title=Tricyclic antidepressant pharmacology and therapeutic drug interactions updated | journal=British Journal of Pharmacology | volume=151 | issue=6 | pages=737–748 | date=July 2007 | pmid=17471183 | pmc=2014120 | doi=10.1038/sj.bjp.0707253}}</ref> Notably, with the sole exception of [[amineptine]], the TCAs have weak [[affinity (pharmacology)|affinity]] for the [[dopamine transporter]] (DAT), and therefore have low efficacy as [[dopamine reuptake inhibitor]]s (DRIs).<ref name="pmid9537821" /> Both [[serotonin]] and [[norepinephrine]] have been highly implicated in [[Depression (mood)|depression]] and [[anxiety (mood)|anxiety]], and it has been shown that facilitation of their activity has beneficial effects on these [[mental disorder]]s.<ref name="pmid9551776">{{cite journal | vauthors=Rénéric JP, Lucki I | title=Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test | journal=Psychopharmacology | volume=136 | issue=2 | pages=190–197 | date=March 1998 | pmid=9551776 | doi=10.1007/s002130050555 | s2cid=8093564}}</ref>

In addition to their [[Reuptake inhibitor|reuptake inhibition]], many TCAs also have high affinity as [[receptor antagonist|antagonists]] at the [[5-HT2|5-HT<sub>2</sub>]]<ref name="pmid7855217">{{cite journal | vauthors=Cusack B, Nelson A, Richelson E | title=Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal=Psychopharmacology | volume=114 | issue=4 | pages=559–565 | date=May 1994 | pmid=7855217 | doi=10.1007/BF02244985 | s2cid=21236268}}</ref> ([[5-HT2A|5-HT<sub>2A</sub>]]<ref name="pmid10379421">{{cite journal | vauthors=Sánchez C, Hyttel J | title=Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal=Cellular and Molecular Neurobiology | volume=19 | issue=4 | pages=467–489 | date=August 1999 | pmid=10379421 | doi=10.1023/A:1006986824213 | s2cid=19490821}}</ref> and [[5-HT2C|5-HT<sub>2C</sub>]]<ref name="pmid10379421" />), [[5-HT6|5-HT<sub>6</sub>]],<ref name="pmid10836139">{{cite journal | vauthors=Branchek TA, Blackburn TP | title=5-ht6 receptors as emerging targets for drug discovery | journal=Annual Review of Pharmacology and Toxicology | volume=40 | pages=319–334 | year=2000 | pmid=10836139 | doi=10.1146/annurev.pharmtox.40.1.319}}</ref> [[5-HT7|5-HT<sub>7</sub>]],<ref name="pmid9303561">{{cite journal | vauthors=Stam NJ, Roesink C, Dijcks F, Garritsen A, van Herpen A, Olijve W | title=Human serotonin 5-HT7 receptor: cloning and pharmacological characterisation of two receptor variants | journal=FEBS Letters | volume=413 | issue=3 | pages=489–494 | date=August 1997 | pmid=9303561 | doi=10.1016/S0014-5793(97)00964-2 | doi-access= | bibcode=1997FEBSL.413..489S | s2cid=7965330}}</ref> [[Alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic]],<ref name="pmid7855217" /> and [[NMDA receptor|NMDA]] [[Receptor (biochemistry)|receptors]],<ref name="pmid2568580">{{cite journal | vauthors=Sills MA, Loo PS | title=Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate | journal=Molecular Pharmacology | volume=36 | issue=1 | pages=160–165 | date=July 1989 | issn=0026-895X | pmid=2568580 | url=https://molpharm.aspetjournals.org/content/molpharm/36/1/160.full.pdf | url-access=subscription}}</ref> and as [[agonist]]s at the [[sigma receptor]]s<ref name="pmid8831113">{{cite journal | vauthors=Narita N, Hashimoto K, Tomitaka S, Minabe Y | title=Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain | journal=European Journal of Pharmacology | volume=307 | issue=1 | pages=117–119 | date=June 1996 | pmid=8831113 | doi=10.1016/0014-2999(96)00254-3}}</ref> ([[Sigma-1 receptor|σ<sub>1</sub>]]<ref name="pmid8831113" /> and [[Sigma-2 receptor|σ<sub>2</sub>]]<ref name="pmid15547788">{{cite journal | vauthors=Volz HP, Stoll KD | title=Clinical trials with sigma ligands | journal=Pharmacopsychiatry | volume=37 | issue=Suppl 3 | pages=S214–S220 | date=November 2004 | pmid=15547788 | doi=10.1055/s-2004-832680 | s2cid=260238757}}</ref>), some of which may contribute to their therapeutic [[efficacy]], as well as their [[side effect]]s.<ref>{{cite web | url=http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/ | last=Guzman | first=Flavio | title=Differences between tricyclic antidepressants and SNRIs mechanism of action | website=Pharmacology Corner | date=29 July 2011 | orig-date=28 April 2010 | publication-place=Mendoza, Argentina | publisher=Author}}</ref> The TCAs also have varying but typically high affinity for antagonising the [[Histamine H1 receptor|H<sub>1</sub>]]<ref name="pmid7855217" /> and [[Histamine H2 receptor|H<sub>2</sub>]]<ref name="pmid20581">{{cite journal | vauthors=Green JP, Maayani S | title=Tricyclic antidepressant drugs block histamine H2 receptor in brain | journal=Nature | volume=269 | issue=5624 | pages=163–165 | date=September 1977 | pmid=20581 | doi=10.1038/269163a0 | s2cid=1153522 | bibcode=1977Natur.269..163G}}</ref><ref name="pmid6150708">{{cite journal | vauthors=Tsai BS, Yellin TO | title=Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa | journal=Biochemical Pharmacology | volume=33 | issue=22 | pages=3621–3625 | date=November 1984 | pmid=6150708 | doi=10.1016/0006-2952(84)90147-3}}</ref> [[histamine receptor]]s, as well as the [[muscarinic acetylcholine receptor]]s.<ref name="pmid7855217" /> As a result, they also act as [[potency (pharmacology)|potent]] [[antihistamine]]s and [[anticholinergic]]s. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.<ref>{{cite journal | vauthors=Uher R, Farmer A, Henigsberg N, Rietschel M, Mors O, Maier W, Kozel D, Hauser J, Souery D, Placentino A, Strohmaier J, Perroud N, Zobel A, Rajewska-Rager A, Dernovsek MZ, Larsen ER, Kalember P, Giovannini C, Barreto M, McGuffin P, Aitchison KJ | display-authors=6 | title=Adverse reactions to antidepressants | journal=The British Journal of Psychiatry | volume=195 | issue=3 | pages=202–210 | date=September 2009 | pmid=19721108 | doi=10.1192/bjp.bp.108.061960 | doi-access=free}}</ref>

