Serum Valproate Concentrations Research Articles

Seizures From Valproate–Carbapenem Interaction

Antiepileptic medication interactions can complicate the management of epilepsy, by either increasing or reducing the effective serum concentrations thereby causing adverse effects or loss of seizure control. A 14-year-old girl with well-controlled juvenile absence epilepsy lost control of her seizures acutely following the administration of carbapenem for pneumonia. Serum valproate concentrations fell by 90% within 48hours following carbapenem and returned to baseline following its discontinuation. Awareness of this clinically significant interaction alters clinical practice by avoiding carbapenem or temporary use of adjunctive medication to prevent the clinical consequences of this significant drug interaction.

1527 Seizure Worsening Caused by Low Serum Valproate Levels from an Interaction between Valproate and Meropenem

BackgroundMeropenem is a carbapenem antibiotic, has a broad spectrum of antimicrobial activity. Valproate is widely used in the treatment of epileptic seizures in children. In last years, low serum concentrations...

Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole

The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co-administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects. Two similarly designed, open-label, single-sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1-7. Following Day 7 was a 2-day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post-lithium or valproate administration on Days 7 and 26. The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C(max) and AUC(τ) , respectively. Furthermore, the addition of aripiprazole did not change the median T(max) of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady-state pharmacokinetics of lithium or valproate. The majority of subjects (76·9% for aripiprazole plus lithium and 68·4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co-administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects.

Vanishing Valproate: Significant Reductions in Serum Levels of Valproate with Meropenem Coadministration

ABSTRACTBackgroundThe first report of a valproate–meropenem interaction was published in 1998 and a warning was issued by the US Food and Drug Administration in 2001. Despite the documentation of this clinically significant drug interaction, there may be limited awareness among clinicians in Australia.Clinical Details: We report a case of a patient stabilised on valproate and topiramate for epilepsy who was started on intravenous meropenem for neutropenic sepsis. Within 48 hours of starting meropenem, the patient experienced multiple tonic–clonic seizures and the trough serum valproate concentration was 161 micromol/L. 2 weeks prior to meropenem initiation, a trough serum valproate concentration was 672 micromol/L. Our patient experienced a 75% reduction in serum valproate concentration within 48 hours of starting meropenem.ConclusionCo‐administration of valproate and meropenem should be avoided due to the rapid onset and extent of the interaction.

Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: Dynamic synergy and therapeutic utility

The omega-3 fatty acid eicosapentaenoic acid (EPA) is a superb nature's medicine, with still unfolding health benefits. Because hepatotoxicity is a prominent adverse drug reaction, we currently attempted a new approach in which EPA was challenged to both alleviate hepatotoxicity and provide synergy with anticonvulsant effects of valproate (VPA). Besides, we verified whether EPA may kinetically modulate the clearance rate of VPA. VPA (500mg/kg p.o., for 2weeks) caused rat hepatotoxicity that was manifested as notable (2- to 4-fold) rise in serum liver enzymes (GGT, ALT, and ALP), increased hepatic levels of lipid peroxides and TNF-α (3- and 7-fold) and activity of myeloperoxidase (MPO, 4-fold), lowering of serum albumin (42%), and depletion of liver reduced glutathione (GSH, 36%). Furthermore, histopathologic examination revealed hepatocellular degeneration, focal pericentral necrosis, infiltration of inflammatory cells, and steatosis. Joint treatment with EPA (300mg/kg) blunted the oxidative stress, TNF-α levels and MPO activity, while enhanced levels of serum albumin and hepatic GSH. EPA also ameliorated most of the hepatocellular anomalies evoked by VPA. Additionally, in a mouse PTZ convulsion model, EPA markedly augmented the anticonvulsant effects of VPA far beyond their single responses. On the other hand, pharmacokinetic analyses revealed that joint EPA administration had no effect on serum VPA concentrations. Collectively, results demonstrate for the first time that the ω-3 FA (EPA) markedly alleviated VPA-induced hepatotoxicity, oxidative stress, and inflammation, while enhanced its anticonvulsant effects without altering its clearance. Therapeutically, these protective and synergy profiles for EPA foster a more safe and efficacious drug combination regimen than VPA.

