Unveiling Valproate induced Hyperammonaemia – Clinical insights from a case series in Psychiatric inpatient setting

Unveiling Valproate induced Hyperammonaemia – Clinical insights from a case series in Psychiatric inpatient setting | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Unveiling Valproate induced Hyperammonaemia – Clinical insights from a case series in Psychiatric inpatient setting Induja Nair, Suvarna Jyothi Kantipudi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8469849/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Valproate is an agent commonly used for its antiepileptic properties, but in psychiatry it is used for its mood stabilising properties.Valproate-induced hyperammonemic encephalopathy (VHE) is rare but potentially life-threatening complication that can occur even at therapeutic drug levels and with normal liver function. Here, we present a series of ten cases, eight males and two females who got admitted to a tertiary health care centre and developed acute-onset drowsiness, nausea, and lethargy within 2-16 days of initiating valproate therapy. All patients had normal liver function tests but significantly elevated serum ammonia levels.Prompt discontinuation of Valproate and administration of lactulose helped reverse the elevated serum ammonia levels. None of the patients who presented withhyperammonaemia progressed to VHE. This highlights the idiosyncratic nature of VHE, and the need for watchfulness in patients on Valproate. Clinicians should monitor for unexplained mental status changes, particularly when accompanied by gastrointestinal symptoms, and promptly assess serum ammonia levels. Failure to promptly recognize and address hyperammonaemia drastically increases the risk of severe, potentially life-threatening complications like VHE. Early diagnosis and prompt intervention are essential to mitigate this risk and avoid progression to the highly fatal stage of encephalopathy. Figures Figure 1 Figure 2 Introduction Valproate is approved for the treatment of seizures, manic or mixed episodes associated with bipolar disorder and for the prevention of migraine headaches 1 . Despite its wide range of uses within psychiatric and neurological settings, it is associated with a spectrum of side effects such as hair-loss, weight gain, bleeding tendencies, GI disturbances, tremors, sedation, polycystic ovarian syndrome, obesity and insulin resistance 2 , 3 .The recommended therapeutic plasma levels range from 45 -125 μg/ml,and some of the side effects can be reduced by dose reduction.. Here, we present are relatively rare but potentially life-threatening adverse effect of Valproate i.e hyperammonemia. The normal range of serum ammonia is between 15 – 45µ/dL and this range may vary from person to person based on age, sex and other factors 3,4 . There is limited data on incidence of Valproate induced hyperammonemia(VIH). A study done in Cleveland, Ohio in 2016, on 347 psychiatric inpatients at a community teaching hospital showed the prevalence of VIH to be 36% and the prevalence of hyperammonemic symptoms in those with VIH was 43.2% 5 . In Indian setting, there were some case reports and case series 6 - 7 . In our tertiary care centre, over the past one year, out of 968 total admissions, 86 were started on Valproate out of which, 10 individuals developed hyperammonemia which we have further discussed below. Case Series This case series is based on retrospective medical record review from a tertiary care urban teaching hospital with a general hospital psychiatry setting. We report ten patients(11.6%) out of 86 in patients who received Valproate in the past year and developed symptoms of VIH. This cohort comprised of eight males and two females, all of whom were 42 years of age or younger. Among them, seven presented with symptoms suggestive of mania and one schizoaffective disorder, one psychosis with mood symptoms and one with organic mood disorder. The duration of presenting complaints of these patients ranged from 1 week to 3 months, with majority experiencing symptoms between 2-3 weeks. All the patients except the one with organic mood disorder had an earlier history of being treated for psychiatric illness, however there were no prior medical records indicative of Valproate use in the past except for 1 patient. At the time of inpatient admission, 8 out of the 9 patients with prior history of psychiatric illness were not taking any psychiatric medications before the onset of symptoms in the current episode. Baseline routine investigations such as complete blood counts, liver function tests, renal function tests, serum electrolytes, random blood sugar levels and ECG were done on admission and found to be within normal limits. One of the patients had Diabetes Mellitus and Systemic Hypertension for which he was on treatment for the past 10 and 5 years respectively and one patient had been diagnosed with hypothyroidism after admission and was started on Thyroxine. The rest of the patients did not have any pre-existing medical co-morbidities. Four of the eight male patients had a history of alcohol consumption for more than 10 years, and one had a history of nicotine use. Patients experienced symptoms of acute onset drowsiness, nausea, and lethargy within 2 to 16 days of Valproate initiation (Table 1,Column 6) . However, there was no frank fluctuation in orientation, and the patients were arousable and obeyed commands. Serum ammonia levels were assessed for all these patients and found to be significantly elevated. INSERT TABLE 1 Following discontinuation of Tab.Valproate and initiation of syrup Lactulose, serum ammonia levels reached normal levels within 3-4 days (Table1,Column 8) . The Naranjo Causality Assessment for this cohort of ten patients results in a consistently high score of +8 , classifying the adverse drug reaction (ADR) as Probable as shown in Table 2 .Further treatment was tailored based on patients’ condition. All the patients had improvement in their symptoms and were followed up for 2 months after discharge, with no further complications