Most, if not all, of the TCAs also [[potency (pharmacology)|potently]] inhibit [[sodium channel]]s and [[L-type calcium channel|<small>L</small>-type calcium channels]], and therefore act as [[sodium channel blocker]]s and [[calcium channel blocker]]s, respectively.<ref name="pmid9435180">{{cite journal | vauthors=Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C | title=Inhibition of neuronal Na+ channels by antidepressant drugs | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=284 | issue=1 | pages=208–214 | date=January 1998 | pmid=9435180 | url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9435180 | access-date=2009-07-20 | url-status=dead | archive-url=https://web.archive.org/web/20210829094529/https://jpet.aspetjournals.org/content/284/1/208.long | archive-date=2021-08-29}}</ref><ref name="pmid18048694">{{cite journal | vauthors=Zahradník I, Minarovic I, Zahradníková A | title=Inhibition of the cardiac L-type calcium channel current by antidepressant drugs | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=324 | issue=3 | pages=977–984 | date=March 2008 | pmid=18048694 | doi=10.1124/jpet.107.132456 | s2cid=24777 | citeseerx=10.1.1.1030.7935}}</ref> The former property is responsible for the high [[mortality rate]] upon [[overdose]] seen with the TCAs via [[cardiotoxicity]].<ref name="pmid10452441">{{cite journal | vauthors=Harrigan RA, Brady WJ | title=ECG abnormalities in tricyclic antidepressant ingestion | journal=The American Journal of Emergency Medicine | volume=17 | issue=4 | pages=387–393 | date=July 1999 | pmid=10452441 | doi=10.1016/S0735-6757(99)90094-3}}</ref> It may also be involved in their efficacy as analgesics, however.<ref name="Cairns2009">{{cite book | author=Brian E. Cairns | title=Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management | url=https://books.google.com/books?id=MTSvERxiCrIC&pg=PA66 | date=1 September 2009 | publisher=John Wiley & Sons | isbn=978-0-470-52221-9 | pages=66–68}}</ref>

In summary, tricyclic antidepressants can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors.

