Objective. —This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided. Data Sources. —Published original articles from human and animal studies and selected reviews. Literature was surveyed utilizing MEDLINE and the Index Medicus . Study Selection. —Original articles from the basic science and human literature consisted entirely of controlled studies based on verified methodologies and, with the exception of the most recent studies, replicated by more than one laboratory. Many of the basic science and clinical studies had been conducted in our own laboratories and clinical research units. Reviews cited were written by acknowledged leaders in the fields of neurobiology, endocrinology, and behavior. Data Extraction. —Independent extraction and cross-referencing by the authors. Data Synthesis. —Stress and related concepts can be traced as far back as written science and medicine. The stress system coordinates the generalized stress response, which takes place when a stressor of any kind exceeds a threshold. The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. There has been an exponential increase in knowledge regarding the interactions among the components of the stress system and between the stress system and other brain elements involved in the regulation of emotion, cognitive function, and behavior, as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of stress system dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders and/or susceptibility to such disorders. Conclusions. —We hope that knowledge from apparently disparate fields of science and medicine integrated into a working theoretical framework will allow generation and testing of new hypotheses on the pathophysiology and diagnosis of, and therapy for, a variety of human illnesses reflecting systematic alterations in the principal effectors of the generalized stress response. We predict that pharmacologic agents capable of altering the central apparatus that governs the stress response will be useful in the treatment of many of these illnesses. ( JAMA . 1992;267:1244-1252)

The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(99)01376-8.pdf

Impact of sleep debt on metabolic and endocrine function

Objectives: The purposes of this study were to identify age-related changes in objectively recorded sleep patterns across the human life span in healthy individuals and to clarify whether sleep latency and percentages of stage 1, stage 2, and rapid eye movement (REM) sleep significantly change with age. Design: Review of literature of articles published between 1960 and 2003 in peer-reviewed journals and meta-analysis. Participants: 65 studies representing 3,577 subjects aged 5 years to 102 years. Measurement: The research reports included in this meta-analysis met the following criteria: (1) included nonclinical participants aged 5 years or older; (2) included measures of sleep characteristics by “all night” polysomnography or actigraphy on sleep latency, sleep efficiency, total sleep time, stage 1 sleep, stage 2 sleep, slow-wave sleep, REM sleep, REM latency, or minutes awake after sleep onset; (3) included numeric presentation of the data; and (4) were published between 1960 and 2003 in peer-reviewed journals. Results: In children and adolescents, total sleep time decreased with age only in studies performed on school days. Percentage of slow-wave sleep was significantly negatively correlated with age. Percentages of stage 2 and REM sleep significantly changed with age. In adults, total sleep time, sleep efficiency, percentage of slow-wave sleep, percentage of REM sleep, and REM latency all significantly decreased with age, while sleep latency, percentage of stage 1 sleep, percentage of stage 2 sleep, and wake after sleep onset significantly increased with age. However, only sleep efficiency continued to significantly decrease after 60 years of age. The magnitudes of the effect sizes noted changed depending on whether or not studied participants were screened for mental disorders, organic diseases, use of drug or alcohol, obstructive sleep apnea syndrome, or other sleep disorders. Conclusions: In adults, it appeared that sleep latency, percentages of stage 1 and stage 2 significantly increased with age while percentage of REM sleep decreased. However, effect sizes for the different sleep parameters were greatly modified by the quality of subject screening, diminishing or even masking age associations with different sleep parameters. The number of studies that examined the evolution of sleep parameters with age are scant among school-aged children, adolescents, and middle-aged adults. There are also very few studies that examined the effect of race on polysomnographic sleep parameters.

https://sites.oxy.edu/clint/physio/article/MetaAnalysisofQuantitativeSleepParametersFromChildhoodtoOldAgeOhayon2004.pdf

Meta-Analysis of Quantitative Sleep Parameters From Childhood to Old Age in Healthy Individuals: Developing Normative Sleep Values Across the Human Lifespan

Seasonal affective disorder (SAD) is a syndrome characterized by recurrent depressions that occur annually at the same time each year. We describe 29 patients with SAD; most of them had a bipolar affective disorder, especially bipolar II, and their depressions were generally characterized by hypersomnia, overeating, and carbohydrate craving and seemed to respond to changes in climate and latitude. Sleep recordings in nine depressed patients confirmed the presence of hypersomnia and showed increased sleep latency and reduced slow-wave (delta) sleep. Preliminary studies in 11 patients suggest that extending the photoperiod with bright artificial light has an antidepressant effect.