observed. INSERT TABLE 2 Discussion Our case series, comprising ten out of 86 patients initiated on Valproate i.e (11.6%), unveils the higher incidence rate of Valproate-induced hyperammonaemia. All have symptoms of hyperammonemia i.e drowsiness, nausea and lethargy within a relatively short duration of Valproate therapy, emphasising the importance of vigilance in monitoring for hyperammonaemia for those started on Valproate. It is well known that elevated levels of ammonia pose risks of neurotoxicity. Some studies have shown that the tendency for hyperammonemia was observed with higher and supra-therapeutic doses of Valproate, although it was later found to occur even with lower levels of Valproate 8 . This was further evidenced by some studies and case reports where serum Valproate levels were assessed in patients who developed hyperammonemia and found to be within normal limits but sometimes at the upper range of the normal limits 8–10 . The valproate levels were not checked for all our cases, as the symptoms developed within a short span after the initiation of Valproate. For those whom we checked, it was within the therapeutic range. We have not assessed other patients who have not developed any symptoms of hyperammonaemia, as it was not clinically indicated. Evidence shows occurrence of asymptomatic hyperammonaemia to be higher than symptomatic, ranging from 16.2% to 52.3%, with unclear clinical implications 10 . On the contrary, some patients may show clinical features of Valproate induced hyperammonemia despite normal ammonia levels, which may be due to toxic compounds like the metabolites of valproate or the possibility of an individual threshold above which cerebral ammonia affects consciousness or that ammonia concentrations in the brain may remain high despite normal serum ammonia levels 8–10 All the patients who developed symptoms of hyperammonaemia in our series had elevated serum ammonia levels on testing. However, none of them have progressed to the VHE due to early intervention in the inpatient setting. The risk factors other than Valproate, predisposing to hyperammonaemia include carnitine deficiency such as a strict vegetarian diet, patients on dialysis and diabetic status, polypharmacy with multiple anti-epileptics, drugs causing excessive inhibition of GABA 11 , and the use of mechanical ventilation 12,13 .Most of the patients do not have these risk factors, except one patient had diabetes,3 had history of alcohol use disorder. One case report went on to claim that concomitant treatment with risperidone could be a potential risk factor for hyperammonemia and further suggested that Risperidone could be interfering with Valproate binding with albumin 9 .Three of our patients were also on Risperidone and two were on olanzapine,but the implications of which need to be further explored. In our case series as well as in the literature reviewed, stoppage of Valproate brought down the serum ammonia levels and additionally, they were started on Lactulose syrup 5,14,15 . Since the metabolism of ammonia in our body depends on carnitine and its deficiency has also been implicated in the development of hyperammonemia, there are articles that recommend the use of L-carnitine to combat the adverse effects of Valproate. A case series and reports even proved this by starting levocarnitine in patients who developed hyperammonemia in response to Valproate. One case report demonstrated the use of antibiotics directed towards ammonia producing bacteria such as Neomycin, Rifaximin and Metronidazole 8 . Despite the literature on the use of L-carnitine to bind to Valproate metabolites and combat carnitine deficiency 16 - 17 , and use of antibiotics 8 (like Neomycin or Rifaximin or Metronidazole) to reduce ammonia-producing bacteria in the gut, these options were not implemented in our immediate management strategy, as the serum ammonia levels have raised after period of non-compliance to levocarnitine, and the clinical significance of ammonia level reduction in asymptomatic patients remains unclear 16 - 17 .In our case series, based on the observations in our tertiary care set up, the only consistent pattern noted was that Valproate induced hyperammonemia seemed to occur in young individuals, below the age of 45 years more often than the older ones and more often in males than in females. The significance of these findings remain to be explored in the future. There is no need for routine monitoring of serum ammonia levels unless indicated by symptoms as rest of the patients who have not checked did not develop VHE.Prompt management with laxatives and withholding Valproate remained the cornerstone for resolution of symptoms of hyperammonemia and normalization of serum ammonia levels. This is similar to how the Valproate induced Hyperammonemia was managed in similar settings in India 18 .Concurrently, changing the mood stabiliser, or adding an antipsychotic medication or Electroconvulsive therapy(ECT) seemed to cause a resolution of psychiatric symptoms and maintenance of clinical stability. There were limitations to our observations as Serum Valproate levels could not be assessed in all and dose response to Valproate couldn’t be quantified. Conclusion Valproate-induced hyperammonemia (VIH) is a serious, yet rare, adverse effect that necessitates early and aggressive management to prevent progression to the highly fatal stage of VHE.Clinicians must maintain a high index of suspicion and promptly assess serum ammonia levels upon any unexplained mental status changes or gastrointestinal symptoms in patients receiving VPA. Further research is imperative to clarify the role of adjunctive therapies such as L-carnitine and antibiotics, and to better understand the long-term clinical implications of asymptomatic hyperammonaemia. Declarations Declaration of Conflicting Interests : There no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Contributor statement : SJK conceptualised the study. IN collected the clinical data and SJK performed the analysis. IN wrote the first draft of the manuscript. SJK