A randomized trial of an NMDA receptor antagonist for reversing corticosteroid effects on the human hippocampus

Abstract

Preclinical and clinical research indicates that excess corticosteroid is associated with adverse effects on the hippocampus. Animal model data suggest that N-methyl-D-aspartate (NMDA) receptor antagonists may block corticosteroid effect on the hippocampus. This translational clinical trial investigated the effect of memantine vs. placebo on hippocampal subfield volume in humans receiving chronic corticosteroid therapy. Men and women (N = 46) receiving chronic prescription corticosteroid therapy were randomized to memantine or placebo in a double-blind, crossover design (two 24-week treatment periods, separated by a 4-week washout) for 52 weeks. Structural magnetic resonance imaging was obtained at baseline and after each treatment. Data were analyzed using repeated measures analysis of variance. Mean corticosteroid dose was 7.69 ± 6.41 mg/day and mean duration 4.90 ± 5.61 years. Controlling for baseline volumes, the left DG/CA3 region was significantly larger following memantine than placebo (p = .011). The findings suggest that an NMDA receptor antagonist attenuates corticosteroid effect in the same hippocampal subfields in humans as in animal models. This finding has both mechanistic and clinical implications. Attenuation of the effect of corticosteroids on the human DG/CA3 region implicates the NMDA receptor in human hippocampal volume losses with corticosteroids. In addition, by suggesting a drug class that may, at least in part, block the effects of corticosteroids on the human DG/CA3 subfield, these results may have clinical relevance for people receiving prescription corticosteroids, as well as to those with cortisol elevations due to medical or psychiatric conditions.

Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK Biobank

“…Some of these effects were detected even after ten years of biochemical remission 22 23. Moreover, a few small studies have shown volumetric reductions in specific brain regions, including the hippocampus and amygdala,27–31 in patients using chronic and/or high-dose synthetic systemic glucocorticoids. Besides these structural abnormalities, several studies in animal models and patients with Cushing disease have also demonstrated widespread reductions in white matter integrity throughout the brain 32–36.…”

Does glucocorticoid exposure explain the association between metabolic dysfunction and tendinopathy?

“…Rotator cuff tendon biopsies taken before and 7 weeks after glucocorticoid injection show a large increase in the proportion of cells positive for NMDA receptor subtype 1 staining that was not seen over the same period in response tendon repair surgery (36). These findings are supported by a recent study showing that 24-week NMDA receptor antagonist administration partly reversed the adverse effects of long-term glucocorticoid treatment on the CA3 region of the hippocampus (86). Together these studies indicate that glutamate and NMDA receptors are involved in tendinopathy and that glucocorticoid exposure both induces glutamate release and enhances stimulation of NMDA receptors leading to neuroexcitotoxic effects.…”

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls

“…This would rather require NMDA-R blockage with an antagonist parallel to MR stimulation. Interestingly, the NMDA-R antagonist memantine improved memory by inducing neurogenesis in mice [ 42 ], and reversed the adverse effects of long-term glucocorticoid administration on hippocampus volume in humans over a period of several months [ 43 ].…”