Tiotixene

Tiotixene is a widely used drug for the treatment of various psychiatric disorders such as schizophrenia, bipolar disorder, mania, and behavioural disturbances.{{cite journal | vauthors = Xin C, Lihong W, Qiuyuan L, Hongzhuo L | title = Injectable long-term control-released in situ gels of hydrochloric thiothixene for the treatment of schizophrenia: preparation, in vitro and in vivo evaluation | journal = International Journal of Pharmaceutics | volume = 469 | issue = 1 | pages = 23–30 | date = July 2014 | pmid = 24751344 | doi = 10.1016/j.ijpharm.2014.04.044 }} The drug regulates behaviour and thoughts, and can also exhibit an anti-depressive effect.{{cite journal | vauthors = Robertson MM, Trimble MR | title = Major tranquillisers used as antidepressants. A review | journal = Journal of Affective Disorders | volume = 4 | issue = 3 | pages = 173–193 | date = September 1982 | pmid = 6127357 | doi = 10.1016/0165-0327(82)90002-7 }}  

The side effect profile is similar to related antipsychotic agents, displaying weight gain, mental distress, and inability to sit still. Other possible symptoms include anticholinergic side effects such as insomnia, blurred vision, and dry mouth.{{cite journal | vauthors = Browne MW | title = Experiences with thiothixene | journal = The British Journal of Psychiatry | volume = 114 | issue = 506 | pages = 123 | date = January 1968 | pmid = 5636080 | doi = 10.1192/bjp.114.506.123 }}{{cite journal | vauthors = Sarai K, Okada M | title = Comparison of efficacy of zotepine and thiothixene in schizophrenia in a double-blind study | journal = Pharmacopsychiatry | volume = 20 | issue = 1 Spec No | pages = 38–46 | date = February 1987 | pmid = 2883680 | doi = 10.1055/s-2007-1017128 | s2cid = 20384816 }} Less frequently encountered side effects are drug-induced movement disorders such as Parkinsonism and tardive dyskinesia.{{cite journal | vauthors = Overall JE, Hollister LE, Shelton J, Kimbell I, Pennington V | title = Broad-spectrum screening of psychotherapeutic drugs: thiothixene as an antipsychotic and antidepressant | journal = Clinical Pharmacology and Therapeutics | volume = 10 | issue = 1 | pages = 36–43 | date = January 1969 | pmid = 4884295 | doi = 10.1002/cpt196910136 | s2cid = 23287102 }}{{cite journal | vauthors = Yesavage JA, Tanke ED, Sheikh JI | title = Tardive dyskinesia and steady-state serum levels of thiothixene | journal = Archives of General Psychiatry | volume = 44 | issue = 10 | pages = 913–915 | date = October 1987 | pmid = 2889439 | doi = 10.1001/archpsyc.1987.01800220085012 }}

The results of various dose-response studies (10–60 mg) indicate a stimulating effect at lower doses, which diminishes as higher doses are administered.{{cite journal | vauthors = Gardos G, Cole JO | title = The dual action of thiothixene | journal = Archives of General Psychiatry | volume = 29 | issue = 2 | pages = 222–225 | date = August 1973 | pmid = 4741513 | doi = 10.1001/archpsyc.1973.04200020056007 }} Overall, the efficacy of thiothixene when compared to other antipsychotic drugs was evaluated to be at least as effective regardless of the optimum dosage.{{cite journal | vauthors = Gallant DM, Bishop MP, Shelton W | title = A preliminary evaluation of P-4657B: a thioxanthene derivative | journal = The American Journal of Psychiatry | volume = 123 | issue = 3 | pages = 345–346 | date = September 1966 | pmid = 5921658 | doi = 10.1176/ajp.123.3.345 }}{{cite journal | vauthors = Bishop MP, Fulmer TE, Gallant DM | title = Thiothixene versus trifluoperazine in newly-admitted schizophrenic patients | journal = Current Therapeutic Research, Clinical and Experimental | volume = 8 | issue = 11 | pages = 509–514 | date = November 1966 | pmid = 4962777 | url = https://pubmed.ncbi.nlm.nih.gov/4962777/ }}

As common with tricyclic psychotherapeutic agents, tiotixene is rapidly and extensively absorbed.{{cite journal | vauthors = Hobbs DC | title = Metabolism of thiothixene | journal = Journal of Pharmaceutical Sciences | volume = 57 | issue = 1 | pages = 105–111 | date = January 1968 | pmid = 5652108 | doi = 10.1002/jps.2600570121 }} Peak serum concentration of the drug is achieved after 1–3 hours.{{cite journal | vauthors = Hobbs DC, Welch WM, Short MJ, Moody WA, Van der Velde CD | title = Pharmacokinetics of thiothixene in man | journal = Clinical Pharmacology and Therapeutics | volume = 16 | issue = 3 | pages = 473–478 | date = September 1974 | pmid = 4415039 | doi = 10.1002/cpt1974163part1473 | s2cid = 42200908 }} After absorption, the compound and its metabolites are spread widely throughout the body.  

