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Affective Alterations in Patients with Cushing’s Syndrome in Remission are Associated with Decreased Brain Derived Neurotrophic Factor and Cortisone Levels

Background

Affective alterations, including anxiety, emotional lability and apathy might persist in patients who suffered Cushing’s, even long after correction of cortisol excess. Studies using magnetic resonance imaging showed some alterations in the brain of patients in remission for Cushing’s. These alterations were mainly at those regions (hippocampus and prefrontal cortex) in which cortisol acts to regulate emotions and response to stress.

Brain-derived neurotrophic factor (BDNF) is a molecule which is present in high quantities in these brain structures and interplays with cortisol to control mood. Indeed, BDNF levels are reduced during chronic stress and in stress-induced mood disorders, including major depression. BDNF levels can be increased by antidepressant treatment.

Hypothesis and methods

The hypothesis of our study was that BDNF is decreased in patients whom previously had Cushing’s and influences their psychological well-being. Our study compared the psychological state of 36 patients in remission from Cushing’s for a mean of 72 months with that of 36 healthy control subjects. We evaluated anxiety, depression, response to stress, and negative/positive emotions. Information was gathered using questionnaires validated in the Spanish population, as well as quality of life through the CushingQoL questionnaire, which was specifically designed for these patients.

We measured cortisol in saliva, a marker of psychological stress and depressive symptoms, routinely used by psychiatrists. Importantly, we also measured cortisone (the biologically inactive form of cortisol) in saliva, thanks to a collaboration with Dr. Brian Keevil, of the Biochemical Department of the University Hospital of South Manchester, Manchester (UK). Cortisone is more abundant than cortisol in saliva and has been demonstrated to reliably reflect the concentrations of cortisol in the blood. This was the first time that salivary cortisone was assessed in patients in remission from Cushing’s.

Results

Psychological symptoms

Our results show that Cushing’s patients in remission had more subclinical depression (clinically relevant depressive symptoms in absence of major depressive disorder) than healthy control subjects. Twenty-four Cushing’s patients (67%) had minimal symptoms, four (11%) mild symptoms, five (14%) moderate symptoms and three (8%) severe symptoms of depression.

Cushing’s patients more frequently reported depressed affect (low mood), vegetative depression (i.e. sleep difficulties, unexplained changes in appetite, loss of the ability to experience pleasure, and poor motor skills), and loss of well-being than the healthy control subjects. Cushing’s patients also had greater stress perception, less positive affect (positive emotions and feelings) and more negative affect (negative emotions and feelings) than healthy control subjects. Cushing’s patients also had a poorer quality of life.

Factors associated with psychological alterations

  • The amount of time elapsed to diagnose Cushing’s was associated with depressive symptoms and poor quality of life. This finding indicates that the longer the duration of exposure to cortisol before Cushing’s is diagnosed and successfully treated, the worse both quality of life and depression severity are for the patient.
  • Levels of BDNF were lower in Cushing’s patients than in healthy control subjects. In particular, patients with lower BDNF levels in the blood had more anxiety, depression and perceived stress, and less affective balance and positive affect. Thus, measurement of BDNF in the blood may help clinicians identify those Cushing’s patients who have a high risk for developing psychological problems and evaluate the degree of psychological impairment in them. Whether such a decrease in BDNF levels reflects sustained alterations in the brain structures regulating mood and stress of patients who have previously been exposed to cortisol excess should be elucidated in futures studies.
  • Low levels of morning salivary cortisone, but not cortisol, were associated with more anxiety and depression in Cushing’s patients. Thus, salivary cortisone may be a more reliable marker than cortisol to assess psychological state in patients.
  • The presence of depressive symptomatology significantly affects patients’ quality of life, wellbeing and daily living, in line with findings observed in patients during the active phase of the disease.

Conclusions

Altered affectivity, mainly anxiety, depressive symptoms, negative mood and impaired response to stress, can persist in patients previously treated for Cushing’s, especially in those experiencing a longer delay to diagnosis. To the best of our knowledge, this is the first report on increased stress perception in this population. Because affective alterations can be treated with antidepressants and/or psychotherapy, patients should discuss their symptoms with their physicians to determine if specific treatments might be of help. Although measurement of BDNF in blood and cortisone in saliva are not currently available in clinical practice, they might be potential markers of mood in Cushing’s patients. In particular, decreased BDNF may be one of the mechanisms whereby psychological alterations are maintained in patients in remission from Cushing’s. Future studies are needed to ascertain whether the therapeutic approaches aimed at improving subclinical depressive symptomatology in these patients might also increase BDNF levels.

By: Elena Valassi, MD, PhD & Iris Crespo M.Psy. PhD

Research Center on Pituitary Diseases, CIBERER 747

Hospital Sant Pau, Autonomous University of Barcelona (UAB)

Barcelona (Spain)

Dr. Elena Valassi is a clinical researcher at the “Research Center for Pituitary Diseases”, Hospital Sant Pau, Barcelona (Spain). She is responsible for data quality of the European Registry on Cushing’s syndrome (ERCUSYN).

Iris Crespo, M.Psy. is a research fellow at the “Research Center for Pituitary Diseases”, Hospital Sant Pau. She earned her PhD at the Autonomous University of Barcelona (Spain) with a dissertation on the neuropsychological disorders in patients with Cushing’s syndrome.

 

Bibliography

  • Valassi E, Crespo I, Keevil BG, Aulinas A, Urgell E, Santos A, Trainer PJ, Webb SM. Affective alterations in patients with Cushing’s syndrome in remission are associated with decreased BDNF and cortisone levels. European Journal of Endocrinology 2017 176 221-231.
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  • Andela CD, van Haalen FM, Ragnarsson O, Papakokkinou E, Johannson G, Santos A et al. Cushing’s syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. European Journal of Endocrinology 2015 173 1-14.
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  • De Bono M, Harrison RF, Whitaker MJ, Eckland D, Artl W, Keevil BG, Ross RJ. Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone. Journal of Clinical Endocrinology and Metabolism, 2016 101:1469-1477.

Summer 2017

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