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Adverse reactions to foods: Relevance to psychiatric disorders
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T. Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized lsolyethylene glycols. Clin Allergy 14:277, I984 Dannaeus A. Inganas M, Johansson SC, Foucard T: Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally administered sodium cromoglycate. Clin Allergy 9:263. 1979 Soothill JF: Food allergy. In Pepys J, Edwards A. editors: The mast cell. London, 1979, Pitman Publishing Ltd, p 825 Berman HA: Cromolyn: past, present, and future. Pediatr Clin North Am 30:915. 1983 Brogden RN, Speight TM, Avery G: Sodium cromoglycate (cromolyn sodium): a review of its mode of action, pharmacology, therapeutic efficacy and use. Drugs 7: 164, 1974 Settipane GA. Klein DE, Boyd GK, et al: Adverse reactions to cromolyn. JAMA 241:81 I. 1979 Sheffer AL, Rocklin RE. Goetzl EJ: Immunologic components of hypersensitivity reactions to cromolyn sodium. N Engl J Med 293 1220, 1975 Bahna PL, Gandhi MD: Milk hypersensitivity. II. Practical aspects of diagnosis, treatment and prevention. Ann Allergy 50:295. 1983 Basomha A. Campos A, Villalmanzo IG, Pelaez A: The effect of sodium cromoglycate (SCG) in patients with food allergies. Acta Ailergol I3(suppl):95, 1977 Esteban MM, Ojeda JA, Laso MT, Pascual C: Oral sodium cromoglycate in food allergy. Acta Allergol 13(suppl): 102. 1977 Freier S: A therapeutic trial of disodium cromoglycate in gastrointestinal allergy. Acta Allergol 13(suppI): 109, 1977 Harries MC. O’Brien IM, Burge PS, Pepys J: Effects of orally administered sodium cromoglycate in asthma and urticaria due to food>. Clin Allergy 8:423, 1978 Dannaeus A, Foucard T, Johansson GO: The effect of orally administered sodium cromoglycate on symptoms of food allergy. (‘Iin Allergy 7:109, 1977 Businco L. Cantani A, Benincori N, Perlini R. Infussi R, De Angelis M. Businco E: Effectiveness of oral sodium cromoglycate (SCG) in preventing food allergy in children. Ann Allergy 5I:47, 1983 Watson JB. Tirnmins J: Food allergy: response to treatment with sodium cromoglycate. Arch Dis Child 54:77, 1979 Vaz GA. Tan LIK, Gerrard JW: Oral cromoglycate in treatment of adverse reactions to foods. Lancet 1:1066. 1978 Ortolani C. Pastorello E, Zanussi C: Prophylaxis of adverse reactions to foods. A double-blind study of oral sodium cro-
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moglycate for the prophylaxis of adverse reactions to foods and additives. Ann Allergy 50:105. 1983 Bernstein IL, Johnson CL: Therapy with cromolyn sodium. Ann Intern Med X9:228, 1978 Denman AJ, Kingsley PJ, Brereton P: Controlled trials of oral disodium cromoglycate in chronic urticaria and suspected food allergy. In Pepys J, Edwards AM, editors: The mast cell-its role in health and disease. London. 1979. Pitman Publishing Ltd. p 597 Molkhou P, Waguet JC: Food allergy and atopic dermatitis in children: treatment with oral sodium cromoglycate. Ann Allergy 47:173. 1981 Lindskov R, Knudsen L: Oral disodium cromoglycate treatment of atopic dermatitis. Allergy 38: 161, 1983 Graham P. Hall-Smith SP, Harris JM. Price ML: A study of hypoallergenic diets and oral sodium cromoglycate in the management of atopic eczema. Br J Deimatol 110:457, 1984 Freier S, Berger H: Disodium cromoglycate in gastrointestinal protein intolerance. Lancet 1:913, 1973 Kocoshis S, Gryboski JD: Use of cromolyn in combined gastrointestinal allergy. JAMA 242:I 169. 1979 Bolin TD: Use of oral sodium cromoglycate in persistent diarrhoea. Gut 21:848, 1980 Gerrard JW: Oral cromoglycate: its value in the treatment of adverse reactions to foods. Ann Allergy 42: 135, 1979 Kingsley PJ: Oral sodium cromoglycate in gastrointestinal allergy. Lancet 2: 101 I, 1974 Ratner PH. Davis SH, Rodriguez LM, DeVillez RL, Kniker WT: The efficacy of rotary elimination diet and of oral cromolyn in the management and prevention of atopic eczema (abstract): International Symposium on Prevention of Allergic Diseases. Florence, June 24-27, 1984 Dahl R: Oral and inhaled sodium cromoglycate in challenge test with food allergens or acetylsalicylic acid. Allergy 36: 161. 1981 Bulks A, Sampson H: Double-blind placebo-controlled trial of oral cromolyn sodium in children with egg hypersensitivity. J AL,-ERG CLIN IMMUNOL 77: 184, 1986 (abst) Dahl R, Zetterstrom (3: The effect of orally administered sodium cromoglycate on allergic reactions caused by food allergens. Clin Allergy 8:419, 1978 Dahl R: Disodium cromoglycate and food allergy. The effect of oral and inhaled disodium cromoglycate in a food allergic patient. Allergy 33:120, 1978 Salberg DJ: Cromolyn in combined gastrointestinal allergy (letter 1. JAMA 244:546. 1980
Adverse reactions to foods: psychiatric disorders John W. Crayton,
and use in treatment
Relevance to
M.D. Chicugo, 111.
From the 1)epartment of Psychiatry, the University of Chicago, Chicago. Ill. Reprint requests: John W. Crayton, M.D., Associate Professor of Psychiatry. The University of Chicago, 5841 S. Maryland Ave., Chicago. IL 60637.
