Phenothiazine-Related Critical Conditions: a Mini-Review
https://doi.org/10.15360/1813-9779-2026-1-2635
Abstract
Objective. The aim of this review is to summarize the pathological mechanisms associated with the toxicity of phenothiazines in overdose.
Materials and methods. A database search was conducted on PubMed, Google Scholar and eLibrary were used to identify original research articles, clinical reports, review articles, editorials, commentaries, and brief communications. Additional sources not identified through the search of these databases were analyzed after reviewing the reference lists of the selected articles. Articles were selected based on the relevance of the title and abstract to the purpose of this review.
Results. This review analyzes the mechanisms of action of phenothiazines in the context of their long-term clinical use and in overdose, as well as the mechanisms of action of proposed potential areas of application of phenothiazines. Clinical manifestations of phenothiazine poisoning are predominantly characterized by antagonism of dopamine D₁–D₄ receptors, histamine H₁ receptors, α₁–α₂ α-adrenergic receptors and muscarinic acetylcholine receptors M₁–M₂. In addition, phenothiazines are able to increase the permeability of the blood-brain barrier through apoptosis, increase global methylation, effectively enhance chemotherapy of some tumors and provide neuroprotection by reducing GFAP production (PKC-δ/NOX/MnSOD pathway).
Conclusions. Given the potential for new applications of phenothiazines, further study of the effects of phenothiazines on the central nervous system in overdose, with a focus on repeat overdose episodes, is important at the morphological level to identify the underlying morphological substrate. Further study of the mechanisms associated with phenothiazine use is needed to develop more effective therapeutic strategies to improve patient outcome, not only in psychiatry but also in other disciplines.
About the Author
D. E. Shumeyko
V. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology; Patrice Lumumba Peoples Friendship University of Russia
Russian Federation
Russian Federation
Denis E. Shumeyko
25 Petrovka Str., Bldg. 2, 107031 Moscow;
6 Miklukho-Maсlaya Str., 117198 Moscow
References
1. López-Muñoz F., Alamo C., Cuenca E., Shen W., Clervoy P., Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005; 17 (3): 113–135. DOI: 10.1080/10401230591002002. PMID: 16433053.
2. Ohlow M. J., Moosmann B. Phenothiazine: the seven lives of pharmacology’s first lead structure. Drug Discov Today. 2011; 16 (3–4): 119–131. DOI: 10.1016/j.drudis.2011.01.001. PMID: 21237283.
3. Ban T. A. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007; 3 (4): 495–500. PMID: 19300578.
4. Gajwani P., Kemp D. E., Muzina D. J., Xia G., Gao K., Calabrese J. R. Acute treatment of mania: an update on new medications. Curr Psychiatry Rep. 2006; 8 (6): 504–509. DOI: 10.1007/s11920-006-0058-3. PMID: 17094930.
5. Healthcare in Russia. 2023. Statistical collection. Federal State Statistics Service; Moscow, 2023: 179 p. UDC 31: 614 (470). https://youthlib.mirea.ru/ru/reader/62292023. (in Rus.).
6. Gorobtsov A. V. Russian statistical yearbook. Moscow: Federal State Statistics Service; 2024. (in Rus.).
7. World Health Organization. Suicide mortality rate (per 100 000 population). DataWhoInt. 2025; http://data.who.int/indicators/i/F08B4FD/16BBF41 (accessed October 21, 2025).
8. Bertuccio P., Amerio A., Grande E., Vecchia C. L., Costanza A., Aguglia A., Berardelli I., et al. Global trends in youth suicide from 1990 to 2020: an analysis of data from the WHO mortality database. eClinicalMedicine. 2024; 70: 102506. DOI: 10.1016/j.eclinm.2024.102506. PMID: 38440131.
9. CDC. Injury data reports. WISQARS. n. d.: https://wisqars.cdc.gov/fatal-injury-trends/ (accessed October 21, 2025).
10. Tournier M., Grolleau A., Cougnard A., Molimard M., Verdoux H. Factors associated with choice of psychotropic drugs used for intentional drug overdose. Eur Arch Psychiatry Clin Neurosci. 2009; 259 (2): 86–91. DOI: 10.1007/s00406-008-0839-2. PMID: 18806918.
11. Hirokawa S., Matsumoto T., Katsumata Y., Kitani M., Akazawa M., Takahashi Y., Kawakami N., et al. Psychosocial and psychiatric characteristics of suicide completers with psychiatric treatment before death: a psychological autopsy study of 76 cases. Psychiatry Clin Neurosci. 2012; 66 (4): 292–302. DOI: 10.1111/j.1440-1819.2012.02343.x. PMID: 22624734.