Seasonal Affective Disorder: A Description of the Syndrome and Preliminary Findings With Light Therapy

I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity, which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results of previous experiments in which ordinary room light was used, these findings establish that the human response to light is qualitatively similar to that of other mammals.

https://science.sciencemag.org/content/sci/210/4475/1267.full.pdf

Light Suppresses Melatonin Secretion in Humans

Patterns of seasonal changes in mood and behavior in Montgomery County, Maryland, were evaluated in randomly selected household samples by lay interviewers using a telephone version of the Seasonal Pattern Assessment Questionnaire. The method for selecting the sample unit was random-digit dialing. We found that 92% of the survey subjects noticed seasonal changes of mood and behavior to varying degrees. For 27% of the sample seasonal changes were a problem and 4.3% to 10% of subjects, depending on the case-finding definition, rated a degree of seasonal impairment equivalent to that of patients with seasonal affective disorder. The seasonal pattern of "feeling worst" exhibited a bimodal distribution with a greater winter and a substantially lower summer peak (ratio, 4.5:1). Younger women who have a problem with seasonal changes and who feel worse on short days tended to exhibit the highest seasonality scores. It is apparent from our study that seasonal affective disorder represents the extreme end of the spectrum of seasonality that affects a large percentage of the general population. The influence of environmental factors on mood disorders and mood changes in the general population might provide valuable insight into pathogenesis, treatment, and prevention of affective illness.

Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland.

Sleep in depressed patients resembles sleep in normal subjects whose circadian rhythms of temperature and rapid-eye-movement sleep are phase-advanced (shifted earlier) relative to their sleep schedules. If this analogy is relevant to the pathophysiology of depressive illness, advancing the time of sleep and awakening should temporarily compensate for the abnormal timing of depressed patients' circadian rhythms. Four of seven manic-depressive patients studied longitudinally spontaneously advanced their times of awakening (activity onset) as they emerged from the depressive phase of their illness. In a phase-shift experiment, a depressed manic-depressive woman was twice brought out of depression for 2 weeks by advancing her sleep period so that she went to sleep and arose 6 hours earlier than usual. The antidepressant effect of the procedure was temporary and similar in duration to circadian desynchronization induced by jet lag in healthy subjects. This result supports the hypothesis that abnormalities of sleep patterns in some types of depression are due to abnormal internal phase relationships of circadian rhythms.

https://science.sciencemag.org/content/sci/206/4419/710.full.pdf

Phase advance of the circadian sleep-wake cycle as an antidepressant

Several investigators have recently challenged the belief that antidepressants can precipitate mania or rapid cycling between mania and depression. With one exception, there appear to be no placebo-controlled studies of switches into mania in bipolar patients during antidepressant treatment. Patients most likely to switch into mania during antidepressant therapy have probably been excluded from maintenance treatment studies and are probably overrepresented in studies at special research facilities. On balance, the available evidence suggests that some bipolar patients become manic, and a few experience rapid cycling, when they are treated with antidepressants. The prevention of these responses will require further research on risk factors and on the antimanic efficacy of coadministered lithium or other mood stabilizers.

Thomas A. Wehr

Papers

Seasonal Affective Disorder: A Description of the Syndrome and Preliminary Findings With Light Therapy

Light Suppresses Melatonin Secretion in Humans

Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland.

Phase advance of the circadian sleep-wake cycle as an antidepressant

Can antidepressants cause mania and worsen the course of affective illness