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Thioridazine (sold under the brand namesMellaril orMelleril) is a first-generationantipsychoticdrug belonging to thephenothiazine drug group and was previously widely used in the treatment ofschizophrenia andpsychosis. The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the United States.[2]
Its primary use in medicine is for the treatment of schizophrenia.[4] It was also tried with some success as a treatment for various psychiatric symptoms seen in people withdementia,[5] but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.[6]
Thioridazine prolongs theQTc interval in a dose-dependent manner.[7] It produces significantly lessextrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect.[8][9] Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa).[10] It has a higher propensity for causinganticholinergic side effects coupled with a lower propensity for causingextrapyramidal side effects and sedation thanchlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity.[11] It is also known to possess a relatively high liability for causingorthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain.[12] As with all antipsychotics thioridazine has been linked to cases oftardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (ortypical) antipsychotics such as thioridazine) andneuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment).[7] Blood dyscrasias such asagranulocytosis,leukopenia andneutropenia are possible with thioridazine treatment.[7] Thioridazine is also associated with abnormal retinal pigmentation after many years of use.[13]Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.[14]
The ratio of 5-HT2A to D2 receptor binding is believed to dictate whether or not most antipsychotics areatypical ortypical. In thioridazine's case its ratio of 5-HT2A to D2 receptor binding is below the level that's believed to be required foratypicality despite its relatively low extrapyramidal side effect liability in practice.[4]
This receptor is believed to be the chief receptor responsible for theanticholinergic side effects of thioridazine (e.g. dry mouth, constipation, blurred vision, etc.). Likely plays a role in thioridazine's low extrapyramidal side effect liability as anticholinergic drugs such asbenzatropine are routinely given to treatextrapyramidal side effects resulting from antipsychotic treatment.[4]
Thioridazine is aracemic compound with twoenantiomers, both of which are metabolized, according to Eap et al., byCYP2D6 into (S)- and (R)-thioridazine-2-sulfoxide, better known asmesoridazine,[16] and into (S)- and (R)-thioridazine-5-sulfoxide.[17] Mesoridazine is in turn metabolized intosulforidazine.[18] Thioridazine is an inhibitor ofCYP1A2 and CYP3A4.[19]
Thioridazine was first synthesized in 1958 by Swiss pharmaceutical companySandoz.[20] It quickly entered widespread clinical use, as there were few alternatives for treating schizophrenia. In 2005, thioridazine was voluntarily discontinued by its manufacturer,Novartis, worldwide because it caused severe cardiac arrhythmias. However, generics remain on the market in some countries.[2][21][22][23] Generic forms of thioridazine however remain on the market in a few countries, usually with restrictions. For example, in the US it is restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects.[24]
The alkylation of 2-Picoline [109-06-8] (1) with formaldehyde gives 2-Pyridineethanol [103-74-2] (2). Forming the quat salt with methyl iodide [74-88-4] leads to 2-(2-hydroxyethyl)-1-methyl-pyridinium iodide [56622-15-2] (3). Catalytic hydrogenation in the presence of hydrochloric acid leads to 2-(2-Chloroethyl)-1-Methylpiperidine [50846-01-0] (4). Alkylation of 2-Methylthiophenothiazine [7643-08-5] (5) in the presence of sodium hydride base completed the synthesis ofThioridazine (6).
^Shvartsburd A, Sajadi C, Morton V, Mirabi M, Gordon J, Smith RC (August 1984). "Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients".Journal of Clinical Psychopharmacology.4 (4):194–198.doi:10.1097/00004714-198408000-00004.PMID6470190.S2CID33161119.
^Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AI, van Driel ML, et al. (March 2013). "Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia".The Cochrane Database of Systematic Reviews.3 (3) CD007726.doi:10.1002/14651858.CD007726.pub2.hdl:1854/LU-3109108.PMID23543555.
^Keks N, McGrath J, Lambert T, Catts S, Vaddadi K, Burrows G, et al. (November 1994). "The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia".Acta Psychiatrica Scandinavica.90 (5):358–365.doi:10.1111/j.1600-0447.1994.tb01607.x.PMID7872041.S2CID40042606.
^Fornaro P, Calabria G, Corallo G, Picotti GB (July 2002). "Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis".Documenta Ophthalmologica. Advances in Ophthalmology.105 (1):41–49.doi:10.1023/A:1015768114192.PMID12152801.S2CID23618581.
^"Thioridazine".LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012.PMID31643669.
^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. Archived fromthe original on 8 November 2013. Retrieved28 October 2013.
^"Mesoridazine".PubChem. National Center for Biotechnology Information.
^Eap CB, Guentert TW, Schãublin-Loidl M, Stabl M, Koeb L, Powell K, et al. (March 1996). "Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin".Clinical Pharmacology and Therapeutics.59 (3):322–331.doi:10.1016/S0009-9236(96)80010-5.PMID8653995.S2CID45135063.
^"Sulforidazine".PubChem. National Center for Biotechnology Information.
^Abdel-Moety EM, Al-Rashood KA (1989). Florey K (ed.).Analytical profiles of drug substances. Vol. 18. London: Academic Press. p. 462.ISBN978-0-08-086113-5.
^Purhonen M, Koponen H, Tiihonen J, Tanskanen A (November 2012). "Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort".Pharmacoepidemiology and Drug Safety.21 (11):1227–1231.doi:10.1002/pds.3346.PMID22941581.S2CID19560432.
^Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, et al. (1958). "Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate".Helvetica Chimica Acta.41 (4):1072–1108.doi:10.1002/hlca.19580410420.
^US 3239514, Renz J, Bourquin JP, "Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position", issued 1966, assigned to Sandoz KK
