Anesth Prog 34:93-98 1990

Psychoneuroimmunology: Potenil Relevnce to

Studies undertaken over the past ten years have patients with chronic pain,2 however, these states are char-
demonstrated that stress and depression can acterized by a number of factors that are likely to be
induce immune alterations, including decreased associated with altered immunity. Patients suffering with
numbers of immunocompetent cells and impaired chronic pain often expenence high levels of stress, demor-
lymphocyte and natural killer cell activity. Factors alization, and depression; they tend to use a variety of
such as age and severity of symptomatology prescribed and selfadministered drugs that may alter im-
influence these effects. The substantial stress and mune processes; and they may also suffer from other
depression associated with chronic pain systemic disorders that can alter the immune system.3 Pain
syndromes and the evidence for opioid states may be associated with changes in endogenous
involvement in immunomodulation suggest that opioids, which are believed to be involved in immunoreg-
immune system changes may occur in some ulation, in addition to eliciting the use of exogenous opi-
patients with chronic facial pain. oids. This presentation will review psychoimmunologic
studies from our laboratory and others suggesting that
stress, depression, and the pain syndrome itself may have
psychoimmunologic consequences in patients with
chronic facial pain.
There is increasing evidence that behavioral and psy-
chological factors can influence the immune system
and that these effects may contribute to the onset and LIFE STRESS AND IMMUNITY
course of disease.' These factors include exposure to
stress, psychological symptoms or syndromes such as de- That psychosocial processes influence immunity was sug-
pression, and the use of alcohol, opioids, and other drugs. gested by studies demonstrating that the brain is involved
Psychoimmunologic changes may be the direct result of in the regulation of the immune system. Evidence, derived
central processes mediated by neural and neuroendocrine primarily from lesion studies, have implicated the mid-
systems, or may be effected behaviorally as by exposure brain, the anterior hypothalamus, and the cerebral hemi-
to immunoactive chemicals or by changes in activity, spheres in both T and B cell activity. Animal studies dem-
sleep, or nutrition that can alter the immune system. Psy- onstrated that a variety of stressors can alter humoral
choimmunologic effects may be exaggerated or mitigated (B cell) and cell-mediated (T-cell) immune responses.'
in patients with concurrent medical disorders that have Effects on both T and B cell functions are associated
immunologic effects. with characteristics of the stressor such as chronicity4 and
Litfle is known conceming immunologic processes in intensity.5 Other research demonstrated influences of
higher cortical function on immune processes. Lauden-
slager and Ryan6 presented evidence that stress-induced
Address correspondence to Steven J. Schleifer, MD, Associate Profes-
suppression of lymphocyte function is related to the ani-
sor, University of Medicine and Dentistry of New Jersey, New Jersey mal's having control over the stressor. Ader and others'
Medical School, Departnent of Psychiatry, 185 South Orange Avenue, found conditioning effects on both humoral and cell-medi-
MSB, E501, Newark, NJ 07103-2757. ated immunity. These animal studies demonstrate that
C 1990 by the American Dental Society of Anesthesiology ISSN 0003-3006/90/$3.50

93
94 Psychoneuroimmunology and Chronic Pain Anesth Prog 34:93-98 1990

specific central nervous system (CNS) behavioral pro- investigated-with most studies of students undergoing
cesses can influence the immune system. academic examinations. Several studies'3'57 found altered
Research on life stress and immunity in man has identi- mitogen responses in psychiatric residents and medical
fied several conditions in which altered, primarily sup- students during examination periods. Kiecolt-Glaser et
pressed immunity occurs. The death of a spouse was al.'4 found lower NK cell function in medical students
among the first life experiences investigated in relation to taking final examinations. In contrast, other moderate
the immune system, as it is one of the most stressful stressful conditions have not been found to alter immune
commonly occurring events. Bereavement has also been measures. Both our group'5 and Linn and Jensen'6 found
linked to medical mortality.78 Bartrop and coworkers9 that otherwise healthy patients hospitalized for elective
first reported alterations in the immune system in the surgery did not show changes in lymphocyte mitogen
bereaved. They found lower mitogen-induced lympho- responses when compared with controls. NK cell activity,
cyte stimulation in bereaved spouses compared with however, which may be more sensitive to minor stress
matched controls, suggesting that the functional capacity states, was not investigated in these studies, and research
of the lymphocyte was altered in the bereaved. including a range of immunologic parameters in various
We investigated bereavement and immunity in a pro- stress conditions is needed.
