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Medical Hypotheses
Abstract - The immune system is proposed as the key to understanding the etiology and
treatment of psychosocial disease. There is a dense communication network between the
immune system and the central nervous system (CNS). Immune cell cytokines, via direct
action on the CNS, induce fever, alter sleep, pain perception and pituitary hormone release
and reduce appetitie and activity in animals. Interleukin-2 and interferon given to humans
result in global behavioral and cognitive pathology. Activation of the immune system by
pathogens produces global cognitive and behavioral pathology also. Recently, controlled
trials have demonstrated that diet can cause psychosocial disease, presumably by an immune
mechanism. Immune system abnormalities have been identified in manic-depressive psychosis,
schizophrenia and alcoholism. Lithium carbonate is not only prophylactic for all three of
these diseases, but it also powerfully stimulates the immune system. This is proposed
as the mechanism of lithiums therapeutic effect. The antipsychotics, haloperidol and the
phenothiazines, affect the immune system also. The rapid development of AIDS dementia
complex can be explained by the remarkable influence the immune system has on the CNS.
Introduction
secret agent appears to be the immune system. Arterial macrophages ingesting altered low density
lipoprotein is probably the key event in the development of lipid filled fibrous plaque (1).
Psychosocial disease has not participated in
the triumphant advances of molecular biology
and modern medicine. The term psychosocial disease covers a broad spectrum of maladaptions
and malfunctionings of the CNS, including mental illness, addictions, criminal behavior, suicide,
violence, educational and employment failure,
poverty, eating disorders, dementias and child
man disease has always resulted in striking advances in understanding, preventing or treating illness. The relationship was shown very early for
infectious disease, but for chronic degenerative
pathologies like atherosclerosis and cancer, insights into the relationship had to wait for basic advances in biomedical science. For example, after 100 years of study, the pathogenesis of
atherosclerosis is now yielding its secret and the
Date received 8 February 1990
Date accepted 27 March 1990
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50
MEDICAL HYPOTHESES
ceptors on human T-lymphocytes were discovered. The CNS produced opioid, methionineenkephalin, binds with those receptors and results in proliferation of T-lymphocytes (3). In contrast, the opioid alpha-endorphin has inhibitory
effects on T-lymphocytes (4). A recent review (5)
with 84 references covers the extensive effects of
acetylcholine on lymphocytes. In addition, somatostatin, vasoactive intestinal peptide, peptide
histidine isoleucine, peptide histidine methionine,
and glucocortical hormones restrain immune cells
whereas dopamine and substance P stimulate immune cells (6, 7, 8). Plats-Salaman (9) has compiled a list of 29 CNS produced neuroregulators that affect immune cell functions, which include the above plus gonadotrophin-releasing
hormone, growth hormine, prolactin, gonadotrophic
hormones, ACTH, thyrotropin stimulating hormone, melanocyte stimulating hormone, vasopressin, oxytocin, insulin, bombesin, and calcitonin. CNS influence on the immune system is extensive, complex and well documented.
The CNS-immune system axis is not a one-way
street. Like ail other regulatory networks, this one
has a feedback circuit; that is, immune cell secretions influence the brain. The significance of
the feedback circuit has not been well appreciated. It is primarily viewed as a mechanism for
the brain to have more accurate and effective control over the immune system. The possibility that
immune cells could have a powerful influence on
the functioning of the CNS, with the organismic
consequences being altered behavior, has been neglected.
Six cytokines, namely, interferons alpha, beta
and gamma, tumor necrosis factor (TNF), interleukin-1 (IL-l), and interleukin-2 (IL-2), induce
fever via direct access to the temperature regulating center in the hypothalamus (2, 9). IL-1 also
promotes sleep, reduces perception of pain, induces the pituitary to release hormones, regulates
nerve growth factor synthesis, suprersses appetite
and reduces locomotion by acting directly on receptors in the hypothalamus and other areas of the
CNS (9).
Having access to the hypothalamus is of considerable practical and theoretical importance, since
the hypothalamus is the premier regulatory center
of the brain. The endocrine system, with all its
long and short term effects on behavior, is controlled there. Pain, pleasure, rage, sleep, hunger,
satiety, addictions, and to a great extent, learning
are controlled at this remarkable center (10, 11).
OF PSYCHOSOCIAL
DISEASE
51
Cytokines administered to human subjects. Cytokines have been given to cancer patients, and
the consequences are global behavioral and cognitive pathology. In a detailed longitudinal study
(13) of 44 metastatic cancer patients given IL-2
and lymphokine-activated killer cells, the majority
experienced profound neuropsychiatric changes.
The severe CNS changes had a 4 - 6 day latency
period before appearance, were dose dependent
and returned to baseline after treatment was discontinued. 42% of the high dose patients had
acute and severe cognitive-behavioral
changes:
delirium, disorientation in time, space and person, delusions, paranoia, irritability, incoherence,
memory loss, inability to concentrate, depression,
agitation, severe fatigue, anorexia and malaise.
