DIVALPROEX SODIUM

Divalproex Sodium (DVPX) has emerged as an effective broad-spectrum alternative to Lithium. It is effective in acute mania (Bowden et al, 1994), rapid cycling and mixed states, with comorbid substance abuse and in secondary bipolar disorder (Calabrese et al, 1996). There are no rigorous prospective studies which have addressed the issue of its efficacy in rapid cycling or mixed states. In an ongoing prophylactic study comparing Divalproex, Lithium and placebo in bipolar disorder, Bowden et al (APA, 1996) reported that, in moderate to severe bipolar disorder, Divalproex was as effective as Lithium and superior to placebo at the end of one year of treatment. However, although there is a body of open labelled data pointing towards the prophylactic efficacy of Divalproex, there is not a single published double-blind study to support this at this time. Divalproex has no proven efficacy in acute bipolar depression.

Bowden et al (1996) in an analysis of data from an acute mania study have reported that Divalproex is more effective when the serum valproic acid level is over 350 mmols/l. Over 700 mmols/l is associated with markedly increased adverse effects. It can have a rapid onset of action, often within 3 days when an oral loading dose of 20 mg/kg/day is used (Keck et al, 1993). Non-adherence rates are 10-25% and lower than with Lithium or Carbamazepine. Neural tube defects occur when it is used in the first trimester of pregnancy. There is relatively low drug-drug interaction when compared with other mood stabilizers and no proven long term risk.

Divalproex sodium has fewer gastrointestinal side effects when compared with valproate, and patients can thus tolerate Divalproex even when the total daily dose is taken two rather than three divided doses.

References
Bowden CL, Brugger AM, Swann AC, Calabrese JR et al. 1994. Efficacy of Divalproex vs Lithium and Placebo in the Treatment of Mania. JAMA. 271:12. 918-924.

Bowden CL, Janicak, PG, Orsulak P et al. 1996. Relation of Serum Valproate Concentration to Response in Mania. Am J Psychiatry. 153:6. 765-770.

Calabrese JR, Fatemi SH, Kujawa M, Woyshville MJ. 1996. Predictors of Response to Mood Stabilizers. J Clin Psychopharmacology. 16. 2. Suppl 1. 24S-30S.

Keck PE, McElroy SL, Tugrul KC, Bennett JA. 1993. Valproate Oral Loading in the Treatment of Acute Mania. J Clin Psychiatry. 54. 305-308.

Predictors of Response and Non-Response to Divalproex

Divalproex is effective in acute mania, rapid cycling, mixed states, secondary bipolar disorder, and may be effective in the presence of personality dysfunction and substance abuse (Calabrese et al, 1996). Because of its efficacy in a variety of clinical presentations of bipolar disorder, growing evidence for prophylactic efficacy, and broad serum therapeutic range it is being increasingly used as a broad spectrum mood stabilizer. Although there is a good body of literature of open studies showing the usefulness of Divalproex, there is no published data from any double-blind placebo controlled study of its efficacy in the prophylaxis of bipolar disorder. There is little evidence to support that Divalproex is efficacious in acute bipolar depression.

References
Calabrese JR, Fatemi SH, Kujawa M, Woyshville MJ. 1996. Predictors of Response to Mood Stabilizers. J Clin Psychopharmacology. 16. 2. Suppl 1. 24S-30S.

Divalproex: Adverse Effects and Interactions

Gastrointestinal, sedative and hematological (thromobocytopenia and leucopenia) side effects with Divalproex (DVPX) appear to be associated with serum levels above 700 mmols/l (Bowden et al, 1993). Serious hepatic side effects have not been reported in subjects above the age of 10. Mild, transient and non-lethal changes in hepatic functioning are common. Hepatic functioning should be particularly monitored when polytherapy is being used. Neural tube defects with DVPX use in the first trimester of pregnancy is around 2% (Lindout et al, 1986). Hair loss or thinning occurs in a small percentage of patients and can be transient and self-limiting. It may be helped with supplementation with selenium and or zinc. Cognitive side effects are lower than with Lithium, thus making DVPX an attractive alternative. Weight gain is not uncommon. There are relatively few drug interactions associated with DVPX. Care should be taken, however, to monitor for bleeding time and bruising when DVPX is used along with any agent that alters platelets or is an anticoagulant. Monitoring of hematological and hepatic functions, and serum levels are needed only if clinically indicated after close monitoring in the first few weeks of therapy with DVPX. (McElroy et al, 1995)

References
Bowden CL, May RB, Sunder TR. 1993. Hematological Manifestations of Long-Term Valproate Therapy. Epilepsia. 34. 1098-1101.

Lindout D, Schmidt D. 1986. In Utero Exposure to Valproate and Neural Tube Defects. Lancet. 1392-1393.

McElroy SL and Keck PE. 1995. Antiepileptic Drugs. Ch. 17, Pg 351-375. In Textbook of Psychopharmacology. Ed. Schatzberg and Nemeroff. APA Press.