RNase H-dependent DNA thresholder modulated by cancer marker concentration.

Threshold antisense oligonucleotide constructs were designed to cleave mRNA within different biomarker concentrations. The mRNA cleavage is activated by 2.6, 7.5 or 39.5 nM of biomarker depending on the construct design. The constructs can be used to differentiate cancer from normal cells by the level of oncogene expression followed by silencing of a targeted gene.

Psychometrics of the Concise Health Risk Tracking Self-Report (CHRT-SR16) Assessment of Suicidality in a Sample of Adults with Moderate to Severe Methamphetamine Use Disorder: Findings from the ADAPT-2 Randomized Trial.

Background: The co-occurrence of suicidality and substance use disorders has been well established, but rating scales to examine suicidal behavior and risk are sparse among participants with substance use disorders. We examined the psychometric properties of the 16-item Concise Health Risk Tracking Scale - Self Report (CHRT-SR16) to measure suicidality among adults with moderate-to-severe methamphetamine use disorder. Methods: Participants (n = 403) with moderate-to-severe methamphetamine use disorder completed the CHRT-SR16 as part of a randomized, double-blind, placebo-controlled pharmacotherapy trial. The CHRT-SR16 factor structure was assessed using confirmatory factor analysis (CFA). Internal consistency was estimated with coefficients alpha (α) and omega (ω), test-retest reliability with intraclass correlation coefficient (ICC) and standard error of measurement, and convergent validity using Spearman's ρ rank order correlation coefficient test between CHRT-SR16 factors and the Patient Health Questionnaire (PHQ-9). The analyses utilized baseline and week 1 data (for test-retest reliability only). Results: CFA revealed a seven-factor model of Pessimism, Helplessness, Social Support, Despair, Impulsivity, Irritability, and Suicidal Thoughts as the best-fitting model. The CHRT-SR16 also exhibited strong internal consistency (α = 0.89; ω = 0.89), test-retest reliability (ICC = 0.78) and convergent validity with the PHQ-9 total score (ρ = 0.62). Conclusion: The CHRT-SR16 showed strong psychometric properties in a sample of participants with primary methamphetamine use disorder. Clinicaltrialsgov Identifier: NCT03078075.

Psychometric properties of the Treatment Effectiveness Assessment in methamphetamine use disorder.

INTRODUCTION: The ability for people living with stimulant use disorder to live meaningful lives requires not only abstinence from addictive substances, but also healthy engagement with their community, lifestyle practices, and overall health. The Treatment Effectiveness Assessment (TEA) assesses components of recovery consisting of four functional domains: substance use, health, lifestyle, and community. This secondary data analysis of 403 participants with severe methamphetamine use disorder tested the reliability and validity of the TEA. METHODS: Participants were enrolled in the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for methamphetamine use disorder. The study used total TEA and domain scores at baseline to assess factor structure and internal consistency, as well as construct validity related to substance cravings (visual analog scale [VAS]), quality of life (quality-of-life assessment [QoL]), mental health (Patient Health Questionnaire-9 [PHQ-9], Concise Health Risk Tracking Scale Self-Report [CHRT-SR16]), and social support (CHRT-SR16). RESULTS: Individual TEA items showed moderate to large correlations with each other (r = 0.27-0.51; p < .001), and strong correlations to the total score (r = 0.69-0.78; p < .001). Internal consistency was strong (coefficient α = 0.73 [0.68-0.77]; coefficient ω = 0.73 [0.69-0.78]). Construct validity was acceptable, with the strongest correlation between the TEA Health item and the general health status item on the QoL (r = 0.53, p < .001). CONCLUSIONS: TEA has acceptable levels of reliability and validity supporting prior similar findings in a sample of participants with moderate to severe methamphetamine use disorder. Results from this study provide support for its use in assessing clinically meaningful changes beyond simply reduced substance use.

The cross-sectional relationship among omega-3 fatty acid levels, cardiorespiratory fitness, and depressive symptoms from the Cooper Center Longitudinal Study.

