6

CHAPTER 2

Stress and illness

Dr David Wheatley MD, FRCPsych
THE relationship between stress and physical illness is two-directional. Stress may cause or aggravate preexisting physical illness and conversely physical illness can constitute a stress factor. As a normal component of life, stress varies greatly between individuals and in particular situations. A failure to cope with stress may adversely affect physical illness. On the other hand, there are many people who thrive under challenging conditions and for whom the removal of such conditions would actually create stress.
Physiological reactions All higher living organisms are programmed with the 'fight or flight' response. Constant fear of attacks by predators makes life in the jungle an existence fraught with ever-present anxiety. We may say that the animal 'stress jungle' is similar to the human 'anxiogenic jungle' (Wheatley, 1990a). Folkow (1971) has described the physiological responses to stress in his description of a grazing antelope under threat of an attack by a lion. Instantaneous release of adrenalin results in diversion of cardiac output from the antelope's gastro-intestinal tract to its skeletal muscle, so that within a 2-second interval it turns to flee. The basic concept of physiological adaptation to situations of stress was propounded by Selye (1936) in his pioneering studies that laid the foundations of stress research. The most current concept suggests that there is feedback regulation of central neurohormonal events whereby an equilibrium is established between the environment, central neurotransmission and pituitaryadrenal activity (Leonard, 1985). Successful adaptation to the environment involves balancing these three components, and excessive over-activity or under-activity of any of them results in stress.
Human stress

These people all had enchanced sympathetic activity, leading to mobilization of free fatty acids and, in the absence of metabolic requirements, conversion of these acids to triglycerides. Their studies showed that tachycardia, ECG changes (including ST segment depression and arrhythmias), and even florid pulmonary oedema can be emotionally induced. Similar findings were reported by O'Donnell et al. (1987), who studied 13 medical students during a 3-month period prior to examinations. In response to this stressful period there were significant increases in the students' production of adrenalin and noradrenalin, associated with increases in plasma cholesterol and low-density lipoprotein. The fact that a wide range of neuropeptides, steroids and endogenous opioid peptide endorphins are also involved in the stress reaction has been demonstrated by Arnetz et al. (1986) using various mental stressors in a laboratory setting. These stressors included a colourword conflict test and mental arithmetic problems. Participants' urinary excretion of adrenalin increased markedly, whereas their urinary control decreased, as did their serum levels of prolactin and glucose. Cholesterol levels and systolic and diastolic blood pressures were slightly increased. Therefore stress, particularly when it is sustained for long periods of time, may produce profound effects on the physiology of human functioning that can lead to overt physical illness.
Psychiatric sequelae

Stress that endangers life is seldom encountered by human beings, but this has been replaced by other more subtle stresses that exert far-reaching effects on the mental processes. Man's fight or flight response is the same as for animals but it is inappropriate for contemporary life and may result in adverse mental and psychological effects that, if perpetuated, may constitute a threat to a person's health. Emotional responses to stress, particularly their effects on the cardiovascular system, have been extensively studied by Taggart and Carruthers (1981), who examined physical and mental stress in such diverse pursuits as car racing, public speaking and parachute jumping. They also studied drivers in heavy traffic conditions.

The immediate reaction to acute stress, as embodied in the fight or flight reaction, is a state of mental alertness involving emotions such as apprehension and anxiety. However, when stress is long continued and the individual has difficulty in coping with it, then depressive illness may develop insidiously under the cloak of continuing anxiety symptoms, the well known 'masked depression'. Furthermore, anxiety, panic disorder, phobias and depression are common psychiatric elements induced by stress. The Maudsley Stress Clinic was established for the investigation and quantification of stress in the following nine areas: social habits (Stockwell, 1985; Jarvic and Pomerleau, 1986), social stress (McKenna and Scholl, 1985), life events, sexual stress (Wheatley, 1983), sleep problems (Wheatley, 1981; Home, 1988), psychiatric problems, old age difficulties (Wheatley, 1982a), menstrual stresses and 'stress and the heart' (Wheatley, 1982b; Wheatley, 1987). A structured questionnaire is used to qualify the presence and degree of stress in each of these areas (Wheatley, 1990b). The clinic takes referrals from general practitioners of patients in whom the doctor suspects 'stress problems' but for whom he or she does

