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Depression - Allergy, Depression and Tricyclic Antidepressants
Allergy, Depression and Tricyclic
Antidepressants
A. Hoffer, M.D., Ph.D.
Journal of Orthomolecular
Psychiatry
Vol. 9, Number 3, 1980
A. Hoffer, M.D., Ph.D.
INTRODUCTION
Psychiatrists have been very reluctant to accept the
idea that depressions, which they know so well, may be caused by allergies to
common environmental molecules such as foods, airborne particles, and chemicals
in water. When patients were depressed and anxious, and at the same time
suffered from diseases accepted as allergic, psychosomatic explanations were
used. This usually meant that a psychological explanation for the presence of
the allergic reactions was invoked. The mood disorder was looked upon as a
natural reaction to the discomfort of the allergic reaction. Asthma for a long
time was one of the seven major psychosomatic diseases. Most psychiatrists still
believe schizophrenic patients can not be allergic, at least not when they are
ill, but it was accepted that schizophrenia and allergic reactions could
alternate.
A few physicians have concluded that allergic reactions are
much more common than one would assume from the psychiatric literature, and that
the allergic reaction causes a variety of symptoms of which mood disorder is
one. The patient with asthma is not depressed because it is hard to breathe-the
depression and the difficulty in breathing are both expressions of an allergic
reaction to one or more foreign types of molecules. Many years ago allergists
recognized that it was possible to be allergic to foods as well as to pollens or
dusts, and described the mood symptoms which were also present. The depression
and anxiety was recognized as a reaction to the allergen, but prime emphasis was
given to the non-psychiatric symptoms. Clinical allergists who are now
practising clinical ecology went one step further when they recognized that
allergic reactions could cause depression and anxiety as the main symptom with
minimal somatic reactions. Dr. T. Randolph (1961, 1966) observed a large number
of allergic depressions. Manic-depressive psychosis, in his opinion, is a
cyclical reaction to a number of allergens ranging from foods to airborne
pollutants. But psychiatrists are unaware of the contributions made by clinical
ecologists such as Randolph (1965), Mandell and Scanlon (1979), and reject the
observations of clinical psychiatric ecologists such as Newbold (1975) and
Philpott (1974, 1979) as well as Sheinkin, Schacter and Hutton (1979).
In
this communication I will summarize the evidence which supports the conclusion
that a large fraction of depressions are responses to environmental molecules,
and that the tricyclics are effective in many patients because of their
antihistaminic properties, not because they act upon the serotonin or
sympathomimetic amine pathways.
DEPRESSION IS A SYMPTOM OF ALLERGIC
REACTIONS
Most patients with somatic symptoms of allergy have a mood
disorder, usually depression and anxiety. I can not recall a patient with
asthma, with a severe allergic itch, or suffering from hives, who was happy.
They all had depression and anxiety ranging from slight to very severe.
Psychosomatic explanations have a long and honourable history but are no more
firmly established today than they were when they were so popular thirty years
ago. They have no predictive value, do not indicate treatment, and no patient is
better because of them. The fact that it makes sense that depression should be a
response to the somatic symptoms does not make this true.
Clinical
ecologists who had little interest in psychiatry described depression as a
common problem in allergic reactions. Rowe and Rowe (1972), pioneers in
establishing food deprivation tests to locate foods which were being reacted to,
wrote that symptoms include "lack of energy and ambition, drowsiness, loginess,
depression, inability to think and concentrate. Temper tantrums and emotional
instability may be present."
I became interested in the relation of
allergies to depression about ten years ago. I also observed that patients who
were found to be allergic usually were depressed. A psychiatrist who neglected
to take a history of allergic reactions would have diagnosed them as a mood
disorder. Later I observed that over half of all the patients who were referred
to me because they were depressed, and who were in fact depressed, had a history
going back many years of somatic allergies. As children they had eczema or
rashes, frequent upper respiratory problems, and asthma or hayfever. Most were
aware of these symptoms which had been treated by their physicians but none
associated the history of allergic reactions with their current mood disorder. I
checked this with a colleague who was known as a specialist in depression but
who did not practise orthomolecular psychiatry. He too was amazed at the high
incidence of somatic allergies in his depressed patients. The association is so
high that any psychiatrists will corroborate it in a few months of observation.
All that is required is to include allergies in the history of the
patient.