OBJECTIVE: Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are implicated in numerous illnesses including depression. The literature is mixed regarding the relationship between n-3 PUFA levels and depression, and studies based on self-reported dietary n-3 PUFA intake may not accurately reflect in vivo levels. METHOD: The current cross-sectional analysis examined the relationship between erythrocyte levels (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and depressive symptoms (Center for Epidemiologic Studies Depression Scale; CESD), adjusting for health-related factors and omega-3 supplement use in 16,398 adults assessed at the Cooper Clinic in Dallas, Texas for preventative medical examinations between April 6, 2009, and September 1, 2020. A three-stage hierarchical linear regression was conducted to examine the EPA and DHA levels on CES-D before and after inclusion of cardiorespiratory fitness (CRF) and high sensitivity C-reactive protein (hs-CRP) in the model. RESULTS: DHA level, but not EPA level, was significantly associated with CES-D scores. Taking omega-3 supplements was associated with lower CES-D scores even when adjusting for CRF, while hs-CRP was non-significantly associated with CES-D scores. These findings suggest that DHA levels are related to depressive symptom severity. Omega-3 PUFA supplement use was associated with lower CES-D scores when controlling for EPA and DHA levels. CONCLUSION: The findings from this cross-sectional study suggest that lifestyle and/or other contextual factors unrelated to EPA and DHA levels may also be associated with depressive symptom severity. Longitudinal studies are needed to evaluate the role of health-related mediators among these relationships.

The Impact of Caregiver Depression on Child Asthma Outcomes: Pathways and Mechanisms.

BACKGROUND: Depression is common in caregivers of children with asthma and is associated with poor outcomes in their child. No prior studies have longitudinally examined caregiver depression remission as a predictor of improvement in child asthma control. OBJECTIVE: This 2-site study examined whether the proportion of time a caregiver was in depression remission predicted subsequent child asthma control at exit. METHOD: Caregivers (n = 205) with current major depressive disorder and their children, ages 7 to 17, with persistent asthma were observed every 4 weeks for 52 weeks. Caregiver depressive symptoms were measured using the 17-item Hamilton Rating Scale for Depression (HRSD). Child asthma was assessed with the (Childhood) Asthma Control Test (cACT/ACT) and spirometry, and depression with the Children's Depression Inventory (CDI). Linear regression analyses were conducted with change in cACT/ACT, CDI, and forced expiratory volume in 1 second (FEV1)% predicted as outcomes and proportion of time the caregiver was in remission (HRSD score ≤ 7) as the predictor. Multilevel mediation analyses examined the role of child depressive symptoms and asthma controller medication adherence. RESULTS: Children were, on average, 54.1% female and 11 years old. Caregiver proportion of time in HRSD-assessed remission of depression was a significant predictor of improvement in cACT/ACT, CDI, and FEV1% predicted. Child CDI score, but not medication adherence, mediated the relationship between caregiver HRSD scores and child asthma control scores. CONCLUSIONS: Improvement in caregiver depression positively influences child asthma outcomes partially through improvement in child depressive symptom severity. Caregiver depression screening and treatment might lead to improvement in child asthma outcomes.

The Concise Health Risk Tracking - Self-Report (CHRT-SR)-A measure of suicidal risk: Performance in adolescent outpatients.

OBJECTIVES: The Concise Health Risk Tracking Self-Report (CHRT-SR) assesses the risk of suicidal behavior. We report its psychometric properties in a representative sample of adolescent outpatients. METHODS: A sample (n = 657) of adolescents (<18 years of age) in primary or psychiatric care completed the 14-item version of CHRT-SR at both baseline and within 3 months. To identify an optimal brief solution for the scale, we evaluated the factor structure of CHRT-SR using multigroup confirmatory factor analysis, and testing measurement invariance across age and gender. The item response theory and classical test theory characteristics of the optimal solution were evaluated. Concurrent validity (both cross-sectional and as a change measure over time) of the optimal solution was assessed by comparing it to another suicide measure. RESULTS: Confirmatory factor analysis identified the 9-item CHRT-SR (CHRT-SR9 ) as the optimal solution. Classical test theory and item response theory indicated excellent fit. Concurrent validity analyses revealed that it can measure both improvement/worsening of suicidality over time. CONCLUSION: The CHRT-SR9 is a brief self-report with excellent psychometric properties in a sample of adolescents that is sensitive to changes in suicidality over time. Its performance in other populations and ability to predict future suicidal events deserves study.