Many required physical restraints and neuroleptic
medication. A total of 71% of the high dose patients had either moderate or severe changes. Only
32% of the low dose patients had moderate to
severe changes. The authors stated the profound
CNS effects were dose limiting for the treatment.
There were no significant personal factors
found that were predictive of the severity of individual CNS response. There were premonitory
symptoms occurring during the first days of treatment which invariably preceeded the more severe
changes. The premonitory symptoms were severe
lethargy, impaired memory, vague responses, slow
responses, illogical and incoherent responses, impaired attention, irritability, mild aphasia, paraphasis, intermittent disorientation, disconnecting
medical equipment, and insistence on leaving (14).
Interferons have also been used on cancer patients with profound CNS consequences. Severe
fatigue was most common and sometimes persisted up to 4 weeks post-treatment. With repetitive doses patients became profoundly and increasingly lethargic, with or without accompanying confusion. Somnolence, decrease of mental status, mood changes (depression), dysphasia, loss of smell and taste, hallucinations and
disorientation in time and place were observed.
(15) In a study of 11 patients, the authors wrote,
All patients became pyrexial and complained of
anorexia, fatigue and general malaise.. . . further
questioning revealed them to be withdrawn, slow
to answer questions and totally disinterested in
their surroundings, sleeping for most of the day
(16). In another study of 10 cancer patients using interferon, all patients appeared duller, inattentive and disinterested within the first week.
Eight patients experienced psychomotor retarda-
52
tion with unequivocal impoverishment of spontaneous movements, gestures, expressions, speech
and thought. They displayed varying degrees
of bradykinesia and social withdrawal consonant with their complaints of decreased energy
and signs of a disinclination to act or think.
. . .They frequently ignored eating, various aspects
of grooming and regular daily activities. Their disinclination to act was rationalized by the patients
as loss of appetite and lack of energy. All patients took daily naps (17). Several paradoxical
changes were noted: 8 patients with significant
anxiety before therapy did not report anxiety after
one month of interferon; likewise suicidal ideation
was eliminated in 4 out of 4 patients, and episodic
depression was reduced in 3 out of 5.
The experiments with IL-2 and interferon provides clear, convincing evidence that cytokines
have an astonishing effect on the CNS. To date,
17 cytokines have been discovered, which means
we still have 15 more to test on humans for behavioral effects. If the first two are a clue to the
other 15 then there remains a rich vein to explore
for immunological causes of psychosocial disease.
MEDICAL HYPOTHESES
illness and psychosocial disease. Indeed, this suggests patients with influenza would be an excellent group to study to gain immunological insight
into the spontaneous production and remission of
mental illness.
IN THE ETIOLOGY
OF PSYCHOSOCIAL
DISEASE
53
54
a Child Eats Make Him Dull, Stupid, or Hyperactive? (37). His answer was yes.
The food allergy-behavior work has been harshly
criticized (38,39,40). May called it quackery. The
claims made about allergic tension-fatigue and/or
allergic toxemia were said to be examples of imaginations deceptive powers (38). There are three
main points to the criticism: 1. misuse of the term
allergy; 2. foods claimed to cause allergic tensionfatigue are not generally supported by positive
skin tests; 3. lack of double-blinded food challenges to support the claims.
Certainly the term allergy was not used in its
strict sense, that is, an IgE mediated process, since
almost all the papers have indicated skin tests have
been useless. A better description would have been
a food-gut-immune system-behavior interaction
of unknown mechanism. The fact that skin tests
are not predictive of the food-behavior problem
should not be of concern since the food-gut-immune system-CNS axis is largely unexplored and
poorly understood. The third and most important
criticism has been answered by three landmark
controlled trials by Egger et al (41, 42, 43).
Their first paper (41) investigated 88 children
with severe migraine using an oligoantigenic elimination diet for 4 weeks followed by doubleblinded food challenge lasting one week for each
new food introduced. 93% of the children recovered on the elimination diet. The double-blinded
challenges demonstrated the effect was not due to
placebo or observer bias. In addition, 41 of the
children with migraine also had behavior disorder and 14 had epilepsy. All but 5 of the children
with behavior disorder had striking improvement
in behavior and 12 out of 14 patients with epilepsy became fit-free even after discontinuing their
medication. Double-blinded food challenges confirmed the results were not due to placebo effect
or observer bias.
Egger et als second paper (42) investigated
76 children with hyperactivity and associated
symptoms, such as fatigue, antisocial behavior,
headache and emotional difficulties. Sixty-two of
the children improved on the elimination diet and
was confirmed with double-blinded food challenge. Skin prick tests were not useful for identifying problem foods. This trial demonstrates that
diet should be taken seriously as a cause of behavior disorder in children.
Their third paper (43) compiled data on 45 epileptic children with migraine. 90% had sharp decrease in seizures during the elimination diet pe-
MEDICAL HYPOTHESES
riod. Over half ceased having seizures on the restricted diet for up to 3 years. Most had stopped
taking their medication. In the double-blinded
rechallenge, seizures were provoked in 15 out of
16 children when given a previously identified active food. No seizures were provoked with safe
foods. Children who had epilepsy without migraine showed no benefit on the elimination diet.
