Tricyclic antidepressants (TCAs) are an older, yet diverse group of antidepressants (as far as their pharmacology and side effects) that are classed together due to the three rings that are present in their chemical structures. Their chief mechanism of action is that they inhibit the reuptake of the monoamine neurotransmitters, especially serotonin and noradrenaline. They also often antagonize the muscarinic acetylcholine receptors, histamine H1 receptors, α1 adrenergic receptors, which are believed to contribute to their side effects such as dry mouth, constipation, blurred vision, dizziness, sedation, memory problems, weight gain, changes in blood sugar levels, orthostatic hypotension, etc. They are also particularly toxic in cases of overdose as most of them have significant effects on the electrical cycle of the heart (what is measured using a ECG).
They are primarily used to treat depression, although different TCAs may have additional uses; refer to the table below.
|Other indications; notes|
|Amineptine||Never approved.||Never approved.||Never approved.||Depression; approved for this indication in Greece, previously approved in Brazil, France, Italy, Portugal and Spain. Removed from the market amidst concerns over its hepatotoxicty, abuse potential and severe acne-type skin reactions.|
|Amitriptyline||Depression.||Major depression; bed-wetting.||Depression.||Neuropathic pain; migraine prevention and urinary urge incontinence. It is on the World Health Organization's List of Essential Medicines (WHO-EM).|
|Amoxapine||Depression.||Never approved.||No longer approved; previously depression.||Schizophrenia.|
|Butriptyline||Never approved.||Never approved.||Once approved for depression, no longer.||Depression; withdrawn from clinical use in Europe.|
|Clomipramine||Obsessive-compulsive disorder (OCD).||OCD, major depression and cataplexy associated with narcolepsy (CD).||Depression, panic disorder, OCD, adjunct in the management of CD.||Premature ejaculation (PE); chronic pain; bed-wetting.|
|Desipramine||Depression.||No longer approved; once approved to treat depression.||No longer approved; once approved to treat depression.||ADHD, cocaine dependence and neuropathic pain.|
|Dibenzepin||Never approved.||Never approved.||Never approved.||Depression, currently approved for clinical use in Czech Republic and Switzerland, once approved in Germany, Israel, Netherlands, Poland and South Africa, amongst other countries.|
|Dosulepin||Not approved.||Major depression.||Depression.||None.|
|Doxepin||Depression, anxiety, insomnia and itching.||Major depression.||Depression; itching in eczema.||Chronic pain.|
|Imipramine||Depression.||Major depression; bed-wetting.||Depression; bed-wetting.||Off-label use including panic disorder and urinary urge incontinence.|
|Lofepramine||Not FDA approved.||Not TGA approved.||Depression.||None.|
|Maprotiline||Depression.||Not TGA approved.||Previously approved for the treatment of depression.||Anxiety associated with depression.|
|Melitracen||Not FDA approved.||Not TGA approved.||Not MHRA approved.||Currently approved in India for the treatment of depression; also approved in Austria, Belgium, China, Hong Kong, India, Singapore, Spain, Switzerland and Thailand in combination with flupentixol for the treatment of anxiety with depression.|
|Nortriptyline||Depression.||Depression.||Depression.||Urinary urge incontinence, neuropathic pain, chronic hives, ADHD and as an aid to quit smoking.|
|Opipramol||Not FDA approved.||Not TGA approved.||Not MHRA approved.||Approved to treat generalized anxiety disorder in Austria, Germany, Greece, Poland, Switzerland and Turkey.|
|Pipofezine||Not FDA approved.||Not TGA approved.||Not MHRA approved.||Approved to treat depression in Russia.|
|Protriptyline||Depression.||Not approved.||Once approved for the treatment of depression; no longer approved, however.||Obstructive sleep apnoea.|
|Tianeptine||Not approved.||Not approved.||Not approved.||Approved for the treatment of depression in Argentina, Austria, Brazil, China, Czech Republic, France, Hungary, India, Indonesia, Malaysia, Mexico, Philippines, Poland, Portugal, Russia, Singapore, Thailand, Turkey, Ukraine and Venezuela. It is also used to treat asthma and irritable bowel syndrome.|
|Trimipramine||Depression.||Depression; discontinued by the TGA in December 2013.||Depression.||None.|
Most TCAs produce anticholinergic, α-adrenergic, antihistamine and cardiotoxic (that is, it alters the electrical activity of the heart, hence leading to ECG anomalies and if severe enough arrhythmias and death) effects.
|Drug||mAChR effects||α effects||H1 effects||Other notable side effects|
|Amineptine||-||-||-||Hepatotoxicity, addiction and severe acne-like skin reactions.|
|Amitriptyline||++++||+++||+++||More prone to cause hepatotoxicity than other antidepressants, although not problematic enough to require regular monitoring.|
|Amoxapine||+||+||+||Movement disorders, high blood prolactin and other metabolic effects. Very toxic to the kidneys in cases of overdose.|
|Lofepramine||+/-||+/-||+/-||Liver injury reported rarely.|
|Tianeptine||-||-||-||Rare cases of liver injury reported.|
- indicates the side effect is negligible/absent.