Food has been reported to affect behavior by altering the levels of central nervous system neurotransmitter substances’, ’ or by the direct actions of psychopharmacologic agents in foods (such as caffeine or phenylethylamine‘,. Indirect effects of foods on be243
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havior via immunologic or allergic mechanisms have been postulated but the evidence available is not yet clear or convincing. The known and postulated effects of food on behavior have stimulated interest in the possibility that adverse reactions to foods might contribute to the development of mental illnesses such as schizophrenia and depression. This article surveys some of the reported assocrations between adverse reactions to foods and psychiatric diagnostic entities. In surveying these reports, two major trends in current psychiatric research should be emphasized. First, it is generally accepted that the expression of all illness, “physical” or “mental,” reflects an intricate interplay between physical and psychologic factors. The patient’s mental state influences how physical illness is experienced and communicated. Consequently, categorization of illness as mental or physical is a simplification that may be useful but may also be misleading. With respect to food sensitivity and behavior, a model similar to that of Mandell and Rose’ may be invoked to illustrate this principle. They hypothesized that the allergic reactions of their patient produced physiologic changes that were perceived by the patient and responded to according to her particular psychologic makeup and the nature of the conflict of immediate concern to her. Such an interactive model suits the complexity of most cases of food and chemical sensitivity with behavioral manifestations. The second principle is that a patient’s mental state may influence the body’s physiologic coping mechanisms, including the reactivity of the immune system. The evidence suggests that immunoreactivity may be altered by, mental dysfunction.Jmh If so, abnormal immunoreactivity to allergens may be secondary to mental illness not causal of it. With these principles in mind, this review summarizes some possible links between adverse reactions to foods and psychiatric disorders. While no putative links have yet been definitively shown. a few areas appear worthv of further study. SCHIZOPHRENIA Dohan et al.’ ’ suggested that wheat ingestion in genetically predisposed individuals may aggravate schizophrenic symptoms and may even be a cause of schizophrenia. Epidemiologic studies suggest that schizophrenia is seldom seen in cultures in which wheat consumption is low, but the incidence rises when wheat IS introduced into the culture.’ Dohan’ also points to a direct relationship between wheat consumption and the number of admissions to mental hospitals for schizophrenia in European countries during World War II as further evidence for a wheatschizophrenia link. These epidemiologic studies could
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not control for important confounding variables, but they stimulated interest in more focused studies of schizophrenic patients. Singh and Kay”’ and Rice et al. ” also report cases of apparently wheat-sensitive schizophrenic individuals, although the percentage of schizophrenics with wheat sensitivity may be relatively small. Further support for the wheat-schizophrenia link comes from studies suggesting that the incidence of antigliadin antibodies in schizophrenics is higher than that in nonschizophrenics, that peptide fragments of wheat gluten can enter the brain of experimental animals,” and that wheat gluten has endorphin-like activity.‘” Recently Jansson et al.“’ described a patient with schizophrenia who dramatically improved on a gluten-free diet. If there is an association, Ireland would seem to be a propitious area to study the relationship because the incidence of both disorders is high.” However, careful studies of gliadin antibody levels in schizophrenic subjects and follow-up intestinal biopsy studies of antibody-positive subjects failed to find any basis for an association. Patients with gluten-sensitive enteropathy and schizophrenia also share certain neuropathologic and immunologic traits that suggest some overlap between the two conditions. Patients with both celiac disease”. ” and schizophrenia” ” show evidence of a peripheral motor neuropathy that may reflect a more widespread nervous system degeneration. Both patient groups also show similar patterns of lymphocyte stimulation with gluten as assessed by migration inhibition factor assay.‘” Not all studies have been supportive of the hypothesis, however. Potkin et al.” reported no effect of a gluten-free diet in schizophrenic subjects and Storms et al.” similarly failed to find a beneficial effect of the diet. By analogy with celiac disease. Dohan” has argued that patients with chronic schizophrenia may not show improvement for many months, if ever, after instituting a gluten-free diet because the effects of the gluten may eventually become reversible. Osborne et al.” studied six patients with chronic schizophrenia on a gluten-free diet for 9 months without seeing any significant improvement. Other foods have rarely been associated with frank psychotic symptoms. Milk produced overt psychotic symptoms during double-blind challenges in a 14year-old girl with a history of gastrointestinal intolerance to milk in childhood.” Kinnell et a1.‘5 failed to find an increased incidence of antifood antibodies in schizophrenic subjects. DEPRESSION While anorexia is the more common response to significant depressive illness, increased appetite is of-
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Reactions
