Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

Abstract

Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington's Disease and Parkinson's Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies.

Figure 1

De novo synthesis of creatine and relation to ATP. The machinery needed to produce endogenous creatine (dashed boxes) and ATP (dotted boxes) is expressed within neurons, oligodendrocytes, and astrocytes, but it is unknown to what extent this arrangement contributes to total brain creatine content. ATP synthesis from carbohydrate (glucose) occurs via three series of metabolic pathways: glycolysis, citric acid cycle (Krebs), and the electron transport chain. When ATP is rapidly depleted, creatine kinase catalyzes the donation of a phosphate group from phosphocreatine (PCr) to ADP, producing more ATP to buffer energy needs. Conversely, when energy is released, an individual phosphate group is cleaved from ATP and bound to creatine to rejoin the PCr pool. This reversible reaction causes a spontaneous byproduct (creatinine) that is excreted from the body, which is why creatine must be replenished daily (AGAT = arginine:glycine amidino transferase; CRT, creatine transporter; GAMT, guanidinoacetate methyltransferace; GAA, guanidinoacetate; SAMe, s-adenylmethionine; SAH, s-adenosylhomocysteine).