Valproate Preparations Research Articles

Antipsychotics, Antiepileptics, and Fabrication: Are We Making It or Faking It?

Antipsychotics, Antiepileptics, and Fabrication: Are We Making It or Faking It?

Do valproate preparations improve agitation in dementia? A Cochrane Review summary with commentary.

Do valproate preparations improve agitation in dementia? A Cochrane Review summary with commentary.

Acute Pancreatitis as a Complication of Antiepileptic Treatment: Case Series and Review of the Literature.

Acute pancreatitis (AP) appears to be rare disease in childhood. In children, it has a different aetiology and course, and requires different management than in adult patients. The diagnosis of AP is based on at least two of the three criteria, which include typical clinical symptoms, abnormalities in laboratory tests and/or imaging studies of the pancreas. There are many known causes leading to AP in children including infections, blunt abdominal trauma, genetic factors, gallstone disease, metabolic disorders, anatomical defects of the pancreas, systemic diseases, as well as drugs, including antiepileptic drugs, and especially preparations of valproic acid. In our study, we present four cases of young patients diagnosed with acute pancreatitis as a complication of valproic acid therapy and we present a review of the literature. We believe that the activity of pancreatic enzymes should be monitored in children treated with valproate preparations in the case of clinical symptoms suggesting AP.

Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study

BackgroundA clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated. MethodsIn this single arm study, five adult subjects, with 29–234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system (clinicaltrials.gov identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol. FindingsThe procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 μg per ml (range 20–120 μg per ml), with corresponding serum levels of 4–14 μg per ml. Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.5–15 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid. InterpretationThe study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal. FundingThe study was funded by Cerebral Therapeutics Inc., Suite 137 12635 East Montview Blvd Aurora CO 80045.

Prescription of Valproate-Containing Medicines in Women of Childbearing Potential who have Psychiatric Disorders: Is It Worth the Risk?

Valproate-containing medicines have long been used in psychiatric practice, principally in the treatment of acute manic episodes, as augmentation agents in the treatment of bipolar and unipolar depressive episodes, and in the prophylaxis of bipolar affective disorder. Many babies are still being born with the adverse consequences of valproate exposure in utero, which include congenital malformations, neurodevelopmental delay, and increased risks of attention-deficit hyperactivity disorder and autism spectrum disorder. Previous measures designed to better inform women about the risks associated with valproate have not been sufficiently effective. This review highlights recent recommendations from influential regulatory and advisory bodies, summarises the relative efficacy and tolerability of valproate preparations in the psychiatric conditions for which they have often been prescribed, and offers practical guidance for the withdrawal and replacement of valproate-containing medicines in women with psychiatric disorders.

Learning disabilities: Interventions and clinical issues

Learning disabilities: Interventions and clinical issues

Use of valproate: Implications for women with intellectual disabilities and the wider interdisciplinary healthcare team

Accessible summary A medicine called valproate is sometimes prescribed for epilepsy and problems with mental health and mood. Valproate is also known as Epilim, Depakote, Convulex, Episenta, Epival, Kentlim, Orlept, Syonell and Valpal. Women with epilepsy and/ or mood problems should not take this medicine when they are pregnant unless, in the case of epilepsy, there is no suitable alternative treatment. Women who have only mood problems should not be given this medicine at all when they are pregnant. If a woman is prescribed valproate, she must use highly effective contraception, so she does not get pregnant. Some woman with intellectual disabilities and epilepsy and/ or mood problems who take this medicine may need help in understanding that they must use contraception. Doctors, nurses and other health and social care workers all need to know about this so that they can advise women with intellectual disabilities of the dangers. AbstractBackgroundIt is well established that valproate, and its valproic acid, sodium valproate, and valproate semisodium forms is a highly teratogenic drug and evidence suggests that use in pregnancy leads to physical birth defects in 10% of children born compared with a background rate of 2% to 3%. Congenital malformations associated with valproate are predominantly neural tube defects, clefting abnormalities, cardiovascular defects, genitourinary defects in males, and musculoskeletal defects. There is also increased risk of developmental delays and this includes delays in walking, talking, poor language skills, memory problems, and low intellectual ability in approximately 30 to 40% children born to mothers taking valproate. Furthermore, developing foetuses, if exposed to valproate in‐utero, are at increased risk of autistic spectrum disorder (approximately three‐fold), and also more likely to develop symptoms of attention‐deficit/hyperactivity disorder. Subsequently valproate preparations prescribed to treat epilepsy are now contraindicated in pregnancy unless there is no suitable alternative treatment. In addition, valproate preparations prescribed for bipolar disorder have an absolute contraindication in pregnancy.Implications for practiceIn order for valproate containing medicines to be prescribed for women of child bearing potential a risk acknowledgment form must be completed annually. For people without capacity to consent the form may be completed by a relative or other appropriate person. However, for people with intellectual disabilities, even with capacity, healthcare professionals need to ensure that the information on the form is accessible in order that they can understand it. They may not choose to give consent for a third party to complete the form on their behalf. Often intellectual disability nurses have a pivotal role, on behalf of the interdisciplinary team (IDT), in identifying women of child bearing potential who are currently prescribed valproate. Notwithstanding the IDT also has a role in engaging with patients during discussions to ensure they understand the conditions of prescribing. It is important that the IDT understand their role in patient engagement to facilitate shared decision making. Therefore, for women with intellectual disabilities with capacity, consent to treatment must be ‘informed’, and all risks will need to be communicated to the woman, exploring alternatives in order to comply with the Montgomery Judgement. Specialist intellectual disability nurses have a pivotal role in discussing appropriate contraceptive advice, and sign‐posting women to local services.ConclusionValproate preparations prescribed to treat epilepsy are contraindicated in pregnancy unless there is no suitable alternative treatment; in addition, valproate preparations prescribed for bipolar disorder have an absolute contraindication in pregnancy. It is imperative that specialist intellectual disability services are able to advise the wider primary health care team on best practice. Additionally, those with prescribing responsibilities, and particularly specialist intellectual disability epilepsy nurses, along with the wider IDT, must be aware of these new regulations.

