Associations of Valproate Doses With Weight Gain in Adult Psychiatric Patients: A 1-Year Prospective Cohort Study

Claire Grosu, PhD; William Hatoum, PharmD; Marianna Piras, PharmD, PhD; Nermine Laaboub, PhD; Setareh Ranjbar, PhD; Franziska Gamma, MD, MSc; Kerstin J. Plessen, PhD; Armin von Gunten, MPhil, MD; Martin Preisig, MD, MPH; Philippe Conus, MD; Chin B. Eap, PhD

J Clin Psychiatry 2024;85(2):23m15008

ABSTRACT

Objective: The aim of this study was to evaluate valproate dose association with weight change, blood glucose, lipid levels, and blood pressure in a psychiatric population.

Methods: Data from 215 patients taking valproate for up to 1 year were collected from 2 longitudinal studies that monitored metabolic variables between 2007 and 2022. Linear mixed-effect models and logistic regressions were used to analyze the associations between valproate doses and metabolic outcomes.

Results: An increase in valproate dose of 500 mg was associated with a weight change of +0.52% per month over a year (P < .001). The association between valproate dose and weight change was evident both before and after 3 months of treatment. Weight increase was greater for treatment durations of < 3 months compared to ≥ 3 months (+0.56%, P < .001 and +0.12%, P = .02 per month, respectively). Using piecewise regression, a significant association between dose and weight gain was observed in patients receiving doses equal to or above the median dose (1,300 mg/d), with a +0.50% increase in weight for each dose increment of 500 mg (P = .004). Among men, each 500 mg dose increment was associated with weight increases of +0.59% per month (P = .004), whereas a trend was observed for women (+0.40%, P = .09). No associations were found between valproate doses and blood glucose, lipid levels, or blood pressure over a 6-month treatment period.

Conclusions: This study provides evidence that valproate dose, mainly for doses at or above 1,300 mg/d, is associated with weight gain in psychiatric patients, suggesting that the lowest effective doses should be prescribed to minimize weight gain.

J Clin Psychiatry 2024;85(2):23m15008

Author affiliations are listed at the end of this article.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Purchase PDF for $40

Members enjoy free PDF downloads on all articles. Join today

References (45)