not have the time or expertise to evaluate them. An analysis of the first 100 patients seen at the clinic, in relation to the principal diagnoses, was undertaken and the results are shown in Table 1 (Wheatley, 1993). In some cases, more than one principal stress was present, for example depression and insomnia together, but nevertheless it is notable that no fewer than 49 patients were suffering from depressive illness according to the Diagnostic and Statistical Manual, Version III Revised (DSM-III-R) of the American Psychiatric Association (Spitzer and Williams, 1987). DSM-III-R provides standardized criteria for the diagnosis of psychiatric disorders and distinguishes between 'major depression' as an illness and depression as an emotion. The results of this analysis illustrate the enormous potential for treatment of associated psychiatric disorders as a means of helping the patient to break the vicious circle of stress-psychiatric illness-stress. Thus, when depression is induced by stress, the very nature of the symptoms further increases the impact of the stress on the individual and decreases the ability to cope with the stress. Depressive illness is a common response to longstanding stress. When the patient is suffering from major depression in association with other stress factors, relief of depression results also in the relief of the morbidity caused by those other stress factors, as illustrated by an analysis of 21 cases of depression. The mean stress profiles of these cases, before and after treatment, are shown in Figure 1. Following the significant relief of depression (p < 0.01) with antidepressant drug therapy, there was concomitant relief in severity of stress due to: social habits, life events, sleep, anxiety, menstruation, stress and the heart (p<0.0l), and social stress (p<0.05). Stress and the heart

Table 1 Stress diagnosis in the first 100 patients seen at the Maudsley Stress Clinic (more than one in some cases). Principal stress
Number
Males 14 4 6 2 21

Females
10 4 3

General anxiety Social phobia Panic disorder Agorophobia Simple phobia

24 8 9 1 3
49

1
1
28

Major depression
Insomnia Organic illness Emotional Situational

20 9 1 1

8 6
-

12 3 I I

The physiological responses to stress are mainly manifested through the cardiovascular system and when stress

is prolonged these physiological responses may become pathological. There is considerable evidence that stress may initiate heart attacks or aggravate heart conditions and continued mental stress may create sustained high blood pressure (Wheatley, 1984). The direct effects of mood on the symptoms of coronary heart disease (CHD) have been studied in a sample of 186 patients with chest pains presenting to a cardiology clinic for diagnostic exercise stress testing (Channer and Rees, 1987). Although patients who were shown not to have coronary heart disease recorded significantly higher anxiety and depression scores, in patients with the disease there was a significant negative correlation between the exercise duration and the degrees of anxiety and depression. Sleep disturbances may adversely affect coronary heart disease. Partinen (1985) has shown that people sleeping less than 6 hours per day have more symptoms of coronary heart disease than those sleeping 7 to 8 hours. Excessive sleep may also be detrimental as the

Social habits Social stress Life events Sex - male

- female

WAfter MBefbre

Sleep

Anxie
Depression
Old age (over 60) Menstrual (females) Stress and the heart
*

**

N = 21 * pc 0.05 ** p< 0.01

I

1I5 T

10

20

30

40

50

60

70

80

90

100

Percentage severty
Figure I Mean stress profiles before and after antidepressant drug treatment (mean duration 1 1.6 weeks) in 21 patients suffering from major depression.

