Invited paper
How does stress affect you? An overview of stress, immunity, depression and disease CLEMENTINE MADDOCK1 AND CARMINE M. PARIANTE2 1
2
Maudsley Hospital, London SE5 8AZ, UK Section of Clinical Neuropharmacology, Institute of Psychiatry, King’s College London, London SE5 8AF, UK
R I A S S U N T O . S c o p o – Il termine “stress” viene spesso usato come sinonimo di “vita moderna”. In questa revisione della letteratura abbiamo valutato la relazione tra lo stress e l’insorgenza o il decorso della depressione maggiore, dei disturbi cardiovascolari e delle malattie tumorali, le maggiori cause di morbidità e di mortalità nel mondo occidentale. Abbiamo anche discusso come i cambiamenti nei parametri del sistema immunitario indotti dallo stress possano essere considerati, almeno in parte, responsabili di questa relazione tra stress e malattia. M e t o d o – Abbiamo condotto una ricerca su Medline per il periodo 1996-2000, utilizzando i termine stress, disease (malattia) e immune system (sistema immunitario), allo scopo di identificare i più recenti sviluppi della ricerca in questo campo. Abbiamo anche rintracciato le più importanti pubblicazioni citate in questi articoli. R i s u l t a t i – Gli studi in letteratura confermano il legame tra lo stress e l’insorgenza della depressione. Lo stress sembra anche avere un effetto negativo sulla prognosi dei disturbi cardiovascolari e delle malattie tumorali, ed evidenze preliminari suggeriscono che interventi di gestione dello stress possono migliorare la sopravvivenza in questi pazienti. Situazioni di stress cronico sono associate ad una soppressione della funzionalità del sistema immunitario, mentre stress acuti hanno un effetto sia attivante, sia inibitorio. La liberazione di citochine infiammatorie, mediatori solubili della risposta immunitaria, può indurre la comparsa di sintomi depressivi. C o n c l u s i o n i – Studi epidemiologici prospettici sono necessari per chiarire il ruolo dello stress nell’insorgenza, decorso e prognosi delle malattie. L’utilizzo di terapie di gestione dello stress allo scopo di migliorare la prognosi dei pazienti con disturbi cardiovascolari, malattie tumorali ed altre malattie croniche, è un’area di ricerca particolarmente interessante. Gli effetti dello stress sul sistema immunitario sono importanti per capire il legame tra stress e malattia. In particolare, l’aumentata produzione di citochine infiammatorie durante situazioni di stress costituisce un possibile meccanismo biologico per spiegare il legame tra stress e depressione. PAROLE CHIAVE: stress, malattie cardiovascolari, cancro, sistema immunitario, citochine, depressione.
Indirizzo per la corrispondenza: Dr. C.M. Pariante, Section of Clinical Neuropharmacology, Institute of Psychiatry, King’s College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK. Fax: +44-(0)-20-7848.0051 E-mail:
[email protected]
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S U M M A R Y – O b j e c t i v e . Stress is a term that has become synonymous with modern life. This review aims to appraise the evidence linking stress with disease with particular reference to the major causes of morbidity and mortality in the Western World, cardiovascular disease, cancer, and depression. Changes in immune parameters in stressful situations were reviewed as a possible pathophysiological mechanism for such effects. M e t h o d – A Medline search was carried out for the period 1996-2000 to identify recent findings in this field using the terms “stress”, “disease”, “immune system”. Relevant references that were found in all identified publications were also followed up. R e s u l t s – There is evidence to link stress with the onset of major depression and with a poorer prognosis in cardiovascular disease and cancer. Few small studies suggest that stress management strategies may help to improve survival. Chronic stress appears to result in suppression of the immune response, whereas immune activation and suppression have been associated with acute stress. Inflammatory cytokines, soluble mediators of the immune response, can result in symptoms of depression. C o n c l u s i o n – Further prospective epidemiologically based studies are needed to clarify the role of stress on disease onset, course, and prognosis. Stress management strategies, aimed at prolonging survival in patients with cardiovascular disease, cancer, and possibly other chronic illnesses, are an exciting area of further research. Immune system changes may account for the relationship between stress and disease. We propose the “stress, cytokine, depression” model as a biological pathway to explain the link between stressful life events and depression. KEYWORDS: stress, cardiovascular disease, cancer, immune system, cytokines, depression. Ricevuto il 2.5.2001 – Accettato il 14.05.2001.
tion (acute e.g. laboratory stressor vs. chronic e.g. incurable disease); quantity (discrete events e.g. bereavement vs. cumulative events e.g. daily hassles); and quality (interpersonal event e.g. divorce vs. non-interpersonal event e.g. earthquake). The perception of, and adaptation to, stressors are accompanied by physiological and behavioural changes. The two principal biological components of the stress response are the hypothalamic-pituitary-adrenal axis and the nor-epinephrine/autonomic (sympathetic) nervous systems. Corticotrophin-releasing hormone (CRH) activates the pituitary-adrenal axis and the sympathetic nervous system leading to increases in glucose, heart rate, and blood pressure. Regulation of the immune response occurs alongside behavioural changes including enhanced arousal and vigilance, and suppression of feeding and reproductive behaviour. This response is temporarily beneficial and without adverse consequences if acute or of a limited duration (Chrousos & Gold, 1992).
