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

Shami Kanekar,Michael D Hoffman,Chandni S Sheth,Perry F Renshaw,Robert Ettaro,Cayla Lynch,Jadeda Brown,Hendrik J Ombach

doi:10.3390/ijms22158195

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.

Highlights

Major depressive disorder (MDD) is a mental health disorder characterized by low mood, which is often chronic and can significantly diminish quality of life
Post hoc tests showed that creatine levels in the female prefrontal cortex (PFC), STR and BST were significantly lower at 2 weeks and 5 weeks vs. 1 week at altitude, while HIP creatine levels were significantly
We further found that creatine monohydrate (CRMH) + selective serotonin reuptake inhibitors (SSRIs) treatment varied in impact on brain creatine and serotonin levels vs. dietary CRMH treatment alone

Summary

Introduction

Major depressive disorder (MDD) is a mental health disorder characterized by low mood, which is often chronic and can significantly diminish quality of life. Rates of MDD and suicide both increase with altitude of residence [4,5,6,7,8,9,10,11,12,13,14], and people at altitude are exposed to hypobaric hypoxia (low partial pressure of oxygen). 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). 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.

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Results

Discussion

Conclusion