HPA Axis in Major Depression: Cortisol, Clinical Symptomatology, and Genetic Variation Predict Cognition

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Abstract

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology, and HPA genetic variation play in cognitive performance. Patients with major depression with psychosis (PMD) and without psychosis (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol, and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms, and variation in genes, NR3C1 (glucocorticoid receptor - GR) and NR3C2 (minercorticoid receptor – MR) that encode for glucocorticoid and mineralcorticoid receptors, predicted cognitive performance. Beyond the effects of cortisol, demographics, and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and healthy controls. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.

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Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.

Antonio Convit, Robert Gold, Bryan Richardson … (2007)

There is evidence that type 2 diabetes mellitus is associated with cognitive impairment. Most studies investigating this association have evaluated elderly individuals, after many years of diabetes, who generally have poor glycaemic control and significant vascular disease. The aim of the current study was to investigate the early cognitive consequences and associated brain correlates of type 2 diabetes. With regard to cognition and brain measures, we compared 23 age-, sex- and education-matched control subjects with 23 mostly middle-aged individuals with relatively well-controlled diabetes of less than 10 years from the time of diagnosis. We found deficits in hippocampal-based memory performance and preservation of other cognitive domains. Relative to control subjects, individuals with diabetes had reductions in brain volumes that were restricted to the hippocampus. There was an inverse relationship between glycaemic control and hippocampal volume; in multivariate regression analysis, HbA(1c) was the only significant predictor of hippocampal volume, accounting for 33% of the observed variance. Other variables commonly associated with type 2 diabetes, such as elevated BMI, hypertension or dyslipidaemia, did not independently contribute to the variance in hippocampal volume. These results suggest that the medial temporal lobe may be the first brain site affected by type 2 diabetes and that individuals in poorer metabolic control may be affected to a greater extent.

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Bidirectional association between depression and type 2 diabetes mellitus in women.

JoAnn Manson, Walter C. Willett, Hsu-An Pan … (2010)

Although it has been hypothesized that the diabetes-depression relation is bidirectional, few studies have addressed this hypothesis in a prospective setting. A total of 65 381 women aged 50 to 75 years in 1996 were observed until 2006. Clinical depression was defined as having diagnosed depression or using antidepressants, and depressed mood was defined as having clinical depression or severe depressive symptoms, ie, a 5-item Mental Health Index (MHI-5) score of 52 or less. Self-reported type 2 diabetes mellitus was confirmed by means of a supplementary questionnaire validated by medical record review. During 10 years of follow-up (531 097 person-years), 2844 incident cases of type 2 diabetes mellitus were documented. Compared with referents (MHI-5 score of 86-100) who had the best depressive symptom scores, participants with increased severity of symptoms (MHI-5 scores of 76-85 or 53-75, or depressed mood) showed a monotonic elevated risk of developing type 2 diabetes (P for trend = .002 in the multivariable-adjusted model). The relative risk for individuals with depressed mood was 1.17 (95% confidence interval [CI], 1.05-1.30) after adjustment for various covariates, and participants using antidepressants were at a particularly higher relative risk (1.25; 95% CI, 1.10-1.41). In a parallel analysis, 7415 cases of incident clinical depression were documented (474 722 person-years). Compared with nondiabetic subjects, those with diabetes had a relative risk (95% CI) of developing clinical depression after controlling for all covariates of 1.29 (1.18-1.40), and it was 1.25 (1.09-1.42), 1.24 (1.09-1.41), and 1.53 (1.26-1.85) in diabetic subjects without medications, with oral hypoglycemic agents, and with insulin therapy, respectively. These associations remained significant after adjustment for diabetes-related comorbidities. Our results provide compelling evidence that the diabetes-depression association is bidirectional.

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Stress and cognition: are corticosteroids good or bad guys?

E. de Kloet, M. Oitzl, M Joëls (1999)

Corticosteroid hormones secreted by the adrenal cortex protect the brain against adverse events and are essential for cognitive performance. However, in recent literature, the central action of corticosteroids has mostly been portrayed as damaging and disruptive to memory formation. We argue that this paradox can be explained by appreciating the specific role of both mineralocorticoid and glucocorticoid receptors in the various stages of information processing. In addition, the context in which corticosteroid-receptor activation takes place is crucial in determining steroid-mediated effects. These effects generally favour adaptive behaviour that is most relevant to the situation. Corticosteroid effects on cognition can, however, turn from adaptive into maladaptive, when actions via the two corticosteroid-receptor types are imbalanced for a prolonged period of time.

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Journal

Journal ID (nlm-journal-id): 9607835

Journal ID (pubmed-jr-id): 20545

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol. Psychiatry

Title: Molecular psychiatry

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date Nihms-submitted: 13 October 2016

Publication date (Electronic): 16 August 2016

Publication date PMC-release: 17 February 2017

Electronic Location Identifier: 10.1038/mp.2016.120

Affiliations

[1 ]Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine

[2 ]Palo Alto University

[3 ]Harvard Medical School and Brigham & Women's Hospital

Author notes

Corresponding author: Jennifer Keller, Ph.D., Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford, CA 94305-5723, Phone: (650) 724-0070, Fax: 650-723-6811, jkeller@ 123456stanford.edu

Article

Manuscript ID: NIHMS793896

DOI: 10.1038/mp.2016.120

PMC ID: 5313380

PubMed ID: 27528460

SO-VID: 0208857e-b42b-40ca-8e1b-2292c73db2b7

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HPA Axis in Major Depression: Cortisol, Clinical Symptomatology, and Genetic Variation Predict Cognition

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Abstract

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Measurement of Glucocorticoid Receptor Signaling in Major Depression

Most cited references 52

Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.

Bidirectional association between depression and type 2 diabetes mellitus in women.

Stress and cognition: are corticosteroids good or bad guys?

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