Introduction to Stress Consequences

George Fink

Stress Consequences, the clinical sequel to the largely basic science-focused Stress Science, starts with a chapter by Harrison and Critchley that outlines the impact of modern brain imaging on our understanding of cognition, emotions and mind. The second chapter by Monroe and Slavich reminds us, with examples, that “It is also commonly assumed that with the accelerating progress of civilization, more and more people are afflicted with mental and physical disorders. Historical accounts, however, suggest that such ideas about stressors, civilization, and disease have been common for quite some time.”

The present work covers most stress consequences – mental, neuropsychological, psychosocial and socio-economic – that are likely to be of relevance to psychiatrists, psychologists, psychotherapists, sociologists, epidemiologists, economists, stress researchers and students. Stress Consequences will also prove of interest to physicians and other health care workers, endocrinologists and neuroendocrinologists, policy and lawmakers and to the lay reader interested in the impact of stress on humans and human society.

The selection of topics and articles that comprise Stress Consequences was based on their importance for understanding stress and its impact, their relevance for psychiatry, medicine and health care delivery, psychology, sociology and economics, their timeliness, and the robustness of their concepts and data. Most of the articles are derived from the recently published Encyclopedia of Stress. Readers are referred to the earlier companion volume, Stress Science, for reviews of the relationship between stress and circadian and seasonal rhythms, neural plasticity and memory, inflammation and immunity, fetal stress and the “thrifty phenotype” hypothesis, feeding, obesity and the metabolic syndrome, disorders of the cardiovascular system and reproductive disorders. Stress Science also reviews some aspects of genetics and genomics, such as the article by Craig on “Genetic Polymorphisms in Stress Response”, which are relevant to Stress Consequences.

Obesity and cardiovascular disorders, introduced in Stress Science and frequently referred to as “epidemics”, receive further coverage in the present volume on Stress Consequences, especially in the sections on “Neuropsychological” and “Socioeconomic”.

What follows is a brief outline of a few points of interest or controversy that perhaps deserve editorial comment.

Some caveats and points of controversy or interest

Posttraumatic Stress Disorder and Hypocortisolemia? Science is a debate, especially when data are subjective as is often the case with symptoms of mood and mental state and when hormonal and neurotransmitter changes may be relatively subtle. This uncertainty problem is exemplified by posttraumatic stress disorder (PTSD). Thus, early studies by Mason and associates (1986) found that urinary-free cortisol levels during hospitalization were significantly lower in PTSD than in major depressive disorder, “bipolar I, manic”, and undifferentiated schizophrenia, but similar to those in paranoid schizophrenia. Mason et al underscored the fact that the low, stable cortisol levels in PTSD patients (Vietnam combat veterans) are remarkable because the overt signs of anxiety and depression in PTSD would usually be expected to be associated with cortisol elevations. Mason et al (1986) conclude that “the findings suggest a possible role of defensive organization as a basis for the low, constricted cortisol levels in PTSD and paranoid schizophrenic patients”.

As explained by Rachel Yehuda (see “HPA Alterations in PTSD” in the present work, and also Yehuda 2006), the apparently low cortisol levels in PTSD are thought to reflect hyper-responsiveness of the hypothalamic-pituitary-adrenal system (HPA) to cortisol (glucocorticoid) negative feedback inhibition (for explanation see Stress Science: Neuroendocrinology). The observation of low cortisol in a disorder – PTSD – precipitated by extreme stress directly contradicts the popular “glucocorticoid cascade hypothesis” which posits that stress-induced increased plasma cortisol concentrations (hypercortisolemia) result in damage to areas of the brain, such as the hippocampus, that are involved in memory and cognition (see articles by BS McEwen, RM Sapolsky and the section on “Neuronal Plasticity-Memory” in Stress Science: McEwen 2007). But of greater concern is the fact that the data of Mason et al (1986) have not been universally replicated. Thus, when compared with levels in normal controls, ambient cortisol concentrations in PTSD over a 24-h period have been reported differently in several different publications as significantly lower, significantly higher, and not significantly different (e.g. Yehuda 2006, and “HPA Alterations in PTSD” in the present work; Young & Breslau 2004). Furthermore, most cortisol levels, high or low, in persons with PTSD are within the normal endocrine range, not suggestive of endocrine pathology.

There is, therefore, room for healthy skepticism about accepting hypocortisolemia as a universal and canonical feature of PTSD or other chronic conditions, such as chronic fatigue syndrome and fibromyalgia. As Rachel Yehuda stresses, the clinical significance of cortisol alterations within the normal endocrine range awaits to be determined by more sophisticated and rigorous neuroendocrine follow-up studies that are likely to involve genetics, genomics, molecular biology and brain imaging.

A different slant on within-normal range cortisol levels is offered by a recent study of 4000 former or current British civil servants (Michael Marmot’s Whitehall II study). Kumari et al (2009) report that statistically low salivary cortisol concentrations at waking predicted new-onset of reported fatigue during an approximately 2.5-year follow-up. It is not clear whether the low cortisol levels are an effect or cause of fatigue. The authors speculate that their findings might also be relevant for conditions such as chronic fatigue syndrome and burnout (see Maslach and Leiter, present volume). However, although statistically significant (over a relatively huge N), it is not clear whether the seemingly small effect size of the difference between the fatigued and non-fatigued groups would enable salivary cortisol to be used to predict fatigue within individuals.

Human hippocampus - does size matter? Much is often made of hippocampal volume (determined in man by magnetic resonance imaging: MRI) and major depressive disorder – indeed, a Medline search draws down nigh on 270 papers on the subject. This issue is dealt with in the present volume by Rubin and Carroll (“Depression and Manic-Depressive Illness”) and Harrison and Critchley (“Neuroimaging and Emotion”). The clear signal that emerges from both of these detailed reviews is that reduction in hippocampal volume, thought by some to reflect the effect of prolonged depression, PTSD or chronic stress (e.g. Lupien et al 2009) is not a consistent finding in major depression. The literature shows that reduction in hippocampal volume cannot be attributed to high levels of cortisol: indeed, reduced hippocampal volume has also been reported in PTSD patients in whom cortisol levels are assumed to be lower than normal (Lupien et al 2009), and in patients with cardiovascular disease (Rubin and Carroll). In a meta-analysis of 2418 patients with major depressive disorder and 1,974 healthy individuals, Koolschijn et al (2009) reported that the MRI data in patients with major depressive disorder showed large volume reductions in frontal regions, especially in the anterior cingulate and orbitofrontal cortex, with smaller reductions in the prefrontal cortex. The hippocampus, the putamen and caudate nucleus showed moderate volume reductions. In a monumental review of the literature, Savitz and Drevets (2009) conclude that “a significant number of studies have failed to find evidence of hippocampal atrophy in depressed patients, and based on these data, we suggest that the following caveat obtains: the majority of studies reporting evidence of hippocampal atrophy have made use of elderly, middle-aged or chronically ill populations”. Clearly, much more research is required to improve our understanding of the relationships between mental symptoms, changes in regional brain volumes and neuroendocrine data.

Corticotropin releasing factor antagonists – novel potential anxiolytics and antidepressants: Numerous studies have shown that major depressive disorder often requires more than one step of treatment to elicit a remission of symptoms. Frequently, a second medication needs to be added to augment the first, which nowadays is usually a selective serotonin reuptake inhibitor [SSRI] (Trivedi et al 2006). Current data raise the question of whether to use augmentation agents (or other treatment combinations) as first-line treatment in an attempt to achieve greater remission rates sooner and in more patients than those associated with the...