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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.

SUBMITTER: Brown ES

PROVIDER: S-EPMC6898191 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Brown E Sherwood ES Kulikova Alexandra A Van Enkevort Erin E Nakamura Alyson A Ivleva Elena I EI Tustison Nicholas J NJ Roberts Jared J Yassa Michael A MA Choi Changho C Frol Alan A Khan David A DA Vazquez Miguel M Holmes Traci T Malone Kendra K

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190610 13

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 ...[more]

PMID: 31181564

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Project description:BackgroundPreclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α(1) receptor antagonist doxazosin on the positive subjective effects of cocaine.MethodsThirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.ResultsDoxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high", "stimulated", "like cocaine", "desire cocaine", "any drug effect", and "likely to use cocaine if had access" (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated", "like cocaine", and "likely to use cocaine if had access" (p<.05). There were trends for doxazosin to reduce ratings of "stimulated", "desire cocaine", and "likely to use cocaine if had access" (p<.10).ConclusionsMedications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.Trial registrationClinicaltrials.gov NCT01062945.

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

Publications

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

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