|Year : 2021 | Volume
| Issue : 2 | Page : 87-93
Neurobiological correlates of burnout
Durva Balkrishna Sail1, Avinash De Sousa2
1 Consultant Psychiatrist, Sterling Hospital, Vadodara, India
2 Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India
|Date of Submission||06-Dec-2021|
|Date of Decision||06-Dec-2021|
|Date of Acceptance||10-Dec-2021|
|Date of Web Publication||12-Jan-2022|
Dr. Avinash De Sousa
Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Maslach defined burnout syndrome first time as a syndrome involving (i) exhaustion, (ii) “depersonalization” – lack of empathy for or detachment from service recipients, and (iii) a reduced sense of professional accomplishment. Burnout leads to changes in autonomic system, immune and endocrine system. The aim of this paper was therefore to provide an overview of the literature on clinically significant burnout and their potential neurobiological and physiological correlates.
Methods: All English articles published between till October 2021 were searched in PubMed, Science-Direct, Medline, GoogleScholar, using the keywords, burnout, hypothalamic-pituitary-adrenal-axis, cortisol, stress, neurobiology, neurogenesis, BDNF, immune, biological, sympathetic, parasympathetic, autonomic nervous system, endocrine, metabolic, cognition, sleep, and neuroimaging in various combinations. The full text of relevant articles was obtained and their reference lists were reviewed for additional studies.
Results: Burnout leads to alteration in autonomic, endocrine and immune system marked by deranged levels of various hormones and immune markers. It is also reflected as neuroimaging changes in various brain structures and may manifest as cognitive changes. Accelerated aging, increased risk of cardiovascular diseases and type II diabetes mellitus, increased allosteric load are some other manifestations of burnout that needs clinical attention.
Conclusion: Future research with more homogeneous clinical samples, prospective experimental designs and challenge tests will help to delineating the underlying biological mechanisms of burnout. This will help to point to potential treatment targets.
Keywords: Burnout, cognition, endocrine system, hypothalamic-pituitary-adrenal-axis, metabolic system, neurobiology, sleep and neuroimaging, stress
|How to cite this article:|
Sail DB, De Sousa A. Neurobiological correlates of burnout. Telangana J Psychiatry 2021;7:87-93
| Introduction|| |
The term “Acedia” was used in the fourth century AD to describe states of listlessness and mental torpor in monastics. The American psychologist Freudenberger introduced the term “burnout.” Maslach defined burnout syndrome first time as a syndrome involving (i) exhaustion, (ii) “depersonalization”– lack of empathy for or detachment from service recipients, and (iii) a reduced sense of professional accomplishment. Emotional exhaustion implies to the depletion of positive emotions towards the recipients of one's care. Depersonalization refers to an excessively callous, detached and cynical attitude towards them. The reduced professional accomplishment indicates an increase in self-appraisals as ineffective, incompetent and/or inadequate for the job. The International Statistical Classification of Diseases and Related Health Problems, 11th revision, listed burnout as a “syndrome resulting from chronic workplace stress that has not been successfully managed” though only as a residual factor that may affect health status, and “is not in itself a current illness or injury. Melamed, Kushnir and Shirom, described burnout as the chronic depletion of an individual's energetic resources as a consequence of chronic stress. According to them, burnout consists of the three dimensions: physical fatigue, emotional exhaustion and cognitive weariness. Burnout can be a consequence of long-term exposure to any situation that is emotionally demanding., In milder form of burnout symptoms that are not sufficiently incapacitating to prevent the employee from working while in clinical burnout there is clinically significant exhaustion and impaired performance, which motivates seeking professional help. Typically, chief complaints can be longstanding fatigue, sleep impairments, and problems with memory and concentration. In nonclinical populations, high burnout scores have shown association with impaired sleep, and some longitudinal studies concluded that poor sleep can be a risk factor for subsequent exhaustion., Cognitive impairment is observed to be associated with burnout mainly in the field of difficulties with working memory, episodic memory and executive functions. Furthermore, burnout vital exhaustion have been linked to somatic morbidity in few studies., This led multiple studies aiming sought to find the physiological mechanisms that may explain the symptomatology of burnout, as well as the links between burnout and bodily disease. The aim of this paper was therefore to provide an overview of the literature on clinically significant burnout and their potential neurobiological and physiological correlates.