A Case of Valproate Induced Hyperammonemic Encephalopathy

A 36-years-old man on phenytoin, levetiracetam, and sodium valproate presented with acute confusion. Routine investigations including serum valproate and phenytoin concentration were normal. His serum ammonia concentration was raised. His valproate was held and 2 days later he recovered with concordant normalisation of serum ammonia concentration. Urea acid cycle disorder was ruled out, and a diagnosis of valproate induced hyperammonemic encephalopathy (VHE) was made. Asymptomatic hyperammonemia occurs in 15–50% of valproate-treated patients, and while the true incidence of VHE is not known, it is a recognized complication of sodium valproate treatment. VHE typically presents acutely with impaired consciousness, lethargy, and vomiting. Valproate concentrations may be in the therapeutic range, and liver function tests are typically “normal.” Treatment for VHE consists of ceasing valproate and providing supportive care. Some have advocated carnitine replacement.

C825T Polymorphism of the GNB3 Gene on Valproate-Related Metabolic Abnormalities in Bipolar Disorder Patients

Valproate (VPA) is a mood stabilizer for treating patients with bipolar disorder (BD). It may cause metabolic abnormalities in certain bipolar patients. However, the genetic factors that influence the susceptibility remain unclear. Genetic polymorphism of the G-protein β3 subunit (GNB3) is reported to be associated with metabolic phenotypes. In the current study, we investigated the possible associations between the GNB3 variation and VPA-induced metabolic abnormalities. Subjects (n = 96) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BD were recruited from the National Cheng Kung University Hospital. Their metabolic indices were measured. The variation of GNB3 C825T showed an association with higher plasma total cholesterol (P = 0.037), triglyceride (P = 0.014), and leptin (P < 0.001) levels in BD patients treated with VPA. After adjusting for age, sex, types of BDs, and serum concentration of VPA, the variation of GNB3 C825T remained significantly associated with the levels of serum leptin and body mass index (BMI; P < 0.001 and P = 0.030, respectively). In addition, the GNB3 C825T showed significant drug-single-nucleotide polymorphism interactions with insulin levels (P = 0.033), triglyceride levels (P = 0.013), leptin levels (P = 0.013), and BMI (P = 0.018). These results indicated that the T allele may be associated with lower serum leptin levels and BMI in BD patients treated with VPA. The current study provides evidence that BD patients who are T allele carriers of the GNB3 C825T polymorphism have a lower risk for VPA-induced metabolic abnormalities. Further studies about the underlying mechanisms of G protein in VPA-induced metabolic abnormalities are warranted.

Ertapenem-Induced Reduction in Valproate Levels: Case Report and Review of the Literature

Increasing the dose of valproatemay not compensate for the reduction, which puts the patientat risk for recurrent seizures. Therefore, close monitoring of valproate levels is necessary when initiating a carbapenemantibiotic in patients whose condition has been stabilized withvalproate therapy. Several case reports of significant reductions in serum valproate concentrations following initiation of carbapenemantibiotics have been published. To the authors’ knowledge,however, there has been no published systematic review of thecarbapenem–valproate interaction. We report a case of ertapenem-induced reduction in valproate concentration anddescribe the extent, clinical relevance, potential mechanisms,and therapeutic options for management of the carbapenem –valproate interaction.

Once daily monotherapy with prolonged-release valproate minitablets given in the evening – a chronopharmacological study

Chronopharmacological investigations concerning efficacy, side effects and circadian serum concentration are lacking for many antiepileptic drugs. In this study 27 patients with focal or generalized epilepsy receiving a single dosage of prolonged-release valproate given in the evening were included. The valproate serum concentration over a course of 24 hours and their correlation with the value measured at 9:00 am was examined. In approximately 60% of the patients the serum level measured at 9:00 am corresponded to the peak value. In an additional 33% of the patients the peak value was reached at either 12:00 midnight or at 3:00 am. During the course of the day all patients showed on average an additional decline in these values compared to the 9:00 am serum level of 41%. In only a third of the patients did the 24-hour profile exhibit an average increase that exceeded the 9:00 am value by as much as 4%. In the case of the 24-hour serum profile, when the daily dosage was weight-correlated no values for the normal dosage range (18 - 24 mg/kg body weight) gave values that exceeded or fell below the so-called therapeutic serum level range (50 - 100 mg/l). Neither seizures nor new adverse reactions occurred in this group. Therefore, in the case of adults and young adults, therapy with valproate prolonged-release at a dose rate of 24 mg/kg preparation given as a single dosage in the evening will be sufficient for seizure control in most patients. The low-dosage group (10 - 17 mg/kg body weight) exhibited values that fell below this range in the afternoon and early evening. The results are discussed with regards to the treatment in young adults and the elderly.

