Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women with Major Depressive Disorder
Even though selective serotonin reuptake inhibitors (SSRIs) have been widely used as safe standard treatments for major depressive disorder (MDD), their relatively modest efficacy and delayed onset of therapeutic response remain clinical challenges.
Creatine monohydrate (creatine) has been approved and ingested as a safe dietary supplement for a decade. Given the preclinical findings that female animals with supplementation of creatine showed antidepressant effects, we reported the finding that women with MDD who received creatine plus standard SSRI showed a more rapid and greater improvement in depressive symptoms relative to those who received only standard SSRI, in the American Journal of Psychiatry, in 2012.
Although creatine administration may involve the restoration of abnormalities in brain energy metabolism related to MDD pathophysiology, the exact neurobiological mechanisms of creatine-induced antidepressant efficacy remain unknown, especially in human. The current study thus investigated improvement in brain metabolism and network in MDD female patients who received the combination of creatine and standard SSRI, escitalopram. Thirty-four women with MDD were randomly assigned to receive either escitalopram plus creatine [creatine group, n=17] or escitalopram plus placebo [placebo group, n=17] for 8 weeks. They participated in neuroimaging assessments at baseline and week 8. Age-matched healthy women were assessed twice at the same intervals. Changes in prefrontal N-acetyl aspartate (NAA) levels and those in rich club connections of the structural brain network, each of which indicate neuronal viability and information integration levels of the brain, were assessed as metabolic and network measures, using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively.
At baseline, female patients showed MDD-related metabolic and network dysfunction. The MDD group relative to the control group showed lower NAA levels in the prefrontal cortex and the structural network disorganization as well as lower rich club connections. Interestingly, lower prefrontal NAA levels and rich club connections were associated with more severe depressive symptoms in women with MDD. This is in line with the rationale that the dysfunction of the prefrontal cortex, abnormalities in brain bioenergetics, and subsequent network disorganization in the brain may contribute to the pathogenesis of MDD in women.
Following 8 weeks of treatment, the creatine group, not the placebo group, showed increases in prefrontal NAA levels and rich club hub connections, suggesting improved brain metabolic function and better communication efficiency within more integrated brain network.
The current results suggest that localized metabolic abnormalities in the prefrontal cortex and brain network disorganization may be neurobiological mechanisms by which combination of creatine with SSRI treatment synergistically produces antidepressant effects.
Our results suggest that localized metabolic dysfunction in the prefrontal region and brain network disorganization may be biological mechanisms by which creatine augmentation of SSRI treatment produces its antidepressant effects. Changes in brain metabolic and network function, assessed using multimodal neuroimaging, could be used as potential markers to indicate disease progression and successful treatment responses in MDD and possibly other disorders. Moreover, the current findings could provide a new insight in terms of the development of novel therapeutic approaches of MDD.
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Yoon S, Kim JE, Hwang J, Kim T-S, Kang HJ, Namgung E, Ban S, Oh S, Yang J, Renshaw PF, Lyoo IK: Effects of creatine monohydrate augmentation on brain metabolic and network outcome measures in women with major depressive disorder. Biological Psychiatry, in press.