ten seen in depressed patients. The increase in appetite may be ;is,sociated with specific food cravings, particularly !‘or chocolate and carbohydrates. While these cravings have usually been attributed to a symbolic “feeding” of the self by a defeated and depleted psyche, Wurtman’s studies’ of the effects of carbohydrate loading on brain neurotransmitter metabolism suggests an alternative hypothesis. Increasing the proportion of carbohydrate in the diet tends to increase the amount of tryptophan entering the brain and consequently raises the amounts of serotonin available for neurotransmissi’on. Since hypoactivity of serotoninergic pathways has been proposed as a mechanism mediating some forms of depression. the carbohydrate craver could be attempting to raise serotonin levels via this mechanism. Evidence that central serotonin levels can influence the proportions of carbohydrate and protein selected in the diet has been used to support this notion ’ A second body of data links allergy to depression. Ossofsky” 37and Nasr et a1.28have reported a high incidence of allergy in depressed patients, although a specific breakdown as to type of allergy was not addressed. In the study of Nasr et al. the incidence of allergy was about 33% in the depressed patients and 2% in a control group of schizophrenic patients. In Ossofsky’s studies the incidence of atopy was more than 70% in the depressed patients. The apparently high incidence of “allergy” in depression requires further study. Since tricyclic antidepressant medications are potent antihistamines,‘” a common histamine-mediated lpathway might be invoked in certain allergic-depressive patients. Little systematic study has been done of food sensitivity in depressed patients. The studies of Rix et al. “’ and Pearson et al.3’ attempted to determine the true incidence off food allergy in allergy clinic patients with psychologic complaints. Ten of their 18 subjects were diagnosed as having depressive neuroses. They were unable to confirm the presence of food allergy in the subjects ,with psychologic complaints that the subjects had attributed to foods. The lack of detail regarding the fo’od challenge methodology makes this study difticult to assess. SOMATIZATION
DISORDER
Perhaps the most commonly encountered type of patient with complaints of food sensitivity and behavioral symptoms will prompt a consideration of the somatization disorders. Patients with numerous unexplained physical symptoms present a special challenge to the physician. These patients require inordinate attention, time, and support. May” has pointed out the remarkable similarity between neurotic symptom? 34 and the allergic tension-fatigue syndrome.“’ This sim-
TABLE
to foods:
Relevance
I. Syndromes
to psychiatric
of multiple
245
disorders
somatic
complaints
Symptoms
Fatigue. sickly Food intolerance
Gastrointestinal symptoms (pain, nausea, vomiting, etc) Arthralgias Myalglas Cognitive deficits (memory, concentration, etc) Palpitations Insomnia Headache Depression Irritability Nasal symptoms Hives Eczem,l Deafness Blindness Loss of voice Convulsions Sexual indifference
Neurasthenia”
Allergic tension fatigue5’
Somatoform disordeP
+
t
+
+ +
+ +
+ +
+ + +
+ + +
+ + +
+ + + + + 0 0 0 0 0 0 0 0
+ + + + + + + + 0 0 0 0 0
+ 0 0 0 0 0 0 0 + + + + +
ilarity of symptom profiles raises the question of how to discriminate between symptoms that are being attributed to food sensitivity and those that stem from neuro5is. The new psychiatric nomenclature published in 1980 collects several disorders characterized by complaints, about physical symptoms under the rubric somatoform disorders.” These conditions include somatization disorder, conversion disorder, psychogenic pain disorder, and hypochondriasis. Specific diagnostic criteria for each of these conditions facilitates our undeistanding of the relationship between physical and paychologic complaints and how to discriminate between the two. It is of interest to trace the evolution of these concepts lover the past 100 years, since this evolution illustrates a variety of approaches to the problem of distinguishing between psychologic and physical conditions,‘7, 3X(Table I). In 1880 Charles Beard” published his (then) widely regarded monograph of neurasthenia, a condition characterized by fatigue, irritability, mental confusion, peculiar intolerances to various foods, and a variety of other somatic complaints. He noted that diet was a particularly important aspect of the treatment of patients with neurasthenia.
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In particular, a fast was found to produce rapid improvement in some patients after 4 or 5 days. Beard’s suggestions were amplified by Mitchell,30 a member of the National Academy of Sciences. Mitchell proposed that patients with neurasthenia lacked the capacity to form these two substances, and his treatment was designed to increase their capacity to form them. Diet was a central aspect to his treatment. He advocated a single-food (diet of boiled skim milk in gradually increasing amounts. While diet was a central feature of both Beard and Mitchell’s systems, they cannot be considered the sole reason for improvement, since both used treatments with multiple modalities including psychotherapy, exercise, hot baths, and, perhaps most of all. intense interest and support by the physician. The term neurasthenia is seldom used today in this country, although it is still commonly used in Europe and the Soviet Union. What happened to neurasthenia (Table I)? Clearly, as originally formulated, neurasthenia encompassed a wide variety of physical and mental disorders. As early as the 1880s more distinct groupings within this rather heterogenous group were being made. Freud” pointed out the differences between the anxiety neuroses and neurasthenia. The hysteric invariably expressed (her) psychologic conflict in physical terms, so that one could always find an intense psychologic dysfunction underlying the somatic dysfunction of the hysteric patient. Psychologic underpinnings were not found in patients with neurasthenia. No primary (intrapsychic) or secondary (interpersonal) gain could be found to explain the development of symptoms in the patients with neurasthenia. Consequently, at this early juncture an important distrnction between hysteria as a predominantly psychologic illness and neurasthenia as a predominantly physiologic illness had been made. In I944 Allen”’ reported. on a large series of patients with a chief complaint of fatigue and weakness. He found that in only 20% of the cases could a physical condition be found to explain the complaints. The other 80% of cases were attributed to neurasthenia or “benign nervousness.” In rebuttal, Randolph”’ proposed that many patients diagnosed as neurasthenic were more accurately described as suffering from allergictension fatigue. Certainly the similarity in symptom constellations in the two disorders is striking. Both are characterized by fatigue, irritability, depression, difficulty concentrating, and a wide variety of physical complaints. The term neurasthenia is no longer used in this country and presumably patients with this diagnosis have been absorbed by other diagnostic entities such as somatization disorder, conversion disorder, dysthymic disorder. and the group of “cardiac neuroses.”
