Patients being treated with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) often require several weeks of therapy before experiencing symptomatic relief, despite the immediate effects of these agents at the synaptic level. Increasing the speed of response can enhance quality of life, since patients continue to experience ongoing morbidity during the period between treatment initiation and treatment response. Moreover, since longer treatment response time is associated with poorer remission rates1, therapeutic interventions aimed at producing a more rapid response to treatment might play an important role in increasing chances of remission, resulting in superior long-term outcomes.

Lyoo, Yoon, Kim, and colleagues conducted the first double-blind, placebo-controlled study of augmenting SSRI treatment with oral creatine monohydrate to accelerate response to antidepressant treatment in patients with major depressive disorder (MDD).2 Creatine has been established as a safe natural product and is used as a dietary supplement in enhancing athletic performance3,4 and has been studied for its beneficial effects in neuromuscular and neurometabolic disorders.5

The researchers hypothesized that since oral supplementation with creatine increases the cerebral reservoir of phosphocreatine in the brain, this increased reservoir may “cause a shift in brain creatine kinase activity and ultimately be used to produce adenosine triphosphate (ATP) from phosphocreatine in response to energy demand.” They also noted that previous studies using magnetic resonance spectroscopy with phosphorus-31 (31P-MRS) suggested that subjects with MDD have “abnormal brain bioenergetics,” including impaired turnover of ATP to phosphocreatine, and that improvement in depressive symptoms was associated with normalization of this turnover process.

The investigators cited additional research demonstrating that the resonance of high phosphocreatine level and low level of b-nucleoside triphosphate at baseline — which is derived mainly from ATP in the brain — was associated with a subsequent positive treatment response to an SSRI and triodothyronine augmentation. This suggests that the “proenergetic effect of creatine supplementation, including efficient regeneration of intracellular high-energy phosphate, may contribute to an earlier and greater response to standard antidepressants.” The researchers additionally noted that their hypothesis regarding the potential antidepressant effects of creatine is supported by recent preclinical evidence from an animal model of depression.6

The eight-week, proof-of-concept study focused on 52 women with MDD. The rationale for choosing female subjects was that abnormal cerebral metabolism associated with depression has been reported to be more common in women than in men, and therefore creatine supplementation may be more beneficial in women. Subjects were randomized to receive escitalopram in addition to either creatine (5g/day, N=25) or placebo (N=27). Efficacy was assessed primarily by changes in the Hamilton Depression Rating Scale (HAM-D) score.