Valproate MOA and Clinical Uses In this video we’ll see an introduction to valproate Flavio Guzmán, MD

Overview Formulations: valproic acid, divalproex sodium, divalproex sodium ER MOA: enhances GABAergic neurotransmission and affects intracellular signaling FDA-approved for epilepsy, migraine and mania Off-label use: maintenance treatment in BD, adjunctive in schizophrenia, impulsivity, and alcohol dependence Let’s see an overview for this video. First, a clarification. The term valproate includes a number of formulations, such as valproid acid, divalproex sodium and divalproex sodium extended release. The mechanism of action of valproate in bipolar disorder is not completely understood. It enhances GABAergic neurotransmission and affects intracellular signaling. Valproate is FDA-approved for epilepsy, migraine and mania. It is commonly used off-label: as maintenance treatment in bipolar disorder, as adjunctive in schizophrenia, as impulsivity treatment and to prevent relapse in alcohol dependence.

Mechanism of action

Mechanism of action Enhancement of GABAergic NT Modulation of VSSC Intracellular signaling Reduces PKC activity in manic patients Inhibits GSK-3 Inhibits histone deacetylase Promotes neuroprotection ERK kinase BCL2 The mechanism of action of valproate in bipolar disorder has not been identified. We know valproate use is associated with enhancement of GABAergic neurotransmission. The modulation of voltage sensitive sodium channels has also been implicated. Intracellular signaling systems are also affected with valproate use. Valproate reduces protein kinase C activity in manic patients, inhibits GSK- 3 and histone deacetylase. Valproate might promote neuroprotection through the activation of ERK kinase and the expression of the gene BCL 2. Rosenberg, G. (2007). The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?. Cellular and Molecular Life Sciences, 64(16), 2090-2103.

Indications

FDA-approved indications Monotherapy and adjunctive Complex partial seizures Simple and complex absence seizures Adjunctive: Multiple seizure types that include absence seizures Seizures Migraine prophylaxis Valproate is an anticonvulsant approved for the treatment of seizures. It is approved as monotherapy and adjunctive treatment for complex partial seizures and for simple and complex absence seizures. Prescribing information also mentions that it is approved as adjunctive treatment for multiple seizure types that include absence seizures. Valproate is also FDA-approved for migraine prophylaxis. Divalproex (Depakote) [Prescribing Information] North Chicago, IL : AbbVie Inc.. Accessed December 2014 Divalproex extended release (Depakote ER) [Prescribing Information] North Chicago, IL : AbbVie Inc.. Accessed December 2014

FDA-approved indications Bipolar disorder Acute mania Divalproex Acute mania and mixed episodes Divalproex ER Regarding approved indications in bipolar disorder, FDA labeling varies according to formulations. Divalproex is approved for acute mania, while divalproex extended release is approved for mania and mixed episodes. These are the only FDA-approved indications in bipolar disorder, valproate is not approved for the treatment of bipolar depression or as maintenance treatment. Divalproex (Depakote) [Prescribing Information] North Chicago, IL : AbbVie Inc.. Accessed December 2014 Divalproex extended release (Depakote ER) [Prescribing Information] North Chicago, IL : AbbVie Inc.. Accessed December 2014

Acute mania Initially studied by Lambert in the late 1960’s Followed by studies from Pope and Bowden Antimanic response: serum levels > 45-50 µg/ml So let’s discuss the use of valproate in the treatment of mania. Valproate was initially studied for this use by Lambert in France in the late 1960’s. The most influential studies were probably those from Pope and Bowden. It was described that serum levels greater than 45-50 ug/mL are associated with antimanic response. Pope, H. G., McElroy, S. L., Keck, E., & Hudson, J. I. (1991). Valproate treatment of Acute Mania: A Placebo-Controlled. Archives of General Psychiatry, 48(1), 62-68.

Mixed states and rapid cycling Might be more effective than lithium for patients with: Mixed states Rapid cycling According to randomized studies, valproate might be more effective than lithium for patients with: mixed states and rapid cycling. In these studies patients with mixed presentations treated with divalproex, showed greater improvements than those treated with lithium. Bowden CL: Predictors of response to divalproex and lithium. J Clin Psychiatry 56:25–30, 1995 Freeman TW, Clothier JL, Pazzaglia P, et al: A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J sychiatry 149:108–111, 1992

Bipolar depression Might be effective in acute bipolar depression Most published studies are limited by sample size Need for trials with larger sample sizes before conclusions can be drawn Publication bias cannot be ruled out Valproate is not approved for the treatment of bipolar depression. However, studies suggest it might be effective. The problem with these studies is that they are limited by sample size. So, there is a need for trials with larger sample sizes before conclusions can be drawn. Also, the authors of a recent review argue that publication bias cannot be ruled out. Reinares, M., et al (2013). A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression. The International Journal of Neuropsychopharmacology, 16(02), 485-496.

Prophylaxis Frequently prescribed Supported mostly by open label studies May be effective as maintenance treatment 6 RCTs lasting 6 to 24 months Lack of clear findings, limited amount of evidence of efficacy Maintenance treatment: more robust evidence for lithium Safety: lithium and valproate had different side effects profiles Consider acceptability and tolerability profile Cochrane review Valproate is frequently prescribed as maintenance treatment in bipolar disorder. It may be effective, this is supported mostly by open label studies. A recent Cochrane review studied 6 randomized controlled trials lasting 6 to 24 months. The reviewers consider there was an lack of clear findings, so the amount of evidence of efficacy is limited. They state that evidence is more robust for the use of lithium and that lithium and valproate have different side effects profiles. Acceptability and tolerability profile should be considered when choosing between lithium or valproate. Linde, M., et al (2013). Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev, 6.

Adjunctive for schizophrenia Combination of valproate + antipsychotic Effective in reducing positive symptoms Valproate might speed response in schizophrenia Unclear if this is sustained after 4 or more weeks Cochrane review No data to support or to refute valproate as agent for schizophrenia The other off-label use for valproate outside bipolar disorder is as adjunctive for schizophrenia. A study by Casey and colleagues found that the combination of valproate and an antipsychotic was significantly more effective than placebo in reducing positive symptoms. Also, valproate might speed response in schizophrenia, but there are no data to show that this effect can be sustained over four or more weeks. A Cochrane review concludes that based on available randomized evidence, there are no data to support or refute the use of valproate as agent for schizophrenia. Casey, D. et al (2003). Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.Neuropsychopharmacology 28(1), 182-192. Schwarz, C., Volz, A., Li, C., & Leucht, S. (2008). Valproate for schizophrenia.Cochrane Database Syst Rev, 3.

Impulsivity, agitation and aggression Several case reports and open label trials Aggression and impulsivity in patients with brain injuries Agitation associated with dementia Impulsivity and affective instability of BPD Valproate is also used for impulsivity, agitation and aggression. This use is based on several case reports and open label trials. Some of the uses include: Aggression and impulsivity in patients with brain injuries Agitation associated with dementia Impulsivity and affective instability in patients with borderline personality disorder Schatzberg, A. Essentials of Clinical Psychopharmacology. Washington, DC: American Psychiatric Pub., 2013. 

Alcohol dependence Off-label use Efficacy in relapse prevention Good option of dual diagnosis patients (BD+ alcohol dependence) May stabilize mood and help in relapse prevention The other off label use for valproate is the treatment of alcohol dependence. Studies suggest it may have efficacy in relapse prevention. It is a good option for dual diagnosis patients (those with bipolar disorder and alcohol dependence). In this group of patients, valproate may stabilize mood and help in relapse prevention. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM: Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism. Arch Gen Psychiatry. 2005;62:37

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