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[[File:Amitriptyline.svg|thumb|right|[[Chemical structure]] of the tricyclic antidepressant [[amitriptyline]]. Notice its three [[functional group|ring]]s.]]
[[File:Imipramine.svg|thumb|right|[[Chemical structure]] of the prototypical and first marketed tricyclic antidepressant [[imipramine]]. Notice its three [[functional group|ring]]s.]]


'''Tricyclic antidepressants''' ('''TCAs''') are [[chemical compound]]s used primarily as [[antidepressant]]s. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade;<ref>Carson VB (2000). [http://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 atom]]s. The [[tetracyclic antidepressant]]s (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
'''Tricyclic antidepressants''' ('''TCAs''') are [[chemical compound]]s used primarily as [[antidepressant]]s. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade;<ref>Carson VB (2000). [http://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 atom]]s. The [[tetracyclic antidepressant]]s (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
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== List of TCAs ==
== List of TCAs ==


Those that preferentially inhibit the reuptake of serotonin (by at least 10 fold over norepinephrine and dopamine) include:
The TCAs include the following agents which are predominantly [[serotonin reuptake inhibitor|serotonin]] and/or [[norepinephrine reuptake inhibitor]]s:

* '''[[Clomipramine]]''' (Anafranil) (~200x selective for serotonin over norepinephrine reuptake)
⚫
* '''[[Imipramine]]''' (Tofranil, Janimine, Praminil)

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10 fold over serotonin and dopamine) include:


<div style="-moz-column-count:2; column-count:2; -webkit-column-count:2;">
⚫
* [[Amitriptyline]] (Tryptomer, Elavil, Endep)
⚫
* [[Amitriptylinoxide]] (Amioxid, Ambivalon, Equilibrin)
⚫
* [[Butriptyline]] (Evadyne)
* [[Clomipramine]] (Anafranil)
⚫
* [[Demexiptiline]] (Deparon, Tinoran)
* [[Desipramine]] (Norpramin, Pertofrane)
* [[Desipramine]] (Norpramin, Pertofrane)
* [[Dibenzepin]] (Noveril, Victoril)
* '''[[Lofepramine]]'''§ (Lomont, Gamanil)

⚫
* [[Dimetacrine]] (Istonil, Istonyl, Miroistonil)
⚫
* '''[[Nortriptyline]]''' (Pamelor, Aventyl, Norpress)
⚫
* [[Dosulepin|Dosulepin/Dothiepin]] (Prothiaden)
⚫
* [[Doxepin]] (Adapin, Sinequan)
⚫
* [[Imipramine]] (Tofranil, Janimine, Praminil)
⚫
* [[Imipraminoxide]] (Imiprex, Elepsin)
* [[Lofepramine]] (Lomont, Gamanil)
⚫
* [[Melitracen]] (Deanxit, Dixeran, Melixeran, Trausabun)
⚫
* [[Metapramine]] (Timaxel)
⚫
* [[Nitroxazepine]] (Sintamil)
⚫
* [[Nortriptyline]] (Pamelor, Aventyl, Norpress)
⚫
* [[Noxiptiline]] (Agedal, Elronon, Nogedal)
⚫
* [[Pipofezine]] (Azafen/Azaphen)
⚫
* [[Propizepine]] (Depressin, Vagran)
* [[Protriptyline]] (Vivactil)
* [[Protriptyline]] (Vivactil)
⚫
* [[Quinupramine]] (Kevopril, Kinupril, Adeprim, Quinuprine)
</div>


Whereas fairly balanced serotonin-norepinephrine reuptake inhibitors include:
and


{{colbegin}}
⚫
* [[Amineptine]] (Survector, Maneon, Directim) - [[Norepinephrine-dopamine reuptake inhibitor]]
⚫
* '''[[Amitriptyline]]''' (Tryptomer, Elavil, Endep)
⚫
* [[Iprindole]] (Prondol, Galatur, Tetran) - [[5-HT2 receptor|5-HT<sub>2</sub> receptor]] [[receptor antagonist|antagonist]]
⚫
* [[Amitriptylinoxide]] (Amioxid, Ambivalon, Equilibrin)
⚫
* [[Opipramol]] (Insidon, Pramolan, Ensidon, Oprimol) - [[Sigma receptor|σ receptor]] [[receptor agonist|agonist]]
* [[Amoxapine]] (Asendin) - can be classed with the [[tetracyclic antidepressants]] (TeCAs) but more frequently classed with the secondary amine TCAs.
⚫
* [[Tianeptine]] (Stablon, Coaxil, Tatinol) - [[Selective serotonin reuptake enhancer]]
⚫
* [[Butriptyline]]† (Evadyne)
⚫
* [[Trimipramine]] (Surmontil) - 5-HT<sub>2</sub> receptor antagonist and moderate-potency [[norepinephrine reuptake inhibitor]].
⚫
* [[Demexiptiline]]† (Deparon, Tinoran)
* [[Dibenzepin]]‡ (Noveril, Victoril)
⚫
* [[Dimetacrine]]† (Istonil, Istonyl, Miroistonil)
⚫
* '''[[Dosulepin|Dosulepin/Dothiepin]]'''§ (Prothiaden)
⚫
* '''[[Doxepin]]''' (Adapin, Sinequan)
⚫
* [[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 other mechanisms beside serotonin-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]]‡ (Stablon, Coaxil, Tatinol) - [[Selective serotonin reuptake enhancer]]
⚫
* '''[[Trimipramine]]''' (Surmontil) - 5-HT<sub>2</sub> receptor antagonist and moderate-potency [[norepinephrine reuptake inhibitor]].

<u>Legend:</u>

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


== History ==
== 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|Rhône-Poulenc's]] chief chemist, [[Paul Charpentier]], from synthetic [[antihistamines]] developed by Rhône-Poulenc in the 1940s.<ref name="assets.cambridge.org">A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens, http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf</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 p.3">Becoming Neurochemical Selves, Nikolas Rose, p.3</ref> Research chemists quickly began to explore other derivatives of chlorpromazine.
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|Rhône-Poulenc's]] chief chemist, Paul Charpentier, from synthetic [[antihistamines]] developed by Rhône-Poulenc in the 1940s.<ref name="assets.cambridge.org">A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens,http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf</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 p.3">Becoming Neurochemical Selves, Nikolas Rose, p.3</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 name="assets.cambridge.org"/> Some testing of Geigy’s imipramine, then known as Tofranil, took place at the [[Münsterlingen Hospital]] near Konstanz.<ref name="Becoming Neurochemical Selves p.3"/> Geigy later became Ciba-Geigy and eventually [[Novartis]].
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 name="assets.cambridge.org"/> Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.<ref name="Becoming Neurochemical Selves p.3"/> 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]].
[[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 p.3"/> This compound has a different three-ring structure from imipramine.
[[Merck & Co.|Merck]] introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.<ref name="Becoming Neurochemical Selves p.3"/> This compound has a different three-ring structure from imipramine.

