The Risk of Endocrine Dysfunction and Metabolic Disorders Antipsychotics in Patients with Schizophrenia during Therapy with Second-Generation

Background: efficacy of atypical antipsychotics in relation to cognitive functions and negative symptoms of schizophrenia, their better safety profile in relation to extrapyramidal symptoms compared with first-generation antipsychotics, accompanied by the frequent occurrence of endocrine and metabolic disorders, which can lead to both low adherence to therapy and reduction in life expectancy. Early diagnosis of these disorders, as well as the development of therapeutic tactics would minimize manifestations of endocrine and metabolic imbalance. The aim of the study was to assess the risk of occurrence and severity of neuroendocrine dysfunction, metabolic disorders in the treatment of patients with schizophrenia with second-generation antipsychotics. Patients and Methods: 76 inpatient patients (43 men and 33 women) aged 18 to 70 years with a diagnosis of paranoid schizophrenia (ICD-10 F20.0) and a positive response to the courses of therapy (at least 30% reduction of the total score on the PANSS scale) were examined. 3 groups of patients who received monotherapy with one of the atypical antipsychotics of the second generation (quetiapine, olanzapine, risperidone) were formed. The studied drugs were either prescribed for the first time upon admission, or were already prescribed before, and dose adjustments was carried out due to an exacerbation of the condition. The duration of the study was 10 weeks (70 days). Clinical and psychopathological, psychometric (PANSS, UKU), anthropometric, laboratory and statistical methods were used. Results: differences in prolactin levels in the studied respondent patients were established depending on the second-generation antipsychotic used for the course of monotherapy. The index of prolactin level during risperidone monotherapy was M ± m = 1401 ± 91 µm/ml, which was twice the upper limit of the physiological norm (M ± m = 96–637 µm/ml). Manifestations of hyperprolactinemia were less with olanzapine monotherapy (M ± m = 781 ± 52 µm/ml). The lowest prolactin level, which corresponded to the norm, was found in the quetiapine monotherapy group (M ± m = 422 ± 48 µm/ml). Changes in prolactin levels associated with the gender of patients were found in the form of a stable tendency to a more pronounced increase in female patients. The greatest statistically significant weight gain (p < 0.5) was recorded in patients receiving olanzapine monotherapy, slightly less when using risperidone and minimal when taking quetiapine (4.9 ± 1.8 kg 3.3 ± 1.1 kg and 0.8 ± 0.3 kg, respectively). The average value of the atherogenicity coefficient at the end of the courses of monotherapy with olanzapine and risperidone exceeded its normative level (3.8 ± 0.4 and 3.4 ± 0.5, respectively). Conclusions: the changes in the endocrine and metabolic profile confirm the results of previous studies. Regular monitoring of anthropometric and laboratory parameters both before and during antipsychotic therapy is recommended as a secondary prevention.

1. Kachanov DA, Usov SA, Molchanov AI. Comparative pharmacological characterization of selected antipsychotic agents. Ural Medical Journal. 2019;5(183):173–177. (In Russ.). doi: 10.25694/URMJ.2019.15.35

2. Kravchenko IV, Chizhikov AI, Lvov NN. Comparative analysis of the effectiveness of neuroleptics in paranoid schizophrenia patients with tonic type of defect and non-suicidal autoaggressive actions under compulsory treatment. Social and Clinical Psychiatry. 2022;32(2):59–64. (In Russ.).

3. Antokhin EY, Vasilieva AV, Antokhina RI. Clinical efficacy, tolerability and effect of cariprazine and olanzapine on social functioning in the therapy of patients with depressive syndrome after the first episode of schizophrenia. Current Therapy of Mental Disorders. 2024;(1):11–23. (In Russ.). doi: 10.21265/PSYPH.2022.60.1.003

4. Stanovaya VV, Ivanov MV. Strategies for correction of antipsychotic-induced hyperprolactinemia. Current Therapy of Mental Disorders. 2022;(1):20–31. (In Russ.). doi: 10.21265/PSYPH.2022.60.1.003

5. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the cover: antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc. Natl. Acad. Sci. U. S. A. 2007;104(9):3456–3459. doi: 10.1073/pnas.0611417104

6. Singh R, Bansal Y, Medhi B, Kuhad A. Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol. 2019 Feb 5;844:231–240. doi: 10.1016/j.ejphar.2018.12.003 Epub 2018 Dec 7. PMID: 30529195.

7. Filileeva OV, Mosolov SN. Equivalent dosages of antipsychotic drugs. Current Therapy of Mental Disorders. 2019;(3):36–44.(In Russ.). doi: 10.21265/PSYPH.2019.49.35981

8. Skryabin VY, Masyakin AV, Nazimova SV. Pharmacoepidemiologic study of safety of antipsychotic drugs based on the analysis of spontaneous reports on the data of “Pharmacovigilance” subsystem. Clinical Pharmacology and Therapy. 2023;32(2):66–72. (In Russ.). doi: 10.32756/0869-5490-2023-2-66-72

9. Dorovskikh IV, Pavlova TA, Gorobets LN. Neuroendocrine sanogenesis during long-term psychopharmacotherapy: predictors and basic mechanisms. Psychiatry and Psychopharmacotherapy. Gannushkin journal. 2021;23(3):56–61. (In Russ.).

