The Possibilities of Rational Antipsychotic Therapy in Patients with Schizophrenia and Comorbid Substance Dependence

Background: substance abuse disorder is widespread among schizophrenic patients. The choice of treatment strategy for a patient with a dual diagnosis presents significant difficulties for the clinician due to the peculiarities of the mutual influence of the two diseases, worse tolerance of psychopharmacotherapy, and low compliance. The aim of review was to analyze the scientific publications on the pathogenesis of comorbid substance use disorders in schizophrenic patients and current strategies of their treatment with antipsychotics considering drug interactions. Materials and Methods: a narrative review of scientific publications was compiled using available sources in the literature, including a search using combinations of keywords «шизофрения», «зависимость от алкоголя», «коморбидность» «антипсихотическая терапия», “schizophrenia”, “alcohol use disorder”, “SUD”, “comorbidity”, “antipsychotic drugs” in Google Scholar, ELibrary.ru, Scopus, PubMed databases. Conclusion: there are various theories designed to explain the mechanism of comorbid addiction formation in patients suffering from schizophrenia. One way or another at present, the common neurobiological basis of these disorders is no doubt, that determines the therapeutic strategy for this group of patients. The available publications shows promising prospects for the effectiveness of 3rd generation antipsychotics in the treatment of comorbid disorders, but further researches are needed.

1. Hunt GE, Large MM, Cleary M, Lai HMX, Saunders JB. Prevalence of comorbid substance use in schizophre nia spectrum disorders in community and clinical settings, 1990–2017: Systematic review and me ta-analysis. Drug Alcohol Depend. 2018;191:234–258. doi: 10.1016/j.drugalcdep.2018.07.011

2. Adan A, Torrens M. Diagnosis and management of addiction and other mental disorders (Dual Disor ders). J Clin Med. 2021;10(6);1307. doi: 10.3390/jcm10061307

3. Otasowie J. Co-occurring mental disorder and substance use disorder in young people: aetiolo gy, assessment and treatment. BJPsych Advance. 2021;27(4):272–281. doi: 10.1192/bja.2020.64

4. Fowles DC. Schizophrenia: diathesis-stress revisit ed. Annu Rev Psychol. 1992. doi: 10.1146/annurev.ps.43.020192.001511

5. Ahn S, Choi Y, Choi W, Jo YT, Kim H, Lee J, Joo S W. Ef fects of comorbid alcohol use disorder on the clinical outcomes of first-episode schizophrenia: a nation wide population-based study. Ann Gen Psychiatry. 2021;20(1):32. doi: 10.1186/s12991-021-00353-3

6. Bühler B, Hambrecht M, Löffier W, an der Heiden W, Häfner H. Precipitation and determination of the onset and course of schizophrenia by substance abuse—a retrospective and prospective study of 232 population-based first illness episodes. Schizo phr Res. 2002;54(3):243–251. doi: 10.1016/S0920 9964(01)00249-3

7. Mueser KT, Drake RE, Wallach MA. (1998). Dual di agnosis: a review of etiological theories. Addict Behav. 1998;23(6):717–734. doi: 10.1016/S03064603(98)00073-2

8. Khantzian EJ. The self-medication hypothesis of sub stance use disorders: A reconsideration and recent applications. Harv Rev Psychiatry. 1997;4(5):231 244. doi: 10.3109/10673229709030550

9. McKernan LC, Nash MR, Gottdiener WH, Ander son SE, Lambert WE, Carr ER. Further evidence of self-medication: Personality factors influencing drug choice in substance use disorders. Psycho dyn Psychiatry. 2015;43(2):243–275. doi: 10.1521/pdps.2015.43.2.243

10. Snezhnevsky AV. A psychiatric diagnosis. Psychiatry (Moscow) (Psikhiatriya). 2009;2(38):68–74. (In Russ.)

11. Stahl SM. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psy chosis: dopamine, serotonin, and glutamate. CNS Spectr. 2018;23(3):187–191. doi: 10.1017/S1092852918001013

12. Van Rossum JM. The significance of dopamine-re ceptor blockade for the mechanism of action of neuroleptic drugs. Arch. Int Pharmacodyn Ther. 1996;160:492–494.