incidence of myocardial infarction was higher in those sleeping 9 hours or more. Poor sleep quality also increases the risk of coronary heart disease and seems to be an indicator of mental and somatic disease. Traditionally, most people sleep at night, but an afternoon siesta, as is the custom in many hot countries, can protect against coronary heart disease. A study in Greece found that a 30-minute siesta may be responsible for an almost 30% reduction in the incidence of non-fatal CHD episodes (Trichopoulos et al., 1988). The importance of assessing personality in relation to stress and cardiovascular disease has been emphasized in a number of reports. Eysenck (1988) considered three such types: cancer-prone, CHD-prone, and not prone to either. He quotes a number of studies in which there was a strong relationship between personality types and mortality from cancer and coronary heart disease. Subsequently, Grossarth-Maticek and Eysenck (1991) have shown in essence that patients with CHD-prone personalities are 27 times more likely to die of coronary heart disease than controls and, even more strikingly, that cancer-prone subjects are no less than 121 times more likely to die from carcinoma! However, Pelosi and Appleby (1992) have cast serious doubts on the validity of these claims. Therefore, the importance of assessing personality in this context remains in doubt. On the other hand, there is considerable evidence that social stresses are of importance. Many social stresses are found in the deprived areas of large cities. McCord and Freeman (1990) examined mortality rates in New York City's Central Harlem Health District, where 96% of the inhabitants are black and 41% live below the poverty line. Age-adjusted mortality from all causes in Harlem was the highest in New York City, more than double that of US whites and 50% higher than that of US blacks. Almost all the excess mortality was among those aged less than 65 years old. The chief causes of this excess were cardiovascular disease (23.5% of the excess) followed by cirrhosis (17.9%), homicide (14.9%) and neoplasms (12.6%). This study provides convincing evidence of the importance of socio-economic factors in the morbidity of cardiovascular disease. Stress is implicated in a number of risk factors for coronary heart disease (Boulenger and Uhde, 1982; Kenny and Darragh, 1985; Onrot et al., 1985). Excessive intake of alcohol and smoking are important examples. Although moderate alcohol consumption may be protective, excessive drinking is undoubtedly dangerous (Jackson et al., 1991; Rimm et al., 1991). The association between heavy smoking and coronary heart disease has been established beyond doubt (Epstein and Jennings, 1986). An adverse association between obesity and coronary heart disease is well documented (Pelkonen et al., 1977; Wood et al., 1991). There are many people who eat more under the minor stresses of everyday life, and motivation to maintain dietary restriction is also psychologically determined. Sexual activity may exert an adverse effect in coronary heart disease (Hellerstein and Friedman, 1970) and sudden deaths do occur during or shortly after intercourse, usually in clandestine circumstances (British Medical Journal, 1976), so that anxiety in relation to sex may be a significant influence.

The fear of succumbing to the ailment that terminated the life of one's forebears can create stress, and heredity is undoubtedly an important risk factor for coronary heart disease (Beckles et al., 1986). In Finland, Rissanen and Nikkila (1977) studied 560 relatives of 104 men who developed angina pectoris before the age of 56, and 498 relatives of 94 controls. The study was conducted in two geographical areas of the country, one with a moderate (South) and another with a high (East) incidence of coronary heart disease. The incidence of death due to coronary heart disease before the age of 65 was 5 times greater for fathers of patients than for fathers of controls. Furthermore, the risk was 5.5 times greater for brothers of patients than for brothers of controls, the comparable figure for sisters being 2.5 times greater than for controls' sisters. Stress and the skin Stress may be a precipitating factor in up to one third of cases of dermatological disease (Walton, 1985). As this author remarked: "Pruritus is an important factor in many diseases, since it produces the itch-scratch vicious cycle. No matter what the cause of the itch, the current emotional state, including anxiety, tension and fear are factors which influence it." Similar results have been reported by Wessely and Lewis (1989), who assessed a random sample of new attenders at a dermatology outpatient clinic and found that 40% were classified as suffering from psychiatric disorder. Psychiatric morbidity was closely related to skin disease in 75%, although it may have been coincidental in the remaining 25%. Arnetz et al. (1991) investigated the role of psychosocial stress in the aetiology and clinical course of psoriasis and atopic dermatitis. They concluded that psychosocial stress did affect skin reactivity and that cognitive factors modulated such effects. Other reviews have also emphasized the importance of stress, psychological and emotional factors in dermatological conditions (Koblenzer, 1988; Folks and Kinney, 1992). Cancer
Research into the aetiology of cancer can only be undertaken in the advanced stages of the disease after conventional methods of treatment have been exhausted, and so is fundamentally inadequate. In consequence, much of the research of stress factors in cancer has been retrospective or is concerned with putative symbiotic effects of stress on the inevitable progression of the illness. Breast cancer has probably been most studied and the effects of psychosocial and stress factors have been extensively reviewed by Cooper (1988). In this context, two contemporary reports illustrate some of the issues involved. In the first of these, Ramirez et al. (1989) studied the influence of life stress on the first recurrence of breast cancer in 50 women whose initial illness had been treated surgically. These were compared to 50 similarly treated patients without recurrence. The two groups of patients were matched for adjuvant chemotherapy, menopausal state, affected lymph nodes, tumour site and histological type of tumour, date of