=== Binding profiles ===
{{See also|Tetracyclic antidepressant#Binding profiles}}

The binding profiles of various TCAs and some [[metabolite]]s in terms of their [[affinity (pharmacology)|affinities]] ({{abbr|K<sub>i</sub>|inhibitory constant}}, {{abbr|nM|nanomolar}}) for various [[receptor (biochemistry)|receptors]] and [[membrane transport protein|transporters]] are as follows:<ref name="PDSP">{{cite web | title=PDSP K<sub>i</sub> Database | work=Psychoactive Drug Screening Program (PDSP) | author1-link=Bryan Roth | author1=Roth, BL | author2=Driscol, J | publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date=14 August 2017 | url=https://pdsp.unc.edu/databases/kidb.php}}</ref>

{| class="wikitable sortable" style="font-size: 80%; text-align: center;"
|+
! Compound !! {{abbrlink|SERT|Serotonin transporter}} !! {{abbrlink|NET|Norepinephrine transporter}} !! {{abbrlink|DAT|Dopamine transporter}} !! [[5-HT1A receptor|5-HT<sub>1A</sub>]] !! [[5-HT2A receptor|5-HT<sub>2A</sub>]] !! [[5-HT2C receptor|5-HT<sub>2C</sub>]] !! [[5-HT6 receptor|5-HT<sub>6</sub>]] !! [[5-HT7 receptor|5-HT<sub>7</sub>]] !! [[alpha-1 adrenergic receptor|α<sub>1</sub>]] !! [[alpha-2 adrenergic receptor|α<sub>2</sub>]] !! [[D2 receptor|D<sub>2</sub>]] !![[H1 receptor|H<sub>1</sub>]] !! [[H2 receptor|H<sub>2</sub>]] !! {{abbrlink|mACh|Muscarinic acetylcholine receptor}} !! [[Sigma-1 receptor|σ<sub>1</sub>]] !! [[Sigma-2 receptor|σ<sub>2</sub>]]
|-
| [[Amineptine]] || >100,000 || 10,000 || 1,000–1,400 || >100,000 || 74,000 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || >100,000 || >100,000 || >100,000 || ≥13,000 || {{abbr|ND|No data}} || >100,000 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Amitriptyline]] || 2.8–4.3 || 19–35 || 3,250 || ≥450 || 18–23 || 4.0 || 65–141 || 93–123 || 4.4–24 || 114–690 || 196–1,460 || 0.5–1.1 || 66 || 9.6 || 300 || {{abbr|ND|No data}}
|-
| [[Amoxapine]] || 58 || 16 || 4,310 || {{abbr|ND|No data}} || 0.5 || 2.0 || 6.0–50 || 41 || 50 || 2,600 || 3.6–160 || 7.9–25 || {{abbr|ND|No data}} || 1,000 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Butriptyline]] || ≥1,360 || 5,100 || 3,940 || 7,000 || 380 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 570 || 4,800 || {{abbr|ND|No data}} || 1.1 || {{abbr|ND|No data}} || 35 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Clomipramine]] || 0.14–0.28 || 38–54 || ≥2,190 || ≥7,000 || 27–36 || 65 || 54 || 127 || 3.2–38 || ≥535 || 78–190 || 13–31 || 209 || 37 || 546 || {{abbr|ND|No data}}
|-
| [[Desipramine]] || 18–163 || 0.63–3.5 || 3,190 || ≥6,400 || 115–350 || 244–748 || {{abbr|ND|No data}} || >1,000 || 23–130 || ≥1,379 || 3,400 || 60–110 || 1,550 || 66–198 ||  ≥1,990 || ≥1,610
|-
| [[Dibenzepin]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || >10,000 || >10,000 || ≥1,500 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || >10,000 || >10,000 || >10,000 || 23 || 1,950 || 1,750 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Dosulepin]] || 8.6–78 || 46–70 || 5,310 || 4,000 || 152 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 419 || 2,400 || {{abbr|ND|No data}} || 3.6–4.0 || {{abbr|ND|No data}} || 25–26 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Doxepin]] || 68–210 || 13–58 || ≥4,600 || 276 || 11–27 || 8.8–200 || 136 || {{abbr|ND|No data}} || 24 || 28–1,270 || 360 || 0.09–1.23 || 174 || 23–80 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Imipramine]] || 1.3–1.4 || 20–37 || 8,500 || ≥5,800 || 80–150 || 120 || 190–209 || >1,000 || 32 || 3,100 || 620–726 || 7.6–37 || 550 || 46 || 332–520 || 327–2,100
|-
| [[Iprindole]] || ≥1,620 || 1,260 || 6,530 || 2,800 || 217–280 || 206 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 2,300 || 8,600 || 6,300 || 100–130 || 200–8,300 || 2,100 || >10,000 || {{abbr|ND|No data}}
|-
| [[Lofepramine]] || 70 || 5.4 || >10,000 || 4,600 || 200 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 100 || 2,700 || 2,000 || 245–360 || 4,270 || 67 || 2,520 || {{abbr|ND|No data}}
|-
| [[Maprotiline]] || 5,800 || 11–12 || 1,000 || {{abbr|ND|No data}} || 51 || 122 || {{abbr|ND|No data}} || 50 || 90 || 9,400 || 350–665 || 0.79–2.0 || 776 || 570 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Norclomipramine]] || 40 || 0.45 || 2,100 || 19,000 || 130 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 190 || 1,800 || 1,200 || 450 || {{abbr|ND|No data}} || 92 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Northiaden]] || 192 || 25 || 2,539 || 2,623 || 141 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 950 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 25 || {{abbr|ND|No data}} || 110 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Nortriptyline]] || 15–18 || 1.8–4.4 || 1,140 || 294 || 5.0–41 || 8.5 || 148 || {{abbr|ND|No data}} || 55 || 2,030 || 2,570 || 3.0–15 || 646 || 37 || 2,000 || {{abbr|ND|No data}}
|-
| [[Opipramol]] || ≥2,200 || ≥700 || ≥3,000 || >10,000 || 120 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 200 || 6,100 || 120–300 || 6.0 || 4,470 || 3,300 || 0.2–50 || 110
|-
| [[Protriptyline]] || 19.6 || 1.41 || 2,100 || 3,800 || 70 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 130 || 6,600 || 2,300 || 7.2–25 || 398 || 25 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Tianeptine]] || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000 || >10,000
|-
| [[Trimipramine]] || 149–2,110 || ≥2,450 || ≥3,780 || 8,000 || 32 || 537 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 24 || 680 || 143–210 || 0.27–1.5 || 41 || 58 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|- class="sortbottom"
| colspan="17" | Values are {{abbr|K<sub>i</sub>|inhibitory constant}} ({{abbr|nM|nanomolar}}). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.
|}

