Editing Tricyclic antidepressant (section)

== 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) and [[Avoidant personality disorder]] (AvPD), [[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> and  [[Autism Spectrum Disorder]] (ASD),<ref>Bhatti I, Thome A, Smith PO, Cook-Wiens G, Yeh HW, Gaffney GR, Hellings JA. A retrospective study of amitriptyline in youth with autism spectrum disorders. J Autism Dev Disord. 2013 May;43(5):1017-27. doi: 10.1007/s10803-012-1647-0. PMID 23135317.</ref> 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]], [[emotional lability|pathological crying and/or laughing]], [[Chronic (medicine)|chronic]] [[hiccup]]s, [[ciguatera poisoning]], and as an [[augmentation (psychiatry)|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.<ref>{{cite journal | 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 name="pmid17471183"/>

=== 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.