operations and "those sociodemographic variables that influence the frequency of life events in the general population". They found that the relative risk of recurrence associated with severe life events was 5.67, but was not significant for life events not rated as severe. As the author comments: "These results suggest a prognostic association between severe life stressors and recurrence of breast cancer." In the second study, Barraclough et al. (1992) followed 204 women prospectively for periods of up to 42 months after surgical treatment of breast cancer. Recurrence occurred in 47 patients (23%) and the hazard ratio associated with severe life events during the year before the initial surgery was found to be 0.43 and during the prospective period 0.88. They concluded that their results gave "no support to the theory that psychosocial stress contributes to relapse of breast cancer", a result diametrically opposed to that of Ramirez et al. (1989). Reports of an association between stress and cancer have led to attempts to modify the impact of stress in such patients, mainly by psychotherapy. Spiegel et al. (1989) undertook a prospective study of the effect of psychosocial intervention on time of survival of 86 patients with metastatic breast cancer. Patients were randomly assigned to receive weekly psychotherapy over 1 year or no psychotherapy and it was found that the mean survival time in those who received therapy was 36.6 months as compared to 18.9 months in those who did not. Quite apart from a possible increase in survival time, psychotherapy may do much to improve the quality of life of cancer patients, as illustrated by Greer et al. (1992), who prospectively observed 174 patients with confirmed malignant disease over a period of 4 months. This project was not concerned with survival per se but rather improvement in the psychological state of the patients. As in the previous study, patients were randomly allocated to receive psychotherapy or not and significant psychological improvement occurred in those so treated in comparison to the controls. Support for the influence of stress in cancer comes from the laboratory, where exacerbation of tumour growth has been demonstrated in mice following acute exposure to uncontrollable, in contrast to controllable, stress (Sklar and Anisman, 1981). Certainly, the evidence would seem to suggest that treatment of the stress factor in cancer is well worthwhile, since it will improve the quality of the patient's life and may even prolong life itself.
Stress and the immune system

That stress may have adverse effects on the immune system has been amply demonstrated by Leonard (1988) in laboratory animals. Stress appears to increase susceptibility to passive anaphylaxis and suppress antibody production and lymphocyte stimulation. In humans there are a number of examples of impairment in immune function due to stressful life events and bereavement. A good example is voodoo death, the rationale of which has been surveyed by Cohen (1988): "The victim must believe that the curse works and that he or she cannot control it. Furthermore, the role of the community and family is crucial, since their support is withdrawn if the cursed person tries to resist his or her