+ indicates the side effect is usually minor/infrequent.
++ indicates a moderate/frequent side effect.
+++ indicates a severe/very frequent side effect.
++++ indicates a very profound side effect.
TCAs are notorious for their toxicity in overdoses; of them amoxapine, maprotiline, desipramine, amitriptyline and doxepin, in order (most to least toxic), are the most toxic. Likewise lofepramine, tianeptine and trimipramine are likely the least toxic.
Most TCAs produce their antidepressant effects by inhibiting the reuptake of serotonin and noradrenaline; some, however, act at different sites. For example, amineptine, is a noradrenaline-dopamine reuptake inhibitor, opipramol is a sigma receptor agonist, tianeptine works by enhancing the reuptake of serotonin while simultaneously modulating the ionotropic glutamate receptors and agonizing the mu and delta opioid receptors and iprindole acts predominantly by antagonizing the 5-HT2 receptors.
Most TCAs have half-lives such that once or twice daily dosing is possible, although there are a couple of exceptions, for instance amoxapine, doxepin, lofepramine and tianeptine need to be dosed two-four times a day. As a general rule of thumb the half-life of a drug tells one how many hours should be between doses, ideally. Unless, of course, the drug has an equally or more active metabolite.
|Drug||Brand names||Plasma protein binding||Metabolism|| Half-life|
|Amitriptyline||Elavil, Endep||?||N-demethylation via CYP2C9, CYP2D6, CYP3A4 to nortriptyline; hydroxylation too.||9-25 hours; 28-31 hours for nortriptyline||qDay Nocte|
|Amoxapine||Asendin, Asendis||90%||Hydroxylated to 7- and 8-hydroxyamoxapine||8 hours; 30 hours for 7-hydroxyamoxapine||q8-12hr.|
|Clomipramine||Anafranil, Placip||97-98%||N-demethylation to desmethylclomipramine.||21 hours; 36 hours (for desmethylclomipramine).||q12-24hr Nocte.|
|Desipramine||Norpramin, Pertofrane||?||CYP2D6-mediated metabolism||15-24 hours||q12-24hr. Nocte.|
|Dosulepin (dothiepin)||Dothep, Prothiaden||?||N-desmethylation.||14-24 hours||q12-24hr. Nocte.|
|Doxepin||Deptran, Sinequan, Zonalon||76%||CYP2C19, CYP2D6-mediated metabolism.||8-24 hours||q12hr.|
|Imipramine||Tofranil, Tolerade||90%||CYP1A2, CYP2C19, CYP2D6-mediated metabolism; mostly via hydroxylation and N-oxidation to desipramine.||9-28 hours||q8-24hr.|
|Maprotiline||Ludiomil||88-89%||N-oxidation and hydroxylation to desmethylmaprotiline and maprotiline-N-oxide.||43 hours (60-90 hours for active metabolites)||qDay.|
|Nortriptyline||Allegron, Aventyl, Pamelor||93-95%||Hydroxylation to 10-hydroxynortriptyline.||28-31 hours||q6-24hr (depends on the use and dosage).|
|Protriptyline||Concordin, Vivactil||92%||Oxidation, hydroxylation and glucuronidation.||55-198 hours||q6-8hr.|
|Tianeptine||Coaxil, Stablon.||95%||Beta-oxidation.||2.5-6.3 hours||q6-12hr.|
- ↑ Kis are a numerical way of stating how potently drugs bind to their respective receptor/transporter sites; the lower the Ki the more potently the drug binds to the protein in question. All in nanomolars (nM).
- ↑ Derived from Martindale and Medscape Reference
- ↑ 1.0 1.1 Brayfield, A, ed. (11 August 2014). "Amineptine Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press.
- ↑ Rossi, S, ed. (July 2014). "Amitriptyline". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 11 August 2014.
- ↑ "WHO Model List of Essential Medicines". WHO. World Health Organization. October 2013. Retrieved 11 August 2014.
- ↑ Apiquian, R; Ulloa, E; Fresan, A; Loyzaga, C; Nicolini, H; Kapur, S (January 2003). "Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study.". Schizophrenia Research 59 (1): 35–9. PMID 12413640. doi:10.1016/S0920-9964(01)00342-5.