and IN were both involved in patient care and clinical follow-up. All authors critically reviewed the manuscript and approved the final version. Data availability statement: The data supporting the findings of this study were generated during routine clinical care. Due to the sensitive nature of patient information and to protect patient confidentiality, the data are not publicly available. De-identified data may be made available from the corresponding author upon reasonable request and with appropriate institutional approvals. Declaration Regarding the Use of Generative AI: None used. Ethics Committee Details This case series was approved by the Departmental Scientific Committee, Department of Psychiatry, xxxxxxxxx. This case series was exempted from review by the Institutional Ethics Committee. Patient Consent Not applicable as the case series is based on review of retrospective medical records. Previous Presentation and Submission : This work was presented as a poster presentation by xxxxx xxxx at xxxxxxx and won the best poster award. This article has not been submitted to other journals. Acknowledgements: The authors would like to thank the patients and their caregivers for their cooperation. We also acknowledge the support of the clinical and nursing staff of the Department of Psychiatry, xxxxxxx, for their assistance in patient care and data collection. References Research C for DE and. Valproate Information, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information (2019, accessed 14 December 2025). Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications . 5th edn. Cambridge: Cambridge University Press. Epub ahead of print 2021. DOI: 10.1017/9781108975292. Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol 2012; 27: 207–222. Rahman M, Awosika AO, Nguyen H. Valproic Acid. In: StatPearls . Treasure Island (FL): StatPearls Publishing, http://www.ncbi.nlm.nih.gov/books/NBK559112/ (2024, accessed 18 April 2024). Baddour E, Tewksbury A, Stauner N. Valproic acid–induced hyperammonemia: Incidence, clinical significance, and treatment management. Ment Health Clin 2018; 8: 73–77. Nair I, Kantipudi SJ. Valproate-induced Hyperammonaemia in a Bipolar Disorder Patient: A Case Report. J Clin Diagn Res . Epub ahead of print 2024. DOI: 10.7860/JCDR/2024/75123.20258. Abhilasha P, Bhatti N, Joseph G, et al. Sodium Valproate-Induced Hyperammonemia: A Case Series in a Tertiary Care Hospital. Cureus 2024; 16: e65390. Vázquez M, Fagiolino P, Maldonado C, et al. Hyperammonemia Associated with Valproic Acid Concentrations. BioMed Res Int 2014; 2014: 1–7. Cheng M, Tang X, Wen S, et al. Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. Compr Psychiatry 2013; 54: 562–567. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry 2012; 34: 290–298. Segura-Bruna N, Rodriguez-Campello A, Puente V, et al. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand 2006; 114: 1–7. Wong Y-CJ, Fan J, Wan A, et al. Valproic Acid–Associated Hyperammonemia: A Systematic Review. J Clin Psychopharmacol 2023; 43: 283–294. Duman B. Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions. Gen Hosp Psychiatry . McMorris T, Chu A, Vu L, et al. Hyperammonemia in patients receiving valproic acid in the hospital setting: A retrospective review. Ment Health Clin 2021; 11: 243–247. Lewis C, Deshpande A, Tesar GE, et al. Valproate-induced hyperammonemic encephalopathy: a brief review. Curr Med Res Opin 2012; 28: 1039–1042. Brown LM, Cupples N, Moore TA. Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: A case series and literature review. Ment Health Clin 2018; 8: 148–154. Cattaneo CI, Ressico F, Valsesia R, et al. Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report. Medicine (Baltimore) 2017; 96: e8117. Vaidyanathan S, Chatorikar S, Praharaj SK, et al. Valproate-Associated Hyperammonemic Encephalopathy: Clinical Correlates and Management Strategies in a Tertiary Care Center. J Clin Psychopharmacol 2023; 43: 145–148. Tables TABLE 1. Clinical profile of patients with Valproate-associated Hyperammonaemia S. No Age Gender Diagnosis Valproate dose/day Duration of Valproate therapy Serum ammonia (µg/dl) Course at hospital 1 37 Male BPAD- current episode mania Alcohol use disorder 1000 mg 7 days 92.1 T. Sodium Valproate was stopped and maintained on Olanzapine 20mg and ECT.Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits. 2 29 Female Schizoaffective disorder 1500 mg 5 days 91.28 T. Sodium Valproate was stopped and changed over to T. Lithium 800mg along with Haloperidol 15mg.Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits. 3 40 Male BPAD- current episode mania 1500 mg 6 days 108.7 T. Sodium Valproate was stopped and changed over to T. Lithium 800mg along with Olanzapine 20mg. Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits. 4 29 Female Psychosis with mood symptoms 1000 mg 11 days 95.29 T. Sodium Valproate was stopped and maintained on Risperidone 3mg Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits. 5 38 Male BPAD- current episode mania 1750 mg 16 days 55.8 T. Sodium Valproate was initiated at a reduced dose of 1000mg(Previously on 1750mg) and added Risperidone 3mg S. ammonia levels were repeated daily and normalised in 3 days. 6 32 Male BPAD- current episode mania 1500 mg 6 days 142 All psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started on Tab. Lithium 900mg and T. Risperidone 8 mg 7 42 Male BPAD- current episode mania 1500 mg 2 days 99.2 All psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later restarted on Tab.Valproate 1000 mg(previously 1500mg) and T. Quetiapine 200 mg. 8 30 Male BPAD- current episode mania 2000 mg 6 days 89.8 All psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started Tab. Lithium 800mg. 9 24 Male BPAD- current episode mania 1000 mg 5 days 66.7 All psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started Tab. Lithium 800mg. 10 40 Male Organic Mood Disorder 1500mg 6 days 71.1 All psychotropics were stopped and the patient was started on Syp. Lactulose 30ml HS. Patient was later started on Tab. Lorazepam 2mg, Tab. Melatonin 3mg, Tab. Aripiprazole 5mg, Tab. Quetiapine 150mg and Tab. Naltrexone 50mg. Table 2: Naranjo causality assessment scale Naranjo Question Response & Score Rationale based on Case series 1. Previous conclusive reports? Yes (+1) Valproate-induced hyperammonemia (HA) and encephalopathy (VHE) are known complications. 