Relationship between chronic obstructive pulmonary disease and cognition in an aging population.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a common and severe respiratory illness. Prior research suggests that COPD may be associated with depression as well as cognitive impairment and increased risk of dementia. Many studies to date have been relatively small, have largely relied on global screening measures to identify cognitive impairment, and have not examined the potential role of comorbid depression on cognition. This cross-sectional study examined the relationship between COPD and multiple cognitive domains at two time points using data from a large longitudinal population database. METHODS: Linear multivariate analyses were conducted using secondary data from the Wisconsin Longitudinal Study to determine the effect of lifetime COPD and depressive symptom severity, assessed with the Center for Epidemiological Studies Depression Scale (CESD), on multiple cognitive outcomes. RESULTS: In both 2004 (n = 1608) and 2011 (n = 1743), lifetime COPD was found to be a non-significant predictor of all cognitive outcomes, while depressive symptom severity predicted significantly lower scores on the immediate recall and digit ordering tasks in 2004 and on all outcomes in 2011. Exploratory analyses in only those with lifetime COPD revealed COPD severity to be a non-significant factor for all outcomes in 2004 and 2011. CONCLUSION: COPD was not significantly associated with cognition. Conversely, higher depressive symptom severity was significantly associated with poorer performance on additional cognitive tasks in 2011 compared to 2004, suggesting that depression may contribute to cognitive decline, dependent upon the context of aging.

Noncanonical prokaryotic X family DNA polymerases lack polymerase activity and act as exonucleases.

The X family polymerases (PolXs) are specialized DNA polymerases that are found in all domains of life. While the main representatives of eukaryotic PolXs, which have dedicated functions in DNA repair, were studied in much detail, the functions and diversity of prokaryotic PolXs have remained largely unexplored. Here, by combining a comprehensive bioinformatic analysis of prokaryotic PolXs and biochemical experiments involving selected recombinant enzymes, we reveal a previously unrecognized group of PolXs that seem to be lacking DNA polymerase activity. The noncanonical PolXs contain substitutions of the key catalytic residues and deletions in their polymerase and dNTP binding sites in the palm and fingers domains, but contain functional nuclease domains, similar to canonical PolXs. We demonstrate that representative noncanonical PolXs from the Deinococcus genus are indeed inactive as DNA polymerases but are highly efficient as 3'-5' exonucleases. We show that both canonical and noncanonical PolXs are often encoded together with the components of the non-homologous end joining pathway and may therefore participate in double-strand break repair, suggesting an evolutionary conservation of this PolX function. This is a remarkable example of polymerases that have lost their main polymerase activity, but retain accessory functions in DNA processing and repair.

Association between headache and suicidality: An analysis of universal suicide screening data at a large urban county hospital.

BACKGROUND: Identifying individuals at increased risk of suicide is important, particularly those who present for treatment for nonpsychiatric chief complaints who may go undetected. It has been found that pain symptoms, such as headache, are associated with suicide, although this association requires further characterization. This study examined specific components of suicidality in relation to headache subtypes. METHODS: This study retrospectively reviewed 2,832,835 nonpsychiatric adult clinical encounters at a large county hospital, where a standardized suicide risk screening tool, the Columbia-Suicide Severity Rating Scale (C-SSRS), was universally implemented. The C-SSRS assesses specific components of suicidality: wish to be dead and suicidal ideation, method, intent, plan, and action. Multivariate logistic regressions were performed to assess the association between headache, as well as headache subtype (migraine, tension, or cluster), and each component of suicidality. RESULTS: There were significant positive associations between presenting with a headache and 2 specific components of suicidality: wish to be dead and suicidal action. Individuals with tension headache may have a lower risk of wishing to be dead compared to those with migraine and cluster headaches. CONCLUSIONS: The association of headaches with specific elements of sui-cidality demonstrates the potential yield of identification of suicide risk among individuals with nonpsychiatric presentations.