12. Tsai S.-J., Hong C.-J., Liou Y.-J. Recent molecular genetic studies and methodological issues in suicide research. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35 (4): 809–817. DOI: 10.1016/j.pnpbp.2010.10.014. PMID: 20977922.
13. Ojanperä I., Kriikku P., Vuori E. Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database. Int J Legal Med. 2016; 130 (5): 1209–1216. DOI: 10.1007/s00414-016-1358-8. PMID: 26987318.
14. Fang J., Gorrod J. W. Metabolism, pharmacogenetics, and metabolic drug–drug interactions of antipsychotic drugs. Cell Mol Neurobiol. 1999; 19 (4): 491–510. DOI: 10.1023/A: 1006938908284. PMID: 10379422.
15. Peroutka S., Snyder S. Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry. 1980; 137 (12): 1518–1522. DOI: 10.1176/ajp.137.12.1518. PMID: 6108081.
16. Suzuki H., Gen K., Inoue Y. Comparison of the anti-dopamine D₂ and anti-serotonin 5-HT 2A activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. J Psychopharmacol (Oxf). 2013; 27 (4): 396–400. DOI: 10.1177/0269881113478281. PMID: 23427194.
17. Li P., L. Snyder G., E. Vanover K. Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem. 2016; 16 (29): 3385–3403. DOI: 10.2174/1568026616666160608084834. PMID: 27291902.
18. Elmorsy E., Elzalabany L. M., Elsheikha H. M., Smith P. A. Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier. Brain Res. 2014; 1583: 255–268. DOI: 10.1016/j.brainres.2014.08.011. PMID: 25139421.
19. Swathy B., Saradalekshmi K. R., Nair I. V., Nair C., Banerjee M. Understanding the influence of antipsychotic drugs on global methylation events and its relevance in treatment response. Epigenomics. 2018; 10 (3): 233–247. DOI: 10.2217/epi-2017-0086. PMID: 29343074.
20. Anagnostis S., Khehra N., Parmar M. S. Encyclopedia of Toxicology (Fourth Edition). 2024; 2: 995–1002. Encyclopedia of Toxicology. Chlorpromazines DOI: 10.1016/B978-0-12-824315-2.00648-5.
21. Irwin S., Slabok M., Debiase P. L., Govier W. M. Perphenazine (trilafon), a new potent tranquilzer and antiemetic. I. Behavioral mode of action. Arch Int Pharmacodyn Ther. 1959; 118 (3–4): 358–374. PMID: 13628255.
22. Hino M., Ono H., Fukuda H. Brain stem involvement in the effects of chlorpromazine on the monosynaptic reflex of the rat lumbar spinal cord. Gen Pharmacol Vasc Syst. 1986; 17 (4): 379–383. DOI: 10.1016/0306-3623 (86)90178-3. PMID: 3758647.
23. Jeanna M Marraffa. Encyclopedia of Toxicology (Fourth Edition). 2024; 7: 539–542. Encyclopedia of Toxicology. Phenothiazines. DOI: 10.1016/B978-0-12-824315-2.00584-4.
24. Takase I., Yamamoto Y., Nakagawa T., Nishi K. A fatal case of potential chronic overdoses of prescribed and proprietary remedies. Hum Exp Toxicol. 2010; 29 (8): 695–699. DOI: 10.1177/0960327109360116. PMID: 20106941.
25. Naeem S., Najam R., Khan S. S., Mirza T., Sikandar B. Neuroprotective effect of diclofenac on chlorpromazine induced catalepsy in rats. Metab Brain Dis. 2019; 34 (4): 1191–1199. DOI: 10.1007/s11011-019-00416-1. PMID: 31055785.
26. Kislov M. A., Trusova D. S., Krupin K. N., Zhiganova M. S., Maksimov A. V. Morphofunctional changes in the neuronal environment in suicide. Forensic Medicine = Sudebnaya Meditsina. 2023; 9 (2): 165–174. DOI: 10.17816/fm723.
27. Courtet P., Giner L., Seneque M., Guillaume S., Olie E., Ducasse D. Neuroinflammation in suicide: toward a comprehensive model. World J Biol Psychiatry. 2016; 17 (8): 564–586. DOI: 10.3109/15622975.2015.1054879. PMID: 26223957.
28. Fernández-Sevillano J., González-Ortega I., MacDowell K., Zorrilla I., López M. P., Courtet P., Gabilondo A., et al. Inflammation biomarkers in suicide attempts and their relation to abuse, global functioning and cognition. World J Biol Psychiatry. 2022; 23 (4): 307–317. DOI: 10.1080/15622975.2021.1988703. PMID: 34730074.
