Features of Inflammatory Response in Juvenile Depression with Attenuated Symptoms of Schizophrenic Spectrum

Background: early nosological qualification of juvenile depression and detection in its structure of specific phenomena of schizophrenic spectrum makes it possible to identify the onset of an endogenous process and to provide timely therapeutic intervention. This becomes possible using an integrated approach based on a psychopathological assessment of patients and the determination of individual immunological indicators of blood.

The objective: to determine the inflammation markers in patients with juvenile depression with attenuated symptoms of schizophrenic spectrum (ASSS) in relation to features of their clinical manifestation and response to therapy.

Patients and methods: 50 patients aged 16 to 25 years with fi rst depressive episode with ASSS (F32.1, F32.2, F32.28, F32.8), of which 26 patients with attenuated psychotic symptoms (APS) and 24 ones with attenuated negative symptoms (ANS). The control group consisted of 19 mentally healthy volunteers. The leukocyte elastase (LE) and D1-proteinase inhibitor (D1-PI) activity and the level of autoantibodies (AB) to S100E and MBP were measured in blood plasma. The ratio of LE to D1-PI activity was defined as a leukocyte-inhibitory index (LII). Clinical and psychometric assessment (HDRS, SOPS, SANS scales) as well as immunological examination were carried out at admission to the hospital and at discharge.

Results: the differences revealed in profiles of immunological parameters in patients with juvenile depression with ASSS reflect the different variants of the inflammatory response to pathological process. Regardless of the identified clinical group, only 24% of patients were characterized by a balanced immune response. The inflammatory response in 76% of cases was accompanied by varying degrees of insufficiency of neutrophils functional activity and an increase in D1-PI activity, i.e. reduced LII. In 44% of cases, a decrease in LII was also accompanied by an increase in the level of AB to S100E. The relationship between immunological profiles and clinical severity of depression with APS and ANS was confirmed. The patients with balanced immune response without an autoimmune component have the best therapeutic response.

Conclusions: the results extend the concepts of the pathogenetic mechanisms of juvenile depression with ASSS and indicate various variants of inflammatory response associated with this pathological condition. Immunological analysis complements the clinical examination of patients in terms of assessing the severity of condition, prediction of the disease course and response to therapy.

1. Fusar-Poli P, Salazar de Pablo G, Correll CU, Meyer-Lindenberg A, Millan MJ, Borgwardt S, Galderisi S, Bechdolf A, Pfennig A, Vedel Kessing L, van Amelsvoort T, Nieman DH, Domschke K, Krebs M-O, Koutsouleris N, McGuire P, Do KQ, Arango C. Prevention of psychosis: advances in detection, prognosis, and intervention. JAMA Psychiatry. 2020;77(7):755–765. doi: 10.1001/ jamapsychiatry.2019.4779

2. Kahn RS, Keefe RSE. Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry. 2013;70(10):1107–1112. doi: 10.1001/jamapsychiatry.2013.155

3. Miettunen J, Immonen J, McGrath J, Isohanni M, Jaaskelainen E. The age of onset of schizophrenia spectrum disorders. In: Girolamo G, McGorry P, Sartorius N. Age of Onset of Mental Disorders. Springer. 2019:55–74. doi: 10.1093/schbul/sby017.659

4. Kline E, Seidman L, Cornblatt B, Woodberry K, Bryant C, Bearden C, Cadenhead K, Cannon T, Mathalon D, McGlashan T, Perkins D, Tsuang M, Walker E, Woods S. Addington J. Depression and clinical highrisk states: Baseline presentation of depressed vs. non-depressed participants in the NAPLS-2 cohort. Schizophrenia Research. 2018;192:357–363. doi: 10.1016/j.schres.2017.05.032

5. Fusar-Poli P. Integrated mental health services for the developmental period (0 to 25 Years): a critical review of the evidence. Frontiers in Psychiatry. doi: 10.3389/fpsyt.2019.00355

6. Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg, A, Weinberger DR, Cannon TD, O’Donovan M, Correll CU, Kane JM, Van Os J, Insel TR. Schizophrenia. Nature Reviews Disease Primers. 2015;1:15067. doi: 10.1038/ nrdp.2015.67

7. Miller BJ, Goldsmith DR. Towards an immunophenotype of schizophrenia: progress, potential mechanisms, and future directions. Neuropsychopharmacology. 2017;42(1):299–317. doi: 10.1038/npp.2016.211

8. Trovão N, Prata J, VonDoellinger O, Santos S, Barbosa M, Coelho R. Peripheral biomarkers for fi rst-episode psychosis — opportunities from the neuroinfl ammatory hypothesis of schizophrenia. Psychiatry Investig. 2019;16(3):177–184. doi: 10.30773/pi.2018.12.19.1

9. Maj C, Tosato S, Zanardini R, Lasalvia A, Favaro A, Leuci E, De Girolamo G, Ruggeri M, Gennarelli M. Correlations between immune and metabolic serum markers and schizophrenia/bipolar disorder polygenic risk score in first-episode psychosis. Early Intervention in Psychiatry. 2020;14:507–511. doi: 10.1111/eip.12906

10. Kopczynska M, Zelek W, Touchard S, Gaughran F, Di Forti M, Mondelli M, Murray R, O’Donovan MC, PaulMorgan B. Complement system biomarkers in first episode psychosis. Schizophrenia Research. 2019;204:16–22. doi: 10.1016/j.schres.2017.12.012