The relative importance of reputation and pride as predictors of employee turnover in an academic medical center.

BACKGROUND: Past research shows a dual role of organizational reputation in an employment context. Prospective and current employees are affected by public perceptions of their employer, as affiliation with an employer widely known for its positive achievements boosts organization-based self-esteem whereas a poor reputation leads to decreased self-esteem and disassociation. Another key construct is engagement, which relates to employee enthusiasm and their attitude toward the organization and their interest in finding employment elsewhere. PURPOSE: The current study examined relationships between engagement, organizational pride, perceived departmental and institutional reputation, and turnover intentions in employees at an academic medical center. METHODS: Participants were 241 faculty, staff, and trainees (63.9% women) in a clinical department at an academic medical center who completed an anonymous online survey that contained the Utrecht Work Engagement Scale, as well as questions about pride, reputation, and turnover intentions. Relationships between engagement, organizational pride, perceived departmental and institutional reputation, and turnover intentions were explored. RESULTS: To determine whether employee engagement mediates the relationship between various predictors and turnover intentions, exploratory mediation models were examined. All of the variables were significantly correlated with each other. Perception of departmental reputation was more strongly associated with engagement, pride, and turnover intentions than was institutional reputation. Engagement fully mediated the relationship between perceived institutional reputation and turnover intentions and partially mediated relationships between departmental reputation and turnover intentions and between pride and turnover intentions. PRACTICE IMPLICATIONS: The findings suggest that perception of one's department may be more important to engagement and pride than perception of the larger institution. Furthermore, relationships between pride and reputation and turnover intentions in an academic medical center appear to be, at least partially, mediated through engagement. In contrast to common practice, turnover reduction efforts might be more effective if they enhance perceived departmental, rather than institutional, reputation.

Anterior cingulate cortex in individuals with depressive symptoms: A structural MRI study.

Several magnetic resonance imaging (MRI) studies have reported reduction in anterior cingulate cortex (ACC) volume in individuals with major depressive disorder (MDD). However, some MRI studies did not find significant ACC volumetric changes in MDD, and sample sizes were generally small. This cross-sectional structural MRI study examined the relationship between current depressive symptoms and ACC volume in a large community sample of 1803 adults. A series of multiple linear regression analyses were conducted to predict right and left ACC volumes using Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) scores, intracranial volume, age, sex, race/ethnicity, alcohol use, tobacco use, and psychotropic medications as predictor variables. Right ACC volume was significantly negatively associated with QIDS-SR scores, while no significant association was found between left ACC volume and QIDS-SR scores. In addition, there was a significant negative association between QIDS-SR scores and right but not left ACC volumes in males, and no significant association between QIDS-SR scores and right or left ACC volumes in females. These findings suggest that right ACC volume is reduced in people with greater self-reported depressive symptom severity, and that this association is only significant in men.

Multivariate Association of Child Depression and Anxiety with Asthma Outcomes.

BACKGROUND: Pediatric asthma is associated with increased health services utilization, missed school days, and diminished quality of life. Children with asthma also report more frequent depressive and anxiety symptoms than children without asthma, which may further worsen asthma outcomes. OBJECTIVE: The current study investigated the relationship between depressive and anxiety symptoms and 4 asthma outcomes (asthma control, asthma severity, lung function, and asthma-related quality of life) in children (N = 205) with moderate to severe persistent asthma. METHODS: The data were analyzed using a canonical correlation analysis, a multivariate framework that allows examination of all variables of interest in the same model. RESULTS: We found a statistically significant relationship between symptoms of depression and anxiety and asthma outcomes (1 - Λ = .372; P < .001). A large effect size suggests that 37.2% of variance is shared between depression and anxiety symptoms and 4 asthma outcomes (particularly asthma control and asthma-related quality of life) in the overall sample. Among girls (vs. boys), asthma control (measured by the Asthma Control Test) emerged as a stronger contributor to asthma outcomes compared with boys. CONCLUSIONS: These results suggest that psychiatric symptoms, especially anxiety, are associated with poor asthma-related quality of life, and more negative perception of asthma control in girls compared with boys (with no observed sex difference in physiological lung function). Clinicians should consider incorporating questions about psychiatric symptoms as part of routine asthma management, and focus patient education on unique differences in which boys and girls perceive their asthma symptoms.

