A Double-blind, Parallel, Randomized, add-on Clinical Trial of Creatine Versus Placebo Added to Antidepressant Treatment of Patients With Major Depressive Episode.

Dr.Boris Nemetz and Prof.Joseph Levine M.D., Beer Sheva Mental Health Center,Israel.

Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency adenosine triphosphate (Wyss & Kaddurah-Daouk, 2000). Recent studies have suggested increased brain utilization of oxygen following oral creatine supplementation (Persky & Brazeua, 2001). Creatine supplementation is widely used in enhancing sports performance, and has been tried in the treatment of neurological, neuromuscular and atherosclerotic disease with a paucity of side effects (Persky & Brazeua, 2001).

Creatine enters the brain via a specialized sodium dependent transporter. Dechent et al (1999) studied the effect of oral creatine supplementation of 20g/day for 4 wk demonstrating a significant increase of mean concentration of total creatine across brain regions (8.7% corresponding to 0.6mM, P < 0.001). Lyoo et al (2003) studied magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine reporting that creatine (0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days) significantly increased brain creatine levels.

Accumulated evidence suggests the possible involvement of altered cerebral energy metabolism in the pathophysiology of depression (Mayberg, 1994). Functional brain imaging studies (positron and single photon emission tomography) have shown decreased blood flow and metabolism in the frontal lobes and basal ganglia in unipolar depression (Kennedy et al, 2001; Derevets et al, 2002).

Proton magnetic resonance spectroscopy studies have studied brain levels of creatine-containing compounds. Kato et al (1992) reported that phosphocreatine was significantly decreased in severely (as opposed to mildly) depressed patients. Dager et al (2004) studied depressed or mixed-state bipolar patients using two-dimensional proton echo-planar spectroscopic imaging, reporting an inverse correlation between severity of depression and white matter creatine levels.