2. ADR appeared after drug administered? Yes (+2) Symptoms (drowsiness, nausea, lethargy) appeared acutely 2 to 16 days after VPA initiation. 3. ADR improved when drug was discontinued? Yes (+1) Symptoms improved, and ammonia levels normalized within 3-4 days after VPA discontinuation and Lactulose initiation. 4. ADR reappeared when re-administered? Do Not Know (0) VPA was cautiously reinitiated in two patients (Case 5, 7), but the outcome regarding recurrence of hyperammonemia is not known, as patients were not followed up after 2 months. 5. Alternative causes could have caused? No (+2) Routine investigations, including Liver Function Tests (LFTs), were normal. 6. Reaction reappeared with placebo? No (+1) Not applicable. 7. Drug detected in toxic concentration? Do Not Know (0) Serum VPA levels were not assessed in most cases; as symptoms developed in short span after Valproate therapy. 8. Severity change with dose? Do Not Know (0) Dose response before discontinuation is not available. 9. Similar reaction previously? No (0)/ Do Not Know (0) There were no prior medical records indicative of VPA use in the past, except for one patient. 10. ADR confirmed by objective evidence? Yes (+1) Confirmed by significantly elevated serum ammonia levels in all patients. Total Naranjo Score +8 Probable Adverse Drug Reaction Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8469849","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":568123827,"identity":"729c7c0c-3c17-4b51-8b85-8357f465b17d","order_by":0,"name":"Induja Nair","email":"","orcid":"","institution":"ACS Medical College and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Induja","middleName":"","lastName":"Nair","suffix":""},{"id":568123828,"identity":"79fd9ee2-055d-4080-83e9-3718c3928135","order_by":1,"name":"Suvarna Jyothi Kantipudi","email":"data:image/png;base64,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","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":true,"prefix":"","firstName":"Suvarna","middleName":"Jyothi","lastName":"Kantipudi","suffix":""}],"badges":[],"createdAt":"2025-12-29 06:38:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8469849/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8469849/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101020138,"identity":"42083400-4757-4c4d-a7d6-c2f95488a513","added_by":"auto","created_at":"2026-01-24 00:42:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58630,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of Valproate metabolism pathways\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8469849/v1/14402e474c3960b616b0b2e0.png"},{"id":101020139,"identity":"2be22f4f-1fb1-4448-b427-694a8a26aa54","added_by":"auto","created_at":"2026-01-24 00:42:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65185,"visible":true,"origin":"","legend":"\u003cp\u003eRole of Carnitine in Valproate metabolism and Valproate-Carnitine interaction\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8469849/v1/08059f739598b8177e23d0bb.png"},{"id":101880687,"identity":"cceea5a8-362c-4b6f-babd-e6354f762c72","added_by":"auto","created_at":"2026-02-04 15:05:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":517737,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8469849/v1/c081cc0f-0e2e-467b-beac-e0e436da97f1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":" Unveiling Valproate induced Hyperammonaemia – Clinical insights from a case series in Psychiatric inpatient setting","fulltext":[{"header":"Introduction","content":"\u003cp\u003eValproate is approved for the treatment of seizures, manic or mixed episodes associated with bipolar disorder and for the prevention of migraine headaches\u003csup\u003e1\u003c/sup\u003e. Despite its wide range of uses within psychiatric and neurological settings, it is associated with a spectrum of side effects such as hair-loss, weight gain, bleeding tendencies, GI disturbances, tremors, sedation, polycystic ovarian syndrome, obesity and insulin resistance\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e.The recommended therapeutic plasma levels range from 45 -125 \u0026mu;g/ml,and some of the side effects can be reduced by dose reduction..\u003c/p\u003e\n\u003cp\u003eHere, we present are relatively rare but potentially life-threatening adverse effect of Valproate i.e hyperammonemia. The normal range of serum ammonia is between 15 \u0026ndash; 45\u0026micro;/dL and this range may vary from person to person based on age, sex and other factors\u0026nbsp;\u003csup\u003e3,4\u003c/sup\u003e.\u0026nbsp;There is limited data on incidence of Valproate induced hyperammonemia(VIH). A study done in Cleveland, Ohio in 2016, on 347 psychiatric inpatients at a community teaching hospital showed the prevalence of VIH to be 36% and the prevalence of hyperammonemic symptoms in those with VIH was 43.2%\u0026nbsp;\u003csup\u003e5\u003c/sup\u003e. In Indian setting, there were some case reports and case series\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e. In our tertiary care centre, over the past one year, out of 968 total admissions, 86 were started on Valproate out of which, 10 individuals developed hyperammonemia which we have further discussed below.