Serum Valproate Concentrations Research Articles

Effect of sodium valproate monotherapy on serum uric acid concentrations in ambulatory epileptic children: A prospective long-term study

Purpose Hyperuricemia has been shown to be related to cardiovascular morbidity and mortality. There is controversial data about the effect of sodium valproate (VPA) monotherapy on serum uric acid concentrations. The purpose of this study was to investigate by a long-term, prospective method, whether treatment with VPA monotherapy may alter serum uric acid concentrations and liver function tests in ambulatory epileptic children. Material and methods Serum uric acid concentrations were determined in 28 ambulatory epileptic children before and at 6, 12 and 24 months of VPA monotherapy. Serum concentrations of biochemical markers of liver and renal function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase ( γ-GT) and creatinine (Cr) were also measured before and at 6, 12 and 24 months of VPA monotherapy. Serum VPA concentrations remained within the therapeutic range (50–100 mg/L) during the period of study. Results No statistically significant changes in serum uric acid concentrations were found at 6, 12 or 24 months of treatment. Serum ALT concentrations were significantly increased at 6 and 12 months of treatment, AST concentrations at 6 and 12 months of treatment and LDH concentrations at 12 months of treatment. Conclusions VPA monotherapy does not have a significant effect on serum uric acid concentrations in ambulatory epileptic children. Further studies are needed to definitively address whether it would be useful for physicians to routinely check for elevated serum uric acid levels in children treated with VPA.

Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics

It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy. The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22). The study duration was 16 months (four phases of 4 months each). VPA pharmacokinetics data were also compared in the different regimens. Mean VPA dosage was of approximately 870 mg/day (approximately 22 mg/kg/day) and mean VPA concentration was of approximately 89 mg/l at 12 h post-dose and of 54 mg/l at 24 h post-dose. By intention in treatment there were no significant differences in efficacy (73%, 83%, 77% and 75%, respectively) or in adverse reaction frequency (56%, 58%, 67% and 46%, respectively). There were significant differences, however, in patient (or parents) preference, the order being ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%). The mean VPA serum concentration fluctuation between 4 h and 0 h post-morning-dose was nonsignificantly lower after CVbid than after ChVbid. Fluctuation was significantly higher after ChVom than after CVbid or ChVbid. The mean VPA serum concentration difference between 12 h and 24 h post-dose was approximately 40 mg/l. Although our results should be confirmed by a larger study, they suggest that the efficacy and tolerability of chrono valproate is similar to that of conventional valproate, and that the main advantage is the once-daily administration.

Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1 Hz rTMS in patients with juvenile myoclonic epilepsy

Objective The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. Methods Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. Results In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. Conclusions Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. Significance The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.

Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania

Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.

Effect of antiepileptic drug monotherapy on urinary pH in children and young adults

Since alkaline urine is a risk factor for urolithiasis, the relationship between antiepileptic drugs and urinary pH was retrospectively studied in epilepsy patients treated with antiepileptic drug monotherapy for more than 1 month. A total of 913 urinary samples from antiepileptic drug-treated patients were compared with 780 age-matched control samples, and with 112 samples from epilepsy patients who had not been treated with antiepileptic drugs. The antiepileptic drugs administered were carbamazepine, valproate, phenobarbital, zonisamide, sulthiame, and phenytoin. The proportion of the acid urine in the valproate-treated patients was lower than that in controls. The proportion of the alkaline urine in the valproate-treated patients was higher than that in controls. This effect was independent of age, sex, and the serum valproate concentration. There was no significant difference in urinary pH among the epilepsy patients treated with other antiepileptic drugs, the epilepsy patients who had not been treated with antiepileptic drugs, and the controls.

Seizure Worsening Caused by Decreased Serum Valproate During Meropenem Therapy

Serum concentrations of valproate were reduced and seizures were exacerbated by concomitant meropenem therapy in a child with a neurodegenerative disorder and epilepsy. In this patient, a rapid decline of valproate serum concentrations was observed on two occasions with meropenem antibiotic therapy. This event was the most likely cause of observed seizure exacerbation. Meropenem should be used with caution in patients treated with valproate owing to the drastic lowering of serum valproate concentration and the consequent risk of seizure worsening.

