Abstract
Rationale
: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined.
Objectives
To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients.
Methods
We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors.
Results
Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (β = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (β = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction.
Conclusions
This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.
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Data availability
The datasets supporting the findings and conclusions presented in this article can be obtained by reasonable request to the corresponding author.
References
American Psychiatric Association (2002) Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 159:1–50
Amitai M, Sachs E, Zivony A et al (2015) Effects of long-term valproic acid treatment on hematological and biochemical parameters in adolescent psychiatric inpatients. Int Clin Psychopharmacol 30:241–248. https://doi.org/10.1097/YIC.0000000000000084
Atmaca M (2009) Valproate and neuroprotective effects for bipolar disorder. Int Rev Psychiatry 21:410–413. https://doi.org/10.1080/09540260902962206
Azorin JM, Findling RL (2007) Valproate Use in Children and adolescents with bipolar disorder. CNS Drugs 21:1019–1033. https://doi.org/10.2165/00023210-200721120-00005
Baandrup L (2020) Polypharmacy in schizophrenia. Basic Clin Pharmacol Toxicol 126:183–192. https://doi.org/10.1111/bcpt.13384
Baldessarini RJ, Tondo L (2000) Does Lithium Treatment still work? Arch Gen Psychiatry 57:187. https://doi.org/10.1001/archpsyc.57.2.187
Baldwin DS, Kosky N (2007) Off-label prescribing in psychiatric practice. Adv Psychiatr Treat 13:414–422. https://doi.org/10.1192/apt.bp.107.004184
Ballon J, Stroup TS (2013) Polypharmacy for schizophrenia. Curr Opin Psychiatry 26:208–213. https://doi.org/10.1097/YCO.0b013e32835d9efb
Barnes TRE, Paton C (2011) Antipsychotic polypharmacy in Schizophrenia. CNS Drugs 25:383–399. https://doi.org/10.2165/11587810-000000000-00000
Bauer LA (2014) Applied Clinical Pharmacokinetics, 3rd edn. McGraw-Hill Education, New York
Bellver MJG, Sánchez MJG, Gonzalez ACA et al (1993) Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications. J Clin Pharm Ther 18:191–197. https://doi.org/10.1111/j.1365-2710.1993.tb00612.x
Bialer M (2007) Extended-release formulations for the treatment of Epilepsy. CNS Drugs 21:765–774. https://doi.org/10.2165/00023210-200721090-00005
Birkett DJ (1994) Pharmacokinetics made easy 9: non-linear pharmacokinetics. Aust Prescr 17
Blanco-Serrano B, Otero MJ, Santos-Buelga D et al (1999) Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data. Biopharm Drug Dispos 20:233–240. https://doi.org/10.1002/(sici)1099-081x(199907)20:5%3C233::aid-bdd179%3E3.0.co;2-5
Bréant V, Charpiat B, Sab JM et al (1996) How many patients and blood levels are necessary for population pharmacokinetic analysis? Eur J Clin Pharmacol 51:283–288. https://doi.org/10.1007/s002280050199
Bryson S, Verma N, Scott P, Rubin P (1983) Pharmacokinetics of valproic acid in young and elderly subjects. Br J Clin Pharmacol 16:104–105. https://doi.org/10.1111/j.1365-2125.1983.tb02151.x
Casey DE, Daniel DG, Wassef AA et al (2003) Effect of Divalproex combined with olanzapine or risperidone in patients with an Acute Exacerbation of Schizophrenia. Neuropsychopharmacology 28:182–192. https://doi.org/10.1038/sj.npp.1300023
Citrome L (2003) Schizophrenia and valproate. Psychopharmacol Bull 37(Suppl 2):74–88
Cloyd JC, Fischer JH, Kriel RL, Kraus DM (1993) Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 53:22–29. https://doi.org/10.1038/clpt.1993.5
Correa T, Rodríguez I, Romano S (2008) Population pharmacokinetics of valproate in Mexican children with epilepsy. Biopharm Drug Dispos 29:511–520. https://doi.org/10.1002/bdd.636
Desoky EL, Fuseau ES, Din Amry EEL, Cosson S V (2004) Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients. Eur J Clin Pharmacol 59:783–790. https://doi.org/10.1007/s00228-003-0699-7
