Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial.
OBJECTIVE
Valproic acid's well-known teratogenicity limits its use in women of childbearing age. Valnoctamide is an analog 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 double-blind, five-week, add-on, controlled trial of valnoctamide in mania. Patients were treated with risperidone at doses of the physician's discretion. Valnoctamide or placebo was begun at doses of 600 mg/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).


RESULTS
Fifteen valnoctamide patients and 17 placebo patients completed at least one post-baseline week and were included in data analysis. In all efficacy measures valnoctamide was more effective than placebo as an add-on to risperidone, using two-way analysis of variance (ANOVA) with time as the within-subject factor. Two-way ANOVA showed a significant effect of time (p < 0.001) and significant interaction between treatment and time (YMRS: p = 0.012; BPRS: p = 0.007; CGI: p = 0.003). Differences between valnoctamide and placebo were significant from week 3 to week 5.


CONCLUSIONS
Valnoctamide could be an important valproate substitute for women of childbearing age with bipolar disorder who may become pregnant.
Bersudsky
Y
Y
Stanley Center for Bipolar Research, Ministry of Health Mental Health Center, Faculty of Health Sciences, Department of Psychiatry, Ben Gurion University of the Negev, Beer Sheva, Israel. yuly@bgu.ac.il
Applebaum
J
J
Gaiduk
Y
Y
Sharony
L
L
Mishory
A
A
Podberezsky
A
A
Agam
G
G
Belmaker
R H
RH
D000328:Adult; D000577:Amides / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010919:Placebos; D011247:Pregnancy; D011569:Psychiatric Status Rating Scales; D018967:Risperidone / Q000008:administration & dosage; D013723:Teratogens / Q000633:toxicity; D016896:Treatment Outcome; D014635:Valproic Acid / Q000009:adverse effects
D000577:Amides; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D004338:Drug Combinations; D010919:Placebos; D013723:Teratogens; C045179:valnoctamide; D014635:Valproic Acid; D018967:Risperidone