Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double‐blind, controlled, add‐on clinical trial

Abstract

Valnoctamide could be an important valproate substitute for women of childbearing age with bipolar disorder who may become pregnant.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…Antimanic efficacy has not been demonstrated for allopurinol (level 1 negative),167 eslicarbazepine/licarbazepine (level 2 negative),168 gabapentin (Level 2 negative), lamotrigine (level 1 negative),143 omega‐3 fatty acids (level 1 negative),169 topiramate (level 1 negative),143 valnoctamide (level 2 negative),170, 171 or zonisamide (level 2 negative)172 (Table 13). …”

Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities

“…Further confirmation of its safety profile has derived from preclinical and clinical investigations of drug-mediated anti-convulsant and mood-stabilizing actions (Barel et al, 1997;Lindekens et al, 2000;Isoherranen et al, 2003;Winkler et al, 2005;Bersudsky et al, 2010;Kaufmann et al, 2010;Mareš et al, 2013;Modi et al, 2017). VCD is effective at a low-micromolar dose level, a slightly reduced level of efficacy compared with ganciclovir (Ornaghi et al, 2016); nonetheless, we found substantial CMV inhibition in vivo with subcutaneous delivery.…”

“…This amount is similar to or less than the dose of existing compounds used to treat CMV in clinical settings; for instance, assuming a 60 kg body weight, ganciclovir can be used from 5 up to 20 mg/kg/d in patients with serious infections (Kotton et al, 2013;Choopong et al, 2016;Genentech USA, 2016). Furthermore, the 5 mg/kg dose of VCD for treating CMV infection is lower than the dose used to attenuate seizures and neuropathic pain in neonatal and adult rodent experiments (Winkler et al, 2005;Kaufmann et al, 2010;Mareš et al, 2013;Shekh-Ahmad et al, 2014) and is less than the 20 mg/kg dose that can be used in humans to treat psychiatric dysfunction (Stepansky, 1960;Goldberg, 1961;Harl, 1964;Bersudsky et al, 2010). Together, these findings suggest that VCD may be able to attenuate CMV in the human brain at doses that should be both effective and tolerable.…”

“…In animal models, VCD shows efficacy in both attenuating epilepsy (Lindekens et al, 2000;Isoherranen et al, 2003;Mareš et al, 2013;Pouliot et al, 2013;Shekh-Ahmad et al, 2014) and reducing neuropathic pain (Winkler et al, 2005;Kaufmann et al, 2010), in part by a mechanism that prolongs miniature IPSCs (Spampanato and Dudek, 2014). VCD shows no teratogenic effects in developing rodents (Radatz et al, 1998;Bersudsky et al, 2010;Shekh-Ahmad et al, 2014;. Surprisingly, we recently found that VCD also inhibits CMV outside the CNS (Ornaghi et al, 2016).…”

“…Therefore, novel anti-CMV strategies with alternative mechanisms of action and safer in vivo profiles are urgently needed. Valnoctamide (VCD) has been marketed since the early 1960s as an anxiolytic drug (Stepansky, 1960;Goldberg, 1961) and subsequently was tested as a mood stabilizer in patients with acute mania (Bersudsky et al, 2010). In animal models, VCD shows efficacy in both attenuating epilepsy (Lindekens et al, 2000;Isoherranen et al, 2003;Mareš et al, 2013;Pouliot et al, 2013;Shekh-Ahmad et al, 2014) and reducing neuropathic pain (Winkler et al, 2005;Kaufmann et al, 2010), in part by a mechanism that prolongs miniature IPSCs (Spampanato and Dudek, 2014).…”