Efficacy of Valproate Maintenance in Patients With Bipolar Disorder and Alcoholism

More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime. Patients with comorbid substance abuse disorders often are excluded from clinical trials. Thus, treatments targeting this high-risk clinical population are lacking. To evaluate the efficacy of divalproex sodium (hereafter referred to as valproate) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism. A 24-week, double-blind, placebo-controlled, randomized parallel-group trial. A university hospital serving as a primary catchment-area hospital and tertiary-care facility. Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence. Intervention All study subjects received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo. Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day. Other alcohol use outcomes included proportion of any drinking days, number of drinks per drinking day, and relapse to sustained heavy drinking. Mood outcomes included changes in depressive and manic symptoms. We used the mixed model to analyze longitudinal data. The first model used time of assessment, bipolar subtype (mixed, manic, or depressed), and treatment group (placebo or valproate) as covariates. The second nested model included the additional covariate of medication adherence. The valproate group had a significantly lower proportion of heavy drinking days (P = .02) and a trend toward fewer drinks per heavy drinking day (P = .055) than the placebo group. When medication adherence was added as covariate, the valproate group had significantly fewer drinks per heavy drinking day (P = .02) and fewer drinks per drinking day (P = .02). Higher valproate serum concentration significantly correlated with improved alcohol use outcomes. Manic and depressive symptoms improved equally in both groups. Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group. Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence. The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer, valproate, in bipolar disorder with co-occurring alcohol dependence.

Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly.

Valproate exhibits a complex pharmacokinetic profile due to concentration-dependent protein binding and clearance. It has been shown that the protein binding of valproate decreases as the serum concentration increases in a young adult population. Furthermore, the percentage of protein binding is lower in the elderly compared with young adults at comparable low therapeutic serum concentrations. The extent of valproate protein binding at higher concentrations in the elderly has not been described. Studies conducted in the elderly have found unbound valproate clearance to be decreased compared with younger adults, although these changes in clearance have not been evaluated at higher therapeutic serum concentrations. We evaluated the pharmacokinetics of valproate (protein binding and clearance) across a wide dosage range in the elderly and measured the impact of this on drug-related side effects using a single-blind within-subject study design in 6 healthy elderly volunteers (aged 65-76 years). Steady-state total and unbound serum valproate concentrations were assessed at 3 doses: 500, 1000, and 1500 mg/d. As doses and valproate serum concentrations increased, the unbound fraction (10.0%, 13.0%, 17.4%) and total clearance (4.8, 6.0, 6.7 mL/h/kg) increased, respectively. Unbound clearance decreased (49.4, 45.8, 39.4 mL/h/kg) with increasing valproate serum concentrations. Drug-induced CNS effects and nausea severity scores correlated with total and unbound serum valproate concentrations. Significant dose-dependent changes in valproate pharmacokinetics were observed in the elderly.

Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy.

We performed volume-selective 1H MR spectroscopy (1H-MRS) on 12 patients on valproate monotherapy to detect valproate in vivo in the brain. We also acquired reference valproate spectra in vitro in subphysiological 15 g/l albumin solution in saline, in which valproate showed two resonance peaks at 0.7 and 1.2 ppm and a minimum detection threshold of 240 mg/l. In vivo 1H-MRS spectra in brain showed peaks between 0.6 and 1.6 ppm. Simultaneous serum valproate concentrations did not correlate with these integrated MRS peaks. On follow-up, changes in these signals also did not correlate with increasing serum valproate levels. The inconsistency of in vivo 1H-MRS signals at varying serum levels and the high detection levels in vitro suggest that valproate signals are missed in vivo because valproate is metabolised or strongly bound, presumably to brain macromolecules.

Acute Valproate Administration Impairs Methionine Metabolism in Rats

Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug.