Egger et als work is powerful support for the
notion that food can cause psychosocial disease.
Their work, along with all the previous literature
on food-behavior, supports the hypothesis in this
paper, namely, the immune system is a key ingredient in psychosocial disease. This hypothesis
provides a much needed explanation for the findings on food-behavior, that is, food-gut interactions can activate the immune system, resulting in
the production of cytokines. The cytokines go to
receptors in the hypothalamus which profoundly
influences behavior.
The literature on immune dysfunction in schizophrenia is difficult to evaluate since striking differences appear, depending on the medication status of the patients studied. For example, deficient IL-2 production was found in untreated
schizophrenic patients (53), but elevations were
reported in two groups of chronically medicated
schizophrenics (54, 55). Depressed levels of polymorphonuclear cells, natural killer cells, IgG, IgA
and IgM have been found along with impaired
function of natural killer cells, macrophages and
t-lymphocytes in various patient groups (56).
In mania and depression there is reduced lymphocyte beta-adrenergic receptor function (57,
58). Depressed patients appear to have reduced
mitogenic responses, but increased IgE antibodies
after exposure to antigen (59).
As early as 1973 it was discovered that lithium
activates the immune system by inducing granulopoiesis (60). It has been used to treat chemotherapy induced neutropenia (61) and there are
case studies claiming benefit for AIDS patients. A
controlled study has begun using lithium on AIDS
to combat hematocytopenias developing during zidovudine therapy (62).
Lithium is a powerful stimulator of granulopoiesis. It increases the production of colony
stimulating factors, which stimulate pluripotent
stem cells. Recent work has suggested lithium
works at a more primitive and fundamental level
than the stem cell (63). The action of lithium on
the immune system is extremely unusual, fundamental and powerful.
It is curious that after 40 years of active research on lithium, there is no understanding of
how lithium works to prevent and treat manic-depressive psychosis, alcoholism and some forms of
schizophrenia (44,45). The possibility of lithiums
beneficial action being mediated through its immune system activation has not been proposed.
It seems more than coincidental that lithium not
only activates the immune system at a fundamental level, but it also benefits three psychosocial
diseases, all three of which have documented immune dysfunction. The immune system involvement of lithium is strong support for the hypothesis of this paper. The immune system-psychosocial
disease hypothesis leads directly to the prediction
that lithiums mechanism of action is mediated
through the immune system. Lithiums long latency period before therapeutic effect is also consistent with an immune mechanism.
DISEASE
55
Other neuroleptic drugs. The slow therapeutic action of neuroleptics is one of the great paradoxes
of psychopharmacology.
Most neuroleptics block
dopamine receptors rapidly after administration,
which is thought to be their mechanism of action.
Why then does it take a week or more for the
antipsychotic effects to emerge? (64). A solution
to the paradox would be a mechanism of action involving the immune system. A surprising amount
of evidence supports that notion.
Recently, haloperidol, a calmodulin antagonist,
was shown to inhibit natural killer activity (65).
Presumably, other neuroleptics such as the phenothiazines, which are also calmodulin antagonists, would have similar effects on natural killer
activity. In an earlier experiment (66), haloperidol
and several phenothiazines blocked Epstein-Barr
virus infection of B-lymphocytes. This remarkable
immune acitivity was thought to work by blocking
calmodulin. In another study (67), the blastogenic
response of cultured T-lymphocytes was powerfully inhibited by phenothiazines, haloperidol and
thiothixene. As early as 1975 it was shown chlorpromazine inhibits concanavalin A induced lymphocyte aggregation and mitogenesis (68). In addition, benzodiazepines bind to a specific receptor
on macrophages (69).
It is evident that the major classes of neuroleptics have significant effects on the immune system.
Much more work needs to be done, but at this
point it is reasonable to propose their immune system involvement is a key, if not dominant, factor
in their antipsychotic action. If this proposal is
correct, it will also explain the long latency of action paradox and eventually lead to a comprehensive understanding of the etiology and treatment
of psychosocial disease.
Conclusion
The astonishing effects of interleukin-2 and interferon on the CNS provide a solid foundation
for the assertion that the immune system plays
a key role in the etiology of psychosocial disease. Consistent with and supportive of that hypothesis is a remarkable amount of diverse data
on: food allergy; lithium and other neuroleptics;
symptoms of infectious disease; AIDS Dementia Complex; blood monocyte migration into the
CNS; the dense two-way communications network
between the CNS and the immune system; and the
direct access of cytokines to the hypothalamus,
56
the premier control center of the brain. This hypothesis provides much needed explanations for:
1. the powerful effect of food on behavior; 2.
the mechanism of action of lithium carbonate and
other antipsychotic drugs; 3. the delayed therapeutic action of neuroleptics; and 4. the rapid onset of AIDS Dementia Complex. This hypothesis,
if correct, will usher in a golden age of psychosocial disease research. The full power of modern
biomedical science could be put into action, since
the immune system is largely blood borne. No
longer will the inaccessability of the brain be the
great barrier to research on psychosocial disease.
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