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Similarly, there is question as to whether allergictension fatigue exists as a distinct diagnostic entity. If it can be validated, subjects with this disorder may be found Im the group of patients now diagnosed to have one of the somatoform or anxiety disorders. Table I suggests that there may be considerable overlap among the three syndromes of multiple somatic complaints. While many of the symptoms are shared by the three syndromes. there are interesting differences in the symptoms. Both neurasthenia and the allergic tension-fatigue syndrome list affective symptoms such as depression and irritability as features while somatoform disorder does not. The allergic tension-fatigue syndrome is the only one of the three to specifically mention common allergic complaints such as hives, eczema, and nasal symptoms. Somatization di’sorder uses clearly “hysteric” symptoms such as blindness, deafness, and convulsions as criteria. These differences, as well as the other specific inclusion and exclusion criteria for somatoform disorder, may help clue the physician in to which of these closely related and overlapping conditions is present. Somatization disorder is characterized by a history of numerous physical complaints of several years’ duration beginning before the age of 30 years. The specific criteria for inclusion in this category are that the patient must report at least 14 (for women) or 12 (for men) symptoms selected from a list of 37 symptoms. It is most important in making this diagnosis that the quality of the patient’s responses, not just the response itself, be monitored. The criteria indicate that it is not necessary that the patient actually experience the symptom, only that they report it. Consequently, this category of illness taps a quality of suggestibility and complaint proneness in the patient.“’ In addition, patients with somatization disorder tend to have a high degree of sociopathic tendencies such as delinquency, fighting, rage attacks, and truancy.“> Early research into this condition by the Washington University group 51.1sindicated that this physical cornplaint-prone group represented a stable category of dysfunction. These patients did not go on to have significant physical illness that later “explained” their illness. They noted that this condition started early in life, usually in the teens or early 20s. Patients who met the criteria for multiple complaints after the age of 30 years were likely to have underlying physical illness. Another important aspect of this work is that patients with fewer than the required number of somatic complaints were diagnosed as having an “undiagnosed medical condition.” These patients tended to go on to show signs and symptoms of a medical condition alnd did not show the stable course of the group with somatization disorder. Since patients with numerous somatic complaints
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Reactions to foods: Relevance to psychiatric
78 1. PART 2
frequently complain of food sensitivities, the distinction between food sensitivity and somatization disorder could be difficult. Forty-eight percent of the patients who met the criteria for somatization disorder complained of food intolerance.46 It would be interesting to determine the distribution of numbers of complaints in food-sensitive individuals and compare those who also meet DSM-III criteriajh for somatization disorder with those who do not. Conversion
disorder
Conversion disorder is diagnosed when there is a predominant physical complaint suggestive of a physical disorder but that is thought to be due to psychologic factors. Patients may develop physical complaints to help lresolve a conflictive problem, avoid some unpleasant or stressful situation, or elicit support from the environment. Individuals with this condition have been helped through suggestion, reassurance, and support. They ordinarily complain of only one symptom and classically show surprisingly little concern for the disability even though it would seem to be extremely disabling. Several featur’es of conversion disorder are helpful in distinguishing it from a true medical condition and, specifically, food sensitivity. True food-sensitive patients would generally lack a clear psychologic “meaning” to their symptoms, gain little by having them, and lack the inappropriate indifference of the patient with conversion disorder toward the condition. Hypochondriasis Hypochondriasis is a condition of unrealistic fear of having a serio’us illness. Patients misinterpret physical signs as abnormal or as indicative of life-threatening illness. They resist reassurance by their physician that no physical illness is present and tend to seek out d physician who will confirm their worst fears. The empha.sisin this condition is on the patient’s unrealistic fears of disorder. Brodsky” studied eight litigants who were seeking damages t‘or disabilities that they claimed were due to being “allergic to everything.” Standard medical evaluations had failed to reveal evidence of damage. Clearly, some patients may incorporate their physical problems into conscious or unconscious attempts to obtain compensation, sympathy, and support. The thorny problem presented by these patients is understanding the interplay between underlying physical factors and psychologic ones. A comprehensive approach to such patients is clearly indicated. Litigants pose special problems since their potential financial gains ma] be large and their sense of outrage at a poison environment intense.
disorders
247
ANXIETY DISORDERS Panic disorder Panic disorder is characterized by intense, recurrent episodles of apprehension or terror associated with fears of death or impending doom. These attacks are commonly associated with dyspnea, palpitations, chest pain or discomfort, choking or smothering sensations, dizziness, vertigo, hot and cold flashes, sweating, faintness, trembling or shaking, and fears of going crazy or dying. Panic disorder research suggests that there may be an underlying physical disorder associated with the condition. Reports of a high incidence of mitral valve prolapse in panic disorder”8 suggest some underlying biologic basis for this condition. In addition, all of the symptoms and signs of a typical panic attack can be reproduced by infusion of sodium lactate, suggesting that some derangement of lactate metabolism may be a mediating factor in the condition.” Anaphylactoid reactions to foods or chemicals could conceivably be ‘confused with this disorder since they share several features such as rapid onset and prominent cardiovascular and autonomic symptoms. However, since anaphylactoid reactions occur in close proximity to food exposure. the relationship to food ingestion is usually readily apparent. Generalized
anxiety
reaction
Generalized anxiety reaction is characterized by persistfznt anxiety for at least 1 month’s duration. The cardinal features are motor tension with fatigability, restlessness, autonomic reactivity such as sweating, palpitations, tachycardia, diarrhea, apprehensive expectations, and hypervigilance. The causes of this disorder are unknown. Some researchers consider anxiety reactions as manifestations of a breakdown in the individual’s capacity to psychologically cope with a stressful situation. and it is clear in some situations that either assisting the patient in coping with some stressful situation or altering the situation leads to successful treatment of the anxiety condition. Benzodiazepine anxiolytic agents are usually effective in controlling these disorders. Confusion over the relationship between cardiac symptoms and symptoms of anxiety is frequently encounte!red. Miles and Cobb”’ attempted to clarify the relationship between neurocirculatory asthenia and neurotic anxiety. They suggested that quantitative differences between the two types could be delineated, with a clearer suggestion of a metabolic or physiologic process present in neurocirculatory asthenia and a clearer suggestion of a psychogenic factor in anxiety. Patients with food complaints often mention anxiety symptoms as food related. In these cases a trial of