10. Abramicheva PA, Smirnova OV. Prolactin receptor isoforms as a basis for tissue-specific diversity of its effects in norm and pathology. Biochemistry. 2019;84(4):461–480. (In Russ.). doi: 10.1134/S0320972519040018

11. Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry. 1999;60:215–220. doi: 10.4088/jcp.v60n0402

12. Evsegneev RA. Metabolic side effects of antipsychotic treatment. Psychiatry, Psychotherapy and Clinical Psychology. 2020;11(1):146–154. (In Russ.). doi: 10.34883/PI.2020.11.1.014

13. Balashova AV, Mamleeva DV, Machekhina LV, Dudinskaya EN. Metabolic consequences of antipsychotic therapy: state of the problem and possible solutions. Obesity and Metabolism. 2022;19(4):431– 441. (In Russ.). doi: 11.4341/omet12935

14. Chomsky AN. The nature of neuroendocrine dysfunctions in patients with schizophrenia respondent to atypical antipsychotics therapy Siberian herald of psychiatry and addiction psychiatry. 2008;2(49):118–119.

15. Kolesnikova GS, Malysheva NM, Zuraeva ZT, Nikankina LV, Melnichenko GA. Determination of prolactin reference intervals for different age groups. Problems of Endocrinology. 2023;69(3):16–23. (In Russ.). doi: 10.14341/probl13095

16. Mosolov SN. Scales of psychometric assessment of schizophrenia symptomatology and the concept of positive and negative disorders. М., 200:238. (In Russ.).

17. Kay SR, Fiszbain A, Opler LA. Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull. 1987;13:261–276. doi: 10.1093/schbul/13.2.261

18. Nazarenko GI, Andropova OV. The algorithmic model of laboratory diagnostics optimization. Rational Pharmacotherapy in Cardiology. 2007;3(4):46–50. (In Russ.).

19. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry. 2002;159(1):133–153. doi: 10.1176/appi.ajp.159.1.133

20. Byerly M, Suppes T, Tran QV. Clinical implications of anti-psychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and cur-rent perspectives. J Clin Psychopharmacol. 2007;27:639– 661. doi: 10.1097/jcp.0b013e31815ac4e5

21. Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics — a review. Hum. Psychopharmacol. Clin. Exp. 2010;25:281–297. doi: 10.1002/hup.1116

22. Inder WJ, Castle D. Antipsychotic-induced hyperprolactinaemia. Aust N Z J Psychiatry. 2011;45:830–837. doi: 10.3109/00048674.2011.589044

23. Gorobets LN., Mazo GE. Hyperprolactinemia during application of second-generation antipsychotics: the principles of prevention, diagnosis and correction. V.M. Bekhterev Review of Psychiatry and Medical Psychology. 2017;(1):63–69. (In Russ.).

24. Kornetova EG, Tiguntsev VV, Kornetov AN, Goncharova AA, Lobacheva OA, Davydov AA, Khardikova SA, Ivanova SA, Semke AV. Sexual differences in the clinical features ofantipsychotic-induced hyperprolactinemia in patients with schizophrenia. Bulletin of Siberian Medicine. 2019;18(3):62–71. doi: 10.20538/1682-0363-2019-3-62-71

25. Kornetova EG, Kornetov AN, Mednova IA, Dubrovskaya VV, Boiko AS, Bokhan NA, Loonen AJM, Ivanova SA. Changes in Body Fat and Related Biochemical Parameters Associated With Atypical Antipsychotic Drug Treatment in Schizophrenia Patients With or Without Metabolic Syndrome. Front. Psychiatry. 2019;10:803. doi: 10.3389/fpsyt.2019.00803

26. Dubrovskaya VV, Kornetova EG, Mednova IA, Dmitrieva EG, Lebedeva EV, Kornetov AN, Semke AV. Visceral obesity in patients with schizophrenia and associated metabolic syndrome receiving antipsychotic therapy. Psikhicheskoye zdorovie [Mental Health]. 2019;12:10–15. (In Russ.). doi: 10.25557/2074-014X-2019-12-10-15

27. Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin. Psychiatry. 2004;65(1):57–61. doi: 10.4088/jcp.v65n0109

28. Jen YW, Hwang TJ, Chan HY, Hsieh MH, Liu CC, Liu CM, Hwu HG, Kuo CH, Lin YT, Chien YL, Chen WJ. Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: A biomarker for rebound in psychotic symptoms. BMC Psychiatry. 2020;20(1):552–558. doi: 10.1186/s12888-020-02957-7

29. Colao A, di Sarno A, Pivonello R, di Somma C, Lombardi G. Dopamine receptor agonists for treating prolactinomas. Expert Opin Investig Drugs. 2002;11(6):787– 800. doi: 10.1517/13543784.11.6.787

30. Melkersson KI, Dahl ML, Hulting AL. Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose- insulin homeostasis and lipid metabolism. Psychopharmacology (Berl). 2004;175:1–6. doi: 10.1007/s00213-004-1922-7

31. Jiang WL, Cai DB, Yin F, Zhang L, Zhao XW, He J, Ng CH, Ungvari GS, Sim K, Hu ML, Zheng W, Xiang YT. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry. 2020;10(1):117. doi: 10.1038/s41398-020-0785-y PMID: 32327628; PMCID: PMC7181777.