\u003c/p\u003e"},{"header":"Case Series","content":"\u003cp\u003eThis case series is based on retrospective medical record review from a tertiary care urban teaching hospital with a general hospital psychiatry setting. We report ten patients(11.6%) out of 86 in patients who received Valproate in the past year and developed symptoms of VIH. This cohort comprised of eight males and two females, all of whom were 42 years of age or younger. Among them, seven presented with symptoms suggestive of mania and one schizoaffective disorder, one psychosis with mood symptoms and one with organic mood disorder. The duration of presenting complaints of these patients ranged from 1 week to 3 months, with majority experiencing symptoms between 2-3 weeks. All the patients except the one with organic mood disorder had an earlier history of being treated for psychiatric illness, however there were no prior medical records indicative of Valproate use in the past except for 1 patient. At the time of inpatient admission, 8 out of the 9 patients with prior history of psychiatric illness were not taking any psychiatric medications before the onset of symptoms in the current episode. Baseline routine investigations such as complete blood counts, liver function tests, renal function tests, serum electrolytes, random blood sugar levels and ECG were done on admission and found to be within normal limits. One of the patients had Diabetes Mellitus and Systemic Hypertension for which he was on treatment for the past 10 and 5 years respectively and one patient had been diagnosed with hypothyroidism after admission and was started on Thyroxine. The rest of the patients did not have any pre-existing medical co-morbidities. Four of the eight male patients had a history of alcohol consumption for more than 10 years, and one had a history of nicotine use. Patients experienced symptoms of acute onset drowsiness, nausea, and lethargy within 2 to 16 days of Valproate initiation\u003cstrong\u003e(Table 1,Column 6)\u003c/strong\u003e. However, there was no frank fluctuation in orientation, and the patients were arousable and obeyed commands. Serum ammonia levels were assessed for all these patients and found to be significantly elevated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eINSERT TABLE 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing discontinuation of Tab.Valproate and initiation of syrup Lactulose, serum ammonia levels reached normal levels within 3-4 days\u003cstrong\u003e(Table1,Column 8)\u003c/strong\u003e. The Naranjo Causality Assessment for this cohort of ten patients results in a consistently high score of \u003cstrong\u003e+8\u003c/strong\u003e, classifying the adverse drug reaction (ADR) as Probable as shown in \u003cstrong\u003eTable 2\u003c/strong\u003e.Further treatment was tailored based on patients\u0026rsquo; condition. All the patients had improvement in their symptoms and were followed up for 2 months after discharge, with no further complications observed.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eINSERT TABLE 2\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur case series, comprising ten out of 86 patients initiated on Valproate i.e (11.6%), unveils the higher incidence rate of Valproate-induced hyperammonaemia. All have symptoms of hyperammonemia i.e drowsiness, nausea and lethargy within a relatively short duration of Valproate therapy, emphasising the importance of vigilance in monitoring for hyperammonaemia for those started on Valproate. It is well known that elevated levels of ammonia pose risks of neurotoxicity. Some studies have shown that the tendency for hyperammonemia was observed with higher and supra-therapeutic doses of Valproate, although it was later found to occur even with lower levels of Valproate\u003csup\u003e8\u003c/sup\u003e. This was further evidenced by some studies and case reports where serum Valproate levels were assessed in patients who developed hyperammonemia and found to be within normal limits but sometimes at the upper range of the normal limits\u0026nbsp;\u003csup\u003e8\u0026ndash;10\u003c/sup\u003e. The valproate levels were not checked for all our cases, as the symptoms developed within a short span after the initiation of Valproate. For those whom we checked, it was within the therapeutic range. We have not assessed other patients who have not developed any symptoms of hyperammonaemia, as it was not clinically indicated. Evidence shows occurrence of asymptomatic hyperammonaemia to be higher than symptomatic, ranging from 16.2% to 52.3%, with unclear clinical implications\u0026nbsp;\u003csup\u003e10\u003c/sup\u003e.\u0026nbsp;On the contrary, some patients may show clinical features of Valproate induced hyperammonemia despite normal ammonia levels, which may be due to toxic compounds like the metabolites of valproate or the possibility of an individual threshold above which cerebral ammonia affects consciousness or that ammonia concentrations in the brain may remain high despite normal serum ammonia levels\u0026nbsp;\u003csup\u003e8\u0026ndash;10\u003c/sup\u003eAll the patients who developed symptoms of hyperammonaemia in our series had elevated serum ammonia levels on testing. However, none of them have progressed to the VHE due to early intervention in the inpatient setting. The \u0026nbsp; risk factors other than Valproate, predisposing to hyperammonaemia include carnitine deficiency such as a strict vegetarian diet, patients on dialysis and diabetic status, polypharmacy with multiple anti-epileptics, drugs causing excessive inhibition of GABA\u003csup\u003e11\u003c/sup\u003e, and the use of mechanical ventilation\u003csup\u003e12,13\u003c/sup\u003e.Most of the patients do not have these risk factors, except one patient had diabetes,3 had history of alcohol use disorder. One case report went on to claim that concomitant treatment with risperidone could be a potential risk factor for hyperammonemia and further suggested that Risperidone could be interfering with Valproate binding with albumin\u003csup\u003e9\u003c/sup\u003e.Three of our patients were also on Risperidone and two were on olanzapine,but the implications of which need to be further explored. In our case series as well as in the literature reviewed, stoppage of Valproate brought down the serum ammonia levels and additionally, they were started on Lactulose syrup\u003csup\u003e5,14,15\u003c/sup\u003e. Since the metabolism of ammonia in our body depends on carnitine and its deficiency has also been implicated in the development of hyperammonemia, there are articles that recommend the use of L-carnitine to combat the adverse effects of Valproate. A case series and reports even proved this by starting levocarnitine in patients who developed hyperammonemia in response to Valproate. One case report demonstrated the use of antibiotics directed towards ammonia producing bacteria such as Neomycin, Rifaximin and Metronidazole\u003csup\u003e8\u003c/sup\u003e.