Clinical and neurobiological effects of creatine supplementation in depressive disorders

Creatine is an endogenous compound that plays a role in cellular energy metabolism, particularly important in metabolically demanding tissues such as the brain. This article outlines the biochemical pathways controlling creatine synthesis through the orchestrated action of the enzymes L-arginine:glycine amidino transferase (AGAT) and guanidinoacetate methyltransferase (GAMT), its cellular uptake via the SLC6A8 transporter, and its intracellular compartmentalization as phosphocreatine—the primary energy store mobilized per unit of time. The literature is analyzed and the interface between these biochemical pathways and neurobiological processes of depression, through mitochondrial dysfunctions, biases of neurotransmission, and neuroprotection mechanisms, is discussed. Through these mechanisms, creatine appears to function as a modulator of mental health, shedding new light on potential treatments for depression. Such work bridges the gap between cellular biochemistry and neuropsychiatry, advancing an understanding of the metabolic role of creatine with emotional regulation.