With the exception of the [[sigma receptor]]s, the TCAs act as [[receptor antagonist|antagonists]] or [[inverse agonist]]s of the receptors and as [[transporter blocker|inhibitors]] of the transporters. Tianeptine is included in this list due to it technically being a TCA, but with a vastly different pharmacology.

Therapeutic levels of TCAs are generally in the range of about 100 to 300&nbsp;ng/mL, or 350 to 1,100&nbsp;nM.<ref name="SchatzbergNemeroff2009">{{cite book | last=Nelson | first=J. Craig | chapter=Tricyclic and tetracyclic drugs | editor-first1=Alan F. | editor-last1=Schatzberg | editor-first2=Charles B. | editor-last2=Nemeroff | title=The American Psychiatric Publishing textbook of psychopharmacology | edition=4th | chapter-url=https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA267 | year=2009 | publication-place=Arlington, Virginia | publisher=American Psychiatric Publishing | isbn=978-1-58562-309-9 | pages=263–287, at pp. 267–271}}</ref> [[Plasma protein binding]] is generally 90% or greater.<ref name="SchatzbergNemeroff2009" />

== Chemistry ==
There are two major groups of TCAs in terms of [[chemical structure]], which most, but not all, TCAs fall into.<ref name="Ghose2013">{{cite book | author=K. Ghose | title=Antidepressants for Elderly People | url=https://books.google.com/books?id=JVn0BwAAQBAJ&pg=PA182 | date=11 November 2013 | publisher=Springer | isbn=978-1-4899-3436-9 | pages=182–}}</ref><ref name="Aronson2009">{{cite book | author=J. K. Aronson | title=Meyler's Side Effects of Psychiatric Drugs | url=https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA7 | year=2009 | publisher=Elsevier | isbn=978-0-444-53266-4 | pages=7–}}</ref><ref name="Anthony2002">{{cite book | author=Patricia K. Anthony | title=Pharmacology Secrets | url=https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39 | year=2002 | publisher=Elsevier Health Sciences | isbn=978-1-56053-470-9 | pages=39–}}</ref> The groupings are based on the tricyclic [[ring system (chemistry)|ring system]].<ref name="Ghose2013" /><ref name="Aronson2009" /><ref name="Anthony2002" /> They are the [[dibenzazepine]]s ([[imipramine]], [[desipramine]], [[clomipramine]], [[trimipramine]], [[lofepramine]]) and the [[dibenzocycloheptadiene]]s ([[amitriptyline]], [[nortriptyline]], [[protriptyline]], [[butriptyline]]).<ref name="Ghose2013" /><ref name="Aronson2009" /> Minor TCA groups based on ring system include the [[dibenzoxepin]]s ([[doxepin]]), the [[dibenzothiepine]]s ([[dosulepin]]), and the [[dibenzoxazepine]]s ([[amoxapine]]).<ref name="Ghose2013" /><ref name="Aronson2009" />

In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of [[substituent|substitutions]] of the [[side chain]] [[amine]].<ref name="Anthony2002" /><ref name="CowenHarrison2012">{{cite book | first1=Philip | last1=Cowen | first2=Paul | last2=Harrison | first3=Tom | last3=Burns | title=Shorter Oxford Textbook of Psychiatry | url=https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532 | date=9 August 2012 | publisher=Oxford University Press | isbn=978-0-19-162675-3 | pages=532–}}</ref> These groups include the [[tertiary amine]]s (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the [[secondary amine]]s (desipramine, nortriptyline, protriptyline).<ref name="Anthony2002" /><ref name="CowenHarrison2012" /> Lofepramine is technically a tertiary amine, but acts largely as a [[prodrug]] of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.<ref name="CowenHarrison2012" /> Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.<ref>{{cite book | editor-first1=Alan F. | editor-last1=Schatzberg | editor-first2=Charles B. | editor-last2=Nemeroff | title=The American Psychiatric Association Publishing textbook of psychopharmacology | edition=5th | url=https://books.google.com/books?id=KfHEDgAAQBAJ&pg=PA306 | year=2017 | publisher=American Psychiatric Publishing | isbn=978-1-58562-523-9 | pages=306–}}</ref> In 2021, a new method was developed at the [[Institute for Bioengineering of Catalonia]] for designing [[Photopharmacology|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. The authors named the strategy "crypto-azologization".<ref name="RiefoloSortino2021">{{cite journal | vauthors=Riefolo F, Sortino R, Matera C, Claro E, Preda B, Vitiello S, Traserra S, Jiménez M, Gorostiza P | display-authors=6 | title=Rational Design of Photochromic Analogues of Tricyclic Drugs | journal=Journal of Medicinal Chemistry | volume=64 | issue=13 | pages=9259–9270 | date=July 2021 | pmid=34160229 | doi=10.1021/acs.jmedchem.1c00504 | hdl-access=free | hdl=2434/855420 | id={{hdl|2445/178992|hdl-access=free}} {{Zenodo|6088090}} | url=https://zenodo.org/records/6088090/files/acs_jmedchem_1c00504.pdf}}</ref>