てんかん患者におけるバルプロ酸ナトリウムとゾニサミドの薬物動態学的相互作用

We retrospectively examined the effects of the combination of zonisamide (ZNS) on the serum valproate (VPA) concentrations in 10 epileptic patients. The serum VPA concentrations at a steady state in VPA and ZNS combination therapy was about 1.1 times as high as those in VPA monotherapy (p<0.01). Furthermore, the extent of change in the VPA concentrations ((VPA concentration in the combination therapy of VPA and ZNS) / (VPA concentration in the VPA monotherapy)) tended to increase in proportion to the serum concentration of ZNS. These results suggest that the pharmacokinetic interaction between these drugs may be clinically negligible, however the serum VPA concentrations should be carefully monitored when the serum ZNS concentration is high.

Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

Purpose: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. Method: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). Results: sixty-two patients (33.6±11.3 years, 47±9.9 kg) receiving LTG monotherapy ( n=19) or polytherapy with VPA ( n=15), inducer(s) ( n=32) or both ( n=5) were evaluated. LTG dose of 369±236 mg per day (8.1±5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8±3.3 μg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/ F) were 0.69±0.2, 1.60±0.65 and 0.2±0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/ F. Conclusion: LTG Cl/ F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.

CHARACTERISTICS AND PHARMACOKINETICS OF VALPROATE USE IN THE NURSING HOME

Valproate use in older adults is increasing, both due to high prevalence of active seizure disorder in the geriatric population and the increasing use of valproate for behavioral disorders. No information is available regarding the basic characteristics of valproate use in nursing homes. The authors found 29 out of 540 (5.4%) residents at a community nursing home received valproate. Nineteen (3.5%) had a behavioral indication or comorbidity, mostly behavioral and psychological symptoms of dementia. Ten (1.9%) had seizure disorder only. There was a significant difference between the valproate serum concentrations achieved for treatment of behavior disorders versus seizures disorders. No difference was found in gender characteristics of valproate use except for weight and valproate volume. Age grouping created significant differences in several characteristics. A dose-serum concentration correlation of 0.85 was found in a group of subjects taking no drugs that interact with valproate, while this correlation was lost in a group with drug interactions present. No significant change in valproate serum concentrations was found from one measurement to another over a period of approximately 3 months in a group of residents on stable valproate dose. These findings lend further support that valproate is safe and well tolerated in the nursing home population, where it is seeing increasing use. These findings also give indications regarding dosing of valproate and regular follow-up of serum concentrations. P80

Prediction of valproate serum concentrations in adult psychiatric patients using Bayesian model estimations with NPEM2 population pharmacokinetic parameters.

Valproate serum concentrations between 45 and 125 microg/mL are associated with the drug's efficacy in acute mania. Adaptive control dosing of valproate has not been fully studied in psychiatry. The objective of this study was to derive population pharmacokinetic (PK) parameters for valproate in healthy volunteers and to test the ability of these PK parameters to estimate concentrations in adult psychiatric patients using a Bayesian program. Population PK parameters for oral valproate were estimated from 18 PK studies in six healthy volunteers (1) using NPEM2. A Bayesian PK program using these population parameters was used to predict valproate concentration-time points in a second cohort of 21 adult psychiatry patients using 0, 1, or 2 prior concentrations. Estimated population parameters (mean +/- SD) were: Ka, 1.15+/-1.75/h; V, 0.14+/-0.042 L/Kg; and CL, 0.902+/-0.133 L/h. Bayesian valproate estimations using these parameters were negatively biased (underestimations) using zero prior concentration and unbiased using 1 or 2 prior concentrations. Mean error values (95% CI) in microg/mL for predictions using 0, 1, or 2 prior concentration-time points were -12.0 (-22.5, -1.5), -9.5 (-19.1, 0.1), and -2.5 (-11.1, 6.1), respectively, and mean absolute error values in microg/mL (95% CI) were 19.8 (12.6, 27.1), 16.3 (9.4, 23.3), and 10.1 (4.9, 15.2), respectively. Population parameters derived from healthy adult volunteers provided biased predictions of valproate concentrations in adult psychiatric patients. However, estimates using 1 or 2 valproate concentration time points predicted future concentrations that were precise and unbiased, given the wide therapeutic target range.

Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients.