Many patents were filed in the 1950s and 1960s concerning variations on these three-ring structures with applications to psychiatric conditions.

These patents cover the structures of the compounds and their mode of chemical synthesis. Understanding of their mode of action as re-uptake inhibitors and development of the serotonin theory of depression came in the years to follow.


== Indications ==
== Indications ==


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 disorder]]s, including [[anxiety disorders]] such as [[generalized anxiety disorder]] (GAD), social phobia (SP) also known as social anxiety disorder, [[obsessive-compulsive disorder]] (OCD), 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), [[attention-deficit hyperactivity disorder]] (ADHD), 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 | author = Glazener C, Evans J, Peto R | title = Tricyclic and related drugs for nocturnal enuresis in children | journal = Cochrane Database Syst Rev | volume = | issue =3 | pages = CD002117 | year = 2003| pmid = 12917922 | doi = 10.1002/14651858.CD002117 | editor1-last = Glazener | editor1-first = Cathryn MA}}</ref> [[narcolepsy]], [[insomnia]], [[pathological]] [[crying]] and/or [[laughter|laughing]], [[Chronic (medicine)|chronic]] [[hiccup]]s, [[ciguatera]] [[poison]]ing, and as an [[augmentation (psychiatry)|adjunct]] in [[schizophrenia]].
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 disorder]]s, including [[anxiety disorders]] such as [[generalized anxiety disorder]] (GAD), social phobia (SP) also known as social anxiety disorder, [[obsessive-compulsive disorder]] (OCD), 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), [[attention-deficit hyperactivity disorder]] (ADHD), 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 | author = Glazener C, Evans J, Peto R | title = Tricyclic and related drugs for nocturnal enuresis in children | journal = Cochrane Database Syst Rev | volume = | issue =3 | pages = CD002117 | year = 2003| pmid = 12917922 | doi = 10.1002/14651858.CD002117 | editor1-last = Glazener | editor1-first = Cathryn MA}}</ref> [[narcolepsy]], [[insomnia]],[[pathological]] [[crying]] and/or [[laughter|laughing]], [[Chronic (medicine)|chronic]] [[hiccup]]s, [[ciguatera]] [[poison]]ing, and as an [[augmentation (psychiatry)|adjunct]] in [[schizophrenia]].


=== Clinical depression ===
=== Clinical depression ===


For many years the TCAs were the first choice for [[pharmacological]] [[therapy|treatment]] of [[clinical depression]]. Although they are still considered to be highly [[efficacy#Healthcare|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, tricyclic antidepressants still are probably more successful in treating [[melancholic depression]] than other antidepressant drug classes.<ref name="pmid7980178">{{cite journal |author=Mitchell PB, Mitchell MS |title=The management of depression. Part 2. The place of the new antidepressants |journal=Aust Fam Physician |volume=23 |issue=9 |pages=1771–3, 1776–81 |year=1994 |month=September |pmid=7980178 }}</ref> Newer antidepressants are thought to have fewer and less severe [[adverse effect|side effect]]s 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.
For many years the TCAs were the first choice for [[pharmacological]] [[therapy|treatment]] of [[clinical depression]]. Although they are still considered to be highly [[efficacy#Healthcare|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, tricyclic antidepressants still are probably more successful in treating [[melancholic depression]] than other antidepressant drug classes.<ref name="pmid7980178">{{cite journal |author=Mitchell PB, Mitchell MS |title=The management of depression. Part 2. The place of the new antidepressants |journal=Aust Fam Physician |volume=23 |issue=9 |pages=1771–3, 1776–81 |year=1994|month=September|pmid=7980178 }}</ref> Newer antidepressants are thought to have fewer and less severe [[adverse effect|side effect]]s 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 still occasionally used for [[treatment-resistant depression]] that has failed to respond to therapy with newer antidepressants.<ref name="pmid10498158">{{cite journal | author = Broquet K | title = Status of treatment of depression | journal = South Med J | volume = 92 | issue = 9 | pages = 846–56 | year = 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 benefit]]s 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 | author = Teicher M, Glod C, Cole J | title = Antidepressant drugs and the emergence of suicidal tendencies | journal = Drug Saf | volume = 8 | issue = 3 | pages = 186–212 | year = 1993 | pmid = 8452661 | doi = 10.2165/00002018-199308030-00002 }}</ref>
Nonetheless, the TCAs are still occasionally used for [[treatment-resistant depression]] that has failed to respond to therapy with newer antidepressants.<ref name="pmid10498158">{{cite journal | author = Broquet K | title = Status of treatment of depression | journal = South Med J | volume = 92 | issue = 9 | pages = 846–56 | year = 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 benefit]]s 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 | author = Teicher M, Glod C, Cole J | title = Antidepressant drugs and the emergence of suicidal tendencies | journal = Drug Saf | volume = 8|issue = 3 | pages = 186–212 | year = 1993 | pmid = 8452661 | doi = 10.2165/00002018-199308030-00002 }}</ref>


=== Attention-deficit hyperactivity disorder ===
=== Attention-deficit hyperactivity disorder ===


The TCAs were used in the past in the clinical treatment of [[ADHD]],<ref name="pmid2676967">{{cite journal | doi = 10.1097/00004583-198909000-00022 | author = Biederman J, Baldessarini R, Wright V, Knee D, Harmatz J | title = A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy | journal = J Am Acad Child Adolesc Psychiatry | volume = 28 | issue = 5 | pages = 777–84 | year = 1989 | pmid = 2676967}}</ref> though they are not typically used anymore on account of being replaced by more effective agents with fewer side effects such as [[atomoxetine]] (Strattera, Tomoxetin, Attentin) and [[stimulant]]s like [[methylphenidate]] (Ritalin, Focalin, Concerta), and [[amphetamine]] (Adderall, 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]]{{Citation needed|date=December 2010}}. 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 | author = Biederman J, Spencer T | title = Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder | journal = Biol Psychiatry | volume = 46 | issue = 9 | pages = 1234–42 | year = 1999 | pmid = 10560028 | doi = 10.1016/S0006-3223(99)00192-4 }}</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 | author = Popper C | title = Antidepressants in the treatment of attention-deficit/hyperactivity disorder | journal = J Clin Psychiatry | volume = 58 | issue = Suppl 14 | pages = 14–29; discussion 30–1 | year = 1997 | pmid = 9418743 }}</ref>
The TCAs were used in the past in the clinical treatment of [[ADHD]],<ref name="pmid2676967">{{cite journal | doi = 10.1097/00004583-198909000-00022 | author = Biederman J, Baldessarini R, Wright V, Knee D, Harmatz J | title = A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy | journal = J Am Acad Child Adolesc Psychiatry | volume = 28 | issue = 5 | pages = 777–84 | year = 1989 | pmid = 2676967}}</ref> though they are not typically used anymore on account of being replaced by more effective agents with fewer side effects such as [[atomoxetine]] (Strattera, Tomoxetin, Attentin) and [[stimulant]]s like [[methylphenidate]](Ritalin, Focalin, Concerta), and [[amphetamine]] (Adderall, 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]]{{Citation needed|date=December 2010}}. 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 | author = Biederman J, Spencer T|title = Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder | journal = Biol Psychiatry | volume = 46 | issue = 9| pages = 1234–42 | year = 1999 | pmid = 10560028 | doi = 10.1016/S0006-3223(99)00192-4 }}</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 | author = Popper C | title = Antidepressants in the treatment of attention-deficit/hyperactivity disorder | journal = J Clin Psychiatry | volume = 58 | issue = Suppl 14 | pages = 14–29; discussion 30–1 | year = 1997 | pmid = 9418743 }}</ref>