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standard anxiolytic medication such as one of the benzodiazepine class of drugs would help discriminate between a generalized anxiety disorder and a foodrelated anxiety state. CHILDHOOD
PSYCHIATRIC
DISORDERS
Most studies of relationships between food sensitivity and childhood psychiatric disorders have been carried out with children who have what is currently termed “attention deficit disorder.” This term has replaced a number of popular terms that have not withstood tests of reliability and validity. Minimal brain dysfunction, hyperkinesis, and learning disability are among the terms formerly used for this group of patients. Attention defcit disorder is characterized by “developmentally inappropriate attention, impulsivity, and hyperactivity.” Inattention may be manifested by a frequent failure to complete tasks, failure to listen, easy distractibility, and difficulty concentrating on schoolwork or other tasks requiring sustained attention. Impulsivity is indicated by the child acting without thinking, shifting from one activity to another, difficulty organizing work, need for supervision, calling out in class, and difficulty awaiting turn in games or group situations. Hyperactivity is indicated by running about or climbing on things excessively, difficulty sitting still or fidgeting excessively, difficulty staying seated, moving about excessively during sleep, and always being “on the go” or “driven by a motor.” The condition begins before the age of 7 years and has lasted at least 6 months. Several articles suggest a relationship between food sensitivity and attention deficit disorder. One particularly intriguing report indicated that transcallosalevoked potential latencies dropped from more than 70 msec to under 20 iafter the institution of a hypoallergenic diet in presumably food-sensitive children with learning disabilities.” Methods of transcallosal potential latency me:asurement are open to question but, if replicated, this report would suggest that interhemispheric communication was dramatically slowed in some food-sensitive, learning-disabled children. Others have been unable to reproduce putative behavioral effects of foods in double-blind challenges. While it has been tempting to assert that the allergic problem “caused” the behavior dysfunction, this conclusion may not be warranted. A more complete explanation of the behavioral dysfunction may need to include an underlying predisposition to behavioral dysfunction based on psychologic or neurophysiologic factors that are (perhaps) aggravated by the allergic condition. For exam,ple, Kittler and Baldwin”’ have
CLIN. IMMUNOL. JULY 1986
reported that food allergy can aggravate the behavioral dysfunction of children with “minimal brain dysfunction.’ ’ Millman et al. ix reported that a combination of psychotherapy and allergy therapy improved the school performance and behavior of a series of learning-disabled children as assessed by several neuropsychologic assessment instruments. CEREBRAL ALLERGY Because of the widespread reports of food sensitivity producing behavioral effects, the question has been raised as to whether food could produce effects on the brain and behavior in the absence of effects on other body systems. Reasoning from analogy with asthma or hay fever, the contention is made that the brain can be singled out for organ-specific “cerebral allergy.” However, a review of the case histories of several workers in this field suggests that individuals with food sensitivity with only brain and behavioral dysfunction must be extremely rare. Virtually all of the several hundred appropriately complete case histories reviewed contained reference to both physical and mental signs and symptoms. Specifically, the patients reported by Randolph” in his article on psychiatric patients reported a variety of allergic symptoms such as rhinitis, hives, bronchitis, and asthma accompanying their psychologic complaints. In Davison’s initial report of “cerebral allergy,“” he summarized results from 87 patients. “In only four of these patients were symptoms of cerebral allergy present alone; in the other 83 cases, from one to seven other allergic manifestations were present. These were usually asthma, hay fever, urticaria, angioedema, eczema, and either gastrointestinal or genitourinary manifestations.” Seventy-two patients had a family history of allergy. Clarkes” surveyed 171 allergists and received case histories from them of behavioral or cerebral reactions to foods. Among the 24 patients presented in his report, all but two also had prominent allergic symptoms at the time of evaluation. It seems likely that occasional patients might have predominantly behavioral complaints but a careful history and physical examination would usually reveal additional physical signs and symptoms. If nearly all patients described as having central nervous system complaints on the basis of allergy in fact have other stigmata of allergic or hypersensitivity disease, the issue shifts somewhat to that of trying to determine whether the allergic condition actually caused the behavioral condition on a physiologic basis or whether the psychologic or behavioral dysfunction is a primarily psychologic reaction to being physically ill.
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SUMMARY
Reactions
AND CONCLUSIONS
There is some evidence in the literature that adverse reactions to foods can contribute to behavioral dysfunction. In view of what is known about food and behavior, this suggestion is entirely plausible. However. clear demonstrations of adverse behavioral reactions to foods have not been reported. The major methodologic problems are those of defining suitable baseline conditions and dealing with large ranges in dose, time course, and severity of reactions among putatively food-sensitive individuals. These problems, although l,arge, are surmountable. Another problem for studies in this area is nomenclature. The imprecision with which terms are used undoubtedly will diminish as the various mechanisms by which food can affect individuals are delineated. Until these issues are clarified, we are confronted with a group of patients who are convinced that their symptoms are somehow related to the food that they eat. Somta basic guidelines may help in the initial screening of these patients. (1) If a history of behavioral dysfunction related to food intolerance occurs in the context of otlher signs of allergy or hypersensitivity. it seems prudent to evaluate and treat the allergic or hypersensitivity condition and note the effect of that treatment on behavior. (2) If the food complaints occur in the context of marked suggestibility and large numbers af unexplained complaints are registered without any evidlence of allergy or hypersensitivity, a diagnosis of somatization disorder should be entertained. (31 If food complaints occur in a patient who does not meet the criteria for somatization disorder, a working diagnosis of undiagnosed medical condition should be entertained. A simple initial approach of a diet and behavior diary followed by an open trial with elimination and challenge with suspected foods may be useful in determining whether further studies are warranted (4) If food complaints occur in a context of clear psychologic conflict and an absence of objective signs of allergy or hypersensitivity. a diagnosis of conversion disorder should be entertained. Such patients are often helped by support, reassurance, and suggestion. (5) :Some patients report that the mere sight of a food
