Metabolic Differentiation in Manic Episode of Bipolar Disorder Compared to Substance-Induced Psychosis and Substance Use Disorder Based on Serum Valproate Level

Abstract

Aim: Valproic acid (VPA) is primarily used in the treatment of epilepsy but also has uses in the treatment of manic episodes in bipolar disorder and substance use disorders. Manic episodes and psychosis may also affect hepatic clearance and drug distribution volume. The aim of this study was to assess the effect of mania and psychosis compared to substance use on VPA pharmacokinetics, specifically changes in total and unbound clearance. Material and Methods: Fifty patients with a manic episode of bipolar disorder, and 51 patients with substance use disorder, 38 of whom were considered as substance-induced psychosis, were included in this retrospective study. All patients received a constant dose of 1000 mg VPA daily for at least five days, and serum VPA concentrations were measured. Results: The mean serum levels of VPA were 59.2±17.4 μg/ml in the substance use disorder group, 60.9±13.5 μg/ml in the substance-induced psychosis group, and 61.8±13.7 μg/ml in the manic episode of bipolar disorder group. No significant difference was found between the groups (p=0.840). When considering substance use disorder and substance-induced psychosis as one group, the mean VPA level of 60.5±14.4 μg/ml in this group showed no significant difference compared to 61.8±13.7 μg/ml in the manic episode of bipolar disorder (p=0.630). Conclusion: After reaching steady-state plasma levels, no significant difference in serum VPA levels was observed between the three groups. This suggests that manic episodes do not lead to a significant increase in VPA metabolism compared to substance use disorder or substance-induced psychosis.

Keywords

• Serum valproate level
• manic episode of bipolar disorder
• substance use disorder
• substance induced psychosis

Bipolar Bozukluğun Manik Epizodunda, Maddeye Bağlı Psikoz ve Madde Kullanım Bozukluğu ile Karşılaştırıldığında Serum Valproat Düzeyine Göre Metabolik Farklılaşma

Abstract

Amaç: Valproik asit (VPA) öncelikle epilepsi tedavisinde kullanılır, ancak aynı zamanda bipolar bozukluktaki manik atakların ve madde kullanım bozukluklarının tedavisinde de kullanımları vardır. Manik ataklar ve psikoz hepatik klerensi ve ilaç dağıtım hacmini de etkileyebilir. Bu çalışmanın amacı, madde kullanımına kıyasla mani ve psikozun VPA farmakokinetiği, özellikle toplam ve bağlanmamış klerensteki değişiklikler üzerindeki etkisini değerlendirmektir. Gereç ve Yöntemler: Bu geriye dönük çalışmaya bipolar bozukluk manik atağı olan 50 hasta ve 38'i maddeye bağlı psikoz olarak değerlendirilen madde kullanım bozukluğu olan 51 hasta dahil edildi. Tüm hastalara en az beş gün boyunca sabit dozda günlük 1000 mg VPA verildi ve serum VPA konsantrasyonları ölçüldü. Bulgular: Ortalama serum VPA düzeyi madde kullanım bozukluğu grubunda 59,2±17,4 μg/ml, maddeye bağlı psikoz grubunda 60,9±13,5 μg/ml ve bipolar bozukluğun manik döneminde ise 61,8±13,7 μg/ml idi. Gruplar arasında anlamlı bir fark bulunamadı (p=0,840). Madde kullanım bozukluğu ve maddeye bağlı psikoz tek grup olarak ele alındığında bu grupta ortalama 60,5±14,4 μg/ml olan VPA düzeyi, bipolar bozukluğun manik dönemindeki 61,8±13,7 μg/ml ile karşılaştırıldığında anlamlı bir fark göstermedi (p=0,630). Sonuç: Kararlı durum plazma seviyelerine ulaştıktan sonra, üç grup arasında serum VPA seviyelerinde anlamlı bir fark gözlenmedi. Bu, mani epizodunun madde kullanım bozukluğu veya maddeye bağlı psikoz ile karşılaştırıldığında VPA metabolizmasında anlamlı bir artışa yol açmadığını düşündürmektedir.

Keywords

• Serum valproat düzeyi
• bipolar bozukluğun manik dönemi
• madde kullanım bozukluğu
• maddeye bağlı psikoz

References

1. Calabresi P, Galletti F, Rossi C, Sarchielli P, Cupini LM. Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms. Trends Pharmacol Sci. 2007;28(4):188-95.
2. Emrich HM, von Zerssen D, Kissling W, Möller HJ. Therapeutic effect of valproate in mania. Am J Psychiatry. 1981;138(2):256.
3. Longo LP, Campbell T, Hubatch S. Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. J Addict Dis. 2002;21(2):55-64.
4. Myrick H, Henderson S, Brady KT, Malcom R, Measom M. Divalproex loading in the treatment of cocaine dependence. J Psychoactive Drugs. 2001;33(3):283-7.
5. Wulff K, Flachs H, Würtz-Jorgensen A, Gram L. Clinical pharmacological aspects of valproate sodium. Epilepsia. 1977;18(2):149-57.
6. Cramer JA, Mattson RH, Bennett DM, Swick CT. Variable free and total valproic acid concentrations in sole- and multi-drug therapy. Ther Drug Monit. 1986;8(4):411-5.
7. Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2013;23(4):236-41.
8. Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364.

9. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695-714.
10. Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: Prevalence, psychobiology, and treatment issues. J Affect Disord. 2002;68(1):1-23.
11. Chen G, Yuan PX, Jiang YM, Huang LD, Manji HK. Lithium increases tyrosine hydroxylase levels both in vivo and in vitro. J Neurochem. 1998;70(4):1768-71.
12. Johannessen CU. Mechanisms of action of valproate: a commentatory. Neurochem Int. 2000;37(2-3):103-10.
13. Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E. Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res. 2005;39(4):355-63.
14. Wang HY, Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorders brains. Biol Psychiatry. 1996;40(7):568-75.
15. Wang HY, Friedman E. Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes. Neuropharmacology. 1999;38(3):403-14.
16. Wang HY, Friedman E. Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder. Biol Psychiatry. 2001;50(5):364-70.
17. Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA. Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl). 2006;184(1):122-9.
18. Bosetti F, Bell JM, Manickam P. Microarray analysis of rat brain gene expression after chronic administration of sodium valproate. Brain Res Bull. 2005;65(4):331-8.
19. Tang Y, Glauser TA, Gilbert DL, Hershey AD, Privitera MD, Ficker DM, et al. Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study. Acta Neurol Scand. 2004;109(3):159-68.
20. Romão J, Gonçalves M, Ribeiro M, André R, Saraiva R, Abreu M. Growing use of valproic acid in substance use disorders. Eur Psychiatry. 2022;65(Suppl 1):S243-4.
21. Leufkens HG, Urquhart J. Variability in patterns of drug usage. J Pharm Pharmacol. 1994;46(Suppl 1):433-7.
22. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posy LM. Pharmacotherapy: A pathophysiologic approach. 6th ed. New York: McGraw-Hill; 2005.
23. Mohammadpour AH, Foroughipour M, Azarpazhooh MR, Khayat MH, Rezaee S, Aghebati T, et al. Comparison of valproic acid clearance between epileptic patients and patients with acute mania. Iran J Basic Med Sci. 2011;14(6):546-50.
24. Sanaee F, Clements JD, Waugh AW, Fedorak RN, Lewanczuk R, Jamali F. Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity. Br J Clin Pharmacol. 2011;72(5):787-97.
25. Al-Quteimat O, Laila A. Valproate interaction with carbapenems: Review and recommendations. Hosp Pharm. 2020;55(3):181-7.
26. Allen MH, Hirschfeld RM, Wozniak PJ, Baker JD, Bowden CL. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry. 2006;163(2):272-5.
27. Akhondzadeh S, Mohajari H, Reza Mohammadi M, Amini H. Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial. BMC Psychiatry. 2003;3:7.
28. Nasreddine W, Dirani M, Atweh S, Makki A, Beydoun A. Determinants of free serum valproate concentration: A prospective study in patients on divalproex sodium monotherapy. Seizure. 2018;59:24-7.
29. Methaneethorn J. A systematic review of population pharmacokinetics of valproic acid. Br J Clin Pharmacol. 2018;84(5):816-34.
30. Centorrino F, Bladessarini RJ, Kando J, Frankenburg FR, Volpicelli SA, Puopolo PR, et al. Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. Am J Psychiatry.1994;151(1):123-5.
31. Boulton DW, Kollia GD, Mallikaarjun S, Kornhauser DM. Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole. J Clin Pharm Ther. 2012;37(5):565-70.
32. Gfroerer J, Dube SR, King BA, Garrett BE, Babb S, McAfee T; Centers for Disease Control and Prevention (CDC). Vital signs: Current cigarette smoking among adults aged ≥18 years with mental illness - United States, 2009-2011. MMWR Morb Mortal Wkly Rep. 2013;62(5):81-7.
33. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199-216.
34. Morrison G, Crockett J, Blakey G, Sommerville K. Phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin Pharmacol Drug Dev. 2019;8(8):1009-31.
35. Machino A, Jitsuiki H, Okamoto Y, Izumitani S, Kimura Y, Suzuki K, et al. The valproate serum level in maintenance therapy for bipolar disorder in Japan. Hiroshima J Med Sci. 2013;62(1):7-12.
36. Yee CS, Vázquez GH, Hawken ER, Biorac A, Tondo L, Baldessarini RJ. Long-term treatment of bipolar disorder with valproate: updated systematic review and meta-analyses. Harv Rev Psychiatry. 2021;29(3):188-95.
37. Vasudev K, Sharma P. Is valproate depressogenic in patients remitting from acute mania? Case Series. Case Rep Psychiatry. 2015;2015:456830.
38. Hsueh YS, Lin CY, Chiu NT, Yang YK, Chen PS, Chang HH. Changes in striatal dopamine transporters in bipolar disorder and valproate treatment. Eur Psychiatry. 2021;64(1):e9.
39. Ho AM, Coombes BJ, Nguyen TTL, Liu D, McElroy SL, Singh B, et al. Mood-stabilizing antiepileptic treatment response in bipolar disorder: a genome-wide association study. Clin Pharmacol Ther. 2020;108(6):1233-42.