Valproate preparations for agitation in dementia.

Agitation has been reported in up to 90% of people with dementia. Agitation in people with dementia worsens carer burden, increases the risk of injury, and adds to the need for institutionalisation. Valproate preparations have been used in an attempt to control agitation in dementia, but their safety and efficacy have been questioned. To determine the efficacy and adverse effects of valproate preparations used to treat agitation in people with dementia, including the impact on carers. We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 7 December 2017 using the terms: valproic OR valproate OR divalproex. ALOIS contains records from all major health care databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. Randomised, placebo-controlled trials that assessed valproate preparations for agitation in people with dementia. Two review authors independently screened the retrieved studies against the inclusion criteria and extracted data and assessed methodological quality of the included studies. If necessary, we contacted trial authors to ask for additional data, including relevant subscales, or for other missing information. We pooled data in meta-analyses where possible. This is an update of a Cochrane Review last published in 2009. We found no new studies for inclusion. The review included five studies with 430 participants. Studies varied in the preparations of valproate, mean doses (480 mg/day to 1000 mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted although some methodological information was missing and one study was at high risk of attrition bias.The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) -2.14 to 2.59; 202 participants, 2 studies; BPRS agitation factor: MD -0.67, 95% CI -1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups or a benefit for the placebo group.Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203 participants, 2 studies; moderate-quality evidence).Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A meta-analysis of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections. This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of SAEs. On the basis of this evidence, valproate therapy cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other medications as effectively and safely as possible.

Therapy with valproate preparations in disabled epilepsy patients in the Republic of Komi

Epilepsy is the widespread and hard to cure disease. The medico-social importance of the problem is caused by the fact that among patients with epilepsy there is a considerable share of able-bodied age persons, most part of whom fail to receive the adequate treatment. The aim of the work is an assessment of demographic indices in epilepsy patients, being on therapy by preparations of valproic acid and having the group of disability in the Komi Republic. By the method of continuous research there were studied data over the period from 2006 for 2009 in patients from the Komi Republic, being on monotherapy by preparations of valproic acid and polytherapy where one ofpreparations was valproic acid. Out of872 patients disability was established in 36% of cases. Most ofpatients were on monotherapy by preparations of valproic acid. In disabled patients, the symptomatic type of epilepsy was mainly observed and generalized toniko-clonic attacks occurred more often than others.

Antiepileptic drugs for the treatment of agitation and aggression in dementia: do they have a place in therapy?

Antiepileptic drugs (AEDs) are a class of medications that have received considerable attention as possible treatments for agitation and aggression in patients with dementia. This attention has been driven in equal measure by promising findings from limited trial and observational data and the desire to find treatments with improved tolerability. Their use, to date, has been largely confined to circumstances where first-line treatments have proven inadequate or are poorly tolerated. In recent years there has been some growth in the evidence base, and we can now make more informed recommendations regarding a number of older AEDs. Carbamazepine continues to have the best evidence to support its use, although the evidence base remains relatively small and concerns regarding tolerability limit its use. There is now more consistent evidence that valproate preparations should not be used for agitation and aggression in dementia. Despite a lack of high-quality data, some results have been reported for several newer medications, including levetiracetam, oxcarbazepine, gabapentin, topiramate and lamotrigine, and a number of these warrant further investigation. Recent findings and implications for clinical practice are discussed.

