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

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

Association between altitude, prescription opioid misuse, and fatal overdoses

Objective: Prescription opioid misuse and fatal overdoses have increased significantly over the last two decades. Living at altitude has been linked to greater reward benefits of other drugs of abuse, and living at altitude may also exacerbate the respiratory depression linked to opioid use. Therefore, we examined the relationships between living at altitude, and prescription opioid misuse and fatal overdoses. Method: State-level past year rates of prescription opioid misuse were retrieved from the Substance Abuse and Mental Health Services Administration. County-level overdose data were extracted from the Centers for Disease Control and Prevention. Multiple linear regression models were fit to determine the relationship between average state elevation and state rates of opioid misuse. Logistic regression models were fit to determine the relationship between county elevation and county-level fatal opioid overdose prevalence. Results: After controlling for state opioid prescribing rates and other confounders, we identified a significant positive association between mean state altitude and state-level opioid misuse rates for women, but not men. We also found a significant positive association between county-level altitude and prevalence of fatal opioid overdose. Conclusions: Living at altitude is thus demographically associated with increasing rates of misuse of prescription opioids, as well as of cocaine and methamphetamine. Animal studies suggest that the hypobaric hypoxia exposure involved with living at altitude may disrupt brain neurochemistry, to increase reward benefits of drugs of abuse. This increased misuse of both stimulants and opioids may increase likelihood of overdose at altitude, with overdoses by opioid use also potentially facilitated by altitude-related hypoxia. Keywords: Prescription opioids, Drug misuse, Opioid overdose, Hypobaric hypoxia, Altitud