| Methods|| |
All English articles published between till October 2021 were searched in PubMed, Science-Direct, Medline, GoogleScholar, using the keywords, burnout, hypothalamic-pituitary-adrenal (HPA)-axis, cortisol, stress, neurobiology, neurogenesis, BDNF, immune, biological, sympathetic, parasympathetic, autonomic, nervous system, endocrine, metabolic, cognition, sleep, and neuroimaging in various combinations. Reference lists of papers were hand searched for further studies. Inclusion of papers was based on English language, published in peer review journals and whether burnout was primarily examined in relation to a biological parameter. The full text of relevant articles was obtained and their reference lists were reviewed for additional studies.
| Results and Discussion|| |
The role of the hypothalamic-pituitary-adrenal axis
During stressful situations, HPA axis gets activated in the limbic system mainly the amygdala and hippocampus. As a result corticotropin releasing hormone is released from the hypothalamus which in turn stimulates adrenocortotropic hormone release from the pituitary which further stimulates glucocorticoids secretion from the adrenal cortex.
Cortisol awakening response and Cortisol levels
Due to diurnal and ultradian variation in cortisol levels make it difficult to measure the same. This led to the development of various approaches including examining the cortisol awakening response (CAR), undertaking serial measures across the day, and probing HPA function through challenge tests. Reduced CAR levels found in majority of studies making burnout a hypocortisolemic state. However, other studies in clinical,, and nonclinical samples, have failed to find impaired CAR. In a study done by Grossi et al. patients on sick leave due to burnout found to have hypocortisolism compared to low and moderate burnout groups. Higher CAR levels observed in female patients with clinical burnout compared to the low burnout group. Whereas these results were less clear in males, as only moderate burnout patients found to have elevated morning cortisol. Chida et al. in their meta-analysis found a positive association between CAR and psychological distress as well as depression while a negative association was observed between CAR and burnout, suggesting that the former displays a hypercortisolemic picture while burnout more displays a hypocortisolemic picture.
Other cortisol measures
An association of emotional exhaustion and global burnout with lower cortisol at time points between 2 pm and bedtime was observed in a study that examined cortisol levels at five different time points across the day. Cross-sectional hair cortisol concentrations provide retrospective examination of HPA activity over the preceding months. Severe burnout group found to have hypercortisolism in the compared to “no burnout” or moderate burnout groups in a population study examining hair cortisol.
The dexamethasone suppression test
This test examines feedback sensitivity of the HPA axis in response to exogenous administration of dexamethasone. Stronger suppression of cortisol in response to the dexamethasone suppression test (DST) was noted in a people with severe burnout symptoms when study was conducted in clinically-defined burnout participants. Intact HPA axis functioning using the DST was found in other studies.,,
Dihydroepiandrosterone sulfate (DHEA-S) is a hormone produced by the adrenal cortex in response to stress and is considered a cortisol “counterbalancing” product. It stimulates neurogenesis, enhances memory, has anxiolytic and antidepressant properties., Some studies have found no differences in DHEA-S levels between burnout and healthy control groups,, while some studies found elevated DHEAS levels in a burnout group compared to controls. A study of clinical burnout sample concluded that more severe burnout symptoms higher the DHEA-S levels. Lennartsson et al. found attenuated DHEA-S production in their study comparing DHEA-S levels before and after an acute psychosocial stress test in comparing a clinical burnout group than healthy controls.
Increase in prolactin level in those with psychosocial stressors with a postulated protective role against psychological stress. In a study of healthy individuals who reported burnout, serum prolactin levels were higher in men with burnout (vs. those without burnout), although prolactin levels did not differ between these two groups in women.
Limited studies have examined thyroid hormones with mixed findings.
Various animal models linked reduced neuroplasticity to stress. Inhibited neurogenesis was observed in monkeys who were exposed to stress by Gould et al. in their study. The possible underlying mechanism can be stress-induced limbic activation causing HPA hyperactivity as downstream release of glucocorticoids affects limbic system by crossing the blood brain barrier.