fate. As a consequence, the voodoo victim feels cast out, isolated, alone, seeing death as the only escape from an intolerable loneliness." Other stressful life events have been reviewed by Laudenslager and Reite (1984), who list a number of ailments which have been associated with antecedent losses or separations, whether real, threatened or imagined. These include diverse conditions such as atherosclerosis, congestive heart failure, hypertension, Raynaud's disease, Cushing's disease, diabetes, Graves' disease, AIDS, cancer, rheumatoid arthritis, lupus erythematosus, colitis, obesity, peptic ulcer, porphyria, asthma, tuberculosis, pneumonia, burns, poisoning, glaucoma, pernicious anaemia, streptococcal infection and menorrhagia. Such effects may be mediated through stimulation of the cortico-hypothalamic-pituitary axis which leads to alteration in immune function, either indirectly by changes in secretion of hormones or neurotransmitters, or directly, by neuronal stimulation of lymphoid tissue (Schindler, 1985). Because the immune system is the body's prime defence against invasion by disease-producing microorganisms, any impairment occurring as a result of stress will have an adverse effect in many infections. The prime example is the human immunodeficiency virus (HIV) which attacks the immune system directly, thereby facilitating the development of a number of secondary infections. Following the initial glandular fever-like illness, a silent chronic infection develops and minor opportunistic infections, skin conditions, lymphadenopathy, and AIDS-related complex (ARC) may later develop (Adler, 1987). The most striking manifestation of the inability of AIDS patients to combat infections is their development of Pneumocystis carinii pneumonia. Stress may influence the immune response to even minor infections encountered in everyday life. For example, Jacobs et al. (1969) compared 29 male college students who were suffering from sore throats with 29 who were symptom free and randomly selected from the college directory. They reported that significantly more disappointment, failure and role crisis appeared in the lives of the students who became ill, as compared to the control students. This study is but one of a number of similar retrospective studies that are always open to the criticisms inherent in such clinical surveys. On the other hand a prospective study was undertaken by Hinkle (1974), who examined a sample of telephone operators once a week over a 6-month period. During this period, the operators kept daily records of events and situations in their lives and colour photographs were taken of their noses and throats. Hinkle found that "life events that occasioned self-reported sadness were likely to be followed by an acute respiratory illness". The psychological factors involved in resistance to the infectious disease have been comprehensively reviewed by Friedman and Glasgow (1966). Early studies such as these can be criticized on the grounds of small numbers, but impressive support for them has been recently provided by Cohen et al. (1991) who investigated psychological stress and susceptibility to the common cold. These workers deliberately infected 394 healthy subjects with nasal drops containing various rhino-viruses and other respiratory viruses and compared them with 26 control individuals who were given

10

saline nasal drops. Infection became established in 82% of the subjects, compared with 19% of the controls, and 38% of the subjects developed clinical colds although none of the controls did so. A 'psychological-stress index' was established based on major stressful events, coping ability and psychological effects. The authors concluded that "psychological stress was associated in a dose-response manner with an increased risk of acute infectious respiratory illness, and this risk was attributable to increased rates of infection rather than to an increased frequency of symptoms after infection". There is also recent evidence linking depressive states and the immune system. The HIV epidemic has stimulated considerable research on measures of immune function and in this context, cell-mediated immune function is one of the most important. HIV attacks thymusderived (T) lymphocytes which carry on their surface a glycoprotein molecule (CD4), the so-called 'leaders of the immunological orchestra' (Beverley and Sattentau, 1987). These cells stimulate a number of immune functions, including the production of natural killer cells (NKC) that, as the name implies, destroy virus-infected cells. NKC activity can be impaired in depression as demonstrated by Irwin (1988), who measured NKC activity in 19 pairs of depressed patients and matched controls. He found that the former had significantly lower activity and that this was correlated with total scores on the Hamilton depression rating scale. Furthermore, the depressed patients showed both a significantly higher white blood cell count and a higher number of neutrophils compared with the control subjects. Irwin concluded that "these data support the role of psychologic processes in mediating immune function". In another paper, Irwin et al. (1990) reported a 50% reduction of NKC cytotoxicity in major depressive disorder, compared with persons who were neither stressed nor depressed. Although evidence is not yet unequivocal, reduced cell-mediated immune function may be significant in depressed patients (Lancet, 1987; Evans et al., 1989).