Allergic reactions may become addictive reactions. This is the
basis for the craving for sugar, alcohol, and even for foods such as milk or
meat. The most accurate way of diagnosing a food allergy is to deprive the
patient of food for a number of days; usually four but sometimes many more are
required. This is done by fasting the patients or placing them upon a diet of
foods that they have used very rarely (Mandell, 1979). Deprivation of the food
until all traces are gone from the gastrointestinal tract will result in a
reduction of all symptoms or in their complete removal. Patients who have food
allergies often feel normal toward the latter part of the fast. When I fasted
four days about six years ago I expected to feel hungry and irritable the whole
four days. For two years I had suffered from a chronic cold and difficulty in
breathing. I was unaware I had an allergy and fasted for other reasons; to my
surprise I was euphoric the fourth day and my cold was gone. I subsequently
discovered I was allergic to milk products.
The first part of the fast is
generally unpleasant; there is a withdrawal reaction like that suffered by a
heavy smoker when smoking is stopped abruptly, or like "cold turkey" heroin
withdrawal of which the addict is so fearful. During these few days, patients
miss the repeated stimulus of the foods they normally eat to which they are
allergic; in a few patients the withdrawal from these foods has been very
severe. One of my patients consumed twelve glasses ofmilk each day-it kept her
going. I was then inexperienced in the technique and results of food deprivation
and I advised her to discontinue milk immediately. Within five days she was in a
deep psychotic depression and I had to admit her to hospital to protect her from
killing herself. Since then I have withdrawn patients slowly, over a period of a
month, if they consume large quantities of any foods. The consumption of large
quantities of food-bread, pastry, sugar-is a clear indication to suspect these
foods as one of the causes of depression and anxiety.
Withdrawal
depression will also account for the diurnal rhythm of depression. Most
illnesses are made worse by fatigue; schizophrenia and physical illnesses tend
to become worse in the evening as patients become more tired. Depression, in
sharp contrast, tends to become better at night, It is common for depressed
persons to feel awful in the morning; they are tired, anxious and depressed. As
the day continues they gradually feel better; after supper they often feel
almost normal. What likely happens is this: in the morning the patients are
suffering from withdrawal, having had no food for 12 hours or so; during the day
foods to which they are allergic are consumed, and by evening there is no
further withdrawal reaction. Each day the cycle is repeated.
Treatment of
the allergy will, in most cases, "cure" the depression. I have seen this in
several hundred patients over the past six years and can no longer doubt this
conclusion. About six years ago a chronic psychotic depressive patient was
referred; he had been deeply depressed for four years. During that time he had
failed to respond to a series of ECT in a psychiatric ward. He was maintained on
injectable tranquilizers which partially controlled his anxiety but left him
incapable of doing more than eating and sleeping in a sheltered environment. I
diagnosed him as a depression with schizophrenic features. He did not respond to
orthomolecular vitamin treatment. After a four day fast he was normal and one
month later was back at work as a high school teacher-he had not been able to
work for five years. The four day fast and subsequent testing showed he was
allergic to cigarette smoking.
Subjects who are free of depression will
note a sudden resurgence when they eat those foods they have been avoiding
either by accident or deliberately. I have found that January tends to bring
back a large number of my patients who were well but who gave way to the holiday
foods so abundant in December, primarily junk foods or food artifacts. I have
referred to a number of associations which support the contention many
depressions are symptoms of allergic reactions.
1. Clinical ecologists
observed a high incidence of depression in their allergic patients.
2. I
observed that a large proportion of depressed patients had earlier in life
suffered from a variety of somatic allergies.
3. Removal of offending
foods or other molecules resulted in relief from depression.
4. The
typical diurnal pattern of deep depression in the morning and relief in the
evening can be explained by the overnight withdrawal from foods one is allergic
to.
5. Depression is common following exposure to allergic foods and may
come on within a few minutes.
THE TRICYCLIC ANTIDEPRESSANTS
The
tricyclic antidepressants are third generation antihistamines. The discovery of
the antihistamines was followed by their use as tranquilizers. Dr. H. Laborit
(Caldwell, 1970) was looking for a centrally active sedative. As a direct result
of his interest chlorpromazine was given to the first patient January 19, 1952.
It is curious that our first use of large doses of vitamin B3 came only a few
months later. But chlorpromazine was patented and owned by a drug company while
vitamin B3 was public domain.
However, the idea of using antihistamines
preceded chlorpromazine by at least three years, A report appeared where it was
claimed that an anti-histamine, benadryl I believe, was combined with ascorbic
acid and helped a small number of schizophrenics. A subsequent report failed to
corroborate, but the idea was already in the medical literature. Failure to
corroborate is very often a function of the intent of the person who
failed.