Thinning of the medial frontal cortex and a bilateral increase in amygdala volumes were found in various neuroimaging studies. Also reduced gray matter volumes found in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC). The caudate and putamen volumes were also reduced, with volume reduction correlated to the level of perceived stress, possibly due to excitotoxic mechanisms. However, no difference in hippocampal and prefrontal volumes was observed by Sandström e et al. In a positron emission tomography study by Jovanovic et al. reported a functional disconnection between the amygdala and ACC/medial prefrontal cortex in the chronic stress group.
Functional magnetic resonance imaging
In a functional magnetic resonance imaging (fMRI) study reported those with occupational burnout was less able to downregulate negative emotions, with reduced functional connectivity between the amygdala and the ACC. Reduced amygdala connectivity with the dlPFC and the motor cortex, whereas stronger connectivity with the amygdala and insular cortex and cerebellum was noted in a study. In another fMRI study, Sandström et al. found patients on work-related long-term sick leave tended to under-recruit prefrontal cortical areas during performance of tasks involving executive function and memory compared to healthy controls and a depressed group.
In a study comparing well-being measures of emotional exhaustion, depersonalization, and overall burnout revealed no significant correlation with between the degree of burnout and activity in cognitive control regions was noted.
Resting-state electroencephalography analysis
The burnout group observed to have significantly lower alpha power in the eyes-open condition compared to the controls. This suggests cortical hyperactivity and greater mental effort suggestive of the possible development of compensatory mechanisms by burnout subjects.
Sertoz et al. identified quantified lower serum BDNF levels in a clinical burnout versus a control group. Several studies replicated similar findings in depressed patients which were reversed by antidepressants.,
Changes in cognition
Tavella et al. concluded cognitive changes as appear integral to the burnout syndrome. In a study done by Sandström et al. found deficits in nonverbal memory, visual and auditory attention. McEwen et al. noted that hippocampal function can be impacted by chronic stress leading to deficits in visuospatial and memory domains. Sandström et al. in their study comparing stress related exhaustion found deficits in attention, response control and visuospatial memory. Selective deficits in executive functioning were observed in a study done by Ohman et al. Olsson et al. reported that patients with burnout had less reaction time with higher number of errors. Oosterholt et al. also found reduced reaction time without any difference in executive function compared to nonclinical and healthy control groups. Cognitive performance was examined by Osterberg et al. in a group of patients with burnout versus nonclinical controls. The patients demonstrated impaired performance in attention and reaction times, but better performance was noted on Wechsler Adult Intelligence Scale-Revised (WAIS-R) digit symbol. Studies concluded complex etiology of cognitive deficits as reduced hippocampal volumes, HPA axis functioning, and increased pro-inflammatory cytokine levels.,
Armon et al. observed bidirectional, reciprocal association between sleep and burnout. Positive correlation with nonrestorative sleep, reduced sleep quality, feeling unrefreshed, and sleepiness/fatigue during the day and burnout in a study which measured sleep problems using Self-report measures. Greater sleep fragmentation, more arousals, less slow wave, and reduced rapid eye movement sleep were observed in objective studies done with an aid of polysomnography. Brand et al. reported relation of burnout symptoms of physical and emotional exhaustion to sleep problems. In a study done by Soderstr€om et al. reported that polysomnography of individuals with high burnout scores has increased arousal periods and more diurnal sleepiness. Canazei et al. concluded a possible therapeutic efficacy of light therapy as it is found to have its positive effect on quality of nighttime sleep.
Bakusic et al. in their systematic review of 25 articles examining DNA found showed differential methylation patterns of the glucocorticoid receptor gene (NR3C1), the serotonin transporter gene (SLC6A4), and the brain derived neurotrophic factor gene in burnout, chronic stress and depression. a genotype-independent hypermethylation of SLC6A4 associated with work stress and burnout was found in a study done by Alasaari et al., whereas Philibert et al. observed association of the S allele of the 5-HTTLPR gene with decreased SLC6A4 expression in patients with major depressive disorder.
Zanaty et al. in their study comparing anesthetists with doctors in less stressful roles found that anesthetist had greater skin aging, increased free radicals, and a shortening of telomere length. Shorter leukocyte telomere lengths were noted in a study population with severe burnout compared to those with no exhaustion.
A 10-year prospective population study of burnout was carried out by Ahola et al. found which concluded that in participants younger than 45 years of age at the time of entry in the study overall burnout and exhaustion were related to all-cause mortality.