== History ==
The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of [[chlorpromazine]] in December 1950 by [[Rhône-Poulenc]]'s chief chemist, Paul Charpentier, from synthetic [[antihistamines]] developed by Rhône-Poulenc in the 1940s.<ref>{{cite book | last=Cunningham Owens | first=David G. | date=11 March 1999 | chapter=The background | pages=1-17, at p. 4 | doi=10.1017/cbo9780511544163.002 | chapter-url=http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf | title=A guide to the extrapyramidal side effects of antipsychotic drugs | publication-place=Cambridge, UK | publisher=Cambridge University Press | isbn=978-0-521-63353-6}}</ref> Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, by 1955 it was already generating significant revenue as an [[antipsychotic]].<ref name="Becoming Neurochemical Selves">{{cite book | last1=Rose | first1=Nikolas | chapter=Becoming Neurochemical Selves | hdl=10822/994593 | chapter-url=https://www.researchgate.net/profile/Nikolas-Rose/publication/30528479_Becoming_Neurochemical_Selves/links/00b7d5217881f50ded000000/Becoming-Neurochemical-Selves.pdf#page=2 | editor-last=Stehr | editor-first=Nico | date=2004 | title=Biotechnology: Between Commerce and Civil Society | location=New Brunswick, New Jersey | publisher=Transaction Publishers | isbn=978-0-7658-0224-8 | doi=10.4324/9781351323048 | pages=89-128, at pp. 90–91<!--pp. 2–3 when standalone-->}}</ref> Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was [[imipramine]], a dibenzazepine analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a [[sedative]] inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist [[Roland Kuhn]] in 1957.<ref>{{cite book | last=Cunningham Owens | first=David G. | date=11 March 1999 | chapter=The background | pages=1-17, at p. 3 | doi=10.1017/cbo9780511544163.002 | chapter-url=http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf | title=A guide to the extrapyramidal side effects of antipsychotic drugs | publication-place=Cambridge, UK | publisher=Cambridge University Press | isbn=978-0-521-63353-6}}</ref> Some testing of Geigy's imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.<ref name="Becoming Neurochemical Selves" /> Geigy later became Ciba-Geigy and eventually [[Novartis]].

[[Dibenzazepine]] derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment to [[GlaxoSmithKline|Smith Kline & French Laboratories]]. The compounds described share a tricyclic backbone different from the backbone of the TCA [[amitriptyline]].

[[Merck & Co.|Merck]] introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.<ref name="Becoming Neurochemical Selves" /> This compound has a different three-ring structure than imipramine.