INTRODUCTION “Stress” is a term that has become synonymous with modern life. There are many commonly held beliefs about the adverse effects of stress, but what is the evidence linking stress and disease? This review will appraise the evidence linking stress with disease with particular reference to the three major causes of morbidity and mortality in the Western world, depression, cardiovascular disease and cancer. A Medline search was carried out for the period 1996-2000 to identify recent findings in this field using the terms “stress”, “disease”, “immune system”. Relevant references that were found in all identified publications were also followed up. The effects of stress on the immune system are considered, as modulation of the immune response can affect an individual’s disease status. Finally, an integrated “stress, cytokine, depression” model is proposed which may be relevant to the pathophysiology of depression.
DOES STRESS MAKE YOU ILL? THE CONCEPT OF STRESS Much attention has been focused on the effects of stress on the two major causes of mortality and morbidity in the Western world, cardiovascular disease and cancer. Identification of risk factors for these diseases and possible mechanisms for modifying such factors is thus an
Stress results when environmental demands exceed a person’s resources to meet those demands (Lazarus & Folkman, 1984). Stress has various dimensions (Herbert & Cohen, 1993). It may be considered in terms of it’s dura-
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area of considerable public health concern. In addition, stress has been linked to exacerbation of diseases related to the immune system including asthma, rheumatoid arthritis, and multiple sclerosis (Wright et al., 1998; Walker et al., 1999; Mohr et al., 2000).
gher risk of both cardiovascular morbidity and mortality (O’Connor et al., 2000). Finally, there is evidence to suggest that stress reduction strategies may be beneficial in patients with CHD. A cohort of 107 patients with coronary ischaemia were randomly assigned to receive usual care, stress management, or exercise training (Blumenthal et al., 1997). At 38 months follow-up the stress management group had the lowest combined rates of death, non-fatal myocardial infarction, and re-vascularisation than the other two groups.
Coronary heart disease There has been widespread interest in the role of stress as a risk factor for coronary heart disease (CHD). One of the most well known studies in this field is that of Friedman & Rosenman (1959) who described “Type A” personality characteristics i.e. excessive competitive drive, aggressiveness, impatience, hostility, and time urgency. Such personality features would seem to create frequent episodes of acute stress for the “type A” individual. CHD incidence was investigated in a prospective epidemiological study of 3,524 men aged 39 to 59 years living in California. At 8 and a half years follow-up, type A behaviour pattern was strongly related to CHD incidence, an association that remained when other risk factors of parental history of CHD, smoking, blood pressure, and cholesterol levels were controlled for (Rosenman et al., 1975). A more recent prospective study investigated whether life events occurring in “Type A” individuals increased the risk of cardiovascular disease. These investigators failed to find such a link with cardiovascular disease although unexpectedly there was an increased mortality from cancer in this group (Hollis et al., 1990). Researchers have also investigated whether life events predict cardiovascular risk. A prospective study of 752 Swedish men aged 50 found that at 7 years follow-up, men who had experienced 3 or more life events in the past year had a significantly greater mortality from all causes (Rosengren et al., 1993). Adequate emotional support appeared to be a protective factor. However, the number of deaths was too small to analyse specific causes of death. The pathological processes involved in CHD are likely to have progressed over many years. Thus it is perhaps not surprising that an acute stressor such as a life event will not predict outcome 1 year later. It may be that more chronic stressors may contribute to such a process. Indeed, a prospective study found that acute and chronic stressors predicted a 3-year re-infarction rate in patients initially admitted with an acute ischaemic event, with chronic stressors and those involving goal frustrations seeming most important (Tennant et al., 1994). Moreover depression, which is associated with a chronic stress response in some patients as measured by HPA axis activation (Checkley, 1996), is associated with a much hi-
Stress and cancer Similar study methods have been utilised to investigate a possible link between stress and cancer. Much of this research has focused on breast cancer. A recent meta-analysis examined whether stressful life events are a risk factor for cancer (Petticrew et al., 1999). 29 studies met the inclusion criteria. These included 14 case-control studies, one prospective cohort study, and 14 limited prospective studies in which women awaiting the results of a breast biopsy are interviewed before the results are known. This attempts to control for recall bias in case control studies in which women are aware of their diagnosis and may be more likely to over-report stressful life events as a result of their illness. The authors found no significant relationship between bereavement and risk of breast cancer (OR 0.9; CI 0.57 to 1.45) or adverse life events and risk of breast cancer (OR 0.8; CI 0.61 to 1.06). Clearly, most of these studies question about life events in the preceding 2, 5, or 10 years and the causative factors for breast cancer act many years, perhaps 20 or more, before the onset of symptoms or the diagnosis of disease (McGee et al., 1996). This could explain why stress does not seem to be a risk factor for breast cancer. However, there are reports that stress may affect outcome of the disease. A number of studies have demonstrated that interventions to reduce psychological stress improve cancer survival. Spiegel et al. (1989) treated women with metastatic breast cancer by means of weekly group therapy. The intervention focused on encouraging a discussion of how to cope with cancer, and the expression of feelings about illness and its physical consequences. Relationships, which developed amongst group members, provided increased social support. A randomised study compared one year of the psychosocial treatment versus a control group. Both groups received routine oncological care. After 10 years of follow-up, the survival time of patients in the intervention group was almost double that of the controls; 36.6 months