spective study of healthy spouses of women with ad-
vanced breast carcinoma. 11 In vitro measures of immunity
were obtained at 6 to 8-week intervals. The mean levels DEPRESSION AND IMMUNITY
of mitogen-induced lymphocyte stimulation before death
of a spouse were compared with that obtained during the Changes in affective state, including the development of
first two months postbereavement and then during the clinically significant depression, could be involved in the
latter part of the postbereavement year. Responses to effects of bereavement and other stressors on immunity.
the mitogens phytohemagglutinin (PHA), concanavalin A Bereavement is associated with persistent changes in
(ConA), and pokeweed mitogen (PWM) were significantly mood state and in appetite functions, sleep, and activity
lower during the first two months postbereavement com- levels that often suggest the presence of clinical affective
pared with those obtained prebereavement. By the end disorder.7",8 Depression, like bereavement, has been as-
of the postbereavement year, mitogen responses had re- sociated with increased medical mortality,'9-2' as well as
turned to prebereavement levels for the majority but not with immune-related disorders.19'22'23 Furthermore, neu-
all of the subjects. roendocrine functions that may influence immunologic
Although individual mitogen data must be interpreted processes are altered in many depressed patients.2425
with caution due to the considerable day to day variability Several studies have suggested that effects of life stress
of the assays,11 our study suggested that there are differing on immunity are associated with depressive reactions. The
response patterns among the bereaved. While many studies of Kiecolt-Glaser et al.'4 and Irwin et al.'2 both
showed a greater than 50% suppression of mitogen re- suggest that life stress results in greater immune suppres-
sponses postbereavement, several spouses showed little sion when affective disturbances are present. These obser-
or no change soon after bereavement. The latter, how- vations suggest that depression may be a major factor in
ever, had decreased mitogen responsivity later in the post- psychoimmunologic processes. Studies of immunity in
bereavement year-when the majority of subjects were patients with clinical affective disorders support this
showing a return to prebereavement levels. This delayed notion.
response group tended to be younger, suggesting that Several reports have noted the presence of autoim-
age may be an important cofactor in psychoimmunologic mune markers in patients with depression.26-28 Studies
processes. Altered nutrition, activity and exercise levels, of lymphocyte activity in depressed patients were first
sleep, and drug use, often found in the widowed, must reported by Cappel and coworkers23 who found altered
also be taken into account, although our subjects did not mitogen responses during the acute phase of depressive
report major changes in these parameters. illness. Similarly, Kronfol and coworkers29 found lower
Another important component of the immune system, mitogen responses in depressed patients than in psychiat-
natural killer (NK) cell activity, also has been found to be ric and normal controls.
altered in relation to bereavement and related stress states. We investigated immune processes in medication-free
Irwin and coworkers'2 studied NK function in women subjects with major depressive disorder studied on the
experiencing a spouse's metastatic cancer and bereave- same day with age- and sex-matched controls. We found
ment. They found lower NK activity in women who had that hospitalized patients with major depression had sig-
experienced major stressful life experiences compared nificantly decreased numbers of circulating lymphocytes
with women who had few life changes. (T and B cells) and decreased lymphocyte mitogen re-
The effects of more minor life stressors have also been sponses (PHA, ConA, and PWM) compared with con-
Anesth Prog 34:93-98 1990 Schleifer et al 95

trols.30 To determine the specificity of these effects, we activity in older and depressed patients may result from
studied ambulatory patients with major depression15 and exaggerated neuroendocrine or autonomic nervous sys-
found that they did not differ from controls. This suggested tem changes in the older depressed patient33-35 imposed
that altered lymphocyte activity in depressed inpatients upon an immune system that has limited adaptive capacity
was related either to the severity of depression or to hospi- due to immunosenescent processes. The age-related im-
talization itself. Studies of otherwise healthy hospitalized mune differences may also relate to differences in the
patients with schizophrenia and of subjects hospitalized depressive disorders found in younger and older patients.