=== Chronic pain ===
=== 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 | author = Micó J, Ardid D, Berrocoso E, Eschalier A | title = Antidepressants and pain | journal = Trends Pharmacol Sci | volume = 27 | issue = 7 | pages = 348–54 | year = 2006 | pmid = 16762426 | doi = 10.1016/j.tips.2006.05.004}}</ref><ref name="pmid9121808">{{cite journal | author = McQuay H, Tramèr M, Nye B, Carroll D, Wiffen P, Moore R | title = A systematic review of antidepressants in neuropathic pain | journal = Pain | volume = 68 | issue = 2–3 | pages = 217–27 | year = 1996 | pmid = 9121808 | doi = 10.1016/S0304-3959(96)03140-5}}</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 [[serotonergic]] and [[noradrenergic]] [[Neuromodulation (biology)|neuromodulation]], among other properties.<ref name="pmid6219612">{{cite journal | author = Botney M, Fields H | title = Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system | journal = Ann Neurol | volume = 13 | issue = 2 | pages = 160–4 | year = 1983 | pmid = 6219612 | doi = 10.1002/ana.410130209}}</ref><ref>{{cite journal |author=Benbouzid M, Gavériaux-Ruff C, Yalcin I, ''et al.'' |title=Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia |journal=Biological Psychiatry |volume=63 |issue=6 |pages=633–6 |year=2008 |month=March |pmid=17693391 |doi=10.1016/j.biopsych.2007.06.016}}</ref><ref>{{cite journal |author=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=717–9 |year=1998 |month=July |pmid=9706370}}</ref> They are also effective in [[migraine]] [[prophylaxis]], though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.
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 | author = Micó J, Ardid D, Berrocoso E, Eschalier A | title = Antidepressants and pain | journal = Trends Pharmacol Sci | volume = 27 | issue = 7 | pages = 348–54 | year = 2006 | pmid = 16762426 |doi = 10.1016/j.tips.2006.05.004}}</ref><ref name="pmid9121808">{{cite journal | author = McQuay H, Tramèr M, Nye B, Carroll D, Wiffen P, Moore R | title = A systematic review of antidepressants in neuropathic pain | journal = Pain | volume = 68 | issue = 2–3 | pages = 217–27 | year = 1996 | pmid = 9121808 | doi = 10.1016/S0304-3959(96)03140-5}}</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[[serotonergic]] and [[noradrenergic]] [[Neuromodulation (biology)|neuromodulation]], among other properties.<ref name="pmid6219612">{{cite journal | author = Botney M, Fields H | title = Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system | journal = Ann Neurol | volume = 13 | issue = 2 | pages = 160–4 | year = 1983 | pmid = 6219612 | doi = 10.1002/ana.410130209}}</ref><ref>{{cite journal |author=Benbouzid M, Gavériaux-Ruff C, Yalcin I, ''et al.'' |title=Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia |journal=Biological Psychiatry |volume=63|issue=6|pages=633–6 |year=2008 |month=March |pmid=17693391 |doi=10.1016/j.biopsych.2007.06.016}}</ref><ref>{{cite journal |author=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=717–9 |year=1998 |month=July |pmid=9706370}}</ref> They are also effective in [[migraine]] [[prophylaxis]], though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.


== Pharmacology ==
== Pharmacology ==


The majority of the TCAs act primarily as [[serotonin-norepinephrine reuptake inhibitor]]s (SNRIs) by blocking the [[serotonin transporter]] (SERT) and the [[norepinephrine transporter]] (NET), respectively, 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 | author = Tatsumi M, Groshan K, Blakely RD, Richelson E. | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur J Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–258 | year = 1997 | pmid = 9537821 | doi = 10.1016/S0014-2999(97)01393-9 }}</ref><ref name="pmid17471183">{{cite journal | author = Gillman PK | title = Tricyclic antidepressant pharmacology and therapeutic drug interactions updated | journal = [[British Journal of Pharmacology]] | volume = 151 | issue = 6 | pages = 737–48 | year = 2007 | month = July | pmid = 17471183 | pmc = 2014120 | doi = 10.1038/sj.bjp.0707253 | url = }}</ref> Notably, the TCAs have negligible [[affinity (pharmacology)|affinity]] for the [[dopamine transporter]] (DAT), and therefore have no efficacy as [[dopamine reuptake inhibitor]]s (DRIs).<ref name="pmid9537821"/> Both [[serotonin]] and [[norepinephrine]] have been highly implicated in [[Depression (mood)|depression]] and [[anxiety]], and it has been shown that facilitation of their activity has beneficial effects on these [[mental disorder]]s.<ref name="pmid9551776">{{cite journal |author=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=190–7 |year=1998 |month=March |pmid=9551776 |doi=10.1007/s002130050555}}</ref>
The majority of the TCAs act primarily as [[serotonin-norepinephrine reuptake inhibitor]]s (SNRIs) by blocking the [[serotonin transporter]] (SERT) and the [[norepinephrine transporter]] (NET), respectively, 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 | author = Tatsumi M, Groshan K, Blakely RD, Richelson E. | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur J Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–258 | year = 1997 |pmid = 9537821 | doi = 10.1016/S0014-2999(97)01393-9 }}</ref><ref name="pmid17471183">{{cite journal | author = Gillman PK | title = Tricyclic antidepressant pharmacology and therapeutic drug interactions updated | journal = [[British Journal of Pharmacology]] | volume = 151 | issue = 6 | pages = 737–48 | year = 2007 | month = July | pmid = 17471183 | pmc = 2014120 | doi = 10.1038/sj.bjp.0707253 | url =}}</ref> Notably, the TCAs have negligible [[affinity (pharmacology)|affinity]] for the [[dopamine transporter]] (DAT), and therefore have no efficacy as [[dopamine reuptake inhibitor]]s (DRIs).<ref name="pmid9537821"/> Both[[serotonin]] and [[norepinephrine]] have been highly implicated in [[Depression (mood)|depression]] and [[anxiety]], and it has been shown that facilitation of their activity has beneficial effects on these [[mental disorder]]s.<ref name="pmid9551776">{{cite journal|author=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=190–7 |year=1998 |month=March |pmid=9551776 |doi=10.1007/s002130050555}}</ref>