It was known shortly after the early antihistamines became
available that they had sedative properties; these were undesirable. The
companies wanted a substance with no sedative properties and maximum
antihistaminic effect. Dr. H. Laborit, a surgeon, wanted just the opposite.
Chlorpromazine represented the first member of this new class of compounds which
had much more central sedative effect and less antihistaminic effect. From
France the tranquilizers rapidly spread into Canada and later into the U.S.A.
Dr. H. Lehmann's report first hit the English literature a few months ahead of
an American investigator.
Psychiatrists did not receive tranquilizers
gratefully, for they were rapidly swinging to the view schizophrenia was a
psychosocial disease with insignificant biochemical features. In this they were
led by the National Institute of Mental Health. This analytically led and
inspired group only began to fund tranquilizer studies after immense pressure
from a large group of senators and congressmen.
This is an early example
of the use of political pressure to achieve a psychiatric improvement.
Tranquilizers were a distinct step forward. Antihistamines fathered the
tranquilizers and later the tricyclic antidepressants. Imipramine was
synthesized in 1948. It is like a phenothiazine tranquilizer with antihistamine
properties. Kuhn (1957) reported its antidepressant properties. Sigg (1968)
summarized its properties:
(a) It was like a weak phenothiazine
tranquilizer.
(b) It potentiated the action of noradrenalin interfering
with uptake and binding. In this it resembles phenothiazines and
antihistamines.
(c) It augments or prolongs many effects of amphetamines
and methamphetamines such as motor activity and hyperthermia. Phenothiazines in
contrast decreased these effects. Imipramine resembled the
antihistamines.
(d) It caused ptosis as did antihistamines.
(e) It
interfered with the histaminergic system.
Sigg discussed previous
suggestions that the antidepressant action of imipramine was due to central
antihistamine properties while noting that certain antihistamines were
antidepressants. In fact I have treated a patient whose addiction to
antihistamines was as powerful as any heroin addiction. Sigg finally concluded
that the antihistamine effect was not a factor "because clinically demonstrated
antidepressant action seems inversely correlated with antihistaminic potency."
But then the concept of cerebral allergy was unknown. There is no necessary
correlation between central and peripheral antihistamine activity. Since Sigg's
review, antihistamine activity of tranquilizers and antidepressants has been
more or less ignored.
However, a new potent antidepressant has appeared.
Mianserin is described in an issue of the British Journal of Clinical
Pharmacology, edited by Peet and Turner (1978). It is as effective an
antidepressant as imipramine or amitriptylene but has fewer side effects. It is
not an anticholinesterase. In the following Table I have listed its properties
and these are compared with the usually accepted properties of the tricyclic
antidepressants.
It is clear we have a new antidepressant which does not
share with the tricyclic antidepressants the usual effect on catecholamines and
on serotonin metabolism. They only have antihistamine
properties.
Imipramine has been used to treat a number of allergic
diseases (Angst and Theobald, 1970). Given intramuscularly, 25 milligrams
partially protected patients against histamine inhalation. It has been used as
an adjunct for treating asthma and has been recommended for the treatment of
various aspects of asthma. It decreases the size of histamine induced weals. It
is a potent antagonist of histamine and bradykinin. In fact, all tricyclics have
moderate to strong antihistamine activity.
Mianserin has also been used
for treating asthma (Peet and Behagel, 1978). Asthmatics given Mianserin had
fewer night attacks. This finding was not pursued because of side effects, i.e.
centrally antidepressant effects. Mianserin is an effective antidepressant which
does not have the two main characteristic actions of tricyclic antidepressants
on catecholamines and serotonin, but is a good
antihistamine.
TABLE 1 COMPARISON OF MIANSERIN AND TRICYCLIC
ANTIDEPRESSANTS
TREATMENT OF FOOD ALLERGY BY TRICYCLIC ANTIDEPRESSANTS
Patients
who have one or two food allergies are easily diagnosed and treated; after the
foods are identified they are avoided. I have avoided all milk products for six
years with little difficulty and have not had a "cold" since then, but many
patients have multiple food allergies and a few seem to react to nearly
everything. They are very difficult to treat successfully and a variety of
procedures have been developed.