29. Torres-Platas S. G., Cruceanu C., Chen G. G., Turecki G., Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014; 42: 50–59. DOI: 10.1016/j.bbi.2014.05.007. PMID: 24858659.
30. Turecki G. The molecular bases of the suicidal brain. Nat Rev Neurosci. 2014; 15 (12): 802–816. DOI: 10.1038/nrn3839. PMID: 25354482.
31. Docherty A., Turecki G., Dwivedi Y. The biological signature (s) of suicide. Biol Psychiatry. 2024; 95 (10): S1–2. DOI: 10.1016/j.biopsych.2024.02.011.
32. Hamidi M., Drevets W. C., Price J. L. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry. 2004; 55 (6): 563–569. DOI: 10.1016/j.biopsych.2003.11.006. PMID: 15013824.
33. Chandley M. J., Szebeni A., Szebeni K., Wang-Heaton H., Garst J., Stockmeier C. A., Lewis N. H., et al. Markers of elevated oxidative stress in oligodendrocytes captured from the brainstem and occipital cortex in major depressive disorder and suicide. Prog Neuropsychopharmacol Biol Psychiatry. 2022; 117: 110559. DOI: 10.1016/j.pnpbp.2022.110559. PMID: 35452747.
34. Dejanovic B., Vukovic-Dejanovic V., Stevanovic I., Stojanovic I., Mandic-Gajic G., Dilber S. Oxidative stress induced by chlorpromazine in patients treated and acutely poisoned with the drug. Vojnosanit Pregl. 2016; 73 (4): 312–317. DOI: 10.2298/VSP140423047D. PMID: 29308860.
35. Matsusue A., Hara K., Kageura M., Kashiwagi M., Lu W., Ishigami A., Gotohda T., et al. An autopsy case of rhabdomyolysis related to vegetamin and genetic analysis of the rhabdomyolysis-associated genes. J Forensic Leg Med. 2010; 17 (1): 46–49. DOI: 10.1016/j.jflm.2009.07.020. PMID: 20083051.
36. Mortensen P. B. The incidence of cancer in schizophrenic patients. J Epidemiol Community Health. 1989; 43 (1): 43–47. DOI: 10.1136/jech.43.1.43. PMID: 2592890.
37. Otręba M., Marek Ł., Stojko J., Rzepecka-Stojko A. Phenothiazine derivatives and their impact on the apoptosis processes: a review. Toxicology. 2023; 492: 153528. DOI: 10.1016/j.tox.2023.153528. PMID: 37127180.
38. Osacka J., Kiss A., Pirnik Z. Possible involvement of apoptosis in the antipsychotics side effects: a mini-review. Clin Exp Pharmacol Physiol. 2022; 49 (8): 836–847. DOI: 10.1111/1440-1681.13671. PMID: 35575958.
39. Hendouei N., Saghafi F., Shadfar F., Hosseinimehr S. J. Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment. Eur J Pharmacol. 2019; 856: 172402. DOI: 10.1016/j.ejphar.2019.05.031. PMID: 31108054.
40. Li H.-J., Zhang Y.-J., Zhou L., Han F., Wang M.-Y., Xue M.-Q., Qi Z. Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel. Eur J Pharmacol. 2014; 735: 38–43. DOI: 10.1016/j.ejphar.2014.04.017. PMID: 24755143.
41. Guo S., Li F., Wills M., Yip J., Wehbe A., Peng C., Geng X., et al. Chlorpromazine and promethazine (C+P) reduce brain injury after ischemic stroke through the PKC‐δ/NOX/MnSOD pathway. Mediators Inflamm. 2022: 688752. DOI: 10.1155/2022/6886752. PMID: 35873710.
42. Boeva E. A., Grebencchikov O. A. Organoprotective properties of argon (review). General Reanimatology = Obshchaya Reanimatologiya. 2022; 18 (5): 44–59. (in Rus&Eng.). DOI: 10.15360/1813-9779-2022-5-44-59.
43. Guan L., Guo S., Yip J., Elkin K. B., Li F., Peng C., Geng X., Ding Y. Artificial hibernation by phenothiazines: a potential neuroprotective therapy against cerebral inflammation in stroke. Curr Neurovasc Res. 2019; 16 (3): 232–240. DOI: 10.2174/1567202616666190624122727. PMID: 31232236.
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Shumeyko D.E. Phenothiazine-Related Critical Conditions: a Mini-Review. General Reanimatology. (In Russ.) https://doi.org/10.15360/1813-9779-2026-1-2635
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