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versus 18.9 months starting from the onset of the intervention. A similar group therapy approach was utilised in the treatment of patients with malignant melanoma (Fawzy et al., 1990a, b; 1993). The intervention consisted of a 6week course focusing on health education, enhancement of problem solving skills, stress management with relaxation techniques, and psychological support. At six months follow-up the intervention group, compared to a randomly selected control group, exhibited lower levels of psychological distress (Fawzy et al.., 1990a). Furthermore, after 5-6 years of follow-up the psychosocial intervention group had a lower rate of death and cancer recurrence than controls (Fawzy et al., 1993.) One possible mechanism whereby stress may be affecting cancer survival is via changes in immune parameters. Natural killer (NK) cells are a distinct sub-population of lymphoid cells that have spontaneous cytolytic activity against a variety of tumour cells and some normal cells. Furthermore, they have a role in resistance to infection with viruses and other microbes (Herberman & Ortaldo, 1981). NK cell function is thus implicated in an individual’s ability to combat cancer. Fawzy et al. (1990b) found an increase in NK cell percentage and NK cytotoxic activity in patients with malignant melanoma who were receiving psychological therapy at six months follow-up. Baseline NK cell activity was found to be predictive of recurrence of malignant melanoma in this cohort. However, the change in NK cell percentage over time was not correlated with the course of illness, and NK activity was not predictive of survival. The effect of stress on NK cell activity has also been investigated in a group of 116 patients treated surgically for invasive breast cancer (Andersen et al., 1998). Prior to surgery, subjects completed a questionnaire assessing intrusive thoughts, avoidant thoughts, and actions concerning cancer, which was used as a measure of psychological stress. An increased stress score was significantly associated with a decline in spontaneous NK cell cytotoxicity. Furthermore, higher stress significantly predicted a diminished NK cell cytotoxicity after stimulation with interferon-gamma (IFN-gamma). NK cells that have been activated by cytokines, including IFN-gamma and interleukin-2 (IL-2), known as lymphokine activated killer (LAK) cells, are highly cytotoxic against a wider variety of tumour cells than those lysed by resting NK cells (Whiteside & Herberman, 1990). Thus, the potential cytotoxic activity of these patients NK cells appears to be reduced. Finally, Andersen and colleagues found that increased stress was significantly associated with reduced T-cell responses as measured by the proliferative response of peripheral blood lymphocytes
to plant lectins and a monoclonal antibody directed against the T-cell receptor.
So, does stress make you ill? In summary, there is thus intriguing, albeit limited data currently available that psychological stress is associated with the outcome of coronary heart disease, breast cancer, and malignant melanoma. Immune parameters, including NK cell cytotoxicity, are also affected by stress levels, and are of importance in the host response to tumour cells. The relationship between stress, disease and the immune system is thus an exciting field for further research.
STRESS AND THE IMMUNE SYSTEM The mechanisms whereby psychological stress may be influencing disease outcome are not clear. We have summarised some of the findings relating to immune system changes in patients with cancer. There have been several studies investigating the effect of stressful situations, both acute and chronic, in otherwise healthy subjects. As outlined below, such stressors have effects on a large number of immune parameters, which are of importance in resistance to infection and disease. The studies below have utilised two kinds of immune assay; enumerative and functional (Herbert & Cohen, 1993). Enumerative assays count the numbers or percentages of different types of white blood cell in peripheral blood. Such assays are useful as a certain number of each type of immune cell is needed in order to respond adequately to an antigenic challenge. Furthermore, a balance of the different cell types is needed for an optimal immune response. Enumerative techniques may also measure immunoglobulin (Ig) levels in saliva or peripheral blood. As most people have been exposed to the common herpes viruses e.g. herpes simplex virus type 1 and EpsteinBarr virus, serum antibody (Ab) to these viruses may be measured with higher levels indicating higher levels of virus replication and thus poorer immune functioning. The functional capacity of human immune cells may be assessed via the lymphocyte proliferative response and NK cell cytotoxic activity, which has been briefly mentioned above. Lymphocyte proliferation is achieved by incubating lymphocytes, in-vitro, with substances (mitogens) capable of non-specifically inducing T or Blymphocytes to divide. It is assumed that the more proliferation that occurs, the more effectively the cells are functioning. NK cell cytotoxic activity assays determi-
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activity at times of stress (Maes et al., 1999). Subjects in the study by Beem et al. (1999) were aged between 50 and 65 and may have been taking hormone replacement therapy. Thus, while these studies demonstrate significant changes in immune parameters following bereavement, larger prospective designs would clarify the time course of such changes and control for possible confounders such as sex, age and health status. Kiecolt-Glaser & Glaser (1991a) have investigated the association of a range of stressful life events with the immune response. This research group initially focused their attention on academic stress among medical students as a commonplace stressful situation. Overall, they demonstrated impaired immune responses during the final examination (stressor) period as compared with preexamination baseline responses. Decreases were noted in NK cell activity, T-cell number, and interferon production from activated lymphocytes. Increased antibody titres to latent herpes viruses, a putative marker of decreased immune cell function, were also noted. Further exploration in this area has revealed that a subject’s psychological perception of the stressor, along with social support, may determine the outcome of the immune response. In a group of 48 medical students receiving a hepatitis B vaccination on the day of an examination, those who became immunised after the first injection were significantly less stressed and anxious than those who did not (Glaser et al., 1992). Those students who reported greater social support demonstrated a stronger immune response to the vaccine at the time of the third inoculation as measured by antibody titres to hepatitis B surface antigen. Some studies have found that acute stress may activate, rather than suppress, some aspects of the immune response. For example, immune activation, as suggested by increased numbers of neutrophils, monocytes, B-cells, and activated T-cells has been observed in students who showed increases in psychological stress (stress responders), the day before an exam. The Perceived Stress Scale was used to measure stress, and results were compared with baseline and post-exam responses (Maes et al., 1999). However, those students who did not show increased stress scores (stress non-responders) did not show many immune system changes. Some of the alterations in immune parameters persisted for several weeks after the exam stress. Female students taking oral contraception containing oestrogen and progesterone derivatives revealed a significantly greater stress induced response in the number of leukocytes, neutrophils and Bcells. Whitehouse et al. (1996) also found evidence of immune activation at the time of exam stress, as sugge-
ne how effectively NK cells kill damaged or altered (e.g. infected, cancerous) cells. Immune cells are incubated, in-vitro, with tumour cells to achieve this measure.
