Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

► Abnormal creatine metabolism is associated with major depressive disorders. ► We examined the efficacy of combined creatine and fluoxetine treatment in rats. ► Long-term creatine supplementation produced antidepressant effects in females only. ► Fluoxetine prolonged the benefit of creatine after repeating forced swim testing. ► The data support a relationship between creatine, serotonin, and ovarian hormones.