Dhillon S, Richens A (1981) Serum protein binding of diazepam and its displacement by valproic acid in vitro [letter]. Br J Clin Pharmacol 12:591–592. https://doi.org/10.1111/j.1365-2125.1981.tb01273.x
Dhillon S, Richens A (1982) Valproic acid and diazepam interaction in vivo. Br J Clin Pharmacol 13:553–560. https://doi.org/10.1111/j.1365-2125.1982.tb01421.x
Ding J, Wang Y, Lin W et al (2015) A Population Pharmacokinetic Model of Valproic Acid in Pediatric patients with Epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation. Clin Pharmacokinet 54:305–317. https://doi.org/10.1007/s40262-014-0212-8
Ette EI, Kelman AW, Howie CA, Whiting B (1995) Analysis of animal pharmacokinetic data: performance of the one point per animal design. J Pharmacokinet Biopharm 23:551–566. https://doi.org/10.1007/BF02353461
Fisher C, Broderick W (2003) Sodium valproate or valproate semisodium: is there a difference in the treatment of bipolar disorder? Psychiatr Bull 27:446–448. https://doi.org/10.1192/pb.27.12.446
Fleming J, Chetty M (2005) Psychotropic drug interactions with Valproate. Clin Neuropharmacol 28:96–101. https://doi.org/10.1097/01.wnf.0000154221.37887.73
Garnham J, Munro A, Slaney C et al (2007) Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J Affect Disord 104:185–190. https://doi.org/10.1016/j.jad.2007.03.003
Gibbs HG, Zimmerman DE, Shermock KM et al (2015) Comparison of free fraction serum valproic acid concentrations between inpatients and outpatients. Am J Health-System Pharm 72:121–126. https://doi.org/10.2146/ajhp140191
Grasela TH, Sheiner LB (1991) Pharmacostatistical modeling for observational data. J Pharmacokinet Biopharm 19:S25–S36. https://doi.org/10.1007/BF01371006
Gugler R, von Unruh GE (1980) Clinical pharmacokinetics of valproic Acid1. Clin Pharmacokinet 5:67–83. https://doi.org/10.2165/00003088-198005010-00002
Gunes A, Bilir E, Zengil H et al (2007) Inhibitory effect of Valproic Acid on Cytochrome P450 2C9 activity in Epilepsy patients. Basic Clin Pharmacol Toxicol 100:383–386. https://doi.org/10.1111/j.1742-7843.2007.00061.x
Haddad PM, Das A, Ashfaq M, Wieck A (2009) A review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol 5:539–551. https://doi.org/10.1517/17425250902911455
Hastie T, Tibshirani R (1987) Generalized additive-models - some applications. J Am Stat Assoc 82:371–386
Hiemke C, Bergemann N, Clement H et al (2018) Consensus guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 51:9–62. https://doi.org/10.1055/s-0043-116492
Iannaccone T, Sellitto C, Manzo V et al (2021) Pharmacogenetics of Carbamazepine and Valproate: focus on polymorphisms of drug metabolizing enzymes and transporters. Pharmaceuticals 14:204. https://doi.org/10.3390/ph14030204
Jankovic SM, Milovanovic JR (2007) Pharmacokinetic modelling of valproate from clinical data in Serbian epileptic patients. Methods Find Exp Clin Pharmacol 29:673. https://doi.org/10.1358/mf.2007.29.10.1116313
Jiang D, Wang L (2004) Population pharmacokinetic model of valproate and prediction of valproate serum concentrations in children with epilepsy. Acta Pharmacol Sin 25:1576–1583
Jiang D, Wang L, Wang Y et al (2007) Population pharmacokinetics of valproate in Chinese children with epilepsy. Acta Pharmacol Sin 28:1677–1684. https://doi.org/10.1111/j.1745-7254.2007.00704.x
Joint Formulary Committee (2012) British national formulary. Pharmaceutical
Jonsson EN, Wade JR, Karlsson MO (1996) Comparison of some practical sampling strategies for population pharmacokinetic studies. J Pharmacokinet Biopharm 24:245–263. https://doi.org/10.1007/BF02353491
Kang J-S, Lee M-H (2009) Overview of Therapeutic Drug Monitoring. Korean J Intern Med 24:1. https://doi.org/10.3904/kjim.2009.24.1.1
Karlsson Lind L, Komen J, Wettermark B et al (2018) Valproic acid utilization among girls and women in Stockholm: impact of regulatory restrictions. Epilepsia Open 3:357–363. https://doi.org/10.1002/epi4.12228
Kennedy D, Koren G (1998) Valproic acid use in psychiatry: issues in treating women of reproductive age. J Psychiatry Neurosci 23:223–228