In addition to their [[Reuptake inhibitor|reuptake inhibition]], many TCAs also have high affinity as [[receptor antagonist|antagonist]]s at the [[5-HT2|5-HT<sub>2</sub>]]<ref name="pmid7855217">{{cite journal | author = Cusack B, Nelson A, Richelson E. | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology (Berl). | volume = 114 | issue = 4 | pages = 559–565 | year = 1994 | pmid = 7855217 | doi = 10.1007/BF02244985 }}</ref> ([[5-HT2A|5-HT<sub>2A</sub>]]<ref name="pmid10379421">{{cite journal |author=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=467–89 |year=1999 |month=August |pmid=10379421 |doi=10.1023/A:1006986824213}}</ref> and [[5-HT2C|5-HT<sub>2C</sub>]]<ref name="pmid10379421"/>), [[5-HT6|5-HT<sub>6</sub>]],<ref name="pmid10836139">{{cite journal | author = Branchek TA, Blackburn TP | title = 5-ht6 receptors as emerging targets for drug discovery | journal = Annual Review of Pharmacology and Toxicology | volume = 40 | issue = | pages = 319–34 | year = 2000 | pmid = 10836139 | doi = 10.1146/annurev.pharmtox.40.1.319 | url = }}</ref> [[5-HT7|5-HT<sub>7</sub>]],<ref name="pmid9303561">{{cite journal |author=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=489–94 |year=1997 |month=August |pmid=9303561 |doi=10.1016/S0014-5793(97)00964-2}}</ref> [[Alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic]],<ref name="pmid7855217"/> and [[NMDA receptor|NMDA]] [[Receptor (biochemistry)|receptor]]s,<ref name="pmid2568580">{{cite journal |author=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=160–5 |year=1989 |month=July |pmid=2568580 |url=http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2568580}}</ref> and as [[agonist]]s at the [[sigma receptor]]s<ref name="pmid8831113">{{cite journal |author=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=117–9 |year=1996 |month=June |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 |author=Volz HP, Stoll KD |title=Clinical trials with sigma ligands |journal=Pharmacopsychiatry |volume=37 Suppl 3 |issue= |pages=S214–20 |year=2004 |month=November |pmid=15547788 |doi=10.1055/s-2004-832680}}</ref>), some of which may contribute to their therapeutic [[efficacy]], as well as their [[side effect]]s.<ref name="urlDifferences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner">{{cite web | url = http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/ | title = Differences between tricyclic antidepressants and SNRIs mechanism of action &#124; Pharmacology Corner| format = | work = | accessdate = }}</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 | author = Green JP, Maayani S | title = Tricyclic antidepressant drugs block histamine H2 receptor in brain | journal = Nature | volume = 269 | issue = 5624 | pages = 163–5 | year = 1977 | month = September | pmid = 20581 | doi = 10.1038/269163a0| url = }}</ref><ref name="pmid6150708">{{cite journal | author = 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 = 3621–5 | year = 1984 | month = November | pmid = 6150708 | doi = 10.1016/0006-2952(84)90147-3| url = }}</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 generally undesirable in [[antidepressant]]s, however, and likely contribute to their large side effect profiles.<ref name="urlDifferences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner"/>
In addition to their [[Reuptake inhibitor|reuptake inhibition]], many TCAs also have high affinity as [[receptor antagonist|antagonist]]s at the [[5-HT2|5-HT<sub>2</sub>]]<ref name="pmid7855217">{{cite journal | author = Cusack B, Nelson A, Richelson E. | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology (Berl). | volume = 114|issue = 4 | pages = 559–565 | year = 1994 | pmid = 7855217 | doi = 10.1007/BF02244985 }}</ref> ([[5-HT2A|5-HT<sub>2A</sub>]]<ref name="pmid10379421">{{cite journal |author=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=467–89|year=1999 |month=August |pmid=10379421 |doi=10.1023/A:1006986824213}}</ref> and [[5-HT2C|5-HT<sub>2C</sub>]]<ref name="pmid10379421"/>),[[5-HT6|5-HT<sub>6</sub>]],<ref name="pmid10836139">{{cite journal | author = Branchek TA, Blackburn TP | title = 5-ht6 receptors as emerging targets for drug discovery | journal = Annual Review of Pharmacology and Toxicology | volume = 40 | issue = |pages = 319–34 |year = 2000 | pmid = 10836139 | doi = 10.1146/annurev.pharmtox.40.1.319 | url = }}</ref> [[5-HT7|5-HT<sub>7</sub>]],<ref name="pmid9303561">{{cite journal |author=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=489–94|year=1997 |month=August |pmid=9303561 |doi=10.1016/S0014-5793(97)00964-2}}</ref> [[Alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic]],<ref name="pmid7855217"/> and [[NMDA receptor|NMDA]] [[Receptor (biochemistry)|receptor]]s,<ref name="pmid2568580">{{cite journal |author=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=160–5 |year=1989|month=July |pmid=2568580 |url=http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2568580}}</ref> and as [[agonist]]s at the[[sigma receptor]]s<ref name="pmid8831113">{{cite journal |author=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=117–9 |year=1996 |month=June |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|author=Volz HP, Stoll KD |title=Clinical trials with sigma ligands |journal=Pharmacopsychiatry |volume=37 Suppl 3 |issue= |pages=S214–20|year=2004|month=November |pmid=15547788 |doi=10.1055/s-2004-832680}}</ref>), some of which may contribute to their therapeutic[[efficacy]], as well as their [[side effect]]s.<ref name="urlDifferences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner">{{cite web | url = http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/ | title = Differences between tricyclic antidepressants and SNRIs mechanism of action &#124; Pharmacology Corner| format = | work = | accessdate = }}</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 | author = Green JP, Maayani S | title = Tricyclic antidepressant drugs block histamine H2 receptor in brain | journal = Nature | volume = 269 | issue = 5624 | pages = 163–5 | year = 1977 | month = September |pmid = 20581 | doi = 10.1038/269163a0| url = }}</ref><ref name="pmid6150708">{{cite journal | author = 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 = 3621–5 | year = 1984 | month = November |pmid = 6150708 |doi = 10.1016/0006-2952(84)90147-3| url = }}</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 generally undesirable in [[antidepressant]]s, however, and likely contribute to their large side effect profiles.<ref name="urlDifferences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner"/>