\u0026nbsp;Despite the\u0026nbsp;literature on the use of L-carnitine to bind to Valproate metabolites and combat carnitine deficiency\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e, and use of antibiotics\u003csup\u003e8\u003c/sup\u003e (like Neomycin or Rifaximin or Metronidazole) to reduce ammonia-producing bacteria in the gut, these options were not implemented in our immediate management strategy, as the serum ammonia levels have raised after period of non-compliance to levocarnitine, and the clinical significance of ammonia level reduction in asymptomatic patients remains unclear\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e.In our case series, based on the observations in our tertiary care set up, the only consistent pattern noted was that Valproate induced hyperammonemia seemed to occur in young individuals, below the age of 45 years more often than the older ones and more often in males than in females. The significance of these findings remain to be explored in the future. There is no need for routine monitoring of serum ammonia levels unless indicated by symptoms as rest of the patients who have not checked did not develop VHE.Prompt management with laxatives and withholding Valproate remained the cornerstone for resolution of symptoms of hyperammonemia and normalization of serum ammonia levels. This is similar to how the Valproate induced Hyperammonemia was managed in similar settings in India\u003csup\u003e18\u003c/sup\u003e.Concurrently, changing the mood stabiliser, or adding an antipsychotic medication or Electroconvulsive therapy(ECT) seemed to cause a resolution of psychiatric symptoms and maintenance of clinical stability. There were limitations to our observations as Serum Valproate levels could not be assessed in all and dose response to Valproate couldn\u0026rsquo;t be quantified.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eValproate-induced hyperammonemia (VIH) is a serious, yet rare, adverse effect that necessitates early and aggressive management to prevent progression to the highly fatal stage of VHE.Clinicians must maintain a high index of suspicion and promptly assess serum ammonia levels upon any unexplained mental status changes or gastrointestinal symptoms in patients receiving VPA. Further research is imperative to clarify the role of adjunctive therapies such as L-carnitine and antibiotics, and to better understand the long-term clinical implications of asymptomatic hyperammonaemia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Conflicting Interests\u003c/strong\u003e: There no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributor statement\u003c/strong\u003e: SJK conceptualised the study. \u0026nbsp;IN collected the clinical data and SJK performed the analysis. IN wrote the first draft of the manuscript. SJK and IN were both involved in patient care and clinical follow-up. All authors critically reviewed the manuscript and approved the final version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e The data supporting the findings of this study were generated during routine clinical care. Due to the sensitive nature of patient information and to protect patient confidentiality, the data are not publicly available. De-identified data may be made available from the corresponding author upon reasonable request and with appropriate institutional approvals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration Regarding the Use of Generative AI:\u003c/strong\u003e None used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Committee Details\u003c/strong\u003e This case series was approved by the Departmental Scientific Committee, Department of Psychiatry, xxxxxxxxx. This case series was exempted from review by the Institutional Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Consent\u003c/strong\u003e Not applicable as the case series is based on review of retrospective medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrevious Presentation and Submission\u003c/strong\u003e: This work was presented as a poster presentation by xxxxx xxxx at xxxxxxx and won the best poster award. This article has not been submitted to other journals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors would like to thank the patients and their caregivers for their cooperation. We also acknowledge the support of the clinical and nursing staff of the Department of Psychiatry, xxxxxxx, for their assistance in patient care and data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eResearch C for DE and. Valproate Information, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information (2019, accessed 14 December 2025).\u003c/li\u003e\n \u003cli\u003eStahl SM. \u003cem\u003eStahl\u0026rsquo;s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications\u003c/em\u003e. 5th edn. Cambridge: Cambridge University Press. Epub ahead of print 2021. DOI: 10.1017/9781108975292.\u003c/li\u003e\n \u003cli\u003eAuron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. \u003cem\u003ePediatr Nephrol\u003c/em\u003e 2012; 27: 207\u0026ndash;222.\u003c/li\u003e\n \u003cli\u003eRahman M, Awosika AO, Nguyen H. Valproic Acid. In: \u003cem\u003eStatPearls\u003c/em\u003e. Treasure Island (FL): StatPearls Publishing, http://www.ncbi.nlm.nih.gov/books/NBK559112/ (2024, accessed 18 April 2024).\u003c/li\u003e\n \u003cli\u003eBaddour E, Tewksbury A, Stauner N. Valproic acid\u0026ndash;induced hyperammonemia: Incidence, clinical significance, and treatment management. \u003cem\u003eMent Health Clin\u003c/em\u003e 2018; 8: 73\u0026ndash;77.\u003c/li\u003e\n \u003cli\u003eNair I, Kantipudi SJ. Valproate-induced Hyperammonaemia in a Bipolar Disorder Patient: A Case Report. \u003cem\u003eJ Clin Diagn Res\u003c/em\u003e. Epub ahead of print 2024. DOI: 10.7860/JCDR/2024/75123.20258.