Comparative teratogenicity analysis of valnoctamide, risperidone, and olanzapine in mice

Bipolar Disord. 2015 Sep;17(6):615-25. doi: 10.1111/bdi.12325. Epub 2015 Aug 20.

Abstract

Objectives: Based on the recent findings from animal studies, it has been proposed that the therapeutic use of valnoctamide, an anxiolytic drug developed in the early 1960s, be extended to treat other neurological disorders such as epilepsy and bipolar disease. Given the scarcity of adequate data on its prenatal toxicity, a comparative teratogenicity study of valnoctamide and two of the most commonly used drugs to treat bipolar disorder, risperidone and olanzapine, was carried out in a mouse model system.

Methods: Pregnant dams were treated with the aforementioned three drugs at the dose levels calculated as an equal proportion of the respective LD50 values of these drugs. The main reproductive indices examined included the numbers of implantations and resorptions, viable and dead fetuses, and fetal gross, visceral and skeletal abnormalities.

Results: The outcomes of the present study indicated that olanzapine was the most teratogenic of the three drugs, inducing maternal-, embryo-, and fetotoxicity. Risperidone also exerted a significant prenatal toxicity, but its adverse effect was less pronounced than that induced by olanzapine. Valnoctamide did not show any teratogenic effect, even when used in relatively higher dosages than olanzapine and risperidone. The observed increased skeletal abnormalities in one of the valnoctamide treatment groups were nonspecific and, as such, signaled a modest developmental delay rather than an indication that the compound could induce structural malformations.

Conclusions: Under our experimental conditions, valnoctamide demonstrated the lowest prenatal toxicity of the three tested drugs.

Keywords: comparative teratogenicity; mice; olanzapine; risperidone; valnoctamide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Anti-Anxiety Agents* / administration & dosage
  • Anti-Anxiety Agents* / adverse effects
  • Antipsychotic Agents* / administration & dosage
  • Antipsychotic Agents* / adverse effects
  • Benzodiazepines* / administration & dosage
  • Benzodiazepines* / adverse effects
  • Bipolar Disorder / drug therapy*
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Olanzapine
  • Pregnancy
  • Pregnancy Complications / drug therapy*
  • Risperidone* / administration & dosage
  • Risperidone* / adverse effects
  • Teratogenesis / drug effects*

Substances

  • Amides
  • Anti-Anxiety Agents
  • Antipsychotic Agents
  • Benzodiazepines
  • valnoctamide
  • Risperidone
  • Olanzapine