It is thought that metabolic, immune and inflammatory mechanisms contribute to cardiovascular disease (CVD). In a study done by Shirom et al. it was observed that emotional burnout was associated with increased levels of cholesterol and triglycerides. Toker et al. conducted a longitudinal study of 8838 apparently healthy employees where baseline burnout levels were found to be associated with an increased risk of coronary heart disease. Gerber et al. in a nonclinical sample, found cardiovascular fitness was associated with decreased symptoms of burnout.
Type II diabetes mellitus
A 4.3-fold increased risk of developing type II diabetes was observed in a longitudinal study of healthy individuals. It is hypothesized release corticosteroid and catecholamine due to stress induces acute phase reactants which stimulates insulin resistance and type II diabetes.
Kitaoka-Higashiguchi et al. found increased body mass index (BMI) levels in a burnout versus a non-burnout group of Japanese managers. By contrast, in a study done by Armon et al. in healthy employees could not establish that obesity predicted burnout but rather they concluded that obesity predicted reductions in subsequent burnout levels.
Diet and exercise
Health-impairing behaviors thought to arise as coping strategies secondary to stress as per a European study of healthy doctors and nurses. Alexandrova-Karamanova et al. found positive association between fast food consumption, infrequent exercise, alcohol consumption and levels of burnout, potentially contributing to the syndrome.
Homeostasis refers to processes that maintain body systems essential for life within narrow operating ranges. (McEwen and Wingfield 2003). Allostasis refers to the short-term bodily adaptation processes to environmental changes, through activation of neural, endocrine, and immune mechanisms, and thus supports homeostasis. “Allostatic load” is an operationalized measure of biological parameters thought to indicate long-term maladaptive load on the body secondary to repeated or chronic stress., Components of allostatic load (AL) include blood pressure, lipids, glucose, insulin, C-reactive protein (CRP), BMI, waist circumference etc. Kitaoka Higashiguchi et al. in their study of “middle managers” in Japan found that changes in body weight, waist circumference, and BMI were greater in managers with burnout versus nonclinical controls. In a Finnish population study reported association of higher scores on burnout with increased AL. However, it is difficult to explain whether such changes were due to burnout or to depression as 60% of the association was found with depression. Juster et al. reported that that increased AL was associated with chronic stress and burnout no difference in AL (based on BMI, BP, CRP, high-density lipoprotein, cholesterol, HbA1C, and glucose) was observed in a study done by Langelaan et al. which compared managers with burnout versus nonclinical controls. A limitation of this study was that all managers were still working which may have been indicative of an “allostatic state” versus an “allostatic load” or “overload” phase.
Immune function and burnout
It has been proposed that chronic low-grade inflammation is associated with chronic stress. CRP is commonly used as a marker of general inflammation and hence chronic low grade inflammation associated with chronic stress can be picked up as slightly to moderately increased CRP levels. However, variation as per gender differences is unclear. Some studies observed no differences between burnout and nonburnout subjects, whereas some studies reported increased CRP levels related to burnout., a positive association between CRP levels and higher burnout scores in women but not in men was observed by Toker et al.
Metlaine et al. in their study of burnout in white collar workers found higher mean leukocyte, neutrophil, and monocyte numbers in them as compared with healthy controls, whereas other studies fail to establish any association between different lymphocytes subsets and burnout.,,
NK cell numbers or activity
Emotional stress has been reported to be associated with decreased NK cell activity., While Bargellini et al. and Mommersteeg et al. found no relation between absolute NK cell numbers and burnout, an association between high burnout depersonalization subscale score and decreased NK cell activity in male office workers was observed by Nakamura et al.
Various studies have evaluated levels of individual cytokines as well as ratios between pro-and anti-inflammatory cytokines in relation to burnout. Grossi et al. reported direct association between tumor necrosis factor α (TNFα) levels in plasma and burnout score. However, they found no relation between burnout score and transforming growth factor beta. In their study, measuring 17 different cytokines Gajewski et al. found no relation between any of the cytokines and emotional exhaustion or depression. However, positive correlation was observed between the plasma concentrations of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-12 with the extent of emotional exhaustion in men but not in women. Jonhdottir et al. observed no significant differences for any of the cytokines between women with exhaustion due to prolonged psychosocial stress and healthy controls. Increased levels of MCP1, EGF and VEGF with no changes in cytokines levels in women exposed to prolonged psychosocial stress was reported by Åsberg et al. Higher plasma TNFα levels, lower IL-4 levels, and a higher TNFα/IL-4 ratio were found to be associated with higher total burnout scores in a study in working school teachers. No association was found between IL-10 levels or TNFα/IL-10 ratios and burnout scores. Mommersteeg et al. observed increased levels of IL-10, but not TNFα, release in response to LPS stimulation in burnout than in healthy controls but no difference in IL-10 or interferon gamma after PHA (T-cell stimulator) was noted.