13. Stępnicki P, Kondej M, Kaczor AA. Current con cepts and treatments of schizophrenia. Molecules. 2018;23(8):2087. doi: 10.3390/molecules23082087

14. Li D, Pan Q, Xiao Y, Hu K. Advances in the study of phencyclidine-induced schizophrenia-like animal models and the underlying neural mechanisms. Schizophrenia. 2024;10(1):65. doi: 10.1038/s41537024-00485-x

15. Howes OD, Bukala BR, Beck K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol.. 2024;20(1);22-35. doi: 10.1038/s41582-023-00904-0

16. Buck SA, Quincy Erickson-Oberg M, Logan RW, Frey berg Z. Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia. Mol Psychiatry. 2022;27(9):3583–3591. doi: 10.1038/s41380-022-01649-w

17. Malik JA, Yaseen Z, Thotapalli L, Ahmed S, Shaikh MF, Anwar S. Understanding translational research in schizophrenia: a novel insight into animal models. Mol Biol Rep. 2023;50(4):3767–3785. doi: 10.1007/s11033-023-08241-7

18. Alabaku O, Yang A, Tharmarajah S, Suda K, Vi god S, Tadrous M. Global trends in antidepressant, atypical antipsychotic, and benzodiazepine use: a cross-sectional analysis of 64 countries. Plos one. 2023;18(4):e0284389. doi: 10.1371/journal.pone.0284389

19. Leshner AI. Addiction is a brain disease. Issues Sci. Technol.. 2004;17:75–80.

20. Ungar-Sargon J. The Neurobiology of Addiction. Addict Res. 2024;8(1):1–7.

21. Kishi T, Sevy S, Chekuri R, Correll CU. Antipsychot ics for primary alcohol dependence: a systematic review and meta-analysis of placebo-controlled tri als. J Clin Psychiatry2013;74(7):1141. doi: 10.4088/ JCP.12r08178

22. Belfiore CI, Galofaro V, Cotroneo D, Lopis A, Trin gali I, Denaro V, Casu M. A Multi-Level Analysis of Biological, Social, and Psychological Determinants of Substance Use Disorder and Co-Occurring Mental Health Outcomes. Psychoactives. 2024;3(2):194–214. doi: 10.3390/psychoactives3020013

23. Asadullin AR, Gasenko KA. Potential Role of Third Generation Antipsychotics in Reducing Dependence in Patients with Bipolar Disorder. Current Thera py of Mental Disorder. 2023;(1):15–22. (In Russ.). doi: 10.21265/PSYPH.2023.46.35.002

24. Gasenko KA, Asadullin AR, Ahmetova EA, Nasyro va RF, Efremov IS. The Role of Sleep Disorders and Modulatory Effect of Melatonin in Formation of Al cohol Dependence in Patients with Schizophrenia. Social and Clinical Psychiatry. 2020;30(3):79–85. (In Russ.).

25. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discov ery and clinical introduction of chlorproma zine. Ann Clin Psychiatry. 2005;17(3):113–135. doi: 10.3109/10401230591002002

26. Ban TA. Fifty years chlorpromazine: a historical per spective. Neuropsychiatr Dis Treat. 2007;3(4):495 500. doi: 10.2147/ndt.s12160195

27. Leucht S, Priller J, Davis JM. Antipsychotic drugs: a concise review of history, classification, indications, mechanism, efficacy, side effects, dosing, and clinical application. Am J Psychiatry. 2024;181(10);865-878. doi: 10.1176/appi.ajp.20240738

28. Cheuk NKW, Tse W, Tsui HKH, Ma CF, Chun JSW, Chung AKK, Chan SKW. A systematic review and meta-anal ysis of the effect of clozapine on cognitive functions in patients with treatment-resistant schizophrenia Schizophr Res. 2024;268:205–222. doi: 10.1016/j.schres.2023.09.027

