An Open Comparative Randomized Study of the Effectiveness and Safety of Risperidone and Sodium Valproate for Secondary Prevention of Relapses of Bipolar Disorder I for 24 Months

Background: Comparative studies of monotherapy with second-generation antipsychotics (SGA) or mood stabilizers in the prevention therapy of Bipolar Disorder (BD) relapses, including those with psychotic symptoms, have not been conducted. Objective: a comparative study of the clinical features of risperidone (RIS) and sodium valproate (SV) in the prevention of relapses of BD. Patients and methods: 96 patients with BD-I (F31, ICD-10) were included, the duration of the disease was at least 2 years, the presence of at least two affective episodes (including psychotic symptoms). Design — open comparative randomized study. Study duration was 24 months. Patients were sequentially divided into groups of RIS and SV, comparable in the number of patients, clinical and sociodemographic indicators. The effectiveness of therapy was determined by comparing the indicators of the dynamics of the course of the disease for 2 years preceding the start of therapy (control period) and 2 years after the treatment beginning. Results: 14 patients dropped out in the first month after the start of therapy due to adverse events, 82 completed the study. The total duration of episodes decreased by 40-60%, the frequency — by 37.2% — 43.3% (p ≤ 0.05). The proportion of responders in the RIS group was 78.1%, SV — 68.3%. Complete suppression of phase formation was observed in 43.75% in the RIS group, in 10.7% — in the SV group. In the RIS group, the total duration of depressive episodes decreased by 38.3% (NS), manic by 65.2% (p ≤ 0.001), in the SV group — by 31.9% (NS) and by 52.9% (p ≤ 0.05), respectively. As to BD with psychotic symptoms, 85% of respondents were in the RIS group, and 50% were in the SV group. The average number of adverse events per patient in the group of SV was 0.9, RIS — 2.1. Conclusions: SV and RIS are comparable in effectiveness with better tolerance of SV. In patients with psychotic symptoms, the effectiveness of RIS was higher than that of SV.

1. Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994;31(4):281-294. doi: 10.1016/0165-0327(94)90104-x PMiD: 7989643

2. Mosolov CN, Kostyukova EG, Kuzavkova MV. Bipolyarnoe affektivnoe rasstroistvo. Diagnostika i terapiya. M: Medpressinform, 2008. (in Russ.).

3. Suppes T, Leverich GS, Keck PE, Nolen WA, Denicoff KD, Altshuler LL, McElroy SL, Rush AJ, Kupka R, Frye MA, Bickel M, Post RM. The Stanley Foundation Bipolar Treatment Outcome Network. ii. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1-3):45-59. doi: 10.1016/s0165-0327(01)00432-3 PMiD: 11869752

4. Morozova MA, Potanin SS, Burminskiy DS, Rupchev GE, Beniashvili AG, Lepilkina TA. impulsivity in Bipolar Affective Disorder: Prevalence and Comorbidity. Psychiatry (Moscow) (Psikhiatriya). 2022;20(1):97-109. (in Russ.). doi: 10.30629/2618-6667-2022-20-1-97109

5. Gignac A, McGirr A, Lam RW, Yatham LN. Recovery and recurrence following a first episode of mania: a systematic review and meta-analysis of prospectively characterized cohorts. J Clin Psychiatry. 2015;76(9):1241-1248. doi: 10.4088/JCP.14r09245 PMiD: 25845021

6. Kostyukova EG. Rasshirenie pokazanii antipsikhotikov vtorogo pokoleniya: ot shizofrenii k bipolyarnomu affektivnomu rasstroistvu. Sovremennaya terapiya psikhicheskikh rasstroistv. 2020;(3):29-37. (in Russ.). doi: 10.21265/PSYPH.2020.79.73.004

7. Mosolov SN. Polveka neirolepticheskoi terapii: osnovnye itogi i novye rubezhi. V kn.: Novye dostizheniya v terapii psikhicheskikh zabolevanii. M., 2002:47-81. (In Russ.).

8. Zarate CA Jr, Tohen M, Banov MD, Weiss MK, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry. 1995;56(3):108-112. PMID: 7883728

9. Lindstrom L, Lindstrom E, Nilsson M, Hoistad M. Maintenance therapy with second generation antipsychotics for bipolar disorder — A systematic review and meta-analysis. J Affect Disord. 2017;213:138-150. doi: 10.1016/j.jad.2017.02.012 Epub 2017 Feb 14. PMID: 28222360

10. Macfadden W, Alphs L, Haskins JT, Turner N, Turkoz I, Bossie C, Kujawa M, Mahmoud R. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11(8):827-839. doi: 10.1111/j.1399-5618.2009.00761.x PMID: 19922552

11. Jauhar S, Young AH. Controversies in bipolar disorder; role of second-generation antipsychotic for maintenance therapy. Int J Bipolar Disord. 2019;7(1):10. doi: 10.1186/s40345-019-0145-0 PMID: 30915592; PMCID: PMC6435763