The drug's metabolism proceeds rapidly and primarily in the liver. Although N-demethyltiotixene was identified as its major metabolite, the metabolic mechanisms remain elusive.{{cite journal | vauthors = Guthrie SK, Hariharan M, Kumar AA, Bader G, Tandon R | title = The effect of paroxetine on thiothixene pharmacokinetics | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 22 | issue = 3 | pages = 221–226 | date = June 1997 | pmid = 9447478 | doi = 10.1046/j.1365-2710.1997.95175951.x | hdl = 2027.42/72596 | hdl-access = free }} After metabolism, most of the material is excreted through the faeces.

{{See also|Antipsychotic#Mechanism of action|Antipsychotic#Comparison of medications}}

Tiotixene shares its mechanism with related thioxanthenes which are all fundamentally used to control schizophrenia. Their mechanism of action involves the inhibition of different receptors, including 5-HT (serotonin), dopaminergic, histaminergic, and adrenergic receptors.{{cite journal | vauthors = Gao S, Han L, Luo D, Xiao Z, Liu G, Zhang Y, Zhou W | title = Deep learning applications for the accurate identification of low-transcriptional activity drugs and their mechanism of actions | journal = Pharmacological Research | volume = 180 | pages = 106225 | date = June 2022 | pmid = 35452801 | doi = 10.1016/j.phrs.2022.106225 | s2cid = 248309731 }} Blocking these receptors results in a reduction of synaptic levels of dopamine, serotonin, and other neurotransmitters that are involved with abnormal excitement in the brain during psychoses.{{Cite journal | vauthors = Bangwal R, Bisht S, Saklani S, Garg S, Dhayani M |date=January 2020 |title=Psychotic Disorders, Definition, Sign and Symptoms, Antipsychotic Drugs, Mechanism of Action, Pharmacokinetics & Pharmacodynamics with Side Effects & Adverse Drug Reactions: Updated Systematic Review Article |url=http://jddtonline.info/index.php/jddt/article/view/3865 |journal=Journal of Drug Delivery and Therapeutics |volume=10 |issue=1 |pages=163–172 |doi=10.22270/jddt.v10i1.3865 |issn=2250-1177|doi-access=free }} This reduction of abnormal neurotransmission activity tends to alleviate the psychotic indications associated with schizophrenia.{{cite journal | vauthors = Patel KR, Cherian J, Gohil K, Atkinson D | title = Schizophrenia: overview and treatment options | journal = P & T | volume = 39 | issue = 9 | pages = 638–645 | date = September 2014 | pmid = 25210417 | pmc = 4159061 }}

Tiotixene acts primarily as a highly potent antagonist of the dopamine D₂ and D₃ receptors (subnanomolar affinity). It is also an antagonist of the histamine H₁, α₁-adrenergic, and serotonin 5-HT₇ receptors (low nanomolar affinity), as well as of various other receptors to a much lesser extent (lower affinity). It does not have any anticholinergic activity. Antagonism of the D₂ receptor is thought to be responsible for the antipsychotic effects of tiotixene.

Thiothixene stimulates macrophages to clear pathogenic cells by inducing arginase 1 and continual efferocytosis.{{Cite web |date=2025-04-09 |title=The antipsychotic drug thiothixene stimulates macrophages to clear pathogenic cells by inducing arginase 1 and continual efferocytosis {{!}} Science Signaling |url=https://web.archive.org/web/20250409204859/https://www.science.org/doi/10.1126/scisignal.ads6584 |access-date=2025-04-09 |website=web.archive.org |doi=10.1126/scisignal.ads6584}}