Kondo T, Tokinaga N, Suzuki A et al (2002) Altered pharmacokinetics and Metabolism of Valproate after replacement of Conventional Valproate with the slow-release formulation in epileptic patients. Pharmacol Toxicol 90:135–138. https://doi.org/10.1034/j.1600-0773.2002.900304.x
Kowatch RA, Scheffer RE, Monroe E et al (2015) Placebo-controlled trial of Valproic Acid Versus Risperidone in Children 3–7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol 25:306–313. https://doi.org/10.1089/cap.2014.0166
Lin K, Cao VFS, Au C, Dahri K (2022) Clinical pharmacokinetic monitoring of free valproic acid levels: a systematic review. Clin Pharmacokinet 61:1345–1363. https://doi.org/10.1007/s40262-022-01171-w
Matalová P, Urbánek K, Anzenbacher P (2016) Specific features of pharmacokinetics in children. Drug Metab Rev 48:70–79. https://doi.org/10.3109/03602532.2015.1135941
May T, Rambeck B (1985) Serum concentrations of Valproic Acid. Ther Drug Monit 7:387–390. https://doi.org/10.1097/00007691-198512000-00004
Methaneethorn J (2017) Population Pharmacokinetics of Valproic Acid in patients with Mania: implication for individualized dosing regimens. Clin Ther 39:1171–1181. https://doi.org/10.1016/j.clinthera.2017.04.005
Methaneethorn J (2018) A systematic review of population pharmacokinetics of valproic acid. Br J Clin Pharmacol 84:816–834. https://doi.org/10.1111/bcp.13510
Monaco F, Cicolin A (1999) Interactions between anticonvulsant and psychoactive drugs. Epilepsia 40. https://doi.org/10.1111/j.1528-1157.1999.tb00888.x
Murphy JE (2011) Clinical pharmacokinetics, 5th edn. ASHP, Bethesda, MD
Murphy A, Wilbur K (2003) Phenytoin–diazepam Interaction. Ann Pharmacother 37:659–663. https://doi.org/10.1345/aph.1C413
Nalivaeva NN, Belyaev ND, Turner AJ (2009) Sodium valproate: an old drug with new roles. Trends Pharmacol Sci 30:509–514. https://doi.org/10.1016/j.tips.2009.07.002
Nau H (1985) Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol 80:243–250. https://doi.org/10.1016/0041-008X(85)90081-X
Nau H (1990) Pharmacokinetic aspects of drug teratogenesis: species differences and structure activity relationships of the anticon-vulsant valproic acid. Acta Pharm Jugosl 40:291–300
NHS Foundation Trust (2016) Medicines Information Bulletin; Vol. 14 No.; January 2016(v2): Valproate for bipolar disorder – formulary status reminder. https://www.oxfordhealthformulary.nhs.uk/docs/vol%2014%20no%201%20Valproate%20for%20bipolar%20disorder%20-%20formulary%20status%20reminder%202016v2.pdf
Owens DC (2019) Sodium valproate in psychiatric practice: time for a change in perception. Br J Psychiatry 215:516–518. https://doi.org/10.1192/bjp.2019.137
Park H-M, Kang S-S, Lee Y-B et al (2002) Population pharmacokinetics of intravenous valproic acid in Korean patients. J Clin Pharm Ther 27:419–425. https://doi.org/10.1046/j.1365-2710.2002.00440.x
Perucca E, Grimaldi R, Gatti G et al (1984) Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 17:665–669. https://doi.org/10.1111/j.1365-2125.1984.tb02401.x
Pisanu C, Heilbronner U, Squassina A (2018) The role of Pharmacogenomics in Bipolar Disorder: moving towards Precision Medicine. Mol Diagn Ther 22:409–420. https://doi.org/10.1007/s40291-018-0335-y
Rakitin A (2020) Why do psychiatrists still prescribe valproate to women of childbearing potential? https://doi.org/10.3389/fpsyt.2020.00739. Front Psychiatry 11:
Royal College of Psychiatrists Psychopharmacology Committee (2017) Use of licensed medicines for unlicensed applications in psychiatric practice, 2nd edn. The Royal College of Psychiatrists, London
Safdar A, Ismail F (2023) A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharm J 31:265–278. https://doi.org/10.1016/j.jsps.2022.12.001
Sani G, Perugi G, Tondo L (2017) Treatment of bipolar disorder in a lifetime perspective: is Lithium still the best choice? Clin Drug Investig 37:713–727. https://doi.org/10.1007/s40261-017-0531-2
Schnetzler J, Préaubert G, Schnetzler F (1988) A valproic acid-diazepam combination as an alternative to neuroleptic treatment. Ann Med Psychol (Paris) 146:325–339