Mohren et al. examined burnout as a risk factor for such illnesses (including the common cold, gastroenteritis, and flu-like illnesses) in a large prospective sample. A possible causal association was found between the same which might be due to HPA axis suppression of the immune system in burnout with exhaustion being the strongest predictor of infection.
| Conclusion|| |
Burnout syndrome arises from underlying chronic psychological stress. This leads to changes in autonomic nervous system, endocrine, and immune processes. Systemic inflammation, immune suppression, metabolic syndrome and CVD can be consequences of burnout in addition to the psychological effects and fatigue. Future research with more homogeneous clinical samples, prospective experimental designs and challenge tests will help to delineating the underlying biological mechanisms of burnout. This will help to point to potential treatment targets.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Finlay-Jones R. Disgust with life in general. Aust N Z J Psychiatry 1983;17:149-52.
Freudenberger HJ. Staff burn-out. J Soc Issues 1974;30:159-65.
Maslach C. 1976. Burned-out. Hum Behav. 5:16-22.
World Health Organization. The ICD-11 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 2018.
Shirom A, Westman M, Shamai O, Carel RS. Effects of work overload and burnout on cholesterol and triglycerides levels: The moderating effects of emotional reactivity among male and female employees. J Occup Health Psychol 1997;2:275-88.
Hallsten L. 34 Burnout and Wornout: Concepts and Data from a National Survey. Research Companion to Organizational Health Psychology; 2005. p. 516.
Jones JW. The Burnout Syndrome: Current Research, Theory, Interventions. London: House Press; 1981.
Asberg M, Grape T, Krakau I, Nygren A, Rohde M, Wahlberg A, et al.
Stress as the cause of mental illness. Lakartidningen 2010;107:1307-10.
Brand S, Beck J, Hatzinger M, Harbaugh A, Ruch W, Holsboer-Trachsler E. Associations between satisfaction with life, burnout-related emotional and physical exhaustion, and sleep complaints. World J Biol Psychiatry 2010;11:744-54.
Carter PA, Dyer KA, Mikan SQ. Sleep disturbance, chronic stress, and depression in hospice nurses: Testing the feasibility of an intervention. Oncol Nurs Forum 2013;40:368-73.
Armon G, Shirom A, Berliner S, Shapira I, Melamed S. A prospective study of the association between obesity and burnout among apparently healthy men and women. J Occup Health Psychol 2008;13:43-57.
Söderström M, Jeding K, Ekstedt M, Perski A, Akerstedt T. Insufficient sleep predicts clinical burnout. J Occup Health Psychol 2012;17:175-83.
Deligkaris P, Panagopoulou E, Montgomery AJ, Masoura E. Job burnout and cognitive functioning: A systematic review. Work Stress 2014;28:107-23.
Appels A, Höppener P, Mulder P. A questionnaire to assess premonitory symptoms of myocardial infarction. Int J Cardiol 1987;17:15-24.
Appels A, Mulder P. Excess fatigue as a precursor of myocardial infarction. Eur Heart J 1988;9:758-64.
Grossi G, Santell B. Quasi-experimental evaluation of a stress management programme for female county and municipal employees on long-term sick leave due to work-related psychological complaints. J Rehabil Med 2009;41:632-8.
Danhof-Pont MB, van Veen T, Zitman FG. Biomarkers in burnout: A systematic review. J Psychosom Res 2011;70:505-24.
De Vente W, Olff M, Van Amsterdam JG, Kamphuis JH, Emmelkamp PM. Physiological differences between burnout patients and healthy controls: Blood pressure, heart rate, and cortisol responses. Occup Environ Med 2003;60 Suppl 1:i54-61.
