Valproic acid is an antiepileptic drug used in different fields of Psychiatry. It is known mostly for its use in managing patients with bipolar affective disorder. In psychiatry of addiction, there is still no approved indications for its usage, but it is widely prescribed in treating alcohol and cocaine abuse, due to the existence of studies in these addictions.

This review aims to clarify the relation between valproic acid and dependences, particularly cocaine.

Non-systematic literature review using a PubMed search, using the following key words: “valproate”; “cocaine use”.

Cocaine dependence can decrease GABA levels in humans. Valproic acid has multiple mechanisms that favour the synthesis of GABA, potentiating its release and postsynaptic GABAergic response. Because of this, valproic acid was found effective in promoting abstinence and in reducing the use of cocaine. There are studies that support the valproic acid’s use in alcohol and cocaine dependences. Valproic acid has been shown to be promising in relapse prevention. It has also showed efficacy in the management of impulsivity and irritability, what makes it useful in managing patients with borderline personality disorder – patients at higher risk for alcohol or substance use disorders.

Cocaine addiction involves different phenomena and may respond to distinct pharmacologic approaches. Although some studies need to be confirmed by larger clinical trials, valproic acid seems a promising agent as one of some potential treatments for cocaine dependence. Further studies are required in this field to come to more reliable conclusions.

No significant relationships.

Hyperammonemic encephalopathy is an unusual side-effect of the treatment with valproic acid. According to several sources, this side effect could be underdiagnosed and underreported.

We present the case of a 54-year-old patient institutionalized in a psychiatric hospital who was referred to a general hospital after an episode of delirium of unknown etiology. The patient had been diagnosed with Schizoaffective disorder 26 years prior to his admittance and had started treatment with valproic acid the previous month.

A case report is presented alongside a review of the relevant literature regarding valproate-induced hyperammonemic encephalopathy, its differential diagnosis and treatment.

During his hospital stay, the patient underwent a complete panel of tests including CT Scan, EEG, toxic panel and complete blood tests. In them the only altered parameter was hyperammonemia, therefore valproic acid was removed and was treated with lactulose and rifaximin to reduce ammonium levels.

Hyperammonemic encephalopathy in the context of the treatment with valproic acid is a side-effect which is more prevalent than what was thought in the past. Valproate could reduce ammonium elimination therefore increasing the levels of the molecule. It should be administered carefully in cases where the patient may be presenting with other causes of increased ammonium metabolism or decreased elimination. It is important to bear in mind this possible side-effect to increase patient’s safety.

No significant relationships.

Valproate is widely used in the treatment of maniac and mixed episodes and is well known to be safe with side effects being mostly related to hepatic disorders and psychomotor retardation.

Raising attention to valproate-induced hypothyroidism that despite the increasing evidence tends to be neglected.

Here, we report a case of a 55-year-old woman, with a previous diagnosis of schizophrenia, treated for many years with 200mg of zuclopenthixol triweekly and 2mg of risperidone daily. Patient developed a maniac episode characterized by elevated mood, sense of grandiosity, increased energy and psychomotor activity, disinhibition and insomnia. No laboratory abnormalities were detected and inpatient treatment was initiated with paliperidone up to 12mg/day and valproate 1000mg/day.

Patient showed progressive clinical recovery attaining full remission within 2 weeks. Despite the absence of clinical side effects and the valproate serum levels of 74.9μg/mL (range 50–100μg/mL), laboratory testing found progressive reduction F-T4 down to 0.45ng/dL (range 0.8–1.5 ng/dL) and a concomitant upregulation of TSH to 73.99mUI/L (range 0.55–4.8mUI/L). Thyroid autoantibodies and thyroid echography were negative. Considering that patient was previously medicated with risperidone, it was suspected that her hypothyroidism was caused by valproate. Normalization of thyroid function was observed after 21 days valproate withdrawal. Patient is currently being treated with 150 mg paliperidone (monthly) with no recurrence of mood or psychotic episodes and maintain normal thyroid function.

Our case emphasizes the need for extended laboratory testing upon prescription of new pharmacological medications as severe analytic alterations can take place in the absence of immediate clinical manifestation.

No significant relationships.

Valproic Acid (VPA) is one of the most commonly used mood stabilizer drugs. Although uncommon, serious adverse effects have been reported. One particularly relevant side effect is the induced encephalopathy, usually secondary to Hyperammonemia. However, some descriptions have shown an altered mental state with normal serum levels of ammonia.

We aim to present a case of VPA induced-encephalopathy without hyperammonemia and emphasize its suspicion when patients taking VPA present altered mental states.

We present a clinical case of VPA induced-encephalopathy without Hyperammonemia and a qualitative review of this topic using the Pubmed database.