- ↑ Apiquian, R; Fresan, A; Ulloa, RE; de la Fuente-Sandoval, C; Herrera-Estrella, M; Vazquez, A; Nicolini, H; Kapur, S (December 2005). "Amoxapine as an atypical antipsychotic: a comparative study vs risperidone.". Neuropsychopharmacology 30 (12): 2236–44. PMID 15956984. doi:10.1038/sj.npp.1300796.
- ↑ Chaudhry, IB; Husain, N; Khan, S; Badshah, S; Deakin, B; Kapur, S (December 2007). "Amoxapine as an antipsychotic: comparative study versus haloperidol.". Journal of Clinical Psychopharmacology 27 (6): 575–81. PMID 18004123. doi:10.1097/jcp.0b013e31815a4424.
- ↑ O'Connor, AB; Noyes, K; Holloway, RG (August 2007). "A cost-effectiveness comparison of desipramine, gabapentin, and pregabalin for treating postherpetic neuralgia.". Journal of the American Geriatrics Society 55 (8): 1176–84. PMID 17661955. doi:10.1111/j.1532-5415.2007.01246.x.
- ↑ Ghanizadeh, A (2013 Jul). "A systematic review of the efficacy and safety of desipramine for treating ADHD.". Current Drug Safety 8 (3): 169–74. PMID 23914752. doi:10.2174/15748863113089990029. Check date values in:
- ↑ Aronoff, GM; Evans, WO (August 1982). "Doxepin as an adjunct in the treatment of chronic pain.". The Journal of Clinical Psychiatry 43 (8 Pt 2): 42–7. PMID 7047506.
- ↑ Rossi, S, ed. (July 2014). "Imipramine". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 11 August 2014.
- ↑ Brayfield, A, ed. (23 September 2011). "Melitracen Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 11 August 2014.
- ↑ Boerner, RJ (November 2007). "Generalisierte Angststörung: Diagnostik und Therapie" [Generalized anxiety disorder (GAD)--diagnosis and therapy] (PDF). Medizinische Monatsschrift fur Pharmazeuten 30 (11): 401–8; quiz 409–10. PMID 18062331. doi:10.3238/arztebl.2013.0300.
- ↑ Smith, IE; Quinnell, TG (2004). "Pharmacotherapies for obstructive sleep apnoea: where are we now?". Drugs 64 (13): 1385–99. PMID 15212557. doi:10.2165/00003495-200464130-00001.
- ↑ Brayfield, A, ed. (13 December 2013). "Tianeptine Sodium". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 11 August 2014.
- ↑ Lechin, F; van der Dijs, B; Lechin, AE (November 2004). "Treatment of bronchial asthma with tianeptine.". Methods and Findings in Experimental and Clinical Pharmacology 26 (9): 697–701. PMID 15632955. doi:10.1358/mf.2004.26.9.872567.
- ↑ Sohn, W; Lee, OY; Kwon, JG; Park, KS; Lim, YJ; Kim, TH; Jung, SW; Kim, JI (September 2012). "Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study.". Neurogastroenterology and Motility 24 (9): 860–e398. PMID 22679908. doi:10.1111/j.1365-2982.2012.01945.x.
- ↑ Chojnacki, C; Walecka-Kapica, E; Mokwinska, M; Romanowski, M; Pawlowicz, M; Chojnacki, J; Klupinska, G (April 2013). "Influence of tianeptine on melatonin homeostasis and psychosomatic symptoms in patients with irritable bowel syndrome." (PDF). Journal of Physiology and Pharmacology 64 (2): 177–83. PMID 23756392.
- ↑ Voican, CS; Corruble, E; Naveau, S; Perlemuter, G (April 2014). "Antidepressant-induced liver injury: a review for clinicians.". The American Journal of Psychiatry 171 (4): 404–15. PMID 24362450. doi:10.1176/appi.ajp.2013.13050709.
- ↑ 19.0 19.1 Kerr, GW; McGuffie, AC; Wilkie, S (July 2001). "Tricyclic antidepressant overdose: a review.". Emergency Medicine Journal 18 (4): 236–41. PMC 1725608. PMID 11435353. doi:10.1136/emj.18.4.236.
- ↑ 20.0 20.1 White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type.". Journal of Medical Toxicology 4 (4): 238–50. PMC 3550116. PMID 19031375. doi:10.1007/BF03161207.
- ↑ Hawton, K; Bergen, H; Simkin, S; Cooper, J; Waters, K; Gunnell, D; Kapur, N (May 2010). "Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose.". The British Journal of Psychiatry 196 (5): 354–8. PMC 2862059. PMID 20435959. doi:10.1192/bjp.bp.109.070219.
- ↑ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 10 August 2014.
- ↑ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill Professional. ISBN 978-0-07-162442-8.