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 channel]]s, and therefore act as [[sodium channel blocker]]s and [[calcium channel blocker]]s, respectively.<ref name="pmid9435180">{{cite journal |author=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=208–14 |year=1998 |month=January |pmid=9435180 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9435180}}</ref><ref name="pmid18048694">{{cite journal | author = 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 = 977–84 | year = 2008 | month = March | pmid = 18048694 | doi = 10.1124/jpet.107.132456 | url = }}</ref> The former property is responsible for the high [[mortality rate]] upon [[overdose]] seen with the TCAs via [[cardiotoxicity]].<ref name="pmid10452441">{{cite journal |author=Harrigan RA, Brady WJ |title=ECG abnormalities in tricyclic antidepressant ingestion |journal=The American Journal of Emergency Medicine |volume=17 |issue=4 |pages=387–93 |year=1999 |month=July |pmid=10452441 |doi=10.1016/S0735-6757(99)90094-3}}</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 channel]]s, and therefore act as [[sodium channel blocker]]s and [[calcium channel blocker]]s, respectively.<ref name="pmid9435180">{{cite journal |author=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=208–14|year=1998 |month=January |pmid=9435180 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9435180}}</ref><ref name="pmid18048694">{{cite journal | author = 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 = 977–84 | year = 2008 | month = March | pmid = 18048694 | doi = 10.1124/jpet.107.132456 | url = }}</ref> The former property is responsible for the high [[mortality rate]] upon [[overdose]] seen with the TCAs via [[cardiotoxicity]].<ref name="pmid10452441">{{cite journal |author=Harrigan RA, Brady WJ |title=ECG abnormalities in tricyclic antidepressant ingestion|journal=The American Journal of Emergency Medicine |volume=17 |issue=4 |pages=387–93 |year=1999 |month=July |pmid=10452441|doi=10.1016/S0735-6757(99)90094-3}}</ref>


=== Binding profiles ===
=== Binding profiles ===


The [[affinity (pharmacology)|affinities]] (K<sub>d</sub> (nM)) of a selection of TCAs have been compared below at an assortment of [[binding site]]s:<ref name="pmid9537821">{{cite journal |author=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=249–58 |year=1997 |month=December |pmid=9537821 |doi=10.1016/S0014-2999(97)01393-9}}</ref><ref name="pmid7855217">{{cite journal |author=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=559–65 |year=1994 |month=May |pmid=7855217 |doi=10.1007/BF02244985}}</ref><ref name="pmid3816971">{{cite journal | author = Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 132 | issue = 2–3 | pages = 115–21 | year = 1986 | month = December | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0| url = }}</ref><ref name="pmid6086881">{{cite journal |author=Richelson E, Nelson A |title=Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=230 |issue=1 |pages=94–102 |year=1984 |month=July |pmid=6086881 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6086881}}</ref>
The [[affinity (pharmacology)|affinities]] (K<sub>d</sub> (nM)) of a selection of TCAs have been compared below at an assortment of[[binding site]]s:<ref name="pmid9537821">{{cite journal |author=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=249–58 |year=1997 |month=December |pmid=9537821 |doi=10.1016/S0014-2999(97)01393-9}}</ref><ref name="pmid7855217">{{cite journal |author=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=559–65 |year=1994 |month=May|pmid=7855217|doi=10.1007/BF02244985}}</ref><ref name="pmid3816971">{{cite journal | author = Wander TJ, Nelson A, Okazaki H, Richelson E| title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 132 | issue = 2–3 | pages = 115–21 | year = 1986 | month = December | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0| url = }}</ref><ref name="pmid6086881">{{cite journal |author=Richelson E, Nelson A |title=Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro |journal=The Journal of Pharmacology and Experimental Therapeutics|volume=230 |issue=1 |pages=94–102 |year=1984 |month=July |pmid=6086881 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6086881}}</ref><ref>{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP) |author = Roth, BL; Driscol, J | url = http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | accessdate = 30 November 2013 | date = 12 January 2011}}</ref>


{| class="wikitable sortable" style="font-size: 85%; text-align: center; width: 60%;"
{| class="wikitable sortable" style="font-size: 85%; text-align: center; width: 80%;"
! '''Compound''' !! '''[[Serotonin transporter|SERT]]''' !! '''[[Norepinephrine transporter|NET]]''' !! '''[[Dopamine transporter|DAT]]''' !! '''[[5-HT1A receptor|5-HT<sub>1A</sub>]]''' !! '''[[5-HT2A receptor|5-HT<sub>2A</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>]]''' !! '''[[Muscarinic acetylcholine receptor|mACh]]'''
! '''Compound''' !! '''[[Serotonin transporter|SERT]]''' !! '''[[Norepinephrine transporter|NET]]''' !! '''[[Dopamine transporter|DAT]]''' !! '''[[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>]]''' !! '''[[Muscarinic acetylcholine receptor|mACh]]'''
|-
|-
| [[Amitriptyline]] || 4.3 || 35 || 3,250 || 320 || 24 || 26 || 815 || 1,230 || 1.03 || 13.8
| [[Amitriptyline]] || 3.13 || 22.4 || 4,430 || 320 || 24 || 6.15 || 103.1 || 114 || 26 || 815 || 1,230 || 1.03 || 13.8
|-
|-
| [[Butriptyline]] || 1,360 || 5,100 || 3,940 || 7,000 || 380 || 570 || 4,800 || ? || 1.1 || 35
| [[Butriptyline]] || 1,360 || 5,100 || 3,940 || 7,000 || 380 || ? || ? || ? || 570 || 4,800 || ? || 1.1 || 35
|-
|-
| [[Clomipramine]] || 0.28 || 38 || 2,190 || 7,000 || 27 || 38 || 3,200 || 190 || 31 || 37
| [[Clomipramine]] || 0.21 || 45.85 || 2,605 || >10,000 || 35.5 || 64.6 || 53.8 || 127 || 3.2 || 525 || 119.8 || 31 || 37
|-
|-
| [[Desipramine]] || 17.6 || 0.83 || 3,190 || 6,700 || 315 || 115 || 6,350 || 3,400 || 85 || 132
| [[Desipramine]] || 179 || 2.27 || 3,190 || >10000 || 315 || ? || ? || ? || 115 || 6,350 || 1,561 || 45.4 || 232.6
|-
|-
| [[Dosulepin]] || 8.6 || 46 || 5,310 || 2,300 || 258 || 470 || 2,400 || ? || 3.6 || 25
| [[Dosulepin]] || 8.6 || 46 || 5,310 || 4,004 || 258 || ? || ? || ? || 470 || 2,400 || ? || 4 || 63.6
|-
|-
| [[Doxepin]] || 68 || 29.5 || 12,100 || 283 || 26 || 24 || 1,185 || 1,380 || 0.21 || 52
| [[Doxepin]] || 68 || 29.5 || 12,100 || 276 || 27 || 8.8 || 136 || ? || 24 || 1,185 || 1,380 || 0.21 || 81.4
|-
|-
| [[Imipramine]] || 1.4 || 37 || 8,500 || 7,650 || 115 || 61 || 3,150 || 1,310 || 24 || 68
| [[Imipramine]] || 1.6 || 51.67 || 8,500 || >10,000 || 118.67 || 120 || 190.3 || 1000 || 61 || 3,150 || 1,310 || 24 || 68
|-
|-
| [[Iprindole]] || 1,620 || 1,262 || 6,530 || 2,800 || 280 || 2,300 || 8,600 || ? || 130 || 2,100
| [[Iprindole]] || 1,620 || 1,262 || 6,530 || 2,800 || 217 || 206 || ? || ? || 2,300 || 8,600 || ? || 130 || 2,100
|-
|-
| [[Lofepramine]] || 70 || 5.4 || 18,000 || 4,600 || 200 || 100 || 2,700 || 2,000 || 360 || 67
| [[Lofepramine]] || 70 || 5.4 || 18,000 || 4,600 || 200 || ? || ? || ? || 100 || 2,700 || 2,000 || 360 || 67
|-
|-
| [[Nortriptyline]] || 18 || 4.37 || 1,140 || 302 || 43 || 58 || 2,265 || 1,885 || 8.2 || 94
| [[Nortriptyline]] || 16.5 || 1.65 || 5,000 || 302 || 43 || 8.5 || 148 || ? || 58 || 2,265 || 1,885 || 8.2 || 94
|-
|-
| [[Protriptyline]] || 19.6 || 1.41 || 2,100 || 3,800 || 70 || 130 || 6,600 || 2,300 || 25 || 25
| [[Protriptyline]] || 19.6 || 1.41 || 2,100 || 3,800 || 70 || ? || ? || ? || 130 || 6,600 || 2,300 || 60 || 25
|-
|-
| [[Trimipramine]] || 149 || 2,450 || 3,780 || 8,000 || 32 || 24 || 680 || 180 || 0.27 || 58
| [[Trimipramine]] || 149 || 2,450 || 3,780 || 8,000 || 32 || ? || ? || ? || 24 || 680 || 180 || 0.27 || 58
|}
|}


