Recent guidance from UK health authorities strongly cautions against the use of valproic acid (VPA) in persons under 55 because of reevaluated risk of teratogenicity.

To summarize the extant literature documenting VPA-associated anatomical, behavioral, and cognitive teratogenicity.

Pubmed, Medline, Cochrane Library, PsychInfo, Embase, Scopus, Web of Science, and Google Scholar were searched in accordance with PRISMA guidelines. Collected data covered study design, participant characteristics, anatomical, behavioral, or cognitive effects, and folic acid outcomes.

122 studies were identified meeting inclusion comprised of studies evaluating anatomical (n = 67), behavioral (n = 28), and cognitive (n = 47) teratogenicity. Twenty studies were identified reporting on the risk mitigation effects of folic acid supplementation. Prenatal VPA exposure is associated with anatomical teratogenicity including major congenital malformations (odds ratio [OR] 2.47–9.30; p < 0.005). Behavioral teratogenicity including autism (OR 1.70–4.38), impaired motor development (OR 7.0), and ADHD (OR 1.39) are also significantly associated with VPA exposure. VPA was associated with intellectual disability and low IQ (hazard ratio [HR] 2.4–4.48, verbal intelligence: Spearman’s ρ = −0.436, respectively). Teratogenic effects were dose-dependent across all domains and were significant when compared with controls and other antiepileptic drugs (eg, carbamazepine, lamotrigine, and levetiracetam). Folic acid supplementation does not significantly reduce the hazard associated with VPA.

VPA is significantly associated with anatomical, behavioral, and cognitive teratogenicity. Folic acid supplementation does not abrogate the risk of teratogenicity associated with VPA exposure. Available evidence supports recommendations to reduce VPA exposure in women of reproductive age.

Valproic acid (VPA) is considered a well-tolerated antiepileptic drug used in Bipolar Disorder as a mood stabilizer. Nevertheless, VPA has been related to several adverse effects. Neutropenia is included as a potential adverse effect, although in clinical practice it is not often measured with regularity.

To report a case of a patient with Bipolar Disorder type 2 and Personality Disorder Cluster B treated with VPA with a neutropenia caused by VPA.

A 61-year-old woman assists to the outpatient psychiatric unit in order to a pharmacological treatment adjustment. A blood test is performed showing a decrease in the levels of neutrophiles in comparison with previous tests. Psychiatric history is revised finding and association between the prescription of VPA and the reduction of neutrophile levels. When this drug was removed, neutrophile levels had increased again up to normal levels.

Due to the relationship between neutropenia and VPA treatment, we decided to discontinue this drug. At the beginning the patient doesn’t agree with the withdrawal of VPA treatment due to its effectiveness in her mood stabilization. Psychoeducation sessions are performed in order to explain risk and benefits of potentials treatment alternatives versus maintaining the same prescription. Finally the patient accepts the switch of the mood stabilizer treatment to oxcarbazepine with a good tolerability and effectiveness.

Periodical blood test monitoring is needed in order to study adverse effects as neutropenia in patients with VPA treatment.

The author has received support from Janssen-Cilag, Otsuka-Lundbeck, Italfármaco, Angelini Pharma and Casen Recordati; and declares no support related to the subject of this article.

Valproic acid is a psychotropic drug used for several years, due to its properties as a mood stabilizer, being considered as first-line treatment for bipolar disorder. In addition to its teratogenic potential, which prevents its recommendation for the treatment of bipolar disorder in women of childbearing age, valproic acid is associated with some side effects, such as gastrointestinal symptoms, alopecia, weight gain, tremor or hepatotoxicity. Hyperammonemia is a side effect that is little described, but relatively frequent, and may progress to variable encephalopathy.

The authors describe a clinical case of a 48-year-old female patient, hospitalized due to a manic episode, who was prescribed valproic acid, in association with lorazepam and olanzapine.

After three days on a dose of 1000mg of valproic acid, the patient began an acute condition of confusion, psychomotor retardation, temporal-spatial disorientation and ataxia. Infection, electrolyte disturbance and acute cerebral event were excluded. Noteworthy only hyperammonemia. Valproic acid was withdrawn and replaced by lithium, with the patient recovering from the confusional state two days later.

Hyperamonemic encephalopathy secondary to valproic acid was concluded. The mechanisms of valproic acid-linked hyperammonemia are not clear, although it appears to be independent of hepatotoxicity. The most studied hypotheses are related to glutamine reabsorption and serum levels carnitine in patients medicated with valproic acid.

It is essential that there is a high level of suspicion in clinicians for this secondary effect of valproic acid, in order to adequately treat the patient who presents with acute confusional conditions, not explained by other complications.

No significant relationships.

