Valproate-Induced Metabolic Syndrome

Abstract

Valproic acid (VPA) and its salts (sodium calcium magnesium and orotic) are psychotropic drugs that are widely used in neurology and psychiatry. The long-term use of VPA increases the risk of developing adverse drug reactions (ADRs), among which metabolic syndrome (MetS) plays a special role. MetS belongs to a cluster of metabolic conditions such as abdominal obesity, high blood pressure, high blood glucose, high serum triglycerides, and low serum high-density lipoprotein. Valproate-induced MetS (VPA-MetS) is a common ADR that needs an updated multidisciplinary approach to its prevention and diagnosis. In this review, we consider the results of studies of blood (serum and plasma) and the urinary biomarkers of VPA-MetS. These metabolic biomarkers may provide the key to the development of a new multidisciplinary personalized strategy for the prevention and diagnosis of VPA-MetS in patients with neurological diseases, psychiatric disorders, and addiction diseases.

Ethnic Aspects of Valproic Acid P-Oxidation

“…Therefore, ideally, the neurologist or psychiatrist should consider all available genetic, physical, dietary, and environmental parameters to make the best possible choice of VPA and dosage when initiating therapy for each individual patient. Once the level of ingested VPA reaches a stable blood level, the study of TDM and active VPA metabolites [2] may be useful to clarify whether ADRs are due to disruption of the pharmacokinetics of VPA and its accumulation [1,37,106].…”

“…However, genetically determined interindividual variability in VPA pharmacokinetics associated with allelic variants in the CYP genes may vary among different ethnic and racial groups of patients with neurological diseases and mental disorders [1,[23][24][25]. This largely depends on the allelic frequency of non-functional and low-functional single nucleotide variants (SNVs) of CYP family genes in different populations, which is important to consider when developing PGx panels and their use in real-life clinical practice around the world [2,26]. The use in PGx panels of studies of allelic variants of CYP genes that have demonstrated a role in altering VPA pharmacokinetics and a significance in the prediction and prevention of VPA-induced ADRs in one ethnic group may not be clinically or economically feasible in another ethnic group.…”

“…SNVs that are located in introns or promoters are associated with a decreased expression of CYPs (risk of developing VPA-induced ADRs) or an increased expression of CYPs (risk of VPA therapeutic resistance) [53,54]. Although most SNVs do not directly or significantly contribute to the pathological phenotypes of IM and PM in patients receiving VPA [55,56], the risk of developing VPA-induced ADRs (e.g., hepatotoxicity [1,19], neurotoxicity [57], teratogenicity [58], metabolic syndrome [2]) may be variable (low, moderate, or high) in representatives of different populations, depending on genetically determined changes in enzymatic activity and/or the expression of CYPs involved in the P-oxidation of VPA. This is important to consider in the development of PGx panels for various ethnic and racial groups of patients and their use in the real clinical practice of a neurologist or psychiatrist [59,60].…”

“…The genotypes studied play an important role in the control of steady-state VPA concentrations in blood serum [24] through TDM and studies of toxic VPA metabolites in biological fluids (blood, urine, saliva, etc.) [2].…”

“…Valproic acid (CH3CH2CH2)2CHCOOH 2-propylpentanoic acid, VPA) is one of the most prescribed psychotropic drugs in neurology and psychiatry [1,2]. Its effectiveness and safety varied between patients, which is explained by individual pharmacokinetics (in particular, the rate of metabolism of VPA and its active metabolites in the liver).…”