12. Quiroz JA, Yatham LN, Palumbo JM, Karcher K, Kushner S, Kusumakar V. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry. 2010;68(2):156-162. doi: 10.1016/j.biopsych.2010.01.015 Epub 2010 Mar 15. PMID: 20227682

13. Vieta E, Montgomery S, Sulaiman AH, Cordoba R, Hu-berlant B, Martinez L, Schreiner A. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol. 2012;22(11):825-835. doi: 10.1016/j.euroneuro.2012.03.004 Epub 2012 Apr 12. PMID: 22503488

14. Vieta E, Herraiz M, Parramon G, Goikolea JM, Fernandez A, Benabarre A. Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre, open study in Spain. J Affect Disord. 2002;72(1):15-19. doi: 10.1016/s0165-0327(01)00481-5 PMID: 12204313

15. Yatham LN, Beaulieu S, Schaffer A, Kauer-Sant'Anna M, Kapczinski F, Lafer B, Sharma V, Parikh SV, Daigneault A, Qian H, Bond DJ, Silverstone PH, Walji N, Milev R, Baruch P, da Cunha A, Quevedo J, Dias R, Kunz M, Young LT, Lam RW, Wong H. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial. Molecular Psychiatry 2016;21:1050-1056. doi: 10.1038/mp.2015.158 published online 13 October 2015.

16. Ghaemi SN, Sachs GS. Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol. 1997;12(6):333-338. doi: 10.1097/00004850-199711000-00006 PMID: 9547135

17. Fountoulakis KN, Nimatoudis I, Iacovides A, Kaprinis G. Report of three cases that received maintenance treatment with risperidone as a mood stabilizer. Ann Gen Hosp Psychiatry. 2004;3(1):10. doi: 10.1186/14752832-3-10 PMID: 15163347; PMCID: PMC420474

18. Ghaemi SN, Hsu DJ, Rosenquist KJ, Katzow JJ, Goodwin FK. Long-term observational comparison of risperidone and olanzapine in bipolar disorder. Ann Clin Psychiatry. 2004;16(2):69-73. doi: 10.1080/10401230490453103 PMID: 15328900

19. Yoshimura R, Ueda N, Shinkai K, Nakamura J. Two cases of bipolar disorder successfully stabilized for five years with a low dose of risperidone and lithium. Pharmacopsychiatry. 2006;39(6):233-234. doi: 10.1055/s-2006-951386 PMID: 17124648

20. Mosolov SN, Kostyukova EG. Bipolyarnoe affektivnoe rasstroistvo. V kn.: Natsional'noe rukovodstvo. Psikhiatriya. Ed. Yu.A. Aleksandrovskiy, N.G. Neznanov. M.: Geotar Media, 2018:704-799. (In Russ.).

21. Mosolov SN, Kostyukova EG, Kuzavkova MV. Profilakticheskoe primenenie antikonvul'santov pri fazno-protekayushchikh endogennykh psikhozakh (sravnitel'noe izuchenie karbamazepina, val'proata natriya i solei litiya). V kn. Antikonvul'santy v psikhiatricheskoi i nevrologicheskoi praktike. Ed. AM Vein, SN Mosolov. SPb.: Meditsinskoe informatsionnoe agentstvo, 1994:72-128. (In Russ.).

22. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000;57(5):481-489. doi: 10.1001/archpsyc.57.5.481 PMID: 10807488

23. Gyulai L, Bowden CL, McElroy SL, Calabrese JR, Petty F, Swann AC, Chou JC, Wassef A, Risch CS, Hirschfeld RM, Nemeroff CB, Keck PE Jr, Evans DL, Wozniak PJ. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28(7):1374-1382. doi: 10.1038/sj.npp.1300190 Epub 2003 May 28. PMID: 12784116

24. Post RM, Roy-Byrne PP, Uhde TW. Graphic representation of the life course of illness in patients with affective disorder. Am. J. Psychiatry 1988;145:844-848. doi: 10.1176/ajp.145.7.844

25. Mosolov SN. Sravnitel'naya effektivnost' profilakticheskogo primeneniya karbonata litiya, karbamazepina, val'proata natriya pri affektivnykh i shizoaffektivnykh psikhozakh. Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova. 1991;(4):78-83. (In Russ.).

26. Mosolov SN. Khronobiologicheskie aspekty normotimicheskogo deistviya antikonvul'santov i solei litiya (eksperimental'noe i klinicheskoe polisomnograficheskoe issledovanie). V kn.: Antikonvul'santy v psikhiatricheskoi i nevrologicheskoi praktike. Ed. AM Vein, SN Mosolov. SPb.: Meditsinskoe informatsionnoe agentstvo, 1994:129-252. (In Russ.).

27. Kuzavkova MV. Kliniko-farmakokineticheskii prognoz effektivnosti normotimikov pri vtorichnoi profilaktike faznoprotekayushchikh endogennykh psikhozov: avtoref. dis. ... k.m.n. М., 2001:17 p.