Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions

Duman, Berker; Can, Kazım Cihan; Ağtaş-Ertan, Ece; Erdoğan, Şeyda; İlhan, Rıfat Serav; Doğan, Özlem; Kumbasar, Hakan; Camsari, Ulas M.

doi:10.1016/j.genhosppsych.2019.05.005

Cited by 30 publications

(28 citation statements)

References 5 publications

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“…Therefore, thrombocytopenia is thought to be a dose-dependent adverse effect of VPA, which is compatible with our result that higher free VPA serum concentration is a risk factor for thrombocytopenia, and a free VPA serum concentration of 14.67 mcg/mL had the optimal discriminating power for the occurrence of thrombocytopenia. The frequency of hyperammonemia in adult patients is highly variable, ranging from 27.8% to 55.3% [23][24][25]. The incidence of hyperammonemia in the current study was 31.6%, which is compatible with rates reported in other studies.…”

Section: Plos Onesupporting

confidence: 90%

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Safety range of free valproic acid serum concentration in adult patients

et al. 2020

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Background Therapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA's highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown. Objective To determine the optimal safety range of free VPA concentration in adult patients. Materials and methods This prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration. Results A total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia.

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Section: Plos Onesupporting

confidence: 90%

“…The frequency of hyperammonemia in adult patients is highly variable, ranging from 27.8% to 55.3% [ 23 – 25 ]. The incidence of hyperammonemia in the current study was 31.6%, which is compatible with rates reported in other studies.…”

Section: Discussionmentioning

confidence: 99%

Safety range of free valproic acid serum concentration in adult patients

et al. 2020

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“…Second, we measured the VPA concentration in a subgroup of animals, hence, we could not examine correlation between plasma VPA and NH 4 concentration. However, most [ 11 , 12 , 14 ], but not all [ 8 , 9 , 32 , 59 ], clinical studies reported that VPA and NH 4 concentrations are not necessarily corelated. Third, we only quantified GS activity as the primary NH 4 metabolizing enzyme in the brain.…”

Section: Discussionmentioning

confidence: 99%

Chronic Valproic Acid Administration Increases Plasma, Liver, and Brain Ammonia Concentration and Suppresses Glutamine Synthetase Activity

et al. 2020

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Asymptomatic valproic acid (VPA)-induced hyperammonemia in the absence of liver impairment is fairly common. However, the underlying mechanisms through which VPA causes elevation in plasma ammonia (NH4) remains under investigation. Male Sprague Dawley rats (n = 72) were randomly allocated to receive VPA 400 mg/kg, 200 mg/kg, or vehicle IP daily for either 8, 14, or 28 consecutive days. The behavioral effects of VPA were assessed. Plasma, liver, and prefrontal cortex (PFC), striatum (Str), and cerebellum (Cere) were collected 1 h post last injection and assayed for NH4 concentration and glutamine synthetase (GS) enzyme activity. Chronic VPA treatment caused attenuation of measured behavioral reflexes (p < 0.0001) and increase in plasma NH4 concentration (p < 0.0001). The liver and brain also showed significant increase in tissue NH4 concentrations (p < 0.0001 each) associated with significant reduction in GS activity (p < 0.0001 and p = 0.0003, respectively). Higher tissue NH4 concentrations correlated with reduced GS activity in the liver (r = −0.447, p = 0.0007) but not in the brain (r = −0.058, p = 0.4). Within the brain, even though NH4 concentrations increased in the PFC (p = 0.001), Str (p < 0.0001), and Cere (p = 0.01), GS activity was reduced only in the PFC (p < 0.001) and not in Str (p = 0.2) or Cere (p = 0.1). These results suggest that VPA-induced elevation in plasma NH4 concentration could be related, at least in part, to the suppression of GS activity in liver and brain tissues. However, even though GS is the primary mechanism in brain NH4 clearance, the suppression of brain GS does not seem to be the main factor in explaining the elevation in brain NH4 concentration. Further research is urgently needed to investigate brain NH4 dynamics under chronic VPA treatment and whether VPA clinical efficacy in treating seizure disorders and bipolar mania is impacted by its effect on GS activity or other NH4 metabolizing enzymes.

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“…However, this study was limited by the lack of criteria for defining symptomatic hyperammonemia. Another prospective, cross-sectional study of 107 patients on valproate for mood disorders or epilepsy found valproate-induced hyperammonemia (VIH) (defined as ammonia > 52 μmol/L) in 55.3% of cases with a dose-dependent association between valproate and blood ammonia level [3].…”

Section: Discussionmentioning

confidence: 99%

A Case of Valproate-Induced Hyperammonemic Encephalopathy

Zafar

Billadeau

Ahmed

2020

Cureus

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A 56-year-old Caucasian male with a history of seizure disorder on long-term prophylaxis with valproate presented with altered mental status, aggressive behavior, decreased oral intake, and frequent myoclonic jerking movements. Electrolyte and other basic metabolic lab testing, liver function testing, and imaging studies were negative for acute abnormalities or infection, though ammonia levels returned markedly elevated, and he also had a macrocytic anemia despite having normal folate and B12 levels. Following discussions with neurology, his valproate was felt to be the inducing factor for his hyperammonemic encephalopathy. After discontinuation of valproate and changing to a new anti-seizure medication, he soon returned to his neurologic baseline. This case report evaluates his presentation and current literature on hyperammonemic encephalopathy induced by valproate.

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Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions

Cited by 30 publications

References 5 publications

Safety range of free valproic acid serum concentration in adult patients

Safety range of free valproic acid serum concentration in adult patients

Chronic Valproic Acid Administration Increases Plasma, Liver, and Brain Ammonia Concentration and Suppresses Glutamine Synthetase Activity

A Case of Valproate-Induced Hyperammonemic Encephalopathy

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