A Double-Blind, Randomized, Placebo-Controlled Trial of Divalproex Extended-Release in the Treatment of Bipolar Disorder in Children and Adolescents

ObjectivesTo compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. MethodIn the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 μg/mL. Sixty-six patients enrolled in the extension study. ResultsIn the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER −8.8 [n = 74]; placebo −7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. ConclusionsThe results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

Concentration of valproate during pregnancy, in the newborn and in breast milk.

The serum-valproate level of four patients with epilepsy was followed during pregnancy. A decrease in serum level occurred late in pregnancy and was followed by a pronounced increase in the first week after delivery. The maternal serum concentration of valproate was compared to that of the umbilical cord. The level in cord blood was 145-219% higher than that in maternal blood. The concentration of valproate in breast milk was found to be 5-10% of the maternal serum concentration. The serum concentration was measured in one breastfed child. The level was 7.6% of the maternal serum concentration. All children were healthy without any signs of intoxication or malformation. Based on our experience, pregnant patients treated with valproate must be carefully controlled especially during the last month of pregnancy and in the first two weeks after delivery. The amount of valproate excreted into the breast milk was negligible and should not prevent breast feeding.

Thyroid Function in Children With Epilepsy Treated With Sodium Valproate Monotherapy

Studies on the effects of sodium valproate (VPA) on thyroid hormone balance in patients with epilepsy are conflicting. The aim of this study was to prospectively evaluate the changes in thyroid profile in children with epilepsy treated with VPA monotherapy. Serum thyroxine, free thyroxine, triiodothyronine, and thyrotropin (TSH) levels were evaluated in 30 children with epilepsy, before and at 6, 12, and 24 months of VPA monotherapy. All children had normal thyroid function before the initiation of VPA treatment. Serum VPA concentrations remained within the therapeutic range (50-100 mg/L) during the period of study. Thyroxine and free thyroxine levels were significantly decreased, whereas TSH levels were significantly increased at 6, 12, and 24 months of VPA therapy. Triiodothyronine levels were significantly decreased only at 24 months of therapy. Thirteen children (43.3%) at 6 months, 14 children (46.6%) at 12 months, and 15 children (50%) at 24 months of treatment had TSH values greater than 5 mIU/mL. Normal serum TSH levels were restored in all 8 children examined at 3 months after withdrawal of medication. Valproate monotherapy may cause significant alteration in thyroid profile in children with epilepsy, occurring early in the course of treatment and persisting as long as VPA is initiated. Therefore, it may be useful to measure serum thyroid hormone concentrations routinely in children with epilepsy taking VPA. Further prospective studies are required to determine the mechanisms and risk factors for development of thyroid disturbance in children treated with VPA monotherapy.

Perspectives on interactions between antiepileptic drugs (AEDs) and antimicrobial agents

In the treatment of seizures and epilepsy associated with central nervous system (CNS) infections, drug-drug interactions may significantly and unexpectedly impact outcome not only of epilepsy but also of the infectious disorders in both emergent and chronic care situations. A case is described in whom, the administration of the antimicrobial agent, meropenem presumably reduced serum valproate concentrations resulting in impaired seizure control. Other situations are reviewed in which interactions between antiepileptic drugs (AEDs) and antimicrobial agents may be of clinical significance. These include: (1) seizure management in individuals with neurocysticercosis, (2) management of seizures in patients with lobar tuberculomas, (3) management of seizures due to cerebral abscess, and (4) management of seizures in HIV-seropositive individuals.