to foods:
Relevance
to psychiatric
disorders
249
These various issues will finally be resolved when the mechanisms mediating these reactions are understood and reliable dia,gnostic tests and effective treatments are developed. REFERENCES 1. Anderson GH, Johnston JL: Nutrient control of bram neurotransmitter synthesis and function. Can J Physiol Pharmacol 61271, 1983 2. Wurtman RJ: Food consumption. neurotransmitter synthesis and human behavior. Expenentia 44:356. 1983 3. Mandell M. Rose GJ: May emotional reactions be precipitated by &ergens. Conn Med 32:300, 1968 4. Ader R, Cohen N: Behaviorally conditioned immunosuppression. Psychosom Med 37:333. 1977 5. Bartrop RW. Luckhurst E, Lazarus L, Kiloh LG. Penny R: Depressed lymphocyte function after bereavement. Lancct i:834, 1977 6. Keller SE. Weiss JM, Schleifer SJ. Miller NE. Stein M: Suppression of immunity by stress: effect ot a graded series of stressorr on lymphocyte stimulation in the rat. Science 213:1397, 1981 7. Dohan FC, Grasberger JC: Relapsed schizophremch: earlier disc’harge from hospital after cereal-free milk-free diet. Am J Psychiatry 130:685, 1973 8. Dohan FC, Harper EH, Clark MH, Bodrigue RB. Zigas V: Is schizophrenia rare if grain is rare? Biol Psychiatry 19:385, 19x4 9. Dohan FC: Cereals and schizophrenia: data and hypothesis. Acta Psychiatr Stand 42:125. 1966 10. Singh MM. Kay SR: Wheat gluten as a pathogemc factor in schizophrenia. Science I91 :40 I, I976 II Rice JR. Ham CH, Gore WE: Another look at gluten in schizophrenia. Am J Psychiatry 135:1417. 1978 12. Hemmings WA, Williams EW: Transport of large breakdown products of dietary protein through the gut wall. Gut 19:715. I978 13 Ziobdrou C, Streaty RA, Klee WA: Opioid peptldes derived from food proteins. The exorphins. J Biol Chem 254:2446. I970 14 Jansson B, Kristjansson E, Nilsson L: Schizophrenic psychotic picture decreased in a patient given gluten-free diet. Lakartidningen 8 I :448, I984 15 Torr:y E, McGuire M, O’Hare A, Walsh D. Spellman MP: Endemic psychosis in western Ireland. Am J Psychiatry 141:966, 1984 16 Cooke WT, Johnson AF, Wolff AL: Vital staining and electron microscopy of the intramuscular nerve endings in the neuropathy of adult coeliac disease. Brain X9:663. 1966 17 Cooke WT. Smith WT: Neurological disorders associated with adult coeliac disease. Brain 89:683, 1966 18 Crqton JW, Meltzer HY: Degeneration and regeneration of motor neurons in psychotic patients. Biol Psychiatry 14:803. 1979 19 Craqton JW. Stalberg E. Hilton-Brown P: The motor unit in psychiatric patients: a single fiber EMG study. J Neural Neurosurg Psychiatry 40:455, 1977 20 Ashkenazi A, Krasilowsky D, Levin S. et al: Immunologic action of psychotic patients to fractions of gluten. Am J Psychiatry 10:1306, 1979 21 Potkin SC?, Weinberger D, Kleinman J, et al: Wheat gluten challenge in schizophrenic patients. Am J Psychiatry 138: 1208, 1981
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22. Storms LH, Clopton JM, Wright C: Effects of gluten on achizophrenia. Arch Gen Psychiatry 39:323, 1982 23. Osborne M. Crayton JW, Javaid J, Davis JM: Lack of effect of a gluten free diet on neuroleptic blood levels in schizophrenic patients. Biol Psychiatry 17:627, 1982 24 Dcnman AhZ: The relevance of immunopathology to research into schizophrenia. In Hemmings J, editor: Biochemistry of schizophrenia and addiction. Lancaster, 1980. MTP Press 25. Kinnell HG. Kirkwood E. Lewis C: Food antibodies in schizophrenia. PsyLhol Mcd 12:85. 1982 26. Ossofsky HJ Endogenous depression in infancy and childhood. Compr Psychiatry 15: I 9, I974 27. Oslofsky HJ Affective and atopic disorders and cyclic AMP. Compr Psychiatry I7:335. 1976 2X. Nasr S. Altman EB. Meltzer HY: Concordance of atopic and atfcctive disorders. J Affect Dis 3:291, 1981 29. Richelson E: Pharmacology of antidepressants in use in the United States J Clin Psychiatry 43:4, 1982 30. Rix KJB, Pearson DJ. Bentley SJ: A psychiatric study of patients with supposed food allergy. Br J Psychiatry 145:121. I984 ?I Pearson DJ, Rix KJ, Bentley SJ: Food allergy: how much in the mind’? A clinical and psychiatric study of suspected food hypersensitivity. Lancet 1: 1259, 1983 32. May CD: Food sensitivity: facts and fancies. Nutr Rev 42:72. I984 33. Marks IM: Research in neurosis: a selective review. I Causes and courses. Psycho1 Med 3:436, 1973 34. Marks IM: Research in neurosis: a selective review. 2. Treatment. Psycho1 Med 4:89. 1974 3.i. Randolph T: Fatigue and weakness of allergic origin (allergic toxemia) to be differentiated from nervous fatigue or neurasthenia. Ann Allergy 3-4:418, 1945-1946 36. DSM-III Diagnostic and statistical manual of mental disorder\. ed 3. M’ashington. DC, 1980, American Psychiatric Association 37. Chatel JC. Peele R: A centennial review of neurasthenia. Am J Psychiatry l-6:1404, 1970 3X. Veith I: Hysteria: the history of a disease. Chicago, 196.5. University of Chicago Press 39 Beard CM: A practical treatise on nervous exhaustion (neurasthema. New York. 1880. William Ward
Summary Dean D. Metcalfe,
IMMUNOL. JULY 1986
40. Mitchell SW: Fat and blood: an essay on the treatment ofcertam forms of neurasthenia and hysteria. ed 8. Philadelphia. 191 1, JB Lippincott Co 41. Freud S: The justification of detaching from neurasthenia a particular syndrome: the anxiety neurosis (I 894). In Early psychoanal!/tic writings. New York, 1963, Collier Books 42. Allen F: The differential diagnosis of ujeakne\a and fatigue. N Engl .I Med 231:414, IV44 43. Randolph T: Allergy as a causative factorof fatigue. irritability, and behavior problems of children. J Pediatric\ 3 I :560. I947 44. Woodruff R. Clayton P, Guze S: Hysteria--studie\ of dragnosib, omcome, and prevalence. JAMA 2 15:425. lY7l 45. Woodruff RA, Guze SR, Clayton P: Hysteria and antisocial behavior Am J Psychiatry l27:957. 1971 46. Perley Ml. Guze S: Hysteria-the stability and usefulnes\ of clinical criteria. N Engl J h4ed 266:42 I. 1962 47. Brodsky CM: “Allergic to everything.” A medical subculture. Psychosomatic\ 24:73 I, I984 48. Klein DF. German JM: Panic disorders and mitral valve prolapse. J Clin Psychiatry (Monogr Ser) 2: 14, 19X4 49. Pitts FN: Lactate, beta-agonists, beta-blockers, and anxiety. J Clin Psychtatty (Monogr Ser) 2:25, 1984 50. Miles HH, Cobb S: Neurocirculatory asthenia anxiety and neurosis. N Engl J Med 245:7l I, 1951 51. Hughes EC: Use of a chemically defined diet in the diagnosis of food sensitivities and the determination of offending mods. Ann Allergy 40:393. 197X 52. Kittler FJ, Baldwin DC: The role of allergic factors in the child with minimal bram dysfunction. Ann Allergy 28:203. I970 53. Millman h4. Campbell MB. Wright K, Johnston A: Allergy and lcamirg disabilities in children. Ann Allergy 36: 149. I976 54. Randolph T: Clinical ecology as it affects the psychiatric patient. Int J Sot Psychiatry 12:245, 1966 55. Davison HM: Cerebral allergy. South Med J 42:712, I942 56. Clarke TW: The relation of iallergy to character problems in children. Ann Allergy 8:175. 1950 57. Rowe AH, Rowe A Jr: Food allergy. Its manifestations and control and the eliminated diets. A compendmm. Springtield. 1972. Charles C Thomas. Pubhsher
and recommendations M.D. Bethesda, Md.