Sportiche S, Geoffroy PA, Brichant-Petitjean C et al (2017) Clinical factors associated with lithium response in bipolar disorders. Australian New Z J Psychiatry 51:524–530. https://doi.org/10.1177/0004867416664794
Stahl SM (2018) Prescriber’s guide – children and adolescents. Cambridge University Press
Stoudemire A (1998) Lithium intolerance in a Medical-Psychiatric Population. Gen Hosp Psychiatry 20:85–90. https://doi.org/10.1016/S0163-8343(97)00129-1
Suzuki T, Uchida H, Takeuchi H et al (2009) Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Hum Psychopharmacology: Clin Experimental 24:628–638. https://doi.org/10.1002/hup.1073
Tan L, Yu J-T, Sun Y-P et al (2010) The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin Neurol Neurosurg 112:320–323. https://doi.org/10.1016/j.clineuro.2010.01.002
The Pharmaceutical Society of Israel (2023) Depalept 500 enteric coated tablets. In: https://drug.co.il/drugs/דפלפט-500-טבליות-מצופות/
Tseng Y-J, Huang S-Y, Kuo C-H et al (2021) Factors to influence the accuracy of albumin adjusted free valproic acid concentration. J Formos Med Assoc 120:1114–1120. https://doi.org/10.1016/j.jfma.2020.09.004
Usman M, Shaukat Q-A, Khokhar MI et al (2022) Comparative pharmacokinetics of valproic acid among Pakistani and South Korean patients: a population pharmacokinetic study. PLoS ONE 17:e0272622. https://doi.org/10.1371/journal.pone.0272622
Varma S, Bishara D, Besag FMC, Taylor D (2011) Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol 1:47–66. https://doi.org/10.1177/2045125311405566
Vasudev K, Goswami U, Kohli K (2000) Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder. Psychopharmacology 150:15–23. https://doi.org/10.1007/s002130000380
Wang S, Li J, Song M et al (2021a) Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia. Sci Rep 11:23150. https://doi.org/10.1038/s41598-021-02628-x
Wang S, Li J, Song M et al (2021b) Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia. Sci Rep 11:23150. https://doi.org/10.1038/s41598-021-02628-x
Winter ME (2010) Basic Clinical Pharmacokinetics, 5th edn. Lippincott Williams & Wilkins Health, Philadelphia, PA
Wolkowitz OM (1993) Rational polypharmacy in schizophrenia. Ann Clin Psychiatry 5:79–80
Wood SN (2017) Generalized additive models. Chapman and Hall/CRC
Wood S (2023) Package ‘mgcv’; R package version 1.9-0
Yatham LN, Kennedy SH, Parikh SV et al (2018) Canadian Network for Mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 20:97–170. https://doi.org/10.1111/bdi.12609
Zaccara G, Messori A, Moroni F (1988) Clinical pharmacokinetics of Valproic acid – 1988. Clin Pharmacokinet 15:367–389. https://doi.org/10.2165/00003088-198815060-00002
Zang Y-N, Guo W, Niu M-X et al (2022) Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder. Eur J Clin Pharmacol 78:405–418. https://doi.org/10.1007/s00228-021-03246-2
Zhu M-M, Li H-L, Shi L-H et al (2017) The pharmacogenomics of valproic acid. J Hum Genet 62:1009–1014. https://doi.org/10.1038/jhg.2017.91
Zink M, Englisch S, Meyer-Lindenberg A (2010) Polypharmacy in schizophrenia. Curr Opin Psychiatry 23:103–111. https://doi.org/10.1097/YCO.0b013e3283366427
Zito JM, Derivan AT, Kratochvil CJ et al (2008) Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring. Child Adolesc Psychiatry Ment Health 2:24. https://doi.org/10.1186/1753-2000-2-24
Acknowledgements
We thank the caregivers at the Child and Adolescent Department of the Geha Mental Health Center, the laboratory team at Beilinson Hospital/Rabin Medical Center, and all the patients who participated in this study.
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MA, TL, ZE, and AW designed the study. ZE collected the data. TL performed the data analysis. MP, PP, JA, UL, and DA aided in interpreting the study’s results. AW supervised the study. MA and TL wrote the manuscript with assistance from all authors.
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Avrahami, M., Liwinski, T., Eckstein, Z. et al. Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06603-y
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DOI: https://doi.org/10.1007/s00213-024-06603-y