IV valproate may be given to patients requiring rapid elevation of serum valproate or for patients unable to take oral medication. Previously we established the loading dose of IV valproate needed to achieve serum concentrations of > 100 ug/ml. This study evaluated the safety of rapid infusion of valproate to achieve high therapeutic levels. Twenty-four infusions of IV valproate were carried out electively in twenty-one patients with epilepsy (ages 2-54 years). The dose ranged from 21-28 mg/kg (mean 24.2 mg/kg). Target infusion rates were 3 or 6 mg/kg per min, yielding an infusion duration of 4.17 or 8.34 min. ECG was monitored; blood pressure was measured before and after infusion. Post infusion serum valproate concentrations were 64-204.1 ug/ml (mean 132.6). There were no significant changes in blood pressure and no ECG abnormalities observed. Transient pain occurred at the site of injection in five patients, associated with redness in two. This appeared to related to the concentration of valproic acid in the infusion fluid. We conclude that a loading dose of IV valproate can be administered safely and rapidly. This finding enables further studies evaluating IV valproate as a non-sedative anticonvulsant in the management of status epilepticus.

Relevancia clínica de las determinaciones seriadas de concentraciones séricas de carbamacepina y valproato sódico

Serum concentrations of valproate (VPA) and carbamazepine (CBZ) were monitored in 66 epileptic out patients to determine then pharmacokinetic profiles. Thirty-eight patients were receiving monotherapy, 17 with CBZ and 28 with VPA, and 28 patients were receiving VPA and CBZ. All were receiving standard (not controlled-release) CBZ or VPA preparations. Blood samples were obtained 2, 4, and 6 hours after the last dose. Serum concentrations were determined by gas chromatography. Mean serum concentrations of patients receiving CBZ were 8.2, 7.3 and 6.4 micrograms/ml for the 2, 4 and 6 hours samples, respectively. Mean serum concentrations of CBZ in the group receiving CBZ + VAP were 7.8, 8.4 and 7.8 micrograms/ml, respectively. Patients receiving VPA had mean serum concentrations of 92.8, 97.8 micrograms/ml, respectively. Those receiving CBZ + VPA had serum concentrations of 69.1, 70.6 and 55.8 micrograms/ml, respectively. Mean variation in the CBZ serum concentrations was 45% (range 7-91%) in patients receiving monotherapy and 31% (range 8-93%) in patients receiving CBZ + VPA. Mean variation in VPA serum levels of the patients receiving CBZ + VPA (56%) was greater than those of patients receiving CPA alone (38%). Subtherapeutic serum levels of either drug were detected in 35% of the patients. The large inter- and intraindividual variability of serum concentrations showed that a single measurement does not reflect the reality or CBZ and VPA clinical kinetics. The results confirm that three samples collected at 2, 4, and 6 hours after the last dose determine a clinically useful kinetic profile.

Safety of high intravenous valproate loading doses in epilepsy patients

Parenteral antiepileptic drugs (AEDs) are required in patients needing emergent treatment or unable to take oral medication. In the two United States trials of IV valproate, only low therapeutic serum levels were achieved. This study evaluated the safety of high loading doses to achieve therapeutic levels rapidly. Twenty-five epilepsy patients without active seizures received a single loading dose of IV valproate (Depacon) based on body weight and infused over 1 hour. Ages were 4–39 years (mean: 13.1 ± 8.6 years). Electrocardiogram (ECG) and electroencephalogram (EEG) were monitored throughout infusion; blood pressure was measured before and after. Serum valproate was measured 10 minutes postinfusion. The IV valproate dose range was 15–44 mg/kg (mean: 28.3 ± 7.4 mg/kg); infusion rates were 0.25–0.73 mg/ kg/minute (mean: 0.47 ± 0.1 mg/kg/minute). Postinfusion serum valproate concentrations were 71–277 μg/ml (mean: 135.3 ± 59.5 μg/ml). There were no significant changes in blood pressure, no redness or tenderness at the IV site, and no ECG abnormalities. One patient with serum valproate ⩾ 200 μg/ml had mild sedation (resolving in 24 hours). We concluded that serum valproate concentrations of ⩾ 100 μg/ml can be achieved rapidly and safely parenterally, a finding with important implications for the treatment of status epilepticus.

Valproate therapy does not deplete carnitine levels in otherwise healthy children.