11. Klyushnik TP, Zozulya SA, Androsova LV, Sarmanova ZV, Otman IN, Dupin AM, Panteleeva GP, Oleichik IV, Abramova LI, Stoliarov SA, Shipilova ES, Borisova OA. Immunological monitoring of endogenous attack-like psychoses. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2014;114(2):37–41. (In Russ.). eLIBRARY ID: 21203410

12. Safarova TP, Yakovleva OB, Androsova LV, Simonov AN, Klyushnik TP. Some infl ammatory factors and immunophenotypes in depression in elderly patients. S.S. Korsakov Journal of Neurology and Psychiatry/ Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2020;120(2):53–58. (In Russ.). doi: 10.17116/jnevro202012002153

13. Zozulya SA, Otman I., Oleichik IV, Anikhovskaya IA, Yakovlev MYu, Klyushnik TP. Conjugacy between processes of systemic infl ammation and systemic endotoxinemia in endogenous psychoses. Siberian Herald of Psychiatry and Addiction Psychiatry. 2020;3(108):17–27. (In Russ.). doi: 10.26617/18103111-2020-3(108)-17-27

14. Kaleda VG, Kliushnik TP, Sarmanova ZV, Otman IN, Dupin AM. Correlations between clinical and immunological parameters in endogenous psychoses with a fi rst episode at the juvenile age. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2009;109(1):16–19. (In Russ.). eLIBRARY ID: 13123343

15. Zozulya SA, Sizov S, Oleichik IV, Klyushnik TP. Clinico-psychopathological and immunological parameters of manic-delusional (including manic-paraphrenic) conditions with grandiose delusion. Social and Clinical Psychiatry. 2019;29(4):5–13. (In Russ.). eLIBRARY ID: 41436104

16. Carrion R, Demmin D, Author A, McLaughlin D, Olsen R, Lencz T, Correll C, Cornblatt B. Duration of attenuated positive and negative symptoms in individuals at clinical high risk: Associations with risk of conversion to psychosis and functional outcome. J. Psychiatr. Res. 2016;81:95–101. doi: 10.1016/j.jpsychires.2016.06.021

17. Dotsenko VL, Neshkova EA, Yarovaya GA. Detection of leukocyte elastase from complex with plasma D1-proteinase inhibitor by it enzymatic activity with a synthetic substrate. Voprosy meditsinskoi khimii. 1994;40(3):20–25. (In Russ.). eLIBRARY ID: 25312132

18. Nartikova VF, Paskhina TS. A unifi ed method for assay of D1-antitrypsin and D2-macroglobulin activity in human serum (plasma). Voprosy meditsinskoi khimii. 1979;25(4):494–499. (In Russ.). eLIBRARY ID: 18235618

19. Klyushnik TP, Zozulya SA, Androsova LV, Sarmanova ZV, Otman IN, Panteleeva GP, Oleichik IV, Kopeiko GI, Borisova OA, Abramova LI, Bologov PV, Stolyarov SA. Laboratory diagnostics in monitoring patients with endogenous psychosis (“Neuroimmune test”): Medical technology. 2nd ed., rev. and updated. Moscow: Publishing House Medical Information Agency, 2016:32. (In Russ.). eLIBRARY ID: 35086721

20. Manda-Handzlik A, Demkow U. The brain entangled: the contribution of neutrophil extracellular traps to the diseases of the central nervous system. Cells. 2019;8(12):1477. doi: 10.3390/cells8121477

21. Groutas WC, Dou D, Alliston KR. Neutrophil elastase inhibitors. Expert Opin. Ther. Pat. 2011;21(3):339– 354. doi: 10.1517/13543776.2011.551115

22. Paramonova NS, Gurina LN, Volkova OA, Karchevsky AA, Sinitsa LN. Sostojanie jelastaza-ingibitornoj sistemy u detej v norme i pri otdel’nyh patologicheskih sostojanijah. Pod red. Paramonovoj N.S. Grodno: Izdatel’stvo GrGMU; 2017:132. (In Russ.). eLIBRARY ID: 36441092

23. Simonov AN, Klyushnik TP, Zozulya SA. Evidence-based psychiatry: paraclinical diagnostics of asthenic syndrome in schizophrenia based on the determination of leukocyte-inhibitory index. Psychiatry (Moscow) (Psikhiatriya). 2020;18(2):6–12. (In Russ.). doi: 10.30629/2618-6667-2020-18-2-6-12

24. Pollak TA, Rogers JP, Nagele RG, Peakman M, Stone JM. Anthony S, David AS., McGuire P. Antibodies in the diagnosis, prognosis, and prediction of psychotic disorders. Schizophrenia Bulletin. 2019;45(1):233–246. doi: 10.1093/schbul/sby021

25. Klyushnik TP, Androsova LV, Zozulya SA, Otman IN, Nikitina VB, Vetlugina TP. Comparative analysis of infl ammatory markers in endogenous and nonpsychotic mental disorders. Siberian Bulletin of Psychiatry and Narcology. 2018;2(99):64–69. (In Russ.). doi: 10.26617/1810-3111-2018-2 (99)-64-69

26. Nazarov PG. Acute inflammatory phase reactants. Spb.: Nauka, 2001:423. (In Russ.). eLIBRARY ID: 23633301.

27. Yakimets AV, Zozulya SA, Oleichik IV, Klyushnik TP. Features of the dynamics of clinical and biological indicators of the asthenic symptom complex in patients with schizophrenia during immunotropic therapy. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2018;118(3):70–76. (In Russ.). doi: 10.17116/jnevro20181183170-76