A 66-year-old woman, with an history of Major Depressive Disorder, previously medicated with Venlafaxine 75mg/day and Mirtazapine 30mg/day, was admitted in our acute psychiatric inpatient unit due to a first manic episode. During the stay, her antidepressants were interrupted, and she was started on VPA, then optimized to 750mg/day. After that, she presented an altered mental state with confusion and prostration. Analytical results were normal including normal ammonia levels and no imagiological abnormalities. Despite these results, we decided to stop VPA empirically. The patient clinical status resolved the day after.

Studies have shown that only a few patients have developed encephalopathy with normal serum levels of ammonia. Although the pathogenesis behind this remains unknown, a few mechanisms have been proposed. Therefore, it is important to remind that even without abnormal analytical status, VPA is a possible cause of encephalopathy. We also emphasize the need for further studies on the mechanisms behind this phenomenon.

No significant relationships.

Previous studies suggested that a disturbance of the dopamine system underlies the pathophysiology of bipolar disorder (BD). In addition, the therapeutic action of medications for treating BD, such as valproate (VPA), might modulate dopamine system activity, but it remains unclear. Here, we aimed to investigate the role of the striatal dopamine transporter (DAT) in BD patients and in social defeat (SD) mice treated with VPA.

We enrolled community-dwelling controls (N = 18) and BD patients (N = 23) who were treated with VPA in a euthymic stage. The striatal DAT availabilities were approached by TRODAT-1 single photon emission computed tomography. We also established a chronic SD mouse model and treated mice with 350 mg/kg VPA for 3 weeks. Behavioral tests were administered, and striatal DAT expression levels were determined.

In humans, the level of striatal DAT availability was significantly higher in euthymic BD patients (1.52 ± 0.17 and 1.37 ± 0.23, p = 0.015). Moreover, the level of striatal DAT availability was also negatively correlated with the VPA concentration in BD patients (r = −0.653, p = 0.003). In SD mice, the expression of striatal DAT significantly increased (p < 0.001), and the SD effect on DAT expression was rescued by VPA treatment.

The striatal DAT might play a role in the pathophysiology of BD and in the therapeutic mechanism of VPA. The homeostasis of DAT might represent a new therapeutic strategy for BD patients.

None.

People with bipolar disorder typically require long-term pharmacological treatment to prevent episodes of depression or mania. However, evidence-based guidelines are often not followed by prescribers and, in some countries, prescribing of lithium is in decline. Polypharmacy is also common in bipolar disorder.

To employ a data linkage approach to describe and evaluate prescribing patterns in bipolar disorder in Scotland between 2009 and 2016.

By linking prescribing data to the electronic Scottish Morbidity Records, we identified a cohort of 23 135 patients with bipolar disorder who were prescribed psychotropic medication between 2009 and 2016. We examined trends in proportions of patients prescribed each of six drug categories. Random effects logistic models examined change in prescribing over years of interest.

The most common form of treatment was antidepressant monotherapy (24.96%), with only 5.90% of patients receiving lithium monotherapy. Prescribing of antipsychotics and anti-epileptics increased from 2009 to 2016 (antipsychotics: odds ratio 1.16, 95% CI 1.15–1.18; anti-epileptics: odds ratio 1.34, 95% CI 1.32–1.36), whereas prescribing of lithium decreased (odds ratio 0.83, 95% CI 0.82–0.85). Prescribing of valproate decreased from 2009–2016 in women, but increased in men (women: odds ratio 0.93, 95% CI 0.90–0.97; men: odds ratio 1.11, 95% CI 1.04–1.18).

Antidepressant monotherapy was the most common form of treatment for bipolar disorder in Scotland and prescribing of lithium has declined between 2009 and 2016. The findings are concerning and represent a gap between treatment guidelines and clinical practice.

None.

We aimed to evaluate clinical note documentation of valproate prescribing and establish the level of knowledge among women of child-bearing potential regarding valproate-associated adverse effects, including teratogenesis, in a regional Irish mental health service.

Of the 42 women prescribed sodium valproate, 21.4% (n = 9) had some documentation in relation to associated risks and 33.3% (n = 14) described an awareness of these risks from consultation with their treating mental health team. On clinical interview, 9.5% (n = 4) of individuals with clear documentation of the risks of teratogenesis described no such awareness. Augmentation with lithium was associated with greater awareness of the teratogenic risks of valproate (P = 0.011).

A clear description of the teratogenic risks of valproate and potential management strategies, including advice regarding contraception and supplementation with folic acid, should be clearly documented and provided repeatedly and in context to all women of child-bearing age who are prescribed valproate.

None.

• • Recognise the role of brain transmitter pathways leading to arousal and to agitation

• • Be aware of mechanisms of action of benzodiazepines, antipsychotics and antihistamines and distinguishing sedation from calming effects

• • Know the recommendations of NICE guidelines for rapid tranquillisation and the findings of the national POMH-UK audit and be able to contribute to local policies

None.

The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI.

To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study.

Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks.

There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression.

C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.