Life-threatening Valproate Overdose Successfully Treated with Haemodialysis

Valproate (VPA) poisoning is an increasing clinical problem. The most common finding in VPA overdose is the depression of the central nervous system, which may progress to coma and death. This type of poisoning is difficult to treat, as no antidote exists. This report describes a case with a 16-year-old girl who poisoned herself with valproate. Initial treatment included naloxone, but she did not respond. She became comatose, with serum VPA concentration of 1320 microg mL(-1). Three sessions of haemodialysis were performed, effectively eliminating VPA and decreasing the serum concentration. The patient regained consciousness and fully recovered.To our knowledge, this is the highest serum VPA concentration reported by now in children aged 16 or less. Haemodialysis has proved to be the treatment of choice for life-threatening acute VPA overdose in children.

THYROID FUNCTION IN EPILEPTIC CHILDREN TREATED WITH SODIUM-VALPROATE MONOTHERAPY: A PROSPECTIVE LONG-TERM STUDY

INTRODUCTION: Sodium valproate (VPA) is widely used for the treatment of partial and generalized epilepsy in childhood and adolescence. The results of studies that have evaluated the effect of VPA monotherapy on thyroid function in children are controversial. OBJECTIVE: The aim of this study was to investigate, prospectively, whether treatment with VPA has an effect on serum thyroid hormone concentrations in epileptic children. METHODS: Serum levels of triiodothyronine, thyroxine, free thyroxine, and thyrotropin were determined in 30 epileptic children (aged 2 to 14 years [mean ± SD: 9.10 ± 3.74 years]) before and after 6, 12, and 24 months of VPA monotherapy. RESULTS: Serum levels of thyroxine and free thyroxine were significantly decreased after 6 (P = .000 and .000, respectively), 12 (P = .000 and .015, respectively), and 24 (P = .000 and .003, respectively) months of treatment with VPA, whereas serum levels of triiodothyronine were significantly decreased only after 24 months of treatment (P = .043). Serum levels of thyrotropin were significantly increased after 6 (P = .000), 12 (P = .000), and 24 (P = .000) months of treatment with VPA. Thirteen children (43.3%) had thyrotropin values higher than the normal-range maximum after 6, 12, and 24 months of VPA monotherapy. Serum VPA concentrations remained within the therapeutic range during the period of study. CONCLUSIONS: Our results showed that VPA monotherapy in childhood may cause early and persistent alterations in thyroid function, which suggests a need for early and careful monitoring of serum thyroid hormone concentrations in epileptic children who receive VPA.

Population pharmacokinetics of valproate in Chinese children with epilepsy

The aim of the present study is to establish a population pharmacokinetic (PPK) model of valproate (VPA) in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups: the PPK model group (n=317) and the PPK valid group (n=100). The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were also calculated. Then, the values between the 2 models were compared. The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was: Ka=3.09 (h(-1)), V/F=20.4 (L), CL/F=0.296 (L/h). The final model was: Ka=0.251+2.24 x (1-HS) (h(-1)), V/F=2.88+0.157 x WT (L), CL/F=0.106(0.98 x CO)+ 0.0157 x AGE (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 (-30.36, -16.70), 3728.96 (2872.72, 4585.20), 39.62 (34.34, 44.90), and -0.06 (-0.14, 0.02), respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 (-4.85, 2.53), 1002.83 (1050.64, 1143.61), 23.04 (21.12, 24.96), and 0.08 (-0.04, 0.20), respectively. The final model was more optimal than the basic model. The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.

A report of two deaths from massive ibuprofen ingestion

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion. CASE 1: A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 microg/mL: the therapeutic range is 10-50 microg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired. CASE 2: A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 microg/mL and serum valproate concentration was 560 microg/mL: the therapeutic range is 50-100 microg/mL. In spite of supportive care and hemodialysis, he expired. We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.

An assessment of the clinical equivalence of valproate chrono and extended release divalproex formulations