Thiothixene has demonstrated toxicity in animal studies and isolated human tissue, displaying cytotoxic effects against various cell types. Observed toxic effects included growth inhibition of mouse fibroblasts, inhibition of protein synthesis by human glioma cells, and inhibition of leukocyte DNA synthesis.{{Cite journal | vauthors = ((J. B. Roerig Division)) |date=March 1968 |title=Thiothixene (Navane) |journal=Clinical Pharmacology & Therapeutics |language=en |volume=9 |issue=2 |pages=282–284 |doi=10.1002/cpt196892282 |s2cid=209106681 |issn=0009-9236}}{{cite journal | vauthors = Munyon WH, Salo R, Briones DF | title = Cytotoxic effects of neuroleptic drugs | journal = Psychopharmacology | volume = 91 | issue = 2 | pages = 182–188 | date = February 1987 | pmid = 2883697 | doi = 10.1007/BF00217059 | s2cid = 20832854 }}

Other compounds within the thioxanthene class have demonstrated hepatotoxicity in rodent experiments, and although anecdotal reports of thiothixene-induced liver failure exist, scientific data regarding the correlation lacks.{{cite journal | vauthors = Abernathy CO, Zimmerman HJ | title = The toxicity of thioxanthene neuroleptics to isolated rat liver cells | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 150 | issue = 2 | pages = 385–389 | date = November 1975 | pmid = 1208553 | doi = 10.3181/00379727-150-39041 | s2cid = 21403569 }} The absence of observational or longitudinal human studies on thiothixene in published literature precludes drawing conclusions regarding the significance of toxic effects at therapeutic dosages.

Thiothixene is a tricyclic compound consisting of a thioxanthene core with a (4-methylpiperazin-1-yl)propylidene side chain.{{cite journal | vauthors = Noori Tahneh A, Bagheri Novir S, Balali E | title = Density functional theory study of structural and electronic properties of trans and cis structures of thiothixene as a nano-drug | journal = Journal of Molecular Modeling | volume = 23 | issue = 12 | pages = 356 | date = November 2017 | pmid = 29177682 | doi = 10.1007/s00894-017-3522-6 | s2cid = 27183246 }} Several methods for the synthesis of thiothixene are described in literature, which all rely on varying thioxanthone derivatives upon which the (4-methylpiperazin-1-yl)propylidene side chain is constructed.{{cite journal | vauthors = Muren JF, Bloom BM | title = Thioxanthene psychopharmacological agents. II. 9-(3-aminopropylidene)-N,N-dimethylthioxanthene-2-sulfonamides | journal = Journal of Medicinal Chemistry | volume = 13 | issue = 1 | pages = 17–23 | date = January 1970 | pmid = 5412109 | doi = 10.1021/jm00295a005 }}

Wyatt et al. described the synthesis of thiothixene via four different routes, three of which originated from the previous findings from Muren et al. One method described the synthesis of thiothixene by acetylation of 9-lithio-N,N-dimethylthioxanthene-2-sulfonamide. After acetylation, a condensation reaction, and an amine exchange the intermediate ketone was obtained. This intermediate was then converted into E- and Z-thiothixene through reduction with NaBH₄, followed by dehydration using POCl₃-pyridine.

Another method described by Muren et al. was performed using N,N-dimethylsulfamoyl-Z-thioxanthen-9-one as starting material. The introduction of the piperazinylpropylidene side chain was performed by a Wittig reaction. Following this, the methylation of the piperazinylpropylidene side chain was executed using various alkylating agents, yielding E- and Z-thiothixene.  

The last method described by Wyatt et al, adapted from the study described by Muren and Bloom, used potassium benzenethiolate and 2-bromo-5-dimethylsulfamoylbenzoic acid as starting material. The resulting acid was treated with copper and PPA to form the thioxanthone intermediate. This ketone intermediate was then treated with the addition of the piperazinylpropylidene side chain and the loss of a water molecule to form Z- and E-Thiothixene.  

The fourth method originating from D.C Hobbs involved condensing thiophenol with 2-chloro-5-dimethylsulfamoylbenzoic acid in an alkaline DMF solution at 130–140 °C. After a ring closure reaction with polyphosphoric acid at 70 °C, the ketone intermediate (N,N-dimethylsulfamoyl-Z-thioxanthen-9-one) was obtained. A wittig reaction was employed to connect the intermediate with the piperazinylpropylidene side chain, leading to the formation of both Z- and E-thiothixene isomers.{{Cite journal | vauthors = Rani A, Aslam M, Pandey G, Pant BN |date=May 2023 |title=A review on synthesis of FDA-approved antipsychotic drugs |journal=Tetrahedron |volume=138 |pages=133430 |doi=10.1016/j.tet.2023.133430 |s2cid=258316664 |issn=0040-4020}}

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