for elective surgery,15 however, found no differences in Our finding of a correlation between severity of depres-
mitogen response from controls indicating that hospitaliza- sion and mitogen response, independent of age, suggest
tion, per se, is not a determining psychoimmunologic fac- that at least some of the immunologic effects of depression
tor. Linn and Jensen16 similarly did not find mitogen are related to the state of depression. They are also consis-
changes in otherwise healthy patients hospitalized for elec- tent with an association between affective symptomatol-
tive surgery. ogy and altered immunity, an effect that may be indepen-
To further investigate the contribution of severity of dent of syndromal status. Affective distress could therefore
depression, hospitalization, age, and gender, we more account for altered immunity both in depressive disorders
recently investigated a sample of 91 hospitalized and am- and in stress-related states such as following bereavement.
bulatory major depressive disorder patients.1" This study
used an expanded battery of immune functions and in-
cluded patients across a range of ages, illness severity, MEDIATION OF IMMUNE CHANGES IN
and sex. As in prior studies, diagnoses of major depressive DEPRESSION AND FOLLOWING STRESS
disorder were made using strict diagnostic criteria31 and
the Hamilton Depression Rating Scale (HDRS)32 was used Depressive disorders are associated with changes in sev-
as the index of severity. Patients were studied on the same eral neuroendocrine systems that can alter immune pro-
day with healthy age- and sex-matched controls. The cesses. Many of these systems are also altered in stress
assays included lymphocyte stimulation by the mitogens conditions and in pain states. Changes in the hypothala-
PHA, ConA, and PWM; quantification of the number of mic-pituitary-adrenal (HPA) axis following stress and in
peripheral blood lymphocytes and lymphocyte subsets; depression, some of which are age-related,33'36 have been
and NK cell activity. demonstrated most consistently.25'36'37 Corticosteroids
The pooled sample of depressed patients did not differ suppress lymphocyte proliferation38 and induce the redis-
from the matched controls (ANOVA) on any of the im- tribution of T-helper cells out of the peripheral blood.39
mune measures, indicating that altered immunity is not Abnormalities in the hypothalamic-pituitary-thyroid
invariably characteristic of all patients with depression. axis,"40 growth hormone,41 and sex steroids42 have also
Significant differences between patients and controls were been demonstrated in depression, and each of these hor-
revealed, however, when age, sex, severity of depression, monal systems has been reported to modulate immune
and hospitalization were considered using hierarchical function.-45 Supporting the heterogeneity of neuroen-
multiple regression techniques [analysis of partial variance docrine psychoimmunologic mechanisms are our findings
(APV)32]. We found that the relationship between age in the rat, that there are both adrenal-dependent and
and lymphocyte function was significantly different in the adrenal-independent stress effects on the immune sys-
controls and the patients for each of the mitogens; a similar tem.46 Alterations in immunity found in depression and
pattern of differences was found for the number of T4 (T- other states may therefore involve diverse neuroendo-
helper) lymphocytes. It appears that, with increasing age crine processes.