From the Mast Cell Physiology Section, Laboratory of Clinical Investigation, Natronal Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 20892 Reprint requests: Dean D. Metcalfe, Head, Mast Cell Physiology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. National Institutes of Health, Bethesda, MD 20892.
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The abundance of mast cells and their release of potent chemical mediators as a result of immunologically mediated activation in mammalian skin, gastrointestinal, and pulmonary tissues are in large part responsible for these tissues being the primary sites of allergic reactions. The accessibility of the skin to
29.
30. 3 I. 32.
33. 34.
35.
36.
37.
3X. 39.
40.
41.
42. 43. 44.
78 1, PART 2
Medications
T. Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized lsolyethylene glycols. Clin Allergy 14:277, I984 Dannaeus A. Inganas M, Johansson SC, Foucard T: Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally administered sodium cromoglycate. Clin Allergy 9:263. 1979 Soothill JF: Food allergy. In Pepys J, Edwards A. editors: The mast cell. London, 1979, Pitman Publishing Ltd, p 825 Berman HA: Cromolyn: past, present, and future. Pediatr Clin North Am 30:915. 1983 Brogden RN, Speight TM, Avery G: Sodium cromoglycate (cromolyn sodium): a review of its mode of action, pharmacology, therapeutic efficacy and use. Drugs 7: 164, 1974 Settipane GA. Klein DE, Boyd GK, et al: Adverse reactions to cromolyn. JAMA 241:81 I. 1979 Sheffer AL, Rocklin RE. Goetzl EJ: Immunologic components of hypersensitivity reactions to cromolyn sodium. N Engl J Med 293 1220, 1975 Bahna PL, Gandhi MD: Milk hypersensitivity. II. Practical aspects of diagnosis, treatment and prevention. Ann Allergy 50:295. 1983 Basomha A. Campos A, Villalmanzo IG, Pelaez A: The effect of sodium cromoglycate (SCG) in patients with food allergies. Acta Ailergol I3(suppl):95, 1977 Esteban MM, Ojeda JA, Laso MT, Pascual C: Oral sodium cromoglycate in food allergy. Acta Allergol 13(suppl): 102. 1977 Freier S: A therapeutic trial of disodium cromoglycate in gastrointestinal allergy. Acta Allergol 13(suppI): 109, 1977 Harries MC. O’Brien IM, Burge PS, Pepys J: Effects of orally administered sodium cromoglycate in asthma and urticaria due to food>. Clin Allergy 8:423, 1978 Dannaeus A, Foucard T, Johansson GO: The effect of orally administered sodium cromoglycate on symptoms of food allergy. (‘Iin Allergy 7:109, 1977 Businco L. Cantani A, Benincori N, Perlini R. Infussi R, De Angelis M. Businco E: Effectiveness of oral sodium cromoglycate (SCG) in preventing food allergy in children. Ann Allergy 5I:47, 1983 Watson JB. Tirnmins J: Food allergy: response to treatment with sodium cromoglycate. Arch Dis Child 54:77, 1979 Vaz GA. Tan LIK, Gerrard JW: Oral cromoglycate in treatment of adverse reactions to foods. Lancet 1:1066. 1978 Ortolani C. Pastorello E, Zanussi C: Prophylaxis of adverse reactions to foods. A double-blind study of oral sodium cro-
45. 46.
47.
48. 49.
50. 51. 52. 53. 54. 55.
56.
57.
58.
59.
60.
of reactions
to foods
moglycate for the prophylaxis of adverse reactions to foods and additives. Ann Allergy 50:105. 1983 Bernstein IL, Johnson CL: Therapy with cromolyn sodium. Ann Intern Med X9:228, 1978 Denman AJ, Kingsley PJ, Brereton P: Controlled trials of oral disodium cromoglycate in chronic urticaria and suspected food allergy. In Pepys J, Edwards AM, editors: The mast cell-its role in health and disease. London. 1979. Pitman Publishing Ltd. p 597 Molkhou P, Waguet JC: Food allergy and atopic dermatitis in children: treatment with oral sodium cromoglycate. Ann Allergy 47:173. 1981 Lindskov R, Knudsen L: Oral disodium cromoglycate treatment of atopic dermatitis. Allergy 38: 161, 1983 Graham P. Hall-Smith SP, Harris JM. Price ML: A study of hypoallergenic diets and oral sodium cromoglycate in the management of atopic eczema. Br J Deimatol 110:457, 1984 Freier S, Berger H: Disodium cromoglycate in gastrointestinal protein intolerance. Lancet 1:913, 1973 Kocoshis S, Gryboski JD: Use of cromolyn in combined gastrointestinal allergy. JAMA 242:I 169. 1979 Bolin TD: Use of oral sodium cromoglycate in persistent diarrhoea. Gut 21:848, 1980 Gerrard JW: Oral cromoglycate: its value in the treatment of adverse reactions to foods. Ann Allergy 42: 135, 1979 Kingsley PJ: Oral sodium cromoglycate in gastrointestinal allergy. Lancet 2: 101 I, 1974 Ratner PH. Davis SH, Rodriguez LM, DeVillez RL, Kniker WT: The efficacy of rotary elimination diet and of oral cromolyn in the management and prevention of atopic eczema (abstract): International Symposium on Prevention of Allergic Diseases. Florence, June 24-27, 1984 Dahl R: Oral and inhaled sodium cromoglycate in challenge test with food allergens or acetylsalicylic acid. Allergy 36: 161. 1981 Bulks A, Sampson H: Double-blind placebo-controlled trial of oral cromolyn sodium in children with egg hypersensitivity. J AL,-ERG CLIN IMMUNOL 77: 184, 1986 (abst) Dahl R, Zetterstrom (3: The effect of orally administered sodium cromoglycate on allergic reactions caused by food allergens. Clin Allergy 8:419, 1978 Dahl R: Disodium cromoglycate and food allergy. The effect of oral and inhaled disodium cromoglycate in a food allergic patient. Allergy 33:120, 1978 Salberg DJ: Cromolyn in combined gastrointestinal allergy (letter 1. JAMA 244:546. 1980
Adverse reactions to foods: psychiatric disorders John W. Crayton,
and use in treatment
Relevance to
M.D. Chicugo, 111.
