Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study

Abstract

Background 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. Methods We recruited 5 female adolescents who had been on fluoxetine (Prozac®) for ≥8 weeks, 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 4 g daily for 8 weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8 weeks apart. Results 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. Limitations Lack of placebo control; and small sample size. Conclusions Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.

The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

“…Through the reversible creatine kinase, creatine raises cellular phosphocreatine levels, which increases the capacity for cellular adenosine triphosphate resynthesis [154]. Creatine monohydrate had been tested in a small case series study as an augmenting agent for SSRI-resistant depression in adolescents with encouraging results [155]. Similarly, creatine augmentation was tested in a small open-label trial of patients with treatment-resistant MDD and bipolar depression with positive results [156].…”

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

“…In this context, creatine administered both systemic and centrally produces antidepressant-like effects in behavioral despair models like the TST [16][17][18]. In addition to the preclinical data, clinical trials have also demonstrated that creatine supplementation produces antidepressant effect and that creatine could be a new approach in the treatment of depression [21,19,20]. However, the mechanisms underlying the homeostatic versus neuromodulatory roles of creatine in the brain still need to be explored.…”

“…Both clinical and preclinical evidence have demonstrated that creatine (N-aminoiminomethyl-N-methylglycine, a substrate of creatine kinase enzyme) improves mood, possibly by restoring brain energy levels and homeostasis [16][17][18][19][20][21][22]. Of note, creatine supplementation has been reported to improve depressive symptoms in 1-2 weeks of treatment in depressive patients, faster than the currently available antidepressants, which require 4-5 weeks to produce their therapeutic effects [19,21].…”

“…Of note, creatine supplementation has been reported to improve depressive symptoms in 1-2 weeks of treatment in depressive patients, faster than the currently available antidepressants, which require 4-5 weeks to produce their therapeutic effects [19,21].…”

Creatine in the brain

“…Another study by Turner et al showed that daily ingestion of 20 grams of creatine monohydrate for 7 consecutive days increased creatine in the precentral gyrus when compared to a placebo by means of a crossover design experiment (7.03 mmol/L after creatine ingestion, 6.44 mmol/L after placebo ingestion) 6) . Furthermore, Kondo et al reported in their study that oral ingestion of 4 grams of creatine monohydrate per day for 8 consecutive weeks resulted in enhancement of the creatine phosphorus level in the brain by 6% among patients with major depressive disorder 7) . On the other hand, Wilkinson et al reported that there were no positive effects on brain creatine in prefrontal white matter after 5 days of oral creatine ingestion in 12 athletes (23 years old on average) 8) .…”