in the middle and later years, patients with major depres- Influences other than those associated with classical
sion have specific concurrent deficits in the numbers of neuroendocrine pathways may alter immunity in depres-
T4 cells and in lymphocyte stimulation responses; the sion and following stress. Autonomic systems may be
altered T-helper cells may contribute to the lymphocyte involved in modulation of immunity,47", and direct neural
functional changes. In contrast to older depressed pa- innervation of lymphoid tissue has been demonstrated.58
tients, depressed young adults may have relatively in- Dysregulated noradrenergic function in depression,35'49-51
creased T4 cells and lymphocyte activity. In addition, a which may be age-related' as may peripheral catechol-
significant effect of severity of depression on lymphocyte amine output following stress, may contribute to altered
function across all ages was found. immunity. We have found pituitary-independent changes
The age-related immune changes in depressed patients, in immunity in stressed hypophysectomized rats,52 provid-
and possibly following bereavement, may represent an ing additional evidence for multiple mechanisms in stress-
interaction between processes associated with depression induced immunomodulation.
and those associated with aging. Suppressed mitogen re- There is increasing interest in the potential role of pep-
96 Psychoneuroimmunology and Chronic Pain Anesth Prog 34:93-98 1990

tides, especially the opioids, in the modulation of immu- and other psychiatric disorders were obtained using a
nity. Endorphins are secreted together with ACTH in standardized semistructured diagnostic interview.56 Cur-
stress conditions and may play an important role in stress rent (24%) and lifetime (69%) prevalence rates of depres-
responses. Effects of endogenous opioids on immune pro- sion among TMPDS cases (adjusted for sampling proce-
cesses have occasioned much interest; however, the re- dures) were much higher than those found in general
search findings have been complex and at times inconsis- population studies.61,62 These results suggest comorbidity
tent. Altered NK activity following exposure to opioid of TMPDS and depression, with further descriptive and
peptides may be age related and mediated via opioid psychophysiological studies indicated. Chronic facial pain
receptors.59 In contrast, opioid effects on mitogen stimula- patients may therefore be at risk for alterations in immu-
tion have been less consistently demonstrated and appear nity and possible secondary systemic morbidities.
to be nonspecific. Shavit et al' have provided provocative We recently initiated a study of immune function in
evidence that opioids may be important modulators of women with TMPDS. The study was undertaken to inves-
immune changes following stressful conditions that are tigate the psychoimmunologic effects of life stress and
also "depressogenic." They found that, in rats, a stress depressive reactions in patients with chronic facial pain,
paradigm inducing opioid-mediated analgesia and associ- particularly in relation to potential interactions among the
ated with leamed helplessness (an animal model of de- dimensions of pain, stress, and depression. Only patients
pression) resulted in suppressed NK function, whereas a otherwise in good health and not currently taking medica-
stress paradigm mediated by nonopioid mechanisms was tions with demonstrated effects on the immune system
not NK suppressive. The opioids, as well as other peptides have been included. This procedure tends to exclude the
such as substance P,59 are of particular relevance to the more severe TMPDS cases.
study of immunity in patients with chronic pain as well as Assessments of life stress, demoralization, and major
depression. depressive disorder have been conducted on 19 TMPDS
patients and 19 age-sex matched controls. Blood for im-
munologic assessments was obtained from patients and
CHRONIC FACIAL PAIN, STRESS, their matched controls on the same day during the morn-
DEPRESSION, AND IMMUNITY ing hours. Immunologic assays included quantitation of
lymphocyte phenotypes and subtypes, mitogen-induced
Chronic facial pain may provide an important model for lymphocyte stimulation, and NK cell numbers and func-
the investigation of psychoimmunologic processes. Syn- tion. Preliminary analysis suggest that there are associa-
dromes such as temporomandibular pain dysfunction syn- tions between demoralization and both mitogen-induced
drome (TMPDS) are associated with substantial functional lymphocyte stimulation and NK activity. They suggest that
morbidity, themselves act as stressors, and are marked changes in the immune system are found in some patients
by a state of pain that is not linked to systemic, hence with chronic pain syndromes. The nature and extent of
potentially immunosuppressive, disease. these effects require systematic investigation.
The point of departure for the present research derived
from striking findings in two of our prior studies on TMPDS
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