Bacterial hepatocyte growth factor receptor agonist stimulates hepatocyte proliferation and accelerates liver regeneration in a partial hepatectomy rat model.

Hepatocyte growth factor (HGF) is central to liver regeneration. The Internalin B (InlB) protein is a virulence factor produced by the pathogenic bacterium Listeria monocytogenes. InlB is known to mimic HGF activity by interacting with the HGF receptor (HGFR) and activating HGFR-controlled signaling pathways. We expressed and purified the HGFR-binding InlB domain, InlB321/15, cloned from the fully virulent clinical L. monocytogenes strain. HGFR and Erk1/2 phosphorylation was determined using Western blotting. The capacity of InlB321/15 to bind HGFR was measured using microscale thermophoresis. Liver regeneration was studied in a model of 70% partial hepatectomy (70%PHx) in male Wistar rats. The nuclear grade parameters were quantified using manual (percentage of binuclear hepatocytes), automated (nuclear diameters), or combined (Ki67 proliferation index) scoring methods. Purified InlB321/15 stimulated HGFR and Erk1/2 phosphorylation and accelerated the proliferation of HepG2 cells. InlB321/15 bound HGFR with Kd = 7.4 ± 1.3 nM. InlB321/15 injected intravenously on the second, fourth, and sixth days after surgery recovered the liver mass and improved the nuclear grade parameters. Seven days post 70% PHx, the liver weight indexes were 2.9 and 2.0%, the hepatocyte proliferation indexes were 19.8 and 0.6%, and the percentages of binucleated hepatocytes were 6.7 and 4.0%, in the InlB321/15-treated and control animals, respectively. Obtained data demonstrated that InlB321/15 improved hepatocyte proliferation and stimulated liver regeneration in animals with 70% hepatectomy.

Association of menopause symptoms with depressive symptom severity in a diverse community-based sample.

The Dallas Heart Study dataset was used to examine relationships between menopausal symptoms and depressive symptom severity in 384 women (37-73 years old) self-reporting as menopausal. Self-reported menopausal symptoms were grouped based on the Menopause-specific Quality of Life Questionnaire (MENQOL). Depressive symptom severity was assessed using the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). The relationship between menopause symptom groups, ethnicity and QIDS-SR was evaluated using multiple linear regression. Endorsement of sexual symptoms was positively associated with QIDS-SR score (ß = .12, p = .031), suggesting that sexual dysfunction during menopause may be a predictor of underlying depressive symptoms.

An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.

OBJECTIVE: The underlying mechanisms of depression remain unclear; however, current literature suggests a relationship between inflammation and depression. The association between the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) and depression has been previously investigated, but the relationship between GlycA, a novel spectroscopic inflammatory biomarker, and depression does not appear to have been examined. METHODS: Data were obtained from The Dallas Heart Study (DHS, conducted between 2000 and 2002), which consisted of a large community-based sample of Dallas County residents (N = 3,033). Depressive symptom severity was assessed with the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). It was hypothesized that the serum GlycA level would be a statistically significant predictor of QIDS-SR scores after control for demographic covariates. Multiple linear regression was used to assess the relationship between GlycA level and QIDS-SR scores. The role of hs-CRP in predicting QIDS-SR scores was also explored. RESULTS: GlycA level was a statistically significant positive predictor of QIDS-SR score (ß = .053, P = .038) with control for sex, age, antidepressant use, ethnicity, smoking status, drinking status, body mass index, and years of education. In a subset of adults with moderate-to-severe depression, GlycA level was not associated with QIDS-SR scores. Additionally, hs-CRP level was not a statistically significant predictor of QIDS-SR scores. CONCLUSIONS: This study found a positive association between the inflammatory biomarker GlycA, but not hs-CRP, and depressive symptom severity in a large multiethnic and multiracial community-based sample. Thus, these results provide the first indication that GlycA may be a potentially useful novel biomarker of depression.