Stressful Life Events Immune system function, as measured by lymphocyte proliferative responses, has been assessed in individuals who have been exposed to the stressful life event of bereavement. Initial studies revealed, as perhaps may be predicted, reduced responses in these individuals. Bartrop et al. (1977) conducted one of the first studies suggesting a link between stressful events and the immune system in humans. Compared with an age, sex, and race matched control group, 26 bereaved spouses showed a reduced lymphocyte proliferative response at 6 weeks post-bereavement, although there was no difference in T and B cell numbers. Similarly, a study of 15 spouses of women with advanced breast carcinoma revealed significantly suppressed lymphocyte responses one and two months following bereavement compared with pre-bereavement levels. There was no comparison with a control group. At 4 to 14 months after bereavement, an intermediate response was achieved. Again, no differences were found in total lymphocyte or T or B cell numbers (Schleifer et al., 1983). However, a recent study comparing 18 widows to 10 married female controls found that the widows showed a higher lymphocyte proliferative response to mitogen at 3 and 7 months post-bereavement, compared to the control group (Beem et al., 1999). There were no differences in natural killer cell activity between the bereaved and control groups. It is interesting that this group showed heightened proliferative responses compared to the control group in this study. However, the immune responses were tested at 3 and 7 months following bereavement, but no comparisons between pre-bereavement and post-bereavement were made. Longitudinally, it is possible that the bereaved subjects actually showed immune suppression compared with pre-bereavement responses. Also, this group consisted solely of women, compared to the previous two studies. Therefore, it is also possible that the stress affects the immune system differently in men and women. Indeed, one study have found that depressed female patients have increased NK activity compared to controls, while decreased NK activity has been described in old male depressed patients (Pariante & Miller, 1995). One mechanism for this may be the different hormonal milieu. For example, there is evidence that women taking oestrogen and progesterone derivatives show heightened immune
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sted by increased B-lymphocyte and activated T lymphocyte counts, increased lymphocyte proliferative responses, and increased NK cell cytotoxicity. In this study, some students were trained in self-hypnosis as a stress management skill. These subjects reported significantly less distress and anxiety than their non-intervention counterparts, but the two groups did not differ with respect to immune function. However, within the self-hypnosis group, those subjects reporting higher levels of relaxation showed enhanced NK cell cytotoxicity over the course of the investigation. These studies provide evidence for changes in immune system function in medical students at the time of examination stress. Both immune suppression and activation have been demonstrated. The psychological response of individuals to exam stress appears to determine whether changes occur. There is no clear explanation as to why some studies suggest enhanced immune function and others suppression at the time of an exam stress. It is possible that subjects in some studies may have experienced chronic stress resulting in adaptation of the immune response e.g. longer time spent preparing for the exam, frequent exams. Alternatively, some of the exam situations e.g. final exams as measured in the Kiecolt-Glaser and Glaser studies may have been perceived as more psychologically stressful than year 1 or 2 exams measured in other studies.
centage of T suppressor/cytotoxic cells, and a significantly lower T helper/suppressor ratio. When subjects were also analysed after division into two groups according to the median age (45 years), older caregivers actually had lower numbers of T cells and T helper cells, and higher antibody titres for cytomegalovirus than their age matched controls. These alterations in immune parameters may be relevant to functioning of the immune system. T helper cells secrete cytokines in order to activate the immune response; T cytotoxic cells have the ability to lyse cells to which they bind; and T suppressor cells act primarily to suppress the function of other T cells. Therefore, a reduction in the T helper population in association with an increase in the T suppressor population, as shown in these subjects, may represent a marker of a decreased immune function. Moreover, as we have said before, an increase in the antibody titres for a virus has been described in a large number of stressful situations and is considered to be a marker of decreased cellular immunity. These results imply that advancing age is a vulnerability factor for immune suppression, should another chronic stressor be present. A third group examined as a model of chronic stress has been mothers of pre-term very low birth weight infants (VLBW). This is a particularly interesting group, who are not only caregivers but also re-establishing immune function after the cellular changes of pregnancy, and therefore may be more vulnerable to stress induced immune down-regulation. An American study compared 50 postpartum women; 25 had pre-term VLBW infants who survived to be discharged home, and 25 had normal weight term infants. Mothers of pre-term VLBW infants had decreased mitogen responses for the first four post-partum months compared to mothers of term infants. There were no differences in health behaviours i.e. diet, smoking, exercise, between the groups. Anxiety and depression failed to account for the relationship and the authors’ postulate that the chronic stressor of caring for a small, fragile infant may have accounted for the changes. There was no difference in NK cell activity between the two groups of mothers (Gennaro et al., 1997). This suggests that not all compartments of the immune system are equally affected by stress. In addition, there may be a time lag before certain immune components are affected.