Mommersteeg PM, Heijnen CJ, Kavelaars A, van Doornen LJ. Immune and endocrine function in burnout syndrome. Psychosom Med 2006;68:879-86.
Mommersteeg PM, Heijnen CJ, Verbraak MJ, van Doornen LJ. Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test. Psychoneuroendocrinology 2006;31:216-25.
Melamed S, Ugarten U, Shirom A, Kahana L, Lerman Y, Froom P. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res 1999;46:591-8.
Moya-Albiol L, Serrano MA, Salvador A. Job satisfaction and cortisol awakening response in teachers scoring high and low on burnout. Span J Psychol 2010;13:629-36.
Grossi G, Perski A, Ekstedt M, Johansson T, Lindström M, Holm K. The morning salivary cortisol response in burnout. J Psychosom Res 2005;59:103-11.
Chida Y, Steptoe A. Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis. Biol Psychol 2009;80:265-78.
Marchand A, Durand P, Juster RP, Lupien SJ. Workers' psychological distress, depression, and burnout symptoms: Associations with diurnal cortisol profiles. Scand J Work Environ Health 2014;40:305-14.
Penz M, Stalder T, Miller R, Ludwig VM, Kanthak MK, Kirschbaum C. Hair cortisol as a biological marker for burnout symptomatology. Psychoneuroendocrinology 2018;87:218-21.
Sonnenschein M, Mommersteeg PM, Houtveen JH, Sorbi MJ, Schaufeli WB, van Doornen LJ. Exhaustion and endocrine functioning in clinical burnout: An in-depth study using the experience sampling method. Biol Psychol 2007;75:176-84.
Onen Sertoz O, Tolga Binbay I, Koylu E, Noyan A, Yildirim E, Elbi Mete H. The role of BDNF and HPA axis in the neurobiology of burnout syndrome. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1459-65.
Wahlberg K, Ghatan PH, Modell S, Nygren A, Ingvar M, Asberg M, et al.
Suppressed neuroendocrine stress response in depressed women on job-stress-related long-term sick leave: A stable marker potentially suggestive of preexisting vulnerability. Biol Psychiatry 2009;65:742-7.
Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009;30:65-91.
Dong Y, Zheng P. Dehydroepiandrosterone sulphate: Action and mechanism in the brain. J Neuroendocrinol 2012;24:215-24.
Grossi G, Perski A, Evengård B, Blomkvist V, Orth-Gomér K. Physiological correlates of burnout among women. J Psychosom Res 2003;55:309-16.
Moch SL, Panz VR, Joffe BI, Havlik I, Moch JD. Longitudinal changes in pituitary-adrenal hormones in South African women with burnout. Endocrine 2003;21:267-72.
Langelaan S, Bakker AB, Schaufeli WB, van Rhenen W, van Doornen LJ. Do burned-out and work-engaged employees differ in the functioning of the hypothalamic-pituitary-adrenal axis? Scand J Work Environ Health 2006;32:339-48.
Lennartsson AK, Sjörs A, Jonsdottir IH. Indication of attenuated DHEA-s response during acute psychosocial stress in patients with clinical burnout. J Psychosom Res 2015;79:107-11.
Lennartsson AK, Billig H, Jonsdottir IH. Burnout is associated with elevated prolactin levels in men but not in women. J Psychosom Res 2014;76:380-3.
Jonsdottir IH, Sjörs Dahlman A. Mechanisms in endocrinology: Endocrine and immunological aspects of burnout: A narrative review. Eur J Endocrinol 2019;180:R147-58.
Eriksson PS, Wallin L. Functional consequences of stress-related suppression of adult hippocampal neurogenesis – A novel hypothesis on the neurobiology of burnout. Acta Neurol Scand 2004;110:275-80.
Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 1998;95:3168-71.
Sapolsky RM. Glucocorticoid toxicity in the hippocampus. Temporal aspects of synergy with kainic acid. Neuroendocrinology 1986;43:440-4.
Savic I. Structural changes of the brain in relation to occupational stress. Cereb Cortex 2015;25:1554-64.
Blix E, Perski A, Berglund H, Savic I. Long-term occupational stress is associated with regional reductions in brain tissue volumes. PLoS One 2013;8:e64065.
Sandström A, Peterson J, Sandström E, Lundberg M, Nystrom IL, Nyberg L, et al.