Menstrual and reproductive function

Dalton (1959, 1968, 1971) has extensively studied psychiatric disorders associated with menstruation and pregnancy, showing that these may start during a girl's schooldays (as evidenced by the effects of menstruation on examinations), continue during the premenstrual phase (psychiatric illness and menstruation) and recur in relation to pregnancy and beyond (puerperal depression). Reid (1991) has reviewed the psychological aspects of the premenstrual syndrome (PMS) and stresses the fact that PMS may be modified by life stress. Specifically a higher incidence has been reported in women with major affective disorders (De Jong et al., 1985). It would therefore seem that women who suffer from premenstrual syndrome are more susceptible to the effects of stress and its psychiatric sequelae during the premenstrual phase. Even when the cyclic manifestations of her reproductive capacity begin to reach their termination in the menopause, a woman may become even more vulnerable to the development of such symptoms, both before, during and after the climacteric (Foldes, 1972; Ballinger, 1990). Cooke (1985) has shown a relationship between the role of psychological and social factors on psychological disturbance during the climacteric, either in conjunction with or independently of, life events. The physiological stress responses in postmenopausal women, before and after hormonal replacement therapy (HRT), have been investigated by Collins et al. (1982). Tiredness, headache, tension and anxiety were significantly reduced, and performance on various cognitive stress tests improved, following treatment. These studies provide further evidence for the stressful nature of the menopause, but particularly in relation to psychosomatic and physical symptoms such as perspiration and hot flushes. The occurrence of depression in the menopause and its relation to stress have been reviewed by Dennerstein (1987). Women in the middle years of life are particularly susceptible to the effects of stress. Other conditions

Sleep and stress

Lack of sleep creates stress which may insidiously undermine the sufferer's health (Mendelson et al., 1984), influencing not only his or her whole life but also exerting an adverse effect on almost every illness known to man. The function of sleep is essentially restorative in nature and physiological and psychological defects may occur when it is disturbed (Monroe, 1967; Adam and Oswald, 1983). Insomnia is an integral component of the psychiatric manifestations of stress, particularly in depressive illness, and reduction in deep sleep accompanies this condition (Mendlewicz and Kerkhofs, 1991). Impairment of sleep may also occur in many physical disorders and its treatment with hypnotic drugs may be an important stress-relieving measure. However, in this context, it should be appreciated that the commonly prescribed benzodiazepine hypnotics improve sleep by increasing light sleep at the expense of deep sleep, unlike the newer compounds such as zolpidem (not yet marketed in the UK) and zopiclone (Jovanovic and Dreyfus, 1982; Wheatley 1985; Herrmann et al., 1988).

Anxiety and stress are associated with asthma attacks (Jacobs et al., 1970; Knapp, 1977; Moran, 1991) and it has long been postulated that a psychiatric element is present in many gastric disorders, notably peptic ulceration and irritable bowel syndrome (Ritchie and Truelove, 1979; Heatley and Rathbone, 1987). Many other disorders have been described in which stress may be an aetiological factor, notably: multiple sclerosis (Elian, 1987; McNamara 1991), rheumatoid arthritis (Moran, 1991), Graves' disease (Winsa et al., 1991) and even diabetes mellitus (Ionescu-Tirgoviste et al., 1987).
Conclusion Stress and illness are intimately related and form a vicious circle whereby the one aggravates the other. In diagnosing the patient under stress, the common coexistence of concealed underlying physical illness must not be overlooked and, when present, treated vigorously

11

with appropriate measures. Conversely, in a patient with a physical disorder, assiduous concern should be directed towards the many stress factors that may be contributing to and aggravating the basic illness.
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