Chronic stressors Care giving has been used as a model of a chronic stressor in a number of studies investigating associated changes in immune function. Those groups studied include caregivers of patients with Alzheimer’s disease, handicapped children, and mothers of very low birth-weight infants. Thus, by their very nature, there is a bias towards female subjects in these studies. Overall, these studies have demonstrated down-regulation of several aspects of the immune response. Care-giving for patients with Alzheimer’s disease has been associated with alterations in lymphocyte sub-populations, increased antibody titres to herpes simplex virus, decreased proliferative responses to mitogens, more days of illness from infectious disease compared to matched controls, impaired antibody responses to an influenza virus vaccine, and a longer latency in wound healing (Kiecolt-Glaser et al., 1987; 1991b; 1995; 1996). Caregivers to patients with Alzheimer’s disease tend to people and 18 age and sex matched controls were compared in terms of immunological parameters. Caregivers had a significantly lower percentage of T-cells, significantly higher per-
CLINICAL RELEVANCE OF IMMUNOLOGICAL CHANGES AND THE ROLE OF CYTOKINES Taken together, these data provide convincing evidence that changes in the immune system occur in response to stress. However, while these studies demonstrate phy-
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siological variability in the immune response to stress, they tell us little about the clinical implications of such changes. Clearly, a potential consequence of stress-induced changes in immune response is suppression of host resistance to infectious agents. This has been suggested by several studies, including the studies above mentioned by Kiecolt-Glaser et al.(1991b) showing increased number of days of illness from infectious diseases in caregivers to Alzheimer’s disease patients. However, more insight into this topic was obtained by a series of “experimental studies” conducted by Cohen et al. (1991; 1998; 1999). These studies found that greater psychological stress is associated with both an increased incidence of upper respiratory tract infections (URTI), and more severe symptoms. To control for exposure to URTI in these studies, participants were intentionally exposed to a virus and monitored in quarantine for infection and illness. Psychological stress was monitored before and during exposure to the virus. In this study, increasing stress was linked to increasing risk of infection in a dose-response manner (Cohen et al., 1991). The nature of the stressor is also important in that acute stress (less than one month long) has not been linked with developing colds, whereas severe chronic stressors (1 month or longer) is associated with a greatly increased risk of disease (Cohen et al., 1998). These findings are in keeping with the experimental evidence described above relating chronic stress (e.g. care giving) with suppression of the immune response. These studies have further contributed to our understanding of the clinical relevance of immunological changes by describing a possible mechanism for the association between stress and symptom severity, namely via an increased production of the proinflammatory cytokine interleukin 6 (IL-6). Epithelial cells produce IL-6 in-vitro and in-vivo when exposed to rhinovirus (Zhu et al. 1996). Cohen et al. (1999) correlated changes in the production of IL-6 with illness severity. Adult volunteer subjects (n=55) were experimentally infected with influenza A virus after completing a measure of psychological stress. Subjects, in quarantine, were monitored for upper respiratory symptoms, mucus production, and nasal lavage levels of IL-6 on a daily basis. Higher psychological stress was associated with increased scores on all three measurements. The authors concluded that these results were consistent with IL-6 acting as a pathway through which stress results in increased symptom severity. In fact, exogenous cytokine administration has been linked with “flu like” symptoms in animals and humans (Kent et al., 1992). Interestingly, different studies have found that stress can induce elevated levels of IL-6 in animals (Zhou et al., 1993; Le May et al., 1990). Moreover, cytokine produc-
tion in response to stress has also been investigated in humans. In medical students experiencing the stressor of examinations, the pro-inflammatory cytokines IL-1b (Dobbin et al., 1991), and TNF-a (Maes et al., 1998) were found to be increased. In another study, both patients with multiple sclerosis, and control subjects, showed increased IL1b and TNF-a production in response to an experimental stressor (Ackerman et al., 1998). Chronic stress, however, has been associated with reduced IL-1 measurement in the local environment of an experimental surgical wound (Kiecolt-Glaser et al., 1995; Glaser et al., 1999). The somewhat contradictory nature of these results may be explained by the nature of the stressor i.e. chronic (care giving for patients with Alzheimers disease, perceived level of daily stressors) rather than more acute events such as a major examination, or an experimental stressor. Generally, immune suppression has been noted in the studies of chronic stress described above. As we will see below, an increased production of proinflammatory cytokines in situations of acute stress may also be one of the biological pathways by which stress leads to depression.
DOES STRESS MAKE YOU DEPRESSED? THE “STRESS, CYTOKINE, DEPRESSION” MODEL Psychological stressors have been linked with onset and relapse of depression. The classic study by Brown & Harris (1978) demonstrated that excess life events occur in the six months before a depressive episode starts. This community based survey in Camberwell, South London, identified vulnerability factors, which increase the risk of depression if a provoking agent is present. Vulnerability factors include having 3 or more children at home under the age of 14, not working outside the home, lack of a confiding relationship, and loss of mother before the age of 11. A further prospective community based study identified low self esteem as a major vulnerability factor, and those showing lack of support from a close tie at the time of crisis were at greatly increased risk of subsequent depression (Brown et al., 1986). It thus appears that a person suffering a chronic stressor (vulnerability factor) and experiencing an acute stressor (life event) is at increased risk of depression. However, the biological mechanisms for such an effect have yet to be elucidated. A “stress, cytokine, depression” model may be one explanation for such an effect. Our hypothesis is that stress can result in proinflammatory cytokine release, which in turn induces behavioural and hormonal changes (“sickness behaviour”) that finally lead to symptoms of depression. Proinflammatory cytokines, like IL-1, IL-6, and tu-
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mour necrosis factor (TNF) regulate the acute phase reaction, an early immune reaction against invading organisms. The acute phase response aims to limit tissue damage, isolate and destroy the invading organism, and set repair functions in motion (Miller et al., 2000). However, such immune activation, while containing damage by invading pathogens, may result in unpleasant and distressing symptoms. In fact, proinflammatory cytokines exhibit the capacity to induce a group of behavioural symptoms referred to as “sickness behaviour” (Kent et al., 1992; Miller et al., 1999). Sickness behaviour commonly accompanies serious viral or bacterial infections and includes fatigue, loss of appetite, sleep disturbance, social withdrawal, decreased libido, depressed mood, and general malaise. Sickness behaviour also occurs in patients undergoing high dose cytokine therapies for neoplastic or viral illness (Miller et al., 1999; Pariante et al., 1999a). The overlap of symptoms in certain psychiatric disorders (especially major depression) with sickness behaviour has raised the possibility that cytokines elicited during stress may contribute to the expression of behavioural alterations in stress related disorders like major depression. This is further supported by studies showing that proinflammatory cytokines have the capacity to stimulate the release of corticotrophin releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) (Besedovsky & Del Rey, 1996), thus inducing a state of hyperactivity of the HPA axis similar to that described in major depression. Finally, and in harmony with the theoretical model that proinflammatory cytokines may play a role in major depression, an increased production of IL-1, TNF, and more consistently IL-6, has been found in patients with major depression by some (Maes et al., 1991; Anisman et al., 1999; Lanquillon et al., 2000), but not all studies (Weizman et al., 1994; Haack et al., 1999).
