Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

Abstract

Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

Effects of Creatine Supplementation on Brain Function and Health

“…Animal research suggests there may be a sex-dependent relationship regarding creatine and depression [ 110 , 112 , 113 , 114 ]. Dietary creatine appears to be more efficacious in female rats compared to male rats [ 110 , 112 ]; however, creatine in combination with other antidepressant drugs does appear to have some benefit in male rodents [ 114 ].…”

“…Animal research suggests there may be a sex-dependent relationship regarding creatine and depression [ 110 , 112 , 113 , 114 ]. Dietary creatine appears to be more efficacious in female rats compared to male rats [ 110 , 112 ]; however, creatine in combination with other antidepressant drugs does appear to have some benefit in male rodents [ 114 ]. The use of creatine has also been investigated in other clinical models where depression is often observed as a secondary consequence of disease, or it results from the treatment.…”

Creatine Activity as a Neuromodulator in the Central Nervous System

“…They showed that creatine treatment improved serotonin deficits in female rats at altitude and has antidepressant efficacy. In male rats at altitude, creatine alone is not antidepressant, while creatine combined with the selective serotonin reuptake inhibitors enhances brain serotonin levels and is an antidepressant (36).…”

“…The antidepressant effect of creatine on the tail suspension test is suppressed by compounds that inhibit serotonin synthesis and increased by co-administration with selective serotonin reuptake inhibitors, like fluoxetine (35). Another study by Kanekar, Ettaro (36) showed that dietary oral creatine monohydrate supplementation can improve brain bioenergetic damage at altitude in rats of both genders and has gender-based effects on regional brain serotonin levels as well as antidepressant effects. They showed that creatine treatment improved serotonin deficits in female rats at altitude and has antidepressant efficacy.…”

Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies

“…Preclinical and clinical studies have reported sexual dimorphisms in the severity and evolution of perinatal encephalopathy and responses to treatment [ 67 , 68 , 69 , 70 ]. There are limited data indicating sex-specific differences in creatine uptake in the adult brain [ 71 ]. However, whether these differences exist in the perinatal brain and are physiologically significant enough to impact on HIE should be considered.…”