The selected ligands act as [[receptor antagonist|antagonist]]s (or [[inverse agonist]]s depending on the site in question) at all [[receptor (biochemistry)|receptor]]s listed and as [[reuptake inhibitor|inhibitor]]s of all [[membrane transport protein|transporter]]s listed.<ref name="pmid9537821"/><ref name="pmid7855217">{{cite journal | author = 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 = 559–65 | year = 1994 | month = May | pmid = 7855217 | doi = 10.1007/BF02244985| url = }}</ref><ref name="pmid3816971"/><ref name="pmid6086881">{{cite journal | author = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 | year = 1984 | month = July | pmid = 6086881 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6086881}}</ref>
The selected ligands act as [[receptor antagonist|antagonist]]s (or [[inverse agonist]]s depending on the site in question) at all[[receptor (biochemistry)|receptor]]s listed and as [[reuptake inhibitor|inhibitor]]s of all [[membrane transport protein|transporter]]s listed.<ref name="pmid9537821"/><ref name="pmid7855217">{{cite journal | author = 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 = 559–65 | year = 1994 | month = May | pmid = 7855217 | doi = 10.1007/BF02244985| url = }}</ref><ref name="pmid3816971"/><ref name="pmid6086881">{{cite journal | author = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 | year = 1984 | month = July | pmid = 6086881 | doi = | url =http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6086881}}</ref>


== Side effects ==
== Side effects ==
Line 120: Line 131:
Many [[adverse effect|side effect]]s 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.
Many [[adverse effect|side effect]]s 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, [[sexual dysfunction]], 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>Gelder, M, Mayou, R. and Geddes, J. 2005. Psychiatry. 3rd ed. New York: Oxford. pp243.</ref> Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.<ref>{{cite journal |author=Chabria SB |title=Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity |journal=J Occup Med Toxicol |volume=1 |issue= |pages=16 |year=2006 |pmid=16846511 |pmc=1540431 |doi=10.1186/1745-6673-1-16 |url=}}</ref>
Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness,[[akathisia]], [[hypersensitivity]], changes in appetite and weight, sweating, [[sexual dysfunction]], 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>Gelder, M, Mayou, R. and Geddes, J. 2005. Psychiatry. 3rd ed. New York: Oxford. pp243.</ref> Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.<ref>{{cite journal |author=Chabria SB |title=Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity |journal=J Occup Med Toxicol|volume=1|issue= |pages=16 |year=2006 |pmid=16846511 |pmc=1540431 |doi=10.1186/1745-6673-1-16 |url=}}</ref>


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.
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.
Line 128: Line 139:
== Discontinuation ==
== Discontinuation ==


[[Antidepressants]] in general may produce a discontinuation syndrome. Since the term "withdrawal" has been linked to addiction to recreational drugs like opioids the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."<ref>{{cite journal |author=Shelton RC |title=The nature of the discontinuation syndrome associated with antidepressant drugs |journal=J Clin Psychiatry |volume=67 Suppl 4 |issue= |pages=3–7 |year=2006 |pmid=16683856 |doi= |url=}}</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 |author=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=939–43 |year=2002 |month=June |pmid=12369270 |doi=10.1016/S0278-5846(02)00209-9}}</ref>
[[Antidepressants]] in general may produce a discontinuation syndrome. Since the term "withdrawal" has been linked to addiction to recreational drugs like opioids the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."<ref>{{cite journal |author=Shelton RC |title=The nature of the discontinuation syndrome associated with antidepressant drugs |journal=J Clin Psychiatry |volume=67 Suppl 4 |issue= |pages=3–7 |year=2006 |pmid=16683856 |doi= |url=}}</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 |author=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=939–43 |year=2002|month=June|pmid=12369270 |doi=10.1016/S0278-5846(02)00209-9}}</ref>
In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.<ref>{{cite web |author=Kent Kunze MD |title=Somatic Therapies in Psychiatry |url= https://angel.dmu.edu/section/default.asp?id=0921%5FPSYC%5F2107%5F01 |publisher= Des Moines University Psychiatry Class}}</ref>
In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.<ref>{{cite web |author=Kent Kunze MD |title=Somatic Therapies in Psychiatry |url= https://angel.dmu.edu/section/default.asp?id=0921%5FPSYC%5F2107%5F01 |publisher= Des Moines University Psychiatry Class}}</ref>


== Interactions ==
== Interactions ==


The TCAs are highly metabolised by the [[Cytochrome P450 oxidase|cytochrome P450]] 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>http://www.preskorn.com/books/ssri_s7.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 (beverage)|alcohol]] and the effects of [[barbiturate]]s and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.
The TCAs are highly metabolised by the [[Cytochrome P450 oxidase|cytochrome P450]] 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>http://www.preskorn.com/books/ssri_s7.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 (beverage)|alcohol]] and the effects of [[barbiturate]]s and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.