Cognitive deficits in relation to personality type and hypothalamic-pituitary-adrenal (HPA) axis dysfunction in women with stress-related exhaustion. Scand J Psychol 2011;52:71-82.
Jovanovic H, Perski A, Berglund H, Savic I. Chronic stress is linked to 5-HT (1A) receptor changes and functional disintegration of the limbic networks. Neuroimage 2011;55:1178-88.
Golkar A, Johansson E, Kasahara M, Osika W, Perski A, Savic I. The influence of work-related chronic stress on the regulation of emotion and on functional connectivity in the brain. PLoS One 2014;9:e104550.
Sandström A, Säll R, Peterson J, Salami A, Larsson A, Olsson T, et al.
Brain activation patterns in major depressive disorder and work stress-related long-term sick leave among Swedish females. Stress 2012;15:503-13.
Durning SJ, Costanzo M, Artino AR Jr., Dyrbye LN, Beckman TJ, Schuwirth L, et al.
Functional neuroimaging correlates of burnout among internal medicine residents and faculty members. Front Psychiatry 2013;4:131.
Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al.
Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54:70-5.
Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005;255:381-6.
Tavella G, Hadzi-Pavlovic D, Parker G. Burnout: Re-examining its key constructs. Psychiatry Res 2020;287:112917.
Sandström A, Rhodin IN, Lundberg M, Olsson T, Nyberg L. Impaired cognitive performance in patients with chronic burnout syndrome. Biol Psychol 2005;69:271-9.
McEwen BS. The neurobiology of stress: From serendipity to clinical relevance. Brain Res 2000;886:172-89.
Ohman L, Nordin S, Bergdahl J, Slunga Birgander L, Stigsdotter Neely A. Cognitive function in outpatients with perceived chronic stress. Scand J Work Environ Health 2007;33:223-32.
Olsson EM, Roth WT, Melin L. Psychophysiological characteristics of women suffering from stress-related fatigue. Stress Health 2010;26:113-26.
Oosterholt BG, Maes JH, Van der Linden D, Verbraak MJ, Kompier MA. Cognitive performance in both clinical and non-clinical burnout. Stress 2014;17:400-9.
Österberg K, Karlson B, Hansen ÅM. Cognitive performance in patients with burnout, in relation to diurnal salivary cortisol: Original research report. Stress 2009;12:70-816.
Sudheimer KD, O'Hara R, Spiegel D, Powers B, Kraemer HC, Neri E, et al.
Cortisol, cytokines, and hippocampal volume interactions in the elderly. Front Aging Neurosci 2014;6:153.
Pesce M, Tatangelo R, La Fratta I, Rizzuto A, Campagna G, Turli C, et al.
Memory training program decreases the circulating level of cortisol and pro-inflammatory cytokines in healthy older adults. Front Mol Neurosci 2017;10:233.
Armon G. Do burnout and insomnia predict each other's levels of change over time independently of the job demand control-support (JDC–S) model? Stress Health 2009;25:333-42.
Toker S, Melamed S. 2017. Stress, recovery, sleep, and burnout. In: Cooper CL, Campbell Quick J, editors. The handbook of stress and health: a guide to research and practice. Chichester (UK): Wiley; p. 168-185.
Ekstedt M, Soderstrom M, Åkerstedt T. Sleep physiology in recovery from burnout. Biol Psychol 2009;82:267-73.
Söderström M, Ekstedt M, Akerstedt T, Nilsson J, Axelsson J. Sleep and sleepiness in young individuals with high burnout scores. Sleep 2004;27:1369-77.
Canazei M, Bassa D, Jimenez P, Papousek I, Fink A, Weiss E. Effects of an adjunctive, chronotype-based light therapy in hospitalized patients with severe burnout symptoms – A pilot study. Chronobiol Int 2019;36:993-1004.
Bakusic J, Schaufeli W, Claes S, Godderis L. Stress, burnout and depression: A systematic review on DNA methylation mechanisms. J Psychosom Res 2017;92:34-44.
Alasaari JS, Lagus M, Ollila HM, Toivola A, Kivimäki M, Vahtera J, et al.
Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. PLoS One 2012;7:e45813.
Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet 2008;147B: 543-9.
