Divalproex sodium, mania

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

In contrast to the large number of studies that have investigated lithium as a maintenance treatment for bipolar disorder, relatively few studies have been made of divalproex sodium, despite its widespread use in the acute treatment of mania. There is evidence from one placebo-controlled study in which lithium was compared with divalproex sodium that the latter drug was better tolerated but that the prevention of relapse did not differ between the drugs. It would therefore appear that a switch to divalproex sodium may be particularly useful in bipolar patients who are experiencing... 

Mania (divalproex sodium delayed-release tablets) Trea men of manic episodes associated with bipolar disorder. 

Mania (divalproex sodium delayed-release tablets) 750 mg/day in divided doses increase as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect or the desired range of plasma concentrations (trough plasma concentrations 50 to 125 mcg/mL). Maximum concentrations generally were achieved within 14 days. Maximum recommended dosage is 60 mg/kg/day. 

Children See Warning Box. The safety and efficacy of divalproex sodium for the treatment of acute mania has not been studied in individuals younger than 18 years of age. Divalproex sodium extended-release tablets are not recommended in children. Use of valproate sodium injection has not been studied in children below 2 years of age. 

Valproic acid, valproate sodium, and (DVP) are carboxylic acid-derivative anticonvulsants. Divalproex sodium is a stable coordination compound consisting of valproic acid and valproate sodium in a 1 1 molar ratio (AHFS, 2000). It is a pro-drug of valproate, dissociating into valproate in the GI tract (AHFS, 2000), and a simple branched-chain carboxylic acid (w-dipropylacetic acid) with antiepileptic activity against a variety of types of seizures (Beydoun et al., 1997). Divalproex sodium has been approved for treating adults with simple and complex absence seizures (Mattson et al., 1992), and for mania. It has shown efficacy across a broad spectrum of BD subtypes (i.e., pure mania, mixed mania, and rapid cycling) (Pope et al., 1991 Bowden et al., 1994). 

Papatheodorou, G. and Kutcher, S.P. (1993) Divalproex sodium treatment in late adolescent and young adult acute mania. Psy-chopharmacol Bull and 29 213-219. 

Papatheodorou, G., Kutcher, S.P., Katie, M., and Szalai, J.P. (1995) The efficacy and safety of divalproex sodium in the treatment of acute mania in adolescents and young adults an open clinical trial. / Clini Psychopharmacol 15 110-116. 

Divalproex sodium was approved by the FDA for the treatment of mania and is commonly used for all phases of bipolar disorder, as well as mood instability due to other causes. 

Three antiepileptic drugs have now been FDA approved as mood stabilizers for the prevention of recurring episodes of mania divalproex sodium (Depakote), extended-release carbamazepine (Equetro), and lamotrigine (Lamictal). Many of these drugs are prescribed to children for the control of epilepsy and, increasingly, for bipolar disorder. A critical question is their effect on the developing mental and emotional function of children, but there is little research on the subject (Loring, 2005). 

Pavuluri MN, Henry DB, Carbray JA, Sampson G, Naylor MW, Janicak PG. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Dis 2004 82S S103-11. 

Revicki DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM. Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder health-related quality of life and medical cost outcomes. J Clin Psychiatry 2003 64 288-94. 

Tohen, M., T. A. Ketter, C. A. Zarate, T. Suppes, M. Frye, L. Altshuler, et al. (2003). Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission a 47-week study. Am J Psychiatry 160(7) 1263-71. 

A randomised, placebo-controlled study in 191 patients found that quetiapine, combined with either lithium or valproate semisodium (divalproex sodium), was superior to lithium or valproate semisodium alone for treating bipolar mania. The incidence of extrapyramidal symptoms in patients receiving quetiapine with lithium or valproate semisodium was similar to those receiving placebo with lithium or valproate semisodium. No special precautions would therefore appear to be necessary on concurrent use. 

However, there is one report of a possible decrease in valproate levels in a 30-year-old man after starting lopinavir/ritonavir. This patient, who had been taking valproic acid 375 mg daily as divalproex sodium for 7 months after an episode of mania, had a subtherapeutic valproic acid level of 197 micromol/L, and the dose was increased to 250 mg three times daily. After 25 days his trough valproic acid level was 495 micromol/L, and an antiretroviral regimen of lamivudine, zidovudine, lopinavir/ritonavir was started, and paroxetine for depression. Four days later he was hy-pomanic and the paroxetine was replaced with sertraline, which the patient discontinued. Twenty-one days later he had become increasingly manic, and the valproic acid level was found to be 238 micromol/L, about 50% lower than the previous level. An increase in valproic acid dose to 1.5 g daily was eventually required to achieve a therapeutic level of 392 micromol/L. 

Oxcarbazepine (1000-2400 mg/day) and divalproex sodium (750-2000 mg/day) have been compared in a 12 week, randomized, double-blind pilot study in 60 patients with acute mania [218 ]. ITie median time to symptomatic remission of and the relapse rate did not differ. There were 22 adverse events in those who took oxcarbazepine group compared with 56 in those who took divalproex. The most common adverse events with oxcarbazepine were nausea (n = 5), dizziness (3), vomiting (4), sedation (3), and dyspepsia (3). 

In a 6-month open study of divalproex sodium extended-release (15 mg/kg/day on day 1 with increases allowed to a maximum of 35 mg/kg) in 226 children and adolescents with acute mania associated with bipolar I disorder the most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%) raised plasma ammonia concentrations were non-symptomatic in all cases [340 J. 

Kakkar AK, Rehan HS, Unni KE, Gupta NK, Chopra D, Kataria D. Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania a pilot study. Eur Psychiatry 2009 24(3) 178-82. 

Redden L, DelBello M, Wagner KD, Wilens TE, Malhotra S, Wozniak P, Vigna NV, Greco 4th N, Kovacs X, Abi-Saab W, Saltarelli M. Depakote ER Pediatric Mania Group. Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder. J Child Adolesc Psychopharmacol 2009 19(1) 83-9. 

I Available in different formulations. Valproate semisodium (divalproex sodirnn in the USA) is a mixture of sodium valproate and valproic acid and is now hcensed in the UK for the treatment of acute mania. 

Controlled Studies A controlled, randomised study compared oral risperidone, sodium divalproex in children and adolescents with bipolar I mania or mixed phase [23/d. Increased weight and BMI were significantly greater with risperidone treatment than with lithium or sodium divalproex treatment. There was a significant increase in LDL-cholesterol and decrease in HDL-cholesterol for the risperidone and sodium divalproex groups QTc prolongation (>440 ms) was reported in 9.0% of risperidone (also greatest increases), 10.0% of lithium and 3.0% of sodium divalproex-treated patients. 

---