Objectives: Valproate's well-known teratogenicity limits its use in young bipolar women of childbearing age. According to toxicologic studies the teratogenicity of valproate stems from its free carboxylic group. Valnoctamide is a derivative of valproate that does not undergo biotransformation to the corresponding free acid. In mice valnoctamide has been shown to be distinctly less teratogenic than valproate. Valnoctamide is an anticonvulsant and we hypothesized that valnoctamide is antimanic.
Methods: We performed a five week double-blind randomized controlled trial of valnoctamide in mania. Patients admitted to the study were treated with risperidone at doses of physician discretion beginning with 2 mg daily. Valnoctamide or placebo was begun at doses of 600 mg per day and increased to 1200 mg after four days. Weekly ratings by a psychiatrist blind to the study drug were conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS), and the Clinical Global Impression (CGI). Weekly blood was drawn for drug levels of valnoctamide measured by gas chromatography. For statistical analysis 17 patients were available for the placebo group and 15 for the valnoctamide group, well matched for age, sex and illness severity.
Results: Valnoctamide was more effective than placebo as add-on to risperidone. (Two-way ANOVA, interaction of treatment and time p=.01 for YMS, p=.007 for BPRS and p=.003 for CGI. Post-hoc LSD differences were significant for week three, four and five.)
Conclusions: Valnoctamide could be an important valproate substitute for young women with bipolar disorder at risk of pregnancy.