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. MethodsThe UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. ResultsOutcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1–2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67–1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58–1.70). ConclusionPrescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

051 Valproate and the risk for congenital malformations; is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs....

Valproate preparations for agitation in dementia

Agitation affects up to 70% of older people with dementia. Valproic acid derivatives have been used for the past 10 years to control agitation in dementia, but no systematic review of the effectiveness of this treatment has been published to date. A systematic review of 2004 examined three randomised, placebo-controlled trials of the effect of valproate therapy on older people with dementia who were agitated. The review was updated (October 2008) to include two additional studies. To determine whether evidence supports the use of valproate preparations in the treatment of agitation of people with dementia. The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 7 February 2008 using the terms: valproic OR valproate OR divalproex* . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. Randomized, placebo-controlled trials with concealed allocation where agitation and dementia of participants were assessed 1. Two reviewers extracted data from published trials 2. Odds ratios of average differences were calculated 3. Only "intention to treat" analyses were included 4. Analysis compared participants treated with valproic acid with controls Meta-analysis in 2004 of the pooled results was limited because of the following problems.In Porsteinsson 2001, although the physicians having direct responsibility for patient care were blinded, a non-blinded physician, who had no direct contact with these physicians, adjusted divalproex sodium dosage on the basis of reports from blinded raters and from confidential laboratory reports. Therefore, because the physician who controlled therapy knew which patients were receiving divalproex, the trial did not satisfy the criterion of concealed allocation.In Tariot 2001, 54% of the treated patients dropped out compared with 29% of control patients. Of all treated patients, 22% dropped out because of adverse effects, and the study had to be discontinued prematurely.The third trial (Sival 2002) had a cross-over design. No results from the first phase of the study were available, and although the statistical section stated, "the t-test for independent samples is used to analyse the two-period cross-over trial", because the samples were not independent - they are the same patients in the treatment and placebo groups - a question must be raised about the correctness of the analyses.The valproate preparation used in the trials varied - one used short-acting sodium valproate, one long-acting divalproex sodium, and the third early-onset acting divalproex sodium. Average doses differed (480 mg/d - 1000 mg/d), as did duration of therapy (3 weeks - 6 weeks), and ways of evaluating patients and their response to therapy.A limited meta-analysis, pooling the results concerning adverse effects (Porsteinsson 2001, Tariot 2001) revealed the following: sedation occurred more frequently in patients treated with valproic acid than in controls. Urinary tract infection was more common among patients treated with valproic acid than controls.An updated systematic review (October 2008) of two new studies (Tariot 2005, Herrmann 2007) applied meta-analysis to the effect of valproate on agitation in demented patients and also combined these studies with the earlier reports to examine adverse effects among valproate treated patients. Because the study of Herrmann et al involved a cross-over design, only those results from the first part of this study were included in the updated review.The new meta-analysis of pooled results showed no improvement of agitation among valproate treated patients, compared with controls, and showed an increase in adverse events (falls, infection, gastrointestinal disorders) among valproate treated patients. The updated review corroborates the earlier findings that valproate preparations are ineffective in treating agitation among demented patients, and that valproate therapy is associated with an unacceptable rate of adverse effects. More research on the use of valproate preparations for agitation of people with dementia is needed. On the basis of current evidence, valproate therapy cannot be recommended for management of agitation in dementia.

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.

Utilization of valproate: extent of inpatient use in the New York State Office of Mental Health.

To describe the extent and type of use of valproate among hospitalized psychiatric patients. A database containing patient information and drug prescription information for every in-patient within the adult civil facilities of the New York State Office of Mental Health was queried. In 1994, 2,888 of 18,668 in-patients received valproate (15.5%). In 1996, 4,247 of 12,444 in-patients received valproate (34.1%). In 1996, approximately 50% of all patients diagnosed as bipolar or schizoaffective, and 28% of all patients diagnosed with schizophrenia, received valproate. Once started on valproate, over 90% remained on it after 2 weeks, with no difference found in the discontinuation rates between valproic acid or divalproex sodium at the end of the initial 14 day period. Patients received valproate for approximately two-thirds of their hospital stay, at a mean dose of 1400 mg/day. 95% also received concomitant antipsychotics, and 20% received concomitant lithium. Use of lithium and carbamazepine was less in 1996 than in 1994, but the magnitude of this change was much less than the increase in utilization of valproate. From 1994 to 1996 valproate use has more than doubled, and it is being used widely in patients with schizophrenia, an off-label indication for which there is only anecdotal support in the literature. Given the lack of difference in early discontinuation rates, there are probably no dramatic differences in side effects for the two preparations of valproate.