\u003c/li\u003e\n \u003cli\u003eAbhilasha P, Bhatti N, Joseph G, et al. Sodium Valproate-Induced Hyperammonemia: A Case Series in a Tertiary Care Hospital. \u003cem\u003eCureus\u003c/em\u003e 2024; 16: e65390.\u003c/li\u003e\n \u003cli\u003eV\u0026aacute;zquez M, Fagiolino P, Maldonado C, et al. Hyperammonemia Associated with Valproic Acid Concentrations. \u003cem\u003eBioMed Res Int\u003c/em\u003e 2014; 2014: 1\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eCheng M, Tang X, Wen S, et al. Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. \u003cem\u003eCompr Psychiatry\u003c/em\u003e 2013; 54: 562\u0026ndash;567.\u003c/li\u003e\n \u003cli\u003eChopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. \u003cem\u003eGen Hosp Psychiatry\u003c/em\u003e 2012; 34: 290\u0026ndash;298.\u003c/li\u003e\n \u003cli\u003eSegura-Bruna N, Rodriguez-Campello A, Puente V, et al. Valproate-induced hyperammonemic encephalopathy. \u003cem\u003eActa Neurol Scand\u003c/em\u003e 2006; 114: 1\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eWong Y-CJ, Fan J, Wan A, et al. Valproic Acid\u0026ndash;Associated Hyperammonemia: A Systematic Review. \u003cem\u003eJ Clin Psychopharmacol\u003c/em\u003e 2023; 43: 283\u0026ndash;294.\u003c/li\u003e\n \u003cli\u003eDuman B. Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions. \u003cem\u003eGen Hosp Psychiatry\u003c/em\u003e.\u003c/li\u003e\n \u003cli\u003eMcMorris T, Chu A, Vu L, et al. Hyperammonemia in patients receiving valproic acid in the hospital setting: A retrospective review. \u003cem\u003eMent Health Clin\u003c/em\u003e 2021; 11: 243\u0026ndash;247.\u003c/li\u003e\n \u003cli\u003eLewis C, Deshpande A, Tesar GE, et al. Valproate-induced hyperammonemic encephalopathy: a brief review. \u003cem\u003eCurr Med Res Opin\u003c/em\u003e 2012; 28: 1039\u0026ndash;1042.\u003c/li\u003e\n \u003cli\u003eBrown LM, Cupples N, Moore TA. Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: A case series and literature review. \u003cem\u003eMent Health Clin\u003c/em\u003e 2018; 8: 148\u0026ndash;154.\u003c/li\u003e\n \u003cli\u003eCattaneo CI, Ressico F, Valsesia R, et al. Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e 2017; 96: e8117.\u003c/li\u003e\n \u003cli\u003eVaidyanathan S, Chatorikar S, Praharaj SK, et al. Valproate-Associated Hyperammonemic Encephalopathy: Clinical Correlates and Management Strategies in a Tertiary Care Center. \u003cem\u003eJ Clin Psychopharmacol\u003c/em\u003e 2023; 43: 145\u0026ndash;148.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTABLE 1. Clinical profile of patients with Valproate-associated Hyperammonaemia\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS. No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValproate dose/day\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of Valproate therapy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum ammonia (\u0026micro;g/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCourse at hospital\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAlcohol \u0026nbsp; \u0026nbsp; use disorder\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1000 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e92.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eT. Sodium Valproate was stopped and maintained on Olanzapine 20mg and ECT.Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eSchizoaffective disorder\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1500 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e91.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eT. Sodium Valproate was stopped and changed over to T. Lithium 800mg along with Haloperidol 15mg.Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e40\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1500 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e108.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eT. Sodium Valproate was stopped and changed over to T. Lithium 800mg along with Olanzapine 20mg. Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003ePsychosis with mood symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1000 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e11 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eT. Sodium Valproate was stopped and maintained on Risperidone 3mg Syrup. Lactulose 30ml HS was added and S. ammonia levels were repeated everyday till the levels reached normal limits.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1750 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e16 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e55.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eT. Sodium Valproate was initiated at a reduced dose of 1000mg(Previously on 1750mg) and added Risperidone 3mg S. ammonia levels were repeated daily and normalised in 3 days. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1500 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eAll psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started on Tab. Lithium 900mg and T. Risperidone 8 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1500 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e99.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eAll psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later restarted on Tab.Valproate 1000 mg(previously 1500mg) and T. Quetiapine 200 mg. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e2000 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e89.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eAll psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started Tab. Lithium 800mg. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eBPAD- current episode mania\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1000 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eAll psychotropics were stopped and patient was started on Syp.Lactulose 15ml HS. Patient was later started Tab. Lithium 800mg. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eOrganic Mood Disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1500mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e71.