Creatine as a New Treatment for Schizophrenia:A Double-Blind Trial

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. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including schizophrenia and major depression, where alterations in brain high-energy phosphate metabolism have been reported.

Kieburtz et al (see: http://www.huntington-study-group.org/Creatine%20abstract.htm) are conducting a double blind clinical trial of creatine in 50 ambulatory Huntington disease subjects randomized to creatine or placebo. Those randomized to creatine receive 3g for 2 months and then 5g for an additional 2 months. There have been no significant adverse events associated with creatine or significant changes in laboratory tests or vital signs. In the creatine treated group creatine plasma levels approximately doubled (210 ± 335 µM vs. 500 ± 125 µM). Kieburtz et al are currently also conducting a multi-center, double-blind study of creatine in patients with Parkinson's disease, funded by the National Institute of Neurological Disorders and Stroke (NINDS). Recently, Rae et al (2003) reported that creatine supplementation (5 grams per day for 6 weeks) had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and Raven's Advanced Progressive Matrices. These findings suggest a role of brain energy capacity in influencing brain cognitive performance and that creatine via its effects on brain energy metabolism may exert beneficial effects on cognition.

Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in the pathophysiology of schizophrenia. Imaging studies have used positron emission tomography (PET) with flurodeoxyglucose (FDG), or functional magnetic resonance imaging (fMRI), 15O magnetic resonance spectroscopy with 31P (31P-MRS) and single photon emission tomography (SPECT), to investigate cerebral metabolic rates in schizophrenia. Most but not all studies reveal decreased metabolism in the frontal cortex in schizophrenia, which was termed hypofrontality. Several studies also observed alterations in brain metabolic rates in other brain regions including the temporal lobes, the thalamus and the basal ganglia, leading to the suggestion of an impairment in the fronto-striatal-thalamic circuitry in schizophrenia rather than in a specific brain region (Andreasen et al. 1997). A direct link to phosphocreatine and ATP energy systems came from studies using 31P-MRS with or without chemical shift imaging, which enabled the measurement of ATP, phosphocreatine and inorganic phosphate. These studies showed reduced ATP in the frontal lobe and in left temporal lobe of schizophrenic patients as compared to controls (Volz et al. 2000). Altered brain energy metabolism could be due to impairment of mitochondria and a variety of studies reviewed recently by Ben Shachar (2002) suggest impaired mitochondrial energy metabolism in schizophrenia.

Interestingly, creatine besides its energy sparing properties was also shown to have neuroprotective properties in a variety of animal models for brain diseases including Huntington and Parkinson diseases, as well as exerting protective effects in animal models for cerebral hypoxia (Persky & Brazeua, 2001).