Bowden CL, Singh V. Valproate in bipolar disorder: 2000 onwards. Acta Psychiatr Scand suppl. 2005;111(s426):13–20. PubMed CrossRef
HCI Solutions. September 6, 2023. https://compendium.ch/
Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016;(11):CD010224. PubMed CrossRef
Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1–13. PubMed CrossRef
Corman CL, Leung NM, Guberman AH. Weight gain in epileptic patients during treatment with valproic acid: a retrospective study. Can J Neurol Sci. 1997;24(3):240–244. PubMed CrossRef
Correll CU, Ng-Mak DS, Stafkey-Mailey D, et al. Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: a real-world analysis. Ann Gen Psychiatry. 2017;16(9):1–8. PubMed CrossRef
Verrotti A, D’Egidio C, Mohn A, et al. Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Obes Rev. 2011;12(5):e32–e43. PubMed CrossRef
De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114–126. PubMed CrossRef
Grootens KP, Meijer A, Hartong EG, et al. Weight changes associated with antiepileptic mood stabilizers in the treatment of bipolar disorder. Eur J Clin Pharmacol. 2018;74(11):1485–1489. PubMed CrossRef
Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br Med J (Clin Res Ed). 1981;283(6291):577–581. PubMed CrossRef
Pylvänen V, Pakarinen A, Knip M, et al. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav. 2006;8(3):643–648. PubMed CrossRef
Novak GP, Maytal J, Alshansky A, et al. Risk of excessive weight gain in epileptic children treated with valproate. J Child Neurol. 1999;14(8):490–495. PubMed CrossRef
Verrotti A, Basciani F, Morresi S, et al. Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology. 1999;53(1):230–232. PubMed CrossRef
Kanemura H, Sano F, Maeda Y, et al. Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy. Seizure. 2012;21(7):496–500. PubMed CrossRef
Dinesen H, Gram L, Andersen T, et al. Weight gain during treatment with valproate. Acta Neurol Scand. 1984;70(2):65–69. PubMed CrossRef
Nair SS, Harikrishnan S, Sarma PS, et al. Metabolic syndrome in young adults with epilepsy. Seizure. 2016;37:61–64. PubMed CrossRef
Fang J, Chen S, Tong N, et al. Metabolic syndrome among Chinese obese patients with epilepsy on sodium valproate. Seizure. 2012;21(8):578–582. PubMed CrossRef
El-Khatib F, Rauchenzauner M, Lechleitner M, et al. Valproate, weight gain and carbohydrate craving: a gender study. Seizure. 2007;16(3):226–232. PubMed CrossRef
Hamed SA, Fida NM, Hamed EA. States of serum leptin and insulin in children with epilepsy: risk predictors of weight gain. Eur J Paediatr Neurol. 2009;13(3):261–268. PubMed CrossRef
Stephen LJ, Kwan P, Shapiro D, et al. Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy. Epilepsia. 2001;42(8):1002–1006. PubMed CrossRef
Bowden CL, Calabrese JR, McElroy SL, et al; Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57(5):481–489. PubMed CrossRef
Zuo S, Fries BE, Szafara K, et al. Valproic acid as a potentiator of metabolic syndrome in institutionalized residents on concomitant antipsychotics: fat chance, or slim to none? P&T. 2015;40(2):126–132. PubMed
Chang HH, Yang YK, Gean PW, et al. The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord. 2010;124(3):319–323. PubMed CrossRef
Delacrétaz A, Glatard A, Dubath C, et al. Valproate is associated with early decrease of high-density lipoprotein cholesterol levels in the psychiatric population. Basic Clin Pharmacol Toxicol. 2021;129(1):26–35. PubMed CrossRef
Pylvänen V, Pakarinen A, Knip M, et al. Characterization of insulin secretion in valproate-treated patients with epilepsy. Epilepsia. 2006;47(9):1460–1464. PubMed CrossRef
Demir E, Aysun S. Weight gain associated with valproate in childhood. Pediatr Neurol. 2000;22(5):361–364. PubMed CrossRef
Aydin K, Serdaroglu A, Okuyaz C, et al. Serum insulin, leptin, and neuropeptide y levels in epileptic children treated with valproate. J Child Neurol. 2005;20(10):848–851. PubMed CrossRef
Martin CK, Han H, Anton SD, et al. Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial. J Psychopharmacol. 2009;23(7):814–825. PubMed CrossRef
Vandenberghe F, Gholam-Rezaee M, Saigí-Morgui N, et al. Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015;76(11):e1417–e1423. PubMed CrossRef
Abosi O, Lopes S, Schmitz S, et al. Cardiometabolic effects of psychotropic medications. Horm Mol Biol Clin Investig. 2018;36(1):/j/hmbci.2018.36.issue-1/hmbci-2017-0065/hmbci-2017-0065.xml. PubMed
de Jong M, Belleflamme J, Dale C, et al. Metabolic syndrome in Dutch patients with bipolar disorder: a cross-sectional study. Prim Care Companion CNS Disord. 2018;20(6):27482. PubMed CrossRef
Dubath C, Delacrétaz A, Glatard A, et al. Evaluation of cardiometabolic risk in a large psychiatric cohort and comparison with a population-based sample in Switzerland. J Clin Psychiatry. 2020;81(3):19m12796. PubMed CrossRef
Musil R, Obermeier M, Russ P, et al. Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf. 2015;14(1):73–96. PubMed CrossRef
Shin JK, Barron CT, Chiu Y-L, et al. Weight changes and characteristics of patients associated with weight gain during inpatient psychiatric treatment. Issues Ment Health Nurs. 2012;33(8):505–512. PubMed CrossRef
Abaseynejad F, Akrami R, Mohebbati R, et al. The effect of sodium valproate on cardiovascular responses in pentylenetetrazol kindling model of epilepsy. Biomed J Sci Tech Res. 2022;42(3):33592–33596.
Zeise ML, Kasparow S, Zieglgänsberger W. Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro. Brain Res. 1991;544(2):345–348. PubMed CrossRef
Kawakami K, Yamada K, Yamada T, et al. Antihypertensive effect of γ-aminobutyric acid-enriched brown rice on spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo). 2018;64(1):56–62. PubMed CrossRef
Shi Z, Yuan B, Taylor AW, et al. Monosodium glutamate is related to a higher increase in blood pressure over 5 years: findings from the Jiangsu Nutrition Study of Chinese adults. J Hypertens. 2011;29(5):846–853. PubMed CrossRef
Verrotti A, Manco R, Agostinelli S, et al. The metabolic syndrome in overweight epileptic patients treated with valproic acid. Epilepsia. 2010;51(2):268–273. PubMed CrossRef
Lee S-Y, Chen S-L, Chang Y-H, et al. Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder. J Psychiatr Res. 2013;47(10):1343–1348. PubMed CrossRef
Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41. PubMed CrossRef
Parsons B, Allison DB, Loebel A, et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res. 2009;110(1-3):103–110. PubMed CrossRef
De Hert M, Cohen D, Bobes J, et al. Physical illness in patients with severe mental disorders, II: barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry. 2011;10(2):138–151. PubMed CrossRef
Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One. 2014;9(4):e94112. PubMed CrossRef
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Focus Am Psychiatr Publ. 2014;12(2):192–204. CrossRef