== Society and culture ==

=== Recreational use ===
A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.<ref>{{cite book | last=Wills | first=Simon | title=Drugs of abuse | edition=2nd | publisher=Pharmaceutical Press | location=London | year=2005 | pages=213 | isbn=978-0-85369-582-0}}</ref> According to the US government classification of psychiatric medications, TCAs are "non-abusable"<ref>{{cite book | author=Center for Substance Abuse Treatment | date=1995 | chapter=Mental health and counseling needs of HIV-infected AOD abusers <!-- | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK64596/ --> | title=Treatment for HIV-infected alcohol and other drug abusers | series=Treatment Improvement Protocol (TIP) series | volume=15 | publication-place=Rockville, Maryland | publisher=Substance Abuse and Mental Health Services Administration <!-- | url=https://www.ncbi.nlm.nih.gov/books/NBK64595/ --> | at=[https://www.ncbi.nlm.nih.gov/books/NBK64596/table/A36258/?report=objectonly Exhibit 4-3 Abuse Potential of Common Psychiatric Medications] | pmid=22514820}}</ref> and generally have low misuse potential.<ref>{{cite book | author=Center for Substance Abuse Treatment | date=2000 | chapter=Mental health treatment <!-- | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK573027/ --> | title=Substance abuse treatment for persons with HIV/AIDS | series=Treatment Improvement Protocol (TIP) series | volume=37 | publication-place=Rockville, Maryland | publisher=Substance Abuse and Mental Health Services Administration <!-- | url=https://www.ncbi.nlm.nih.gov/books/NBK64923/ --> | at=[https://www.ncbi.nlm.nih.gov/books/NBK573027/table/ch3.t2/?report=objectonly Figure 3-4: Abuse potential of common psychiatric medications] | pmid=22514843}} Republished without revision in {{cite book | author=Center for Substance Abuse Treatment | date=2014 | title=Substance abuse treatment for persons with HIV/AIDS | series=Treatment Improvement Protocol (TIP) series | volume=37 | publication-place=Rockville, Maryland | publisher=Substance Abuse and Mental Health Services Administration | url=https://www.ncbi.nlm.nih.gov/books/NBK64923/pdf/Bookshelf_NBK64923.pdf#page=110 | p=83-84}}</ref> 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. <!--Despite tianeptine's recreational value, many people use it as a nootropic and follow other countries' usage guidelines, such as France, as a way to treat their depression if other antidepressants don't work. Their prescription guidelines are 12.5&nbsp;mg three times a day, and not to exceed 50&nbsp;mg in one day. Tianeptine has no recreational value when taken at that dosage and kept under 50&nbsp;mg a day.--> <!--Many people report that tianeptine has treated their depression when SSRIs or SNRIs haven't.--> Several cases of the misuse<ref name="isbn0-85369-582-2" /> of amitriptyline alone<ref name="pmid8456167">{{cite journal | vauthors=Wohlreich MM, Welch W | title=Amitriptyline abuse presenting as acute toxicity | journal=Psychosomatics | volume=34 | issue=2 | pages=191–193 | year=1993 | pmid=8456167 | doi=10.1016/S0033-3182(93)71918-0 | quote=The patient denied any alcohol or substance abuse, and no signs of withdrawal were noted in the hospital...On examination, Ms. B. denied suicidal ideation or intent but did admit to taking over 800 mg of amitriptyline per day for the past 3 years after being started on the drug for depression. She clearly described a euphoria associated with amitriptyline, noting that it gave her a "buzz" and that she felt "numbed up" and calm about 30 minutes after ingestion. The patient expressed fears of being addicted to the amitriptyline and desired inpatient hospitalization for medication adjustment and education.