Special Diets
Of these the
rotation diets have been most successful. However, there is a lot of patient
resistance toward these, and their families may also resist. They tend to make
patients totally preoccupied with food and eating, and often they simply do not
work. Fasting has been used; I have had several patients who were much improved
by a four day fast who had no food allergies on subsequent tests. On returning
to their no junk diet which they had been on before the fast they remained well
for a long time. The fast appeared to have a clearing
function.
Vitamins
Some of the vitamins have anti-allergy
properties and have proven helpful. Niacin releases histamine and lowers
histamine levels in the body. I have observed in many patients that they
required very large doses of niacin, 1 to 12 grams per day or more, until they
eliminated those foods they were allergic to. In many patients, eliminating milk
promptly reduced the amount of niacin that was required and could be tolerated
from 12 to 3 grams per day. Ascorbic acid reacts with histamine in vitro and
presumably in the blood; it rapidly inactivates it. it has been very helpful in
dealing with allergic reactions associated with insect bites, rashes,
etcetera.
Enzymes
Ideally, foods which are completely digested
to their component amino acids, sugars, and fatty acids ought not to cause
allergic reactions. If, however, larger fragments are left, dipeptides or
disaccharides or other more complicated molecules, then one would expect more
allergic reactions. These larger fragments can easily cross into the blood and
even into the brain, across the blood/brain barrier; this has been established
by tracer studies.
Perhaps these large or macro-molecules are responsible for
the toxic reactions to some food. Following this line of reasoning it is
possible a deficiency in the secretion of digestive enzymes, either from the
pancreas or the intestinal walls, might be a factor; finally it would follow
that replacing these enzymes would be helpful. Some of my patients have been
helped and I have several who are able to eat foods which previously made them
ill; they took pancreatic enzymes before eating. But others were not helped and
several suffered allergic reactions to the enzyme, either to the capsule, its
color, or to the contents. But patients who have been helped remain very
grateful. We require careful, large scale clinical trials to examine the
therapeutic role of enzymes and nutrient supplements.
Tricyclic
Antidepressants
In a recent paper (1979) 1 described the use of an
antidepressant, Clomipramine, to treat obsessions and depression. There I
suggested that antihistamine properties of tricyclic antidepressants played a
role and I referred to several patients whose multiple food allergies came under
control by using small daily doses of tricyclic antidepressants. I suggest these
antidepressants should be tried when other therapeutic measures have
failed.
Imipramine has been used for treating children's allergies even
though clinicians using it this way have been unaware of the relationship.
Imipramine has been effective in treating enuresis in children but not every
child responds. Gerrard (1973) established that enuresis in some children is due
to an allergic reaction of the bladder. it becomes smaller, presumably due to
increased tension and thickening of the bladder wall. When the offending food is
removed the bladder relaxes and in a few weeks they are normal. Reintroducing
the offending food, often milk, quickly re-establishes the bedwetting problem.
Perhaps these are the children who responded best to imipramine. I have also
used tricyclic antidepressants for obesity and to control voracious appetites
for certain foods, as well as for a number of somatic allergic
reactions.
Many obese patients have a voracious appetite for foods to
which they are allergic. They will eat a loaf of bread in an hour, will drink 16
glasses of milk in a day, will eat a pound of chocolate in a few minutes. These
are allergic reactions gone wild and have become severe addictions. I have found
that for many of these the tricyclics help reduce the intensity of the desire
for these foods, and have helped many obese patients bring their weight down
slowly.
Antidepressants may be very helpful in treating children with
learning and behavioural disorders; probably half of these children suffer from
cerebral allergies. Speer (1970) described the allergic tension state as "a
clinical allergic state which is marked by diffuse neuropsychic overactivity. It
includes both a motor component (hyperkinesis) and a sensory component
(hyperesthesia). Usually both are present in the oversensitive allergic
child."
CONCLUSION
Tricyclic antidepressants are
antidepressants largely because of their antihistaminic properties. This
conclusion is based upon the following observations:
1. The close
association between depression and allergies. It is rare to find one without the
other; when one is relieved, so is the other.
2. Mianserin is a powerful
antidepressant which differs from the tricyclics in having no effect on the
metabolism in the brain of catecholamines or serotonin. It is a good
antihistamine, a property common to the tricyclics as well.
3. Tricyclic
antidepressants are useful in treating allergic reactions no matter what form
they have taken. This ranges from allergic addiction such as obesity to
enuresis.
I suggest neuropsychopharmacologists once more examine
seriously the antihistaminic properties of the antidepressants.