pression. Changes are seen in many immune parameters examined during stressful situations, both acute, and chronic. The clinical significance of such changes is not clear. One study has correlated changes in an immune parameter (IL-6) with worse clinical symptoms of an upper respiratory tract infection (Cohen et al., 1999). Some of these changes in immune parameters, namely the increased production of proinflammatory cytokines, may have a role spreading beyond the simple regulation of the immune response into affecting mood and behaviour. Indeed, the ability of proinflammatory cytokines, namely IL-1, IL-6, and TNF, to induce “sickness behaviour”, symptoms which are present in depression, has led to the concept that cytokines may be a key factor in the pathophysiology of depression. We have proposed a “stress, cytokine, depression” model of depression, which features cytokines as key mediators in this process (see figure 1). Figure 1. - The «stress, cytokine, depression» model.
CONCLUSION Our group is currently investigating this model by a variety of approaches. Firstly, we have investigated the biological mechanisms by which proinflammatory cytokines may induce depressive symptoms. Specifically, we have described the molecular step by which the proinflammatory cytokine IL-1 may induce changes in the HPA axis that resemble those present in patients with depression (Pariante et al., 1999b). Of note is that these molecular changes induced by proinflammatory cytokines seems to be opposite to those induced by antidepressants (Pariante et al., 1997b). Secondly, we have been looking at the relationship between previous or recent
This review has focused upon the association between stress, disease, depression, and the immune system. There is currently somewhat conflicting evidence as to whether stress is a risk factor for cancer and cardiovascular disease, and further prospective community based studies would clarify this issue. Stress appears to be associated with a poorer prognosis in both these conditions, and the small numbers of studies available suggest that stress management therapies are associated with improved survival. Stressful life events and situations are also related to onset and relapse in major de-
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psychiatric history and psychopathological symptoms induced by treatment with interferon-alpha for chronic viral hepatitis (Pariante et al., 1999a; Carpiniello et al., 1998). In fact, interferon-alpha also increases proinflammatory cytokine production. More recently, we have been assessing symptoms of depression, fatigue and general well being in a prospective cohort study of patients undergoing a novel formulation (pegylated) of interferon-alpha therapy to treat Hepatitis C. We believe that the possibility that stressful life experiences may contribute to the onset of depression via the production of proinflammatory cytokines represents an interesting thoretical framework in which further hypotheses regarding the biological mechanisms of the pathogenesis of depression can be investigated and generated.
system disorders. Journal of the American Medical Association 267, 1244-1252. Cohen S., Tyrrell D.A.J. & Smith A.P. (1991). Psychological stress and susceptibility to the common cold. New England Journal of Medicine 325, 606-612. Cohen S., Frank E., Doyle W.J., Skoner D.P., Rabin B.S. & Gwaltney Jr J.M. (1998). Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychology 17, 214-223. Cohen S., Doyle W.J. & Skoner D.P. (1999). Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosomatic Medicine 61, 175-180. Dobbin J.P., Harth M., McCain G.A., Martin R.A. & Cousin K. (1991). Cytokine production and lymphocyte transformation during stress. Brain, Behaviour, and Immunity 5, 339-348. Fawzy F.I., Cousins N., Fawzy N.W., Kemeny M.E., Elashoff R. & Morton D. (1990a). A structured psychiatric intervention for cancer patients. I. Changes over time in methods of coping and affective disturbance. Archives of General Psychiatry 47, 720-725. Fawzy Fawzy F.I., Kemeny M.E., Fawzy N.W., Elashoff R., Morton D., Cousins N. & Fahey J.L. (1990b). A structured psychiatric intervention for cancer patients. II. Changes over time in immunological measures. Archives of General Psychiatry 47, 729-735. F.I., Fawzy N.W., Hyun C.S., Elashoff R., Guthrie D., Fahey J.L. & Morton D.L. (1993). Malignant melanoma: effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Archives of General Psychiatry 50, 681-689. Friedman M. & Rosenman R.H. (1959). Association of specific overt behaviour pattern with blood and cardiovascular findings: blood cholesterol level, blood clotting time, incidence of arcus senilis and clinical coronary artery disease. Journal of the American Medical Association 169, 1286-1296. Gennaro S., Fehder W., Nuamah I.F., Campbell D.E. & Douglas S.D. (1997). Caregiving to very low birthweight infants: a model of stress and immune response. Brain, Behaviour, and Immunity 11, 201-215. Glaser R., Kiecolt-Glaser J.K., Bonneau R.H., Malarkey W., Kennedy S. & Hughes J. (1992). Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosomatic Medicine 54, 22-29. Glaser R., Kiecolt-Glaser J.K., Marucha P.T., MacCallum R.C., Laskowski B.F. & Malarkey W.B. (1999). Stress related changes in pro-inflammatory cytokine production in wounds. Archives of General Psychiatry 56, 450-456. Haack M., Hinze-Selch D., Fenzel T., Kraus T., Kuhn M., Schuld A. & Pollmacher T. (1999). Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. Journal of Psychiatric Research 33, 407-418. Herberman R.B. & Ortaldo J.R. (1981). Natural Killer cells: their role in defences against disease. Science 214, 24-30. Herbert T.B. & Cohen S. (1993). Stress and immunity in humans: a meta- analytic review. Psychosomatic Medicine 55, 364-379. Hollis J.F., Connett J.E., Stevens V.J. & Greenlick M.R. (1990). Stressful life events, type A behaviour, and the prediction of cardiovascular and total mortality over six years. Journal of Behavioural Medicine 13, 263-280. Kent S., Bluthe R., Kelley K.W. & Dantzer R (1992). Sickness behaviour as a new target for drug development. Trends in Pharmacological Sciences 13, 24-28. Kiecolt-Glaser J.K., Glaser R., Shuttleworth E.C., Dyer C.S., Ogrocki
REFERENCES Ackerman K.D., Martino M., Heyman R., Moyna N.M. & Rabin B.S. (1998). Stressor-induced alteration of cytokine production in multiple sclerosis patients and controls. Psychosomatic Medicine 60, 484-491. Andersen B.L., Farrar W.B., Golden-Kreutz D., Kutz L.A., MacCallum R., Courtney M.E. & Glaser R. (1998). Stress and immune responses after surgical treatment for regional breast cancer. Journal of the National Cancer Institute 90, 30-36. Anisman H., Ravindran A.V., Griffiths J. & Merali Z. (1999). Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Molecular Psychiatry 4, 182-188. Bartrop R.W., Lazarus L., Luckherst E. & Kiloh L.H. (1977). Depressed lymphocyte function after bereavement. Lancet 1, 834-836. Beem E.E., Hooijkaas H., Cleiren M.H.P.D., Schut H.A.W., Garssen B., Croon M.A., Jabaaij L., Goodkin K., Wind H. & de Vries M.J. (1999). The immunological and psychological effects of bereavement: does grief counselling really make a difference? A pilot study. Psychiatry Research 85, 81-93. Besedovsky H.O. & Del Rey A. (1996). Immune-neuro-endocrine interaction: facts and hypotheses. Endocrine Review 17, 64-102. Blumenthal J.A., Jiang W., Babyak M.A., Krantz D.S., Frid D.J., Coleman R.E., Waugh R., Hanson M., Appelbaum M., O’Connor C. & Morris J.J. (1997). Stress management and exercise training in cardiac patients with myocardial ischaemia. Effects on prognosis and evaluation of mechanisms. Archives of Internal Medicine 157, 2213-2223. Brown G.W. & Harris T.O. (1978). Social Origins of Depression: a Study of Psychiatric Disorder in Women. Tavistock Publications’: London. Brown G.W., Andrews B., Harris T., Adler Z. & Bridge L. (1986). Social support, self-esteem and depression. Psychological Medicine 16, 813-831. Carpiniello B., Orru’ M.G., Baita A., Pariante C.M. & Farci M.G. (1998). Mania induced by alpha-interferon withdrawal. Archives of General Psychiatry 55, 88-89. Checkley S. (1996). The neuroendocrinology of depression and chronic stress. British Medical Bulletin 52, 597-617. Chrousos G.P. & Gold P.W. (1992). The Concepts of stress and stress
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
90
How does stress affect you? An overview of stress, immunity, depression and disease P. & Speicher C.E. (1987). Chronic stress and immunity in family caregivers of Alzheimer’s disease victims. Psychosomatic Medicine 49, 523-535. Kiecolt-Glaser J.K. & Glaser R. (1991a). Stress and immune function in humans. In Psychoneuroimmunology, 2nd ed. (ed. R. Ader, D.L. Felter and Cohen N.), pp. 849-867. Academic Press: New York. Kiecolt-Glaser J.K., Dura J.R., Speicher C.E., Trask O.J. & Glaser R. (1991b). Spousal caregivers of dementia victims: longitudinal changes in immunity and health. Psychosomatic Medicine 53, 345-362. Kiecolt-Glaser J.K., Marucha P.T., Malarkey W.B., Mercado A.M. & Glaser R. (1995). Slowing of wound healing by psychological stress. Lancet 346, 1194-1196. Kiecolt-Glaser J.K., Glaser R., Gravenstein S., Malarkey W.B. & Sheridan J. (1996). Chronic stress alters the immune response to influenza virus vaccine in older adults. In Proceedings of the National Academy of Sciences USA 93, pp. 3043-3047. Lanquillon S., Krieg J.C., Bening-Abu-Shach U. & Vedder H. (2000). Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22, 370-379. Lazarus R.S. & Folkman S. (1984). StressAppraisal, and Coping. Springer: New York. Le May L.G., Vander A.J. & Kluger M.J. (1990). The effects of psychological stress on plasma interleukin-6 activity in rats. Physiology and Behaviour 47, 957-961. Maes M., Bosmans E., Meltzer H.Y., Scharpe S. & Suy E. (1991). Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? American Journal of Psychiatry 150, 1189-93. Maes M., Song C., Lin A., De Jongh R., Van Gastel A., Kenis G., Bosmans E., De Meester I., Benoy I., Neels H., Demedts P., Janca A., Scharpe S. & Smith R.S. (1998). The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10, 313318. Maes M., Van Bockstaele D.R., Van Gastel A., Song C., Schotte C., Neels H., DeMeester I., Scharpe S. & Janca A. (1999). The effects of psychological stress on leukocyte subset distribution in humans: evidence of immune activation. Neuropsychobiology 39, 1-9. McGee R., Williams S. & Elwood M. (1996). Are life events related to the onset of breast cancer? Psychological Medicine 26, 441-447. Miller A.H., Pariante C.M. & Pearce B.P. (1999). Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression. Advances in Experimental Medicine and Biology 461, 107-116. Miller A.H., Pearce B.P. & Pariente C.M. (2000). Immune system and central nervous system interactions. In Comprehensive Textbook of Psychiatry, 7th ed. (ed. H.I. Kaplan and B.J. Sadock), pp. 113133. Lippincott Williams and Wilkins: Phildelphia. Mohr D.C., Goodkin D.E., Bacchetti P., Boudewyn A.C., Huang L., Marrietta P., Cheuk W. & Dee B. (2000). Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 55, 55-61. O’Connor C.M., Gurbel P.A. & Serebruany V.L. (2000). Depression and ischaemic heart disease. American Heart Journal 140, S6369. Pariante C.M. & Miller A.H. (1995). Natural killer cell activity in major depression: a prospective study of the in-vivo effects of desmethylimipramine treatment. European Neuropsychopharmacology , Suppl. 5, 83-88. Pariante C.M., Carpiniello B., Orru M.G., Sitzia R., Piras A., Farci A.M.G., Del Giacco G.S., Piludu G. & Miller A.H. (1997a). Chronic caregiving stress alters peripheral blood immune parameters:
the role of age and severity of stress. Psychotherapy and Psychosomatics 66, 199-207. Pariante C.M., Pearce B.D., Pisell T.L., Owens M.J. & Miller A.H. (1997b). Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. Molecular Pharmacology 52, 571-581. Pariante C.M., Orrù M.G., Baita A., Farci M.G. & Carpiniello B. (1999a). Treatment with interferon-alpha in patients with chronic hepatitis and mood or anxiety disorders. Lancet, 354, 131-132. Pariante C.M., Pearce B.D., Pisell T.L., Sanchez C.I., Po C., Su C. & Miller A.H. (1999b). The pro-inflammatory cytokine, interleukin1-alpha, reduces glucocorticoid receptor translocation and function. Endocrinology 140, 4359-4366. Petticrew M., Fraser J.M. & Regan M.F. (1999). Adverse life-events and risk of breast cancer: a meta-analysis. British Journal of Health Psychology 4, 1-17. Rosengren A., Orth-Gomer K., Wedel H. & Wilhelmsen L. (1993). Stressful life events, social support, and mortality in men born in 1933. British Medical Journal 307, 1102-1105. Rosenman R.H., Brand R.J., Jenkins C.D., Friedman M., Straus R. & Wurm M. (1975). Coronary heart disease in the Western collaborative group study. Journal of the American Medical Association 233, 872-877. Schleifer S.J., Keller S.E., Camerino M., Thornton J.C. & Stein M. (1983). Suppression of lymphocyte stimulation following bereavement. Journal of the American Medical Association 250, 374377. Spiegel D., Bloom J.R., Kraemer H.C. & Gottheil E. (1989). Effects of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 2, 888-891. Tennant C.C., Palmer K.J., Langeluddecke P.M., Jones M.P. & Nelson G. (1994). Life event stress and myocardial reinfarction: a prospective study. European Heart Journal 15, 472-478. Walker J.G., Littlejohn G.O., McMurray N.E. & Cutolo M. (1999). Stress system response and rheumatoid arthritis: a multilevel approach. Rheumatology 38, 1050-1057. Weizman R., Laor N., Podliszewski E., Notti I., Djaldetti M. & Bessler H. (1994). Cytokine production in major depressed patients before and after clomipramine treatment. Biological Psychiatry 35, 42-47. Whitehouse W.G., Dinges D.F., Carota Orne E., Keller S.E., Bates B.L., Bauer N.K., Morahan P., Haupt B.A., Carlin M.M., Bloom P.B., Zaugg L. & Orne M.T. (1996). Psychosocial and immune effects of self-hypnosis training for stress management throughout the first semester of medical school. Psychosomatic Medicine 58, 249263. Whiteside T.L. & Herberman R.B. (1990). Characteristics of natural killer cells and lymphocyte-activated killer cells. Immunology and Allergy Clinics of North America 10, 663-704. Wright R.J., Rodriguez M. & Cohen S. (1998). Review of psychosocial stress and asthma: an integrated biopsychosocial approach. Thorax 53, 1066-1074. Zhou D., Kusnecov A.W., Shurin M.R., DePaoli M. & Rabin B.S. (1993). Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 133, 2523-2530. Zhu Z., Tang W., Ray A., Wu Y., Einarsson P.O., Landry M., Gwaltney J. & Elias J.A. (1996). Rhinovirus stimulation of interleukin-6 in-vivo and in-vitro: evidence for nuclear factor kB-dependent transcriptional activation. Journal of Clinical Investigation 97, 421-430.
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
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B. Moreno Küstner, F. Torres González, J.D. Luna Del Castillo
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