}}</ref><ref name="pmid15226578">{{cite journal | vauthors=Singh GP, Kaur P, Bhatia S | title=Dothiepin dependence syndrome | journal=Indian Journal of Medical Sciences | volume=58 | issue=6 | pages=253–254 | date=June 2004 | pmid=15226578 | url=http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2004;volume=58;issue=6;spage=253;epage=254;aulast=Singh}}</ref> or together with methadone<ref name="isbn0-85369-582-2">{{cite book | last=Wills | first=Simon | title=Drugs of abuse | edition=2nd | publisher=Pharmaceutical Press | location=London | year=2005 | pages=215–216 | isbn=978-0-85369-582-0}}</ref><ref name="pmid682328">{{cite journal | vauthors=Cohen MJ, Hanbury R, Stimmel B | title=Abuse of amitriptyline | journal=JAMA | volume=240 | issue=13 | pages=1372–1373 | date=September 1978 | pmid=682328 | doi=10.1001/jama.240.13.1372}}</ref> or in other drug dependent patients<ref name="pmid2400006">{{cite journal | vauthors=Delisle JD | title=A case of amitriptyline abuse | journal=The American Journal of Psychiatry | volume=147 | issue=10 | pages=1377–1378 | date=October 1990 | pmid=2400006 | doi=10.1176/ajp.147.10.1377b | quote=Ms. A, a 24-year-old abuser of alcohol and cannabis, consulted her family physician because of anxiety, depression, and insomnia. Unaware of her drug abuse, he prescribed amitriptyline, 200 mg. About 30 minutes after taking each dose, she would experience relief from her symptoms that lasted about 2 hours. By increasing the dose, she found she could intensify these effects and prolong them for up to several hours. Her "high" consisted of feelings of relaxation, giddiness, and contentment.Frequently, this progressed to incoordination, slurred speech, and confusion. Sometimes she would forget how much she had taken and ingest up to 2&nbsp;g.}}</ref><ref name="pmid16225078">{{cite journal | vauthors=Sein Anand J, Chodorowski Z, Habrat B | title=Recreational amitriptyline abuse | language=en | journal=Przegląd Lekarski | type=Case report | volume=62 | issue=6 | pages=397–398 | year=2005 | publication-place=Kraków | publisher=Wydawnictwo Przegląd Lekarski | pmid=16225078 | issn=0033-2240 | oclc=1424404558 | s2cid=27766729 | url=http://www.uck.gda.pl/files/Recreational-Amitryptyline.pdf | url-status=dead | archive-url=https://web.archive.org/web/20231202121821/http://www.uck.gda.pl/files/Recreational-Amitryptyline.pdf | archive-date=2023-12-02}}</ref> and of dosulepin with alcohol<ref name="pmid17567406">{{cite journal | vauthors=Lepping P, Menkes DB | title=Abuse of dosulepin to induce mania | journal=Addiction | volume=102 | issue=7 | pages=1166–1167 | date=July 2007 | pmid=17567406 | doi=10.1111/j.1360-0443.2007.01828.x}}</ref> or in methadone patients<ref name="pmid8520352">{{cite journal | vauthors=Dorman A, Talbot D, Byrne P, O'Connor J | title=Misuse of dothiepin | journal=BMJ | volume=311 | issue=7018 | pages=1502 | date=December 1995 | pmid=8520352 | pmc=2543748 | doi=10.1136/bmj.311.7018.1502b}}</ref> have been reported.