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003eAll psychotropics were stopped and the patient was started on Syp. Lactulose 30ml HS. Patient was later started on Tab. Lorazepam 2mg, Tab. Melatonin 3mg, Tab. Aripiprazole 5mg, Tab. Quetiapine 150mg and Tab. Naltrexone 50mg.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003eTable 2: Naranjo causality assessment scale\u003c/strong\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNaranjo Question\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse \u0026amp; Score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRationale based on Case series\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1. Previous conclusive reports?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eYes (+1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eValproate-induced hyperammonemia (HA) and encephalopathy (VHE) are known complications.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e2. ADR appeared after drug administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eYes (+2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eSymptoms (drowsiness, nausea, lethargy) appeared acutely 2 to 16 days after VPA initiation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e3. ADR improved when drug was discontinued?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eYes (+1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eSymptoms improved, and ammonia levels normalized within 3-4 days after VPA discontinuation and Lactulose initiation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e4. ADR reappeared when re-administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDo Not Know (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eVPA was cautiously reinitiated in two patients (Case 5, 7), but the outcome regarding recurrence of hyperammonemia is not known, as patients were not followed up after 2 months.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e5. Alternative causes could have caused?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eNo (+2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eRoutine investigations, including Liver Function Tests (LFTs), were normal.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e6. Reaction reappeared with placebo?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eNo (+1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eNot applicable.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e7. Drug detected in toxic concentration?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDo Not Know (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eSerum VPA levels were not assessed in most cases; as symptoms developed in short span after Valproate therapy.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e8. Severity change with dose?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDo Not Know (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eDose response before discontinuation is not available.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e9. Similar reaction previously?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eNo (0)/ Do Not Know (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eThere were no prior medical records indicative of VPA use in the past, except for one patient.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e10. ADR confirmed by objective evidence?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003eYes (+1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eConfirmed by significantly elevated serum ammonia levels in all patients.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Naranjo Score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProbable Adverse Drug Reaction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8469849/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8469849/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eValproate is an agent commonly used for its antiepileptic properties, but in psychiatry it is used for its mood stabilising properties.Valproate-induced hyperammonemic encephalopathy (VHE) \u0026nbsp;is rare but potentially life-threatening complication that can occur even at therapeutic drug levels and with normal liver function. Here, we present a series of ten cases, eight males and two females who got admitted to a tertiary health care centre and developed acute-onset drowsiness, nausea, and lethargy within 2-16 days of initiating valproate therapy. All patients had normal liver function tests but significantly elevated serum ammonia levels.Prompt discontinuation of Valproate and administration of lactulose helped reverse the elevated serum ammonia levels. None of the patients who presented withhyperammonaemia progressed to VHE. This highlights the idiosyncratic nature of VHE, and the need for watchfulness in patients on Valproate. Clinicians should monitor for unexplained mental status changes, particularly when accompanied by gastrointestinal symptoms, and promptly assess serum ammonia levels. Failure to promptly recognize and address hyperammonaemia drastically increases the risk of severe, potentially life-threatening complications like VHE. Early diagnosis and prompt intervention are essential to mitigate this risk and avoid progression to the highly fatal stage of encephalopathy.\u003c/p\u003e","manuscriptTitle":" Unveiling Valproate induced Hyperammonaemia – Clinical insights from a case series in Psychiatric inpatient setting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-24 00:42:17","doi":"10.21203/rs.3.rs-8469849/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a443874-d729-4492-8dae-7f291866cc16","owner":[],"postedDate":"January 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-24T00:42:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-24 00:42:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8469849","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8469849","identity":"rs-8469849","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}