29. McCutcheon RA, Marques TR, Howes OD. Schizophre nia—an overview. JAMA psychiatry. 2020;77(2):201 210. doi: 10.1001/jamapsychiatry.2019.3360

30. Kinon BJ, Lieberman JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psy chopharmacology. 1996;124(1):2–34. doi: 10.1007/BF02245602

31. Jezsó B, Kálmán S, Farkas KG, Hathy E, Vincze K, Kovács-Schoblocher D, Réthelyi JM. Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocam pal Neurogenesis. Biomolecules. 2024;14(6):688. doi: 10.3390/biom14060688

32. Meltzer HY, Gadaleta E. Contrasting typical and atyp ical antipsychotic drugs. Focus. 2021;19(1):3–13. doi: 10.1176/appi.focus.2020005

33. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Ro senheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsy chotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209–23. doi: 10.1056/NEJ Moa051688 Epub 2005 Sep 19. Erratum in: N Engl J Med. 2010 Sep 9;363(11):1092–3. PMID: 16172203.

34. Zemach S, Zohar J. The importance of proper naming A review of Neuroscience-based Nomenclature (NbN). Asian J Psychiatr.. 2024:104317. doi: 10.1016/j.ajp.2024.104317

35. Ricci V, Sarni A, Martinotti G, Maina G. Compara tive analysis of third-generation antipsychotics in first-episode schizophrenia: efficacy, safe ty, and cognitive impacts. A narrative review. Int Clin Psychopharmacol. 2024:10–1097. doi: 10.1097/YIC.0000000000000559

36. Bordet C, Garcia P, Salvo F, Touafchia A, Galinier M, Sommet A, Montastruc F. Antipsychotics and risk of QT prolongation: a pharmacovigilance study. Psycho pharmacology 2023;240(1):199–202. doi: 10.1007/s00213-022-06293-4

37. Skryabin VY, Martinotti G, Franck J, Zastrozhin MS. Acute alcoholic hallucinosis: A review. Psychopathol ogy. 2023;56(5):383–390. doi: 10.1159/000528573

38. Celik M, Gold MS, Fuehrlein B. A narrative review of current and emerging trends in the treatment of alcohol use disorder. Brain Sci. 2024;14(3):294. doi: 10.3390/brainsci14030294

39. Barabassy A, Dombi ZB, Csehi R, Djuric D. Navigating Schizophrenia Treatment: Balancing Symptom Re lief and Long-Term Needs. 2024. doi: 10.5772/inte chopen.1005488

40. Ward K, Citrome L. Tolerability and safety outcomes of first-line oral second-generation antipsychotics in patients with schizophrenia. Expert Opin Drug Saf. 2024;23(4):399–409. doi: 10.1080/14740338.2024.2328812

41. Chiappini S, Cavallotto C, Mosca A, Di Carlo F, Piro T, Giovannetti G, ... Martinotti G. Investigating the effectiveness of brexpiprazole in subjects with schizophrenia spectrum illness and co-occurring substance use disorder: a prospective, multicentric, real-world study. Pharmaceuticals. 2024;17(4):535. doi: 10.3390/ph17040535

42. Martinotti G, Orsolini L, Fornaro M, Vecchiotti R, De Berardis D, Iasevoli F, Di Giannantonio M. Aripipra zole for relapse prevention and craving in alcohol use disorder: current evidence and future perspectives. Expert Opin Investig Drugs. 2016;25(6):719–728. doi: 10.1080/13543784.2016.1175431

43. Pirc Marolt T, Kramar B, Bulc Rozman K, Šuput D, Mil isav I. Aripiprazole reduces liver cell division. Plos one. 2020;15(10);e0240754. doi: 10.1371/journal.pone.0240754