Zanaty OM, El Metainy S, Abdelmaksoud R, Demerdash H, Aliaa DA, El Wafa HA. Occupational stress of anesthesia: Effects on aging. J Clin Anesth 2017;39:159-64.
Ahola K, Sirén I, Kivimäki M, Ripatti S, Aromaa A, Lönnqvist J, et al.
Work-related exhaustion and telomere length: A population-based study. PLoS One 2012;7:e40186.
Gerber M, Lindwall M, Lindegård A, Börjesson M, Jonsdottir IH. Cardiorespiratory fitness protects against stress-related symptoms of burnout and depression. Patient Educ Couns 2013;93:146-52.
Kitaoka-Higashiguchi K, Morikawa Y, Miura K, Sakurai M, Ishizaki M, Kido T, et al.
Burnout and risk factors for arteriosclerotic disease: Follow-up study. J Occup Health 2009;51:123-31.
Alexandrova-Karamanova A, Todorova I, Montgomery A, Panagopoulou E, Costa P, Baban A, et al.
Burnout and health behaviors in health professionals from seven European countries. Int Arch Occup Environ Health 2016;89:1059-75.
McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43:2-15.
Hintsa T, Elovainio M, Jokela M, Ahola K, Virtanen M, Pirkola S. Is there an independent association between burnout and increased allostatic load? Testing the contribution of psychological distress and depression. J Health Psychol 2016;21:1576-86.
Juster RP, Sindi S, Marin MF, Perna A, Hashemi A, Pruessner JC, et al.
A clinical allostatic load index is associated with burnout symptoms and hypocortisolemic profiles in healthy workers. Psychoneuroendocrinology 2011;36:797-805.
Seeman TE, Singer BH, Rowe JW, Horwitz RI, McEwen BS. Price of adaptation-allostatic load and its health consequences. MacArthur studies of successful aging. Arch Intern Med 1997;157:2259-68.
McEwen BS. Stressed or stressed out: What is the difference? J Psychiatry Neurosci 2005;30:315-8.
von Känel R, Bellingrath S, Kudielka BM. Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J Psychosom Res 2008;65:51-9.
Jonsdottir IH, Hägg DA, Glise K, Ekman R. Monocyte chemotactic protein-1 (MCP-1) and growth factors called into question as markers of prolonged psychosocial stress. PLoS One 2009;4:e7659.
Metlaine A, Sauvet F, Gomez-Merino D, Boucher T, Elbaz M, Delafosse JY, et al.
Sleep and biological parameters in professional burnout: A psychophysiological characterization. PLoS One 2018;13:e0190607.
Bargellini A, Barbieri A, Rovesti S, Vivoli R, Roncaglia R, Borella P. Relation between immune variables and burnout in a sample of physicians. Occup Environ Med 2000;57:453-7.
Mohren DC, Swaen GM, Kant IJ, van Amelsvoort LG, Borm PJ, Galama JM. Common infections and the role of burnout in a Dutch working population. J Psychosom Res 2003;55:201-8.
Gajewski PD, Boden S, Freude G, Potter GG, Claus M, Bröde P, et al.
Executive control, ERP and pro-inflammatory activity in emotionally exhausted middle-aged employees. Comparison between subclinical burnout and mild to moderate depression. Psychoneuroendocrinology 2017;86:176-86.
Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Psychoneuroimmunology and psychosomatic medicine: Back to the future. Psychosom Med 2002;64:15-28.
Dragoş D, Tănăsescu MD. The effect of stress on the defense systems. J Med Life 2010;3:10-8.
Nakamura H, Nagase H, Yoshida M, Ogino K. Natural killer (NK) cell activity and NK cell subsets in workers with a tendency of burnout. J Psychosom Res 1999;46:569-78.
Asberg M, Nygren A, Leopardi R, Rylander G, Peterson U, Wilczek L, et al.
Novel biochemical markers of psychosocial stress in women. PLoS One 2009;4:e3590.
Toker S, Shirom A, Shapira I, Berliner S, Melamed S. The association between burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and fibrinogen in men and women. J Occup Health Psychol 2005;10:344-62.
Johnson TV, Abbasi A, Master VA. Systematic review of the evidence of a relationship between chronic psychosocial stress and C-reactive protein. Mol Diagn Ther 2013;17:147-64.