== Overdose ==
== Overdose ==
Line 154: Line 165:


[[Tricyclic_antidepressant_overdose#Treatment|Treatment of TCA overdose]] depends on severity of symptoms:<br />
[[Tricyclic_antidepressant_overdose#Treatment|Treatment of TCA overdose]] depends on severity of symptoms:<br />
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 [[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.<br />
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 [[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.<br />
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).<br />
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).<br />
Treatment is otherwise supportive.
Treatment is otherwise supportive.
Line 161: Line 172:


{{Expand section|date=December 2010}}
{{Expand section|date=December 2010}}
A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.<ref>{{cite book |author=Wills, Simon |title=Drugs Of Abuse, 2nd Edition |publisher=Pharmaceutical Press |location=London |year=2005 |pages=213 |isbn=0-85369-582-2 |oclc= |doi= |accessdate=}}</ref> According to the US government classification of psychiatric medications, TCAs are "non-abusable"<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.36258 |title=Exhibit 4-3 Abuse Potential of Common Psychiatric Medications |accessdate=2007-05-25 |work=Health Services/Technology Assessment Text (HSTAT)|publisher=U.S. [[National Library of Medicine]]}}</ref> and generally have low abuse potential.<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.67504 |title=Figure 3-4: Abuse Potential of Common Psychiatric Medications |accessdate=2007-05-25 |work=Health Services/Technology Assessment Text (HSTAT)|publisher=U.S. [[National Library of Medicine]]}}</ref> Several cases of the misuse<ref name="isbn0-85369-582-2" /> of amitriptyline alone<ref name="pmid8456167">{{cite journal |author=Wohlreich MM, Welch W |title=Amitriptyline abuse presenting as acute toxicity |journal=Psychosomatics |volume=34 |issue=2 |pages=191–3 |year=1993 |pmid=8456167 |doi= 10.1016/S0033-3182(93)71918-0|url= |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 |author=Singh GP, Kaur P, Bhatia S |title=Dothiepin dependence syndrome |journal=Indian J Med Sci |volume=58 |issue=6 |pages=253–4 |year=2004 |month=June |pmid=15226578 |doi= |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 |author=Wills, Simon |title=Drugs Of Abuse, 2nd Edition |publisher=Pharmaceutical Press |location=London |year=2005 |pages=215–216 |isbn=0-85369-582-2 |oclc= |doi= |accessdate=}}</ref><ref name="pmid682328">{{cite journal |author=Cohen MJ, Hanbury R, Stimmel B |title=Abuse of amitriptyline |journal=JAMA |volume=240 |issue=13 |pages=1372–3 |year=1978 |month=September |pmid=682328 |doi= 10.1001/jama.240.13.1372|url=}}</ref> or in other drug dependent patients<ref name="pmid2400006">{{cite journal |author=Delisle JD |title=A case of amitriptyline abuse |journal=Am J Psychiatry |volume=147 |issue=10 |pages=1377–8 |year=1990 |month=October |pmid=2400006 |doi= |url=| 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 g.}}</ref><ref name="pmid16225078">{{cite journal |author=Sein Anand J, Chodorowski Z, Habrat B |title=Recreational amitriptyline abuse |journal=Prz. Lek. |volume=62 |issue=6 |pages=397–8 |year=2005 |pmid=16225078 |doi= |url=}}</ref> and of dothiepin with alcohol<ref name="pmid17567406">{{cite journal |author=Lepping P, Menkes DB |title=Abuse of dosulepin to induce mania |journal=Addiction |volume=102 |issue=7 |pages=1166–7 |year=2007 |month=July |pmid=17567406 |doi=10.1111/j.1360-0443.2007.01828.x |url=}}</ref> or in methadone patients<ref name="pmid8520352">{{cite journal |author=Dorman A, Talbot D, Byrne P, O'Connor J |title=Misuse of dothiepin |journal=BMJ |volume=311 |issue=7018 |pages=1502 |year=1995 |month=December |pmid=8520352 |pmc=2543748 |doi= 10.1136/bmj.311.7018.1502b|url=}}</ref> have been reported.
A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.<ref>{{cite book|author=Wills, Simon |title=Drugs Of Abuse, 2nd Edition |publisher=Pharmaceutical Press |location=London |year=2005 |pages=213|isbn=0-85369-582-2 |oclc= |doi= |accessdate=}}</ref> According to the US government classification of psychiatric medications, TCAs are "non-abusable"<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.36258 |title=Exhibit 4-3 Abuse Potential of Common Psychiatric Medications |accessdate=2007-05-25 |work=Health Services/Technology Assessment Text (HSTAT)|publisher=U.S. [[National Library of Medicine]]}}</ref> and generally have low abuse potential.<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.67504 |title=Figure 3-4: Abuse Potential of Common Psychiatric Medications |accessdate=2007-05-25 |work=Health Services/Technology Assessment Text (HSTAT)|publisher=U.S. [[National Library of Medicine]]}}</ref> Several cases of the misuse<ref name="isbn0-85369-582-2" /> of amitriptyline alone<ref name="pmid8456167">{{cite journal |author=Wohlreich MM, Welch W|title=Amitriptyline abuse presenting as acute toxicity |journal=Psychosomatics |volume=34 |issue=2 |pages=191–3 |year=1993|pmid=8456167|doi= 10.1016/S0033-3182(93)71918-0|url= |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 |author=Singh GP, Kaur P, Bhatia S |title=Dothiepin dependence syndrome |journal=Indian J Med Sci |volume=58 |issue=6 |pages=253–4 |year=2004 |month=June |pmid=15226578 |doi= |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 |author=Wills, Simon |title=Drugs Of Abuse, 2nd Edition |publisher=Pharmaceutical Press |location=London|year=2005|pages=215–216 |isbn=0-85369-582-2 |oclc= |doi= |accessdate=}}</ref><ref name="pmid682328">{{cite journal |author=Cohen MJ, Hanbury R, Stimmel B |title=Abuse of amitriptyline |journal=JAMA |volume=240 |issue=13 |pages=1372–3 |year=1978 |month=September|pmid=682328 |doi= 10.1001/jama.240.13.1372|url=}}</ref> or in other drug dependent patients<ref name="pmid2400006">{{cite journal|author=Delisle JD|title=A case of amitriptyline abuse |journal=Am J Psychiatry |volume=147 |issue=10 |pages=1377–8 |year=1990|month=October |pmid=2400006|doi= |url=| 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 g.}}</ref><ref name="pmid16225078">{{cite journal |author=Sein Anand J, Chodorowski Z, Habrat B|title=Recreational amitriptyline abuse|journal=Prz. Lek. |volume=62 |issue=6 |pages=397–8 |year=2005 |pmid=16225078 |doi= |url=}}</ref>and of dothiepin with alcohol<ref name="pmid17567406">{{cite journal |author=Lepping P, Menkes DB |title=Abuse of dosulepin to induce mania |journal=Addiction |volume=102|issue=7 |pages=1166–7 |year=2007 |month=July |pmid=17567406 |doi=10.1111/j.1360-0443.2007.01828.x|url=}}</ref> or in methadone patients<ref name="pmid8520352">{{cite journal |author=Dorman A, Talbot D, Byrne P, O'Connor J|title=Misuse of dothiepin |journal=BMJ|volume=311 |issue=7018 |pages=1502 |year=1995 |month=December |pmid=8520352 |pmc=2543748 |doi= 10.1136/bmj.311.7018.1502b|url=}}</ref>have been reported.


