Adolescent major depressive disorder (MDD) is a life-threatening brain disease with limited interventions. Treatment resistance is common, and the illness burden is disproportionately borne by females. 31-Phosphorus magnetic resonance spectroscopy (³¹P MRS) is a translational method for in vivo measurement of brain energy metabolites.

We recruited 5 female adolescents who had been on fluoxetine (Prozac�) for ≥8weeks, but continued meet diagnostic criteria for MDD with a Children's Depression Rating Scale-Revised (CDRS-R) raw score ≥40. Treatment response was measured with the CDRS-R. ³¹P MRS brain scans were performed at baseline, and repeated following adjunctive creatine 4g daily for 8weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8weeks apart.

The mean CDRS-R score declined from 69 to 30.6, a decrease of 56%. Participants experienced no Serious Adverse Events, suicide attempts, hospitalizations or intentional self-harm. There were no unresolved treatment-emergent adverse effects or laboratory abnormalities. MDD participants' baseline CDRS-R score was correlated with baseline pH (p=0.04), and was negatively correlated with beta-nucleoside triphosphate (β-NTP) concentration (p=0.03). Compared to healthy controls, creatine-treated adolescents demonstrated a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up ³¹P MRS brain scans.

Lack of placebo control; and small sample size.

Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.