Valproic acid (VPA) is a commonly prescribed medication for epilepsy, migraine and especially bipolar disorder therapy. Although the common adverse effect associated with VPA are typically benign, less common adverse effects can occur; these include acute pancreatitis.

Describe the clinical and therapeutic characteristics of a case of acute pancreatitis induced by VPA with a review of the literature.

We report the case of a patient who presented an acute pancreatitis induced by VPA. The data was collected from the patient’s medical file. A review of the literature was performed by selecting articles from the PubMed search engine using ‘acute pancreatitis and valproic acid’ and ‘drug induced acute pancreatitis’ as key words.

This is a 51-year-old male patient with a history of type 2 diabetes, dyslipidaemia and psychiatric follow-up for bipolar disorder type I on lithium. He was admitted for a resistant depressive episode. We opted for the combination of two mood stabilizers (VPA and lithium). On the third day of treatment, the patient reported epigastric pain with incoercible vomiting. Laboratory tests showed increased levels of pancreatic enzymes and a biological inflammatory syndrome. The diagnosis of acute stage A pancreatitis was made.VPA was discontinued and the patient was put on symptomatic treatment with favourable outcome after one week. The etiological investigation ruled out other causes of acute pancreatitis. As a result, iatrogenic origin was retained.

This case supports the idea that acute pancreatitis may be induced by VPA, it has no predictable factors.

No significant relationships.

Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA.

We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation.

Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding.

We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.

Pseudobulbar affect/emotional incontinence is a potentially disabling condition characterized by expressions of affect or emotions out of context from the normal emotional basis for those expressions. This condition can result in diagnostic confusion and unrelieved suffering when clinicians interpret the emotional expressions at face value. In addition, the nomenclature, etiology, and treatment for this condition remain unclear in the medical literature.

We report the case of a 60-year-old woman with multiple sclerosis who was referred to an inpatient psychiatry unit with complaints of worsening depression along with hopelessness, characterized by unrelenting crying. Our investigation showed that her symptoms were caused by pseudobulbar affect/emotional incontinence stemming from multiple sclerosis.

The patient's history of multiple sclerosis and the fact that she identified herself as depressed only because of her incessant crying suggested that her symptoms might be due to the multiple sclerosis rather than to a depressive disorder. Magnetic resonance imaging demonstrated a new plaque consistent with multiple sclerosis lateral to her corpus callosum. Her symptoms resolved completely within three days on valproic acid but returned after she was cross-tapered to dextromethorphan plus quinidine, which is the FDA-approved treatment for this condition.

This case provides important additional information to the current literature on pseudobulbar affect/emotional incontinence. The existing literature suggests a selective serotonin reuptake inhibitor (SSRI) and dextromethorphan/quinidine (Nuedexta) as first-line treatments; however, our patient was taking an SSRI at the time of presentation without appreciable benefit, and her symptoms responded to valproic acid but not to the dextromethorphan/quinidine. In addition, the case and the literature review suggest that the current nomenclature for this constellation of symptoms can be misleading.

Studies show that anti-epileptic drugs increase oxidative stress. Thus, low-density lipoprotein oxidation increases and atherogenesis is induced. Paraoxonase-associated high-density lipoprotein protects low-density lipoprotein and high-density lipoprotein oxidation. The effects of anti-epileptic drugs on paraoxonase activity has not been investigated yet. The aim of this study is to investigate the effect of anti-epileptic drugs on paraoxonase activity, lipid profiles, folat, vitamin B12, homocysteine, thyroid hormones, apolipoprotein A-1, total anti-oxidant capacity, malondialdehyd, nitric oxide, and oxidised low-density lipoprotein. The association with carotid–femoral pulse wave velocity and current biochemical parameters had been searched for assessing the effects of anti-epileptic drugs on the vascular system.

We recruited 59 epileptic patients treated with anti-epileptic drugs and 23 controls (group IV) at least 6 months ago. The epileptic group was divided into three groups by receiving anti-epileptic drugs as follows: group I: carbamazepine, group II: valproic acid, and group III: carbamazepine and valproic acid. Arterial distensibility was assessed with the Complior device.

There was no difference between the current biochemical parameters in epileptic children. Serum-free T4 was decreased, when compared with group IV. Thyroid-stimulating hormone was increased in group II, compared with group IV. The carotid–femoral pulse wave velocity was increased in group III, compared with group IV. The carotid–femoral pulse wave velocity was correlated with thyroid-stimulating hormone and valproic acid levels.

Anti-epileptic drugs may induce atherogenesis by affecting the thyroid hormones. According to the current data, the effects of thyroid hormones on vascular system may be independent of other biochemical markers. Epileptic patients using anti-epileptic drugs must be followed closely for arterial stiffness, and also for the development and progression of atherosclerosis.