== References ==
== References ==

Revision as of 13:57, 30 November 2013

Chemical structure of the prototypical and first marketed tricyclic antidepressant imipramine. Notice its three rings.

Tricyclic antidepressants (TCAs) are chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade;[1] they are named after their chemical structure, which contains three rings of atoms. The tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants which typically have more favorable side-effects profiles such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and the norepinephrine reuptake inhibitors (NRIs) like reboxetine, though they are still sometimes prescribed for certain indications.

List of TCAs

Those that preferentially inhibit the reuptake of serotonin (by at least 10 fold over norepinephrine and dopamine) include:

  • Clomipramine (Anafranil) (~200x selective for serotonin over norepinephrine reuptake)
  • Imipramine (Tofranil, Janimine, Praminil)

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10 fold over serotonin and dopamine) include:

Whereas fairly balanced serotonin-norepinephrine reuptake inhibitors include:

and the following are TCAs that act via other mechanisms beside serotonin-norepinephrine reuptake inhibition:

Legend:

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

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.[2] 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.[3] 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.[2] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[3] Geigy later became Ciba-Geigy and eventuallyNovartis.

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

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.[3] This compound has a different three-ring structure from imipramine.

Indications

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD),dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder, obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), attention-deficit hyperactivity disorder (ADHD), 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),[4] narcolepsy, insomnia,pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly 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, tricyclic antidepressants still are probably more successful in treating melancholic depression than other antidepressant drug classes.[5] Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose (see therapeutic index) are far wider in comparison.

Nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants.[6]They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.[7]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,[8] though they are not typically used anymore on account of being replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin, Attentin) and stimulants like methylphenidate(Ritalin, Focalin, Concerta), and amphetamine (Adderall, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency ofdopamine and norepinephrine activity in the prefrontal cortex of the brain[citation needed]. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[9] Notably, the TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.[10]

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.[11][12] 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 viaserotonergic and noradrenergic neuromodulation, among other properties.[13][14][15] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Pharmacology

The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of thesynapticconcentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[16][17] Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[16] Bothserotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[18]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[19] (5-HT2A[20] and 5-HT2C[20]),5-HT6,[21] 5-HT7,[22] α1-adrenergic,[19] and NMDA receptors,[23] and as agonists at thesigma receptors[24] (σ1[24] and σ2[25]), some of which may contribute to their therapeuticefficacy, as well as their side effects.[26] The TCAs also have varying but typically high affinity for antagonising the H1[19] and H2[27][28] histamine receptors, as well as the muscarinic acetylcholine receptors.[19] As a result, they also act as potent antihistamines andanticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.[26]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[29][30] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[31]

Binding profiles

The affinities (Kd (nM)) of a selection of TCAs have been compared below at an assortment ofbinding sites:[16][19][32][33][34]

Compound SERT NET DAT 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7 α1 α2 D2 H1 mACh
Amitriptyline 3.13 22.4 4,430 320 24 6.15 103.1 114 26 815 1,230 1.03 13.8
Butriptyline 1,360 5,100 3,940 7,000 380 ? ? ? 570 4,800 ? 1.1 35
Clomipramine 0.21 45.85 2,605 >10,000 35.5 64.6 53.8 127 3.2 525 119.8 31 37
Desipramine 179 2.27 3,190 >10000 315 ? ? ? 115 6,350 1,561 45.4 232.6
Dosulepin 8.6 46 5,310 4,004 258 ? ? ? 470 2,400 ? 4 63.6
Doxepin 68 29.5 12,100 276 27 8.8 136 ? 24 1,185 1,380 0.21 81.4
Imipramine 1.6 51.67 8,500 >10,000 118.67 120 190.3 1000 61 3,150 1,310 24 68
Iprindole 1,620 1,262 6,530 2,800 217 206 ? ? 2,300 8,600 ? 130 2,100
Lofepramine 70 5.4 18,000 4,600 200 ? ? ? 100 2,700 2,000 360 67
Nortriptyline 16.5 1.65 5,000 302 43 8.5 148 ? 58 2,265 1,885 8.2 94
Protriptyline 19.6 1.41 2,100 3,800 70 ? ? ? 130 6,600 2,300 60 25
Trimipramine 149 2,450 3,780 8,000 32 ? ? ? 24 680 180 0.27 58

The selected ligands act as antagonists (or inverse agonists depending on the site in question) at allreceptors listed and as inhibitors of all transporters listed.[16][19][32][33]

Side effects

Many 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, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.[35] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[36]

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 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.

Discontinuation

Antidepressants in general may produce a discontinuation syndrome. Since the term "withdrawal" has been linked to addiction to recreational drugs like opioids the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[37]Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[38] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[39]

Interactions

The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.[40] Drugs that prolong the QT interval including antiarrhythmics such asquinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

Overdose

Main article: Tricyclic antidepressant overdose

TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[41] 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 they are rapidly absorbed from 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:[42]

  1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
  2. 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)
  3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
  4. Pulmonary effects: hypoventilation resulting from CNS depression
  5. Gastrointestinal effects: decreased or absent bowel sounds

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 charcoal pre-mixed with water, which adsorbs the drug in the 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  recommended in TCA poisoning.
If there is metabolic acidosis, 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).
Treatment is otherwise supportive.

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[43] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[44] and generally have low abuse potential.[45] Several cases of the misuse[46] of amitriptyline alone[47][48] or together with methadone[46][49] or in other drug dependent patients[50][51]and of dothiepin with alcohol[52] or in methadone patients[53]have been reported.

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