Zynerva Mechanism of Action

Pharmacology: Citicoline is a derivative of choline and cytidine that is involved in the biosynthesis of lecithin. It is claimed to increase blood flow and oxygen consumption in the brain and has been given in the treatment of cerebrovascular disorders, Parkinsonism, and head injury. Citicoline is an interneuronal communication enhancer. It increases the neurotransmission levels because it favors the synthesis and production speed of dopamine in the striatum acting then as a dopaminergic agonist thru the inhibition of tyrosine-hydroxylase.
Citicoline acts as a presynaptic cholinergic agent which favors the synthesis of acetylcholine. It also decreases the release of serotonin.
Citicoline makes the neurons more active, causing the astrocytes to loosen their grip on the capillaries, thus improving microcirculation. It has the ability to slightly increase cerebral blood flow and exerts an anti-aggregation effect on platelets.
Pharmacodynamics: When administered orally, it is absorbed almost completely and its bioavailability is approximately the same when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the body, cross the blood brain barrier, and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the cellular membrane and microsomes.
The concept that administration of exogenous Citicoline can augment the synthesis of neural membrane phospholipid is attractive, because accelerated replacement or repair plays a critical role in maintaining the healthy function of numerous physiological processes. It has shown therapeutic efficacy in a variety of diseases in which membrane disorder, dysfunction, or degeneration result in cellular and tissue ischemia and necrosis.
Pharmacokinetics: Citicoline is a water-soluble compound with greater than 90% bioavailability. Pharmacokinetic studies in healthy adults have shown oral doses of Citicoline to be rapidly absorbed, with less than 1% excreted in the feces. Plasma levels peak in a biphasic manner, at 1 hour after ingestion followed by a second larger peak at 24 hours post-dosing.
Citicoline is metabolized in the gut wall and liver. The byproducts of exogenous Citicoline formed by hydrolysis in the intestinal wall are choline and cytidine. Following absorption, choline and cytidine are dispersed throughout the body, enter systemic circulation for utilization in various biosynthetic pathways and cross the blood-brain barrier for re-synthesis into Citicoline in the brain.
Pharmacokinetic studies using Citicoline show Citicoline elimination occurs mainly via respiratory CO2 and urinary excretion, in two phases, mirroring the biphasic plasma peaks. The initial peak in plasma concentration is followed by a sharp decline, which then slows over the next 4-10 hours. In the second phase, an initially rapid decline after the 24-hour plasma peak is similarly followed by a slower elimination rate. The elimination half-life is 56 hours for CO2 and 71 hours for urinary excretion.