From the 1)epartment of Psychiatry, the University of Chicago, Chicago. Ill. Reprint requests: John W. Crayton, M.D., Associate Professor of Psychiatry. The University of Chicago, 5841 S. Maryland Ave., Chicago. IL 60637.
Food has been reported to affect behavior by altering the levels of central nervous system neurotransmitter substances’, ’ or by the direct actions of psychopharmacologic agents in foods (such as caffeine or phenylethylamine‘,. Indirect effects of foods on be243
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Cravtor!
havior via immunologic or allergic mechanisms have been postulated but the evidence available is not yet clear or convincing. The known and postulated effects of food on behavior have stimulated interest in the possibility that adverse reactions to foods might contribute to the development of mental illnesses such as schizophrenia and depression. This article surveys some of the reported assocrations between adverse reactions to foods and psychiatric diagnostic entities. In surveying these reports, two major trends in current psychiatric research should be emphasized. First, it is generally accepted that the expression of all illness, “physical” or “mental,” reflects an intricate interplay between physical and psychologic factors. The patient’s mental state influences how physical illness is experienced and communicated. Consequently, categorization of illness as mental or physical is a simplification that may be useful but may also be misleading. With respect to food sensitivity and behavior, a model similar to that of Mandell and Rose’ may be invoked to illustrate this principle. They hypothesized that the allergic reactions of their patient produced physiologic changes that were perceived by the patient and responded to according to her particular psychologic makeup and the nature of the conflict of immediate concern to her. Such an interactive model suits the complexity of most cases of food and chemical sensitivity with behavioral manifestations. The second principle is that a patient’s mental state may influence the body’s physiologic coping mechanisms, including the reactivity of the immune system. The evidence suggests that immunoreactivity may be altered by, mental dysfunction.Jmh If so, abnormal immunoreactivity to allergens may be secondary to mental illness not causal of it. With these principles in mind, this review summarizes some possible links between adverse reactions to foods and psychiatric disorders. While no putative links have yet been definitively shown. a few areas appear worthv of further study. SCHIZOPHRENIA Dohan et al.’ ’ suggested that wheat ingestion in genetically predisposed individuals may aggravate schizophrenic symptoms and may even be a cause of schizophrenia. Epidemiologic studies suggest that schizophrenia is seldom seen in cultures in which wheat consumption is low, but the incidence rises when wheat IS introduced into the culture.’ Dohan’ also points to a direct relationship between wheat consumption and the number of admissions to mental hospitals for schizophrenia in European countries during World War II as further evidence for a wheatschizophrenia link. These epidemiologic studies could
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not control for important confounding variables, but they stimulated interest in more focused studies of schizophrenic patients. Singh and Kay”’ and Rice et al. ” also report cases of apparently wheat-sensitive schizophrenic individuals, although the percentage of schizophrenics with wheat sensitivity may be relatively small. Further support for the wheat-schizophrenia link comes from studies suggesting that the incidence of antigliadin antibodies in schizophrenics is higher than that in nonschizophrenics, that peptide fragments of wheat gluten can enter the brain of experimental animals,” and that wheat gluten has endorphin-like activity.‘” Recently Jansson et al.“’ described a patient with schizophrenia who dramatically improved on a gluten-free diet. If there is an association, Ireland would seem to be a propitious area to study the relationship because the incidence of both disorders is high.” However, careful studies of gliadin antibody levels in schizophrenic subjects and follow-up intestinal biopsy studies of antibody-positive subjects failed to find any basis for an association. Patients with gluten-sensitive enteropathy and schizophrenia also share certain neuropathologic and immunologic traits that suggest some overlap between the two conditions. Patients with both celiac disease”. ” and schizophrenia” ” show evidence of a peripheral motor neuropathy that may reflect a more widespread nervous system degeneration. Both patient groups also show similar patterns of lymphocyte stimulation with gluten as assessed by migration inhibition factor assay.‘” Not all studies have been supportive of the hypothesis, however. Potkin et al.” reported no effect of a gluten-free diet in schizophrenic subjects and Storms et al.” similarly failed to find a beneficial effect of the diet. By analogy with celiac disease. Dohan” has argued that patients with chronic schizophrenia may not show improvement for many months, if ever, after instituting a gluten-free diet because the effects of the gluten may eventually become reversible. Osborne et al.” studied six patients with chronic schizophrenia on a gluten-free diet for 9 months without seeing any significant improvement. Other foods have rarely been associated with frank psychotic symptoms. Milk produced overt psychotic symptoms during double-blind challenges in a 14year-old girl with a history of gastrointestinal intolerance to milk in childhood.” Kinnell et a1.‘5 failed to find an increased incidence of antifood antibodies in schizophrenic subjects. DEPRESSION While anorexia is the more common response to significant depressive illness, increased appetite is of-
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Reactions
ten seen in depressed patients. The increase in appetite may be ;is,sociated with specific food cravings, particularly !‘or chocolate and carbohydrates. While these cravings have usually been attributed to a symbolic “feeding” of the self by a defeated and depleted psyche, Wurtman’s studies’ of the effects of carbohydