Sex differences in the antidepressant-like effects of ketamine

Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl D-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.