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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]
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
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How does stress affect you? An overview of stress, immunity, depression and disease
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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Clementine Maddock and Carmine M. Pariante
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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How does stress affect you? An overview of stress, immunity, depression and disease
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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Clementine Maddock and Carmine M. Pariante
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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How does stress affect you? An overview of stress, immunity, depression and disease
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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Clementine Maddock and Carmine M. Pariante
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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How does stress affect you? An overview of stress, immunity, depression and disease
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-
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
89
Clementine Maddock and Carmine M. Pariante
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.
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