Objective: No guideline currently exists to choose the clinically equivalent dose of divalproex extended release (ER) formulation while switching over from valproate chrono formulation. To address this issue, we evaluated the serum valproate concentration following switch over from valproate chrono to divalproex ER in persons with epilepsy. Materials and Methods: An open label study was conducted in two parts, each for a period of two months. During Part I, patients on regular twice-daily dose of valproate chrono were switched over to once daily divalproex ER (DESVAL ER® ) based on the dose escalation recommended when switching over from divalproex DR to ER formulation as the guideline. During Part II, we switched from valproate chrono to divalproex ER with same dosage. Serum valproate concentration, seizure frequency and side effects were assessed serially for two months after changeover and compared with the preswitch data. Results: During Part I, compared to the baseline level, there was a significant increase in mean serum valproate level at two months (67.0 ± 28.4 mg/ml versus 91.9 ± 3.5 mg/ml, P 0.004). With the same dose conversion during Part II, the mean valproate level did not significantly differ before and after the switch (81.5 mg/dl versus 85.7 mg/dl, P 0.08). The mean monthly seizure frequencies and serum ammonia levels did not change during either part. No significant adverse effects occurred. Conclusion: The results of this open label study with small number of patients need to be replicated among larger patient sample through a randomized control design before recommending same dose conversion from valproate chrono to divalproex ER without change in efficacy and tolerability,

Evaluation of renal tubular function in children taking anti‐epileptic treatment

To assess the effects of anti-epileptic drugs on renal tubular function. Urinary N-acetyl-beta-D-glucosaminidase activity was measured in 114 epileptic children (mean age 5.6 +/- 1.1 years) who were undergoing monotherapy with valproate (n = 46), carbamazepine (n = 34), lamotrigine (n = 13) and combined therapy with valproate+carbamazepine (n = 21). The urinary N-acetyl-beta-D-glucosaminidase index of valproate (P < 0.01), carbamazepine (P < 0.05) and polytherapy group (P < 0.01) were significantly elevated when compared with that of the control group. No significant difference in N-acetyl-beta-D-glucosaminidase levels was found between the lamotrigine group and the control subjects. We found that the distribution of the N-acetyl-beta-D-glucosaminidase values of patients depended significantly on the length of therapy (P < 0.01). The level of urinary excretion of N-acetyl-beta-D-glucosaminidase was significantly higher in the patients who were taking long-term treatment (>10 years) with valproate, carbamazepine and combined therapy than those taking therapy shorter than 10 years (P < 0.01). The mean serum concentrations of valproate and carbamazepine were 68.7 +/- 17.44 microg/mL and 5.41 +/- 1.23 microg/mL, respectively. There was a significant correlation between the serum concentration of valproate and urinary N-acetyl-beta-D-glucosaminidase levels (r = 0.44, P < 0.01). There was also a significant correlation between the serum concentration of carbamazepine and N-acetyl-beta-D-glucosaminidase excretion (r = 0.52, P < 0.01). The present study demonstrated that in patients treated with valproate and carbamazepine, an impairment of tubular function can be present, whereas lamotrigine does not cause any significant change.

A Randomized, Placebo-Controlled, Multicenter Study of Divalproex Sodium Extended Release in the Treatment of Acute Mania

The efficacy and safety of divalproex sodium extended release (divalproex ER) were evaluated in patients hospitalized for acute mania associated with bipolar I disorder, manic or mixed type (DSM-IV-TR criteria). Following screening and washout of psychotropic medications, 377 patients were randomly assigned in a 1:1 ratio to 21 days of double-blind treatment with divalproex ER (N = 192) or placebo (N = 185). Daily dosage was initiated at 25 mg/kg, increased 500 mg on day 3, and adjusted to serum valproate concentrations of 85 to 125 microg/mL. The Mania Rating Scale (MRS) was used to assess efficacy. Patients remained hospitalized at least 15 days during blinded treatment. The study was conducted from April 2003 to May 2004. Improvement from baseline on the MRS was significantly greater among patients who received divalproex ER compared with placebo at the first on-treatment rating assessment, day 5, and all subsequent ratings through day 21 (p = .013). Furthermore, the proportion of patients achieving at least 50% improvement from baseline in MRS was significantly higher in patients receiving divalproex ER (48%) than in patients receiving placebo (34%) (p = .012). Five of the 11 MRS items improved significantly more in patients receiving divalproex ER than placebo: less need for sleep (p <or= .01), more energetic (p <or= .05), increased activity (p <or= .05), generalized motor hyperactivity (p <or= .05), and racing thoughts (p <or= .001). Side effects associated with divalproex ER included somnolence, dizziness, and gastrointestinal complaints. The results indicate that dival-proex ER is effective and safe for the treatment of mania episodes in bipolar I patients. ClinicalTrials.gov identifier NCT00060905.