To determine whether children with epilepsy undergoing valproate (VPA) antiepileptic therapy and who are otherwise healthy have a lower serum level of carnitine (CAR) and a higher plasma level of plasma ammonia than do normal children. A total of 45 children with epilepsy, 6.3 to 21.7 years of age, who were treated solely with VPA and were free of abnormal neurologic findings or nutritional problems were randomly selected (VPA-treated group). An age-matched control group (n = 45) was selected from subjects without epilepsy (control group). Total (T) and free (F) serum CAR, serum VPA concentration, and the plasma ammonia level were measured and analyzed. Serum VPA concentration exhibited a weak negative correlation with both T- (r = -0.34) and F-CAR (r = -0.41). The T-CAR levels were 55.7 +/- 12.4 and 57.6 +/- 12.1 mM, and the F-CAR levels 42.7 +/- 9.9 and 44.4 +/- 9.9 mM in the VPA-treated and control groups, respectively. Thus, there was no significant difference in T- or F-CAR levels between the VPA-treated and control groups. Plasma ammonia levels were the same in the two groups: 26 +/- 9.2 and 29.4 +/- 11.8 mM in the VPA-treated and control groups, respectively. There was no significant correlation between blood ammonia and either T- (r = +0.024) or F-CAR (r = -0. 026). Children on a regular diet ingest a sufficient amount of CAR that more than meets their daily CAR requirement. The level of neither T- nor F-CAR in patients with epilepsy and without severe neurologic or nutritional problems being treated with VPA appeared to be affected by VPA therapy. Because the blood CAR level depends on nutritional condition rather than on blood VPA concentration, CAR deficiency caused by VPA is not likely to occur in this population. The usefulness of supplementation of CAR for this type of patient with epilepsy, therefore, must be reevaluated carefully.

Clinical correlates of response to valproate in geriatric inpatients.

The efficacy of valproate for the management of adults with bipolar disorder has been repeatedly demonstrated in several studies. Patients with mixed states, rapid cycling, and EEG abnormalities have been shown to respond favorably to valproate. Valproate is also being increasingly used in disorders with aggressive or agitated features, such as the behavioral disorders of dementia; yet, few studies have documented the utility of valproate in geriatric patients. The need to document safe and effective pharmacologic agents to treat geriatric mood and behavioral disorders continues to increase with the growing elderly population. We conducted a retrospective study of the use of valproate in patients consecutively hospitalized over a 5-year period on a psychiatric unit. Thirty-nine patients over age 60 were identified and then categorized into non-, partial, and full responders based on Clinical Global Impression ratings. Information on diagnosis, age, valproate dose and serum concentration, psychiatric symptoms, medical comorbidity, concurrent psychotropic medications, and side effects was collected. Results suggest that responders to valproate (full or partial) over the age of 60 years were more likely to be female, younger, carry a diagnosis of bipolar disorder, and achieve higher serum valproate concentrations. Full responders had fewer psychotic symptoms but usually displayed manic symptoms. The date of this study suggests the need for controlled clinical trials to clarify the utility and clinical predictors of response to valproate in the geriatric population.

Effect of carnitine on measures of energy levels, mood, cognition, and sleep in adolescents with epilepsy treated with valproate

Valproate therapy has been associated with significant decreases in serum-free carnitine plasma concentrations. This double-blind, placebo-controlled cross-over study investigated the usefulness of carnitine supplementation in affecting perceived energy levels in a group of adolescents with epilepsy treated with valproate monotherapy. Eleven males and eight females received a randomized placebo phase and a treatment phase that consisted of L-carnitine, 1 gm twice daily for 5–6 weeks. Baseline, phase I, and phase II measurements included free and total carnitine, valproate serum concentration, venous ammonia concentration, self- and parent-ratings of mood state and energy levels, a screening test for cognitive ability, and 1-week sleep records. No significant group differences between carnitine and placebo conditions were found on any of the cognitive, mood, energy, or sleep measures. Only 2 out of 19 had low baseline serum carnitine. In conclusion, carnitine supplementation appears to have no discernable effects in this healthy sample and should be reserved for those patients on valproate with clinical evidence of carnitine deficiency.