44. Lombardozzi G, Trovini G, Amici E, Kotzalidis GD, Per rini F, Giovanetti V, De Filippis S. Brexpiprazole in pa tients with schizophrenia with or without substance use disorder: an observational study. Front Psychiatry. 2023;14:1321233. doi: 10.3389/fpsyt.2023.1321233

45. Stahl SM. Mechanism of action of cariprazine. CNS spectr. 2016;21(2):123–127. doi: 10.1017/ S1092852916000043 46. Grunze H. The role of the D3 dopamine receptor and its partial agonist cariprazine in patients with schizophrenia and substance use disorder. Expert Opin Pharmacother2023;24(18):1985–1992. doi: 10. 1080/14656566.2023.2266359

46. Yuan S, Jiang SC, Zhang ZW, Li ZL, Hu J. Substance Addiction Rehabilitation Drugs. Pharmaceuticals. 2024;17(5):615. doi: 10.3390/ph17050615

47. Szerman N, Vega P, Roncero C, Peris L, Grau-López L, Basurte-Villamor I. Cariprazine as a maintenance treatment in dual schizophrenia: a 6-month obser vational study in patients with schizophrenia and cannabis use disorder. Int Clin Psychopharmacol 2024;10:1097. doi: 10.1097/YIC.0000000000000568

48. Fountoulakis KN, Ioannou M, Tohen M, Haarman BC, Zarate JrCA. Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties: A hypothesis based on data. Eur Neu ropsychopharmacol.. 2023;72:30–39. doi: 10.1016/j.euroneuro.2023.03.009

49. Galaj E, Newman AH, Xi ZX. Dopamine D3 recep tor-based medication development for the treat ment of opioid use disorder: Rationale, progress, and challenges. Neurosci Biobehav Rev. 2020;114:38–52. doi: 10.1016/j.neubiorev.2020.04.024

50. Truong TT, Li B. Case series: cariprazine for treatment of methamphetamine use disorder. The Am J Addict. 2022;316(1):85–88. doi: 10.1111/ajad.13241

51. Gogarnoiu ES, Vogt CD, Sanchez J, Bonifazi A, Saab E, Shaik AB, Newman AH. Dopamine D3/D2 receptor ligands based on cariprazine for the treatment of psychostimulant use disorders that may be dual diagnosed with affective disorders. J Med Chem. 2023:66(3):1809–1834. doi: 10.1021/acs.jmed chem.2c01624

52. Montero-Hernandez G, Alberdi-Páramo I, Pérez-Lom bardo M, Rodríguez-Quijano J, Pemán-Rodríguez J, Ibáñez-Vizoso JE. New drugs in the treatment of dual psychosis: use of cariprazine in schizophre nia, other psychotic disorders and use of cocaine. A case series in a specific outpatient psychiatric clinic for substance use disorders. Eur. Psychia try. 2024;67(S1):S294–S295. doi: 10.1192/j.eurp sy.2024.613

53. Ricci V, De Berardis D, Maina G. Third-generation antipsychotics and lurasidone in the treatment of substance-induced psychoses: A narrative review. Healthcare. MDPI, 2024;12(3):339. doi: 10.3390/healthcare12030339

54. Ricci V, De Berardis D, Martinotti G, Maina G. New insight in psychotic cannabis withdrawal: case series and brief overview. Riv Psichiatr.. 2024;59(6):316 321. doi: 10.1708/4386.43840

55. Uribe S. Substance Use Disorders and the Behavioral Effects of Novel and Existing Compounds. (Master’s thesis, Rowan University). 2022.

56. Grunze H. The role of the D3 dopamine receptor and its partial agonist cariprazine in patients with schizophrenia and substance use disorder. Expert Opin Pharmacother. 2023;24(18): 1985-1992. doi: 10. 1080/14656566.2023.2266359

57. Pejušković B, Munjiza Jovanović A, Pešić D. Exploring cariprazine as a treatment option for varied depres sion symptom clusters. Front Psychiatry. 2024 Sep 25;15:1442699. doi: 10.3389/fpsyt.2024.1442699 PMID: 39386892; PMCID: PMC11461305.