A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding.

Microbial communities are self-controlled by repertoires of lethal agents, the antibiotics. In their turn, these antibiotics are regulated by bioscavengers that are selected in the course of evolution. Kinase-mediated phosphorylation represents one of the general strategies for the emergence of antibiotic resistance. A new subfamily of AmiN-like kinases, isolated from the Siberian bear microbiome, inactivates antibiotic amicoumacin by phosphorylation. The nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. Crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation exclusively in the case of a closed active site that counteracts substrate promiscuity. AmiN kinase is a member of the previously unknown subfamily representing the first evidence of a specialized phosphotransferase bioscavenger.

Quantitative assessment of chaperone binding to amyloid aggregates identifies specificity of Hsp40 interaction with yeast prion fibrils.

Yeast self-perpetuating protein aggregates (yeast prions) provide a framework to investigate the interaction of misfolded proteins with the protein quality control machinery. The major component of this system that facilitates propagation of all known yeast amyloid prions is the Hsp104 chaperone that catalyzes fibril fragmentation. Overproduction of Hsp104 cures some yeast prions via a fragmentation-independent mechanism. Importantly, major cytosolic chaperones of the Hsp40 group, Sis1 and Ydj1, oppositely affect yeast prion propagation, and are capable of stimulating different activities of Hsp104. In this work, we developed a quantitative method to investigate the Hsp40 binding to amyloid aggregates. We demonstrate that Sis1 binds fibrils formed by the Sup35NM protein with higher affinity compared to Ydj1. Moreover, the interaction of Sis1 with the fibrils formed by the other yeast prion protein, Rnq1, is orders of magnitude weaker. We show that the deletion of the dimerization domain of Sis1 (crucial for the curing of [PSI+] by excess Hsp104) decreases its affinity to both Sup35NM and Rnq1 fibrils. Taken together, these results suggest that tight binding of Hsp40 to the amyloid fibrils is likely to enhance aggregate malpartition instead of fibril fragmentation.

The Relationship Between Cumulative Exogenous Corticosteroid Exposure and Volumes of Hippocampal Subfields and Surrounding Structures.

PURPOSE/BACKGROUND: Glucocorticoids are a class of hormones that include naturally occurring cortisol and corticosterone, as well as prescription drugs commonly used to manage inflammatory, autoimmune, and allergic conditions. Adverse effects, including neuropsychiatric symptoms, are common. The hippocampus appears to be especially sensitive to the effects of glucocorticoids. However, to our knowledge, no studies to date have examined hippocampal subfields in humans receiving glucocorticoids. We examined patients on chronic glucocorticoid regimens to determine relationships between dose and duration of treatment, and hippocampal subfields, and related regions volumes. METHODS/PROCEDURES: The study included adult men and women receiving at least 5 mg daily of prednisone equivalents for at least 6 months. Volumes of brain regions were measured via magnetic resonance imaging. A multivariate general linear model was used for analysis, with brain volumes as dependent variables and age, sex, and cumulative corticosteroid exposure, as predictors. FINDINGS/RESULTS: The study population consisted of 81 adult outpatients (43 male) on corticosteroids (mean dose, 7.88 mg; mean duration, 76.75 months). Cumulative glucocorticoid exposure was negatively associated with left and right hippocampal dentate gyrus/CA3 volume. In subsequent subgroup analysis, this association held true for the age group older than the median age of 46 years but not for the younger age group. IMPLICATIONS/CONCLUSIONS: This finding is consistent with previous studies showing detrimental effects of elevated glucocorticoids on the hippocampus but further suggests that the dentate gyrus and CA3 regions are particularly vulnerable to those effects, which is consistent with animal models of chronic stress but has not been previously demonstrated in humans.

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

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.