== List of TCAs ==
Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:
* [[Butriptyline]]† (Evadyne) (relatively weak serotonin reuptake inhibitor)
* '''[[Clomipramine]]''' (Anafranil)
* '''[[Imipramine]]''' (Tofranil, Janimine, Praminil)
* '''[[Trimipramine]]''' (Surmontil) (relatively weak serotonin reuptake inhibitor)

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:
* [[Desipramine]] (Norpramin, Pertofrane)
* [[Dibenzepin]]‡ (Noveril, Victoril)
* [[Lofepramine]]§ (Lomont, Gamanil)
* '''[[Maprotiline]]''' (Ludiomil) – can be classed with the TCAs though more frequently classed with the TeCAs
* '''[[Nortriptyline]]''' (Pamelor, Aventyl, Norpress)
* [[Protriptyline]] (Vivactil)

Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

{{colbegin}}
* '''[[Amitriptyline]]''' (Elavil, Endep)
* [[Amitriptylinoxide]] (Amioxid, Ambivalon, Equilibrin)
* [[Amoxapine]] (Asendin) – can be classed with the TeCAs but more frequently classed with the TCAs
* [[Demexiptiline]]† (Deparon, Tinoran)
* [[Dimetacrine]]† (Istonil, Istonyl, Miroistonil)
* '''[[Dosulepin]]'''§ (Prothiaden)
* '''[[Doxepin]]''' (Adapin, Sinequan)
* [[Fluacizine]]† (Phtorazisin)
* [[Imipraminoxide]]† (Imiprex, Elepsin)
* [[Melitracen]]§ (Deanxit, Dixeran, Melixeran, Trausabun)
* [[Metapramine]]† (Timaxel)
* [[Nitroxazepine]]‡ (Sintamil)
* [[Noxiptiline]]‡ (Agedal, Elronon, Nogedal)
* [[Pipofezine]]‡ (Azafen/Azaphen)
* [[Propizepine]]† (Depressin, Vagran)
* [[Quinupramine]]† (Kevopril, Kinupril, Adeprim, Quinuprine)
{{colend}}

And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:
* [[Amineptine]]‡ (Survector, Maneon, Directim) – [[norepinephrine–dopamine reuptake inhibitor]]
* [[Iprindole]]† (Prondol, Galatur, Tetran) – [[5-HT2 receptor|5-HT<sub>2</sub> receptor]] [[receptor antagonist|antagonist]]
* [[Opipramol]]‡ (Insidon, Pramolan, Ensidon, Oprimol) – [[sigma receptor|σ receptor]] [[receptor agonist|agonist]]
* '''[[Tianeptine]]'''&nbsp;§ (Stablon, Coaxil, Tatinol) – atypical [[μ-opioid receptor]] agonist

Legend:

{{Plainlist|
* † indicates products which have been withdrawn from the market worldwide.
* ‡ indicates products which are not available in any country in which English is an official language.
* § indicates products which are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
* '''Bolded names''' indicates products which are available in at least three countries in which English is an official language.
}}

== See also ==

* [[List of antidepressants]]

== References ==
{{Reflist}}

== Further reading ==
* {{cite journal | vauthors=Gillman PK | title=Tricyclic antidepressant pharmacology and therapeutic drug interactions updated | journal=British Journal of Pharmacology | volume=151 | issue=6 | pages=737–748 | date=July 2007 | pmid=17471183 | pmc=2014120 | doi=10.1038/sj.bjp.0707253}}

== External links ==
* {{MeshName|Tricyclic+Antidepressive+Agents}}

{{Antidepressants}}
{{Navboxes
| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 =
{{Adrenergic receptor modulators}}
{{Dopamine receptor modulators}}
{{Histamine receptor modulators}}
{{Ion channel modulators}}
{{Monoamine reuptake inhibitors}}
{{Muscarinic acetylcholine receptor modulators}}
{{Serotonin receptor modulators}}
{{Sigma receptor modulators}}
}}
{{Tricyclics}}

[[Category:Chemical classes of psychoactive drugs]]
[[Category:Tricyclic antidepressants| ]]