Pharmacokinetics of slow-release preparations of sodium valproate.

Pharmacokinetics of slow-release preparations of sodium valproate.

Pharmacokinetics of slow‐release preparations of sodium valproate

Pharmacokinetics of slow‐release preparations of sodium valproate

Comparison of Anticonvulsant Efficacy of Valproate During Prolonged Treatment with One and Three Daily Doses or Continuous (“Controlled Release”) Administration in a Model of Generalized Seizures in Rats

Recently, sustained-release (SR) preparations of valproate (VPA) have been developed to minimize or prevent problems associated with plasma level fluctuations during therapy with conventional preparations. In the present experiments, the anticonvulsant activity of VPA was assessed during prolonged treatment with different administration protocols using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion seizure threshold model in rats. To simulate a controlled-release (CR) preparation, VPA was infused in a constant rate through chronically implanted intrajugular catheters in some of the experiments. In all experiments, the PTZ seizure threshold was repeatedly determined in individual rats with chronically implanted catheters at daily intervals. Injection of saline three times daily in a control group showed that the PTZ seizure threshold was stable throughout the experiment. Acute administration of VPA 200 mg/kg intraperitoneally (i.p.) significantly increased the seizure threshold. During prolonged treatment with three daily doses of 200 mg/kg i.p., anticonvulsant activity markedly increased on the second day of treatment and thereafter compared to the acute effect of VPA, although plasma levels measured at each seizure threshold determination did not differ significantly. This increase in anticonvulsant activity of VPA during prolonged treatment was much less pronounced with one instead of three daily doses. One daily intraperitoneal injection of VPA (200 mg/kg) plus continuous, constant-rate intravenous infusion of 400 mg/kg/day led to a marked increase in anticonvulsant activity similar to that in the experiment with three daily doses, indicating that not the peak levels but the duration of maintenance of active drug concentrations was important for development of enhanced anticonvulsant activity.(ABSTRACT TRUNCATED AT 250 WORDS)

徐放性バルプロ酸製剤（デパケンＲ錠，ＮＩＫ‐２４０）の生物学的同等性と体内動態の比較検討

Bioavailability and pharmacokinetic study of slow release preparations of sodium valproate (Depakene-R Tablets, NIK-240) were investigated by a cross-over design in six healthy volunteers. When bioavailability parameters were compared between two preparations after a single dose of 600mg of each drug was administered orally, there was difference in maximum serum concentration (Cmax), but no difference was found in areas under the serum concentration-time curve (AUC), peak time (Tmax), mean residence time (MRT) and variance of residence time (VRT). The pharmacokinetic parameters were estimated according to one-compartment open models with three different absorption steps (first-order or zero-order absorption step with lag time, two first-order input steps) by simultaneous least squares curve fitting method.The firstorder absorption with lag time model fitted better to describe pharmacokinetics of the two preparations than the other models, but pharmacokinetic parameters (Ke, Ka, Vd, lag time) showed no differences in the two preparations.These results indicate that two preparations were comparable to the extent of bioavailability, but not comparable to the rate of bioavailability. NIK-240 was released more slowly than Depakene-R Tablets and predictions regarding multiple dosing show that NIK-240 can provide smaller fluctuations in plasma valproic acid level than Depakene-R Tablets.These results were important for the administration of slowrelease preparations in the drug monitoring and the drug administration regimen.

Possible Induction of Systemic Lupus Erythematosus by Valproate

Two patients developed clinical and laboratory evidence of systemic lupus erythematosus (SLE) during treatment with valproate (VPA) preparations. The first patient, a 47-year-old man, had fever, malaise, and thrombocytopenia 1 month after VPA was added to phenytoin (PHT) and primidone (PRM). He developed high titers of antinuclear antibodies (ANA) and anti-DNA antibodies, and hypocomplementemia. After discontinuation of PHT and VPA, steroid and immunoglobulin treatment was required for 4 weeks before his condition improved. The second patient, a 28-year-old woman, had been followed for idiopathic leukopenia for 3 years and had previously experienced fever and lymphadenopathy from PHT. After 4 months of divalproex therapy, she developed confusion, joint pain, and a dramatic increase in seizure frequency. She also developed high titers of ANA and anti-DNA antibodies and hypocomplementemia, along with a further decrease in white blood cell (WBC) count. These responded to steroid therapy and withdrawal of divalproex. Three months later, reintroduction of divalproex was followed by a return of ANA in low titer, which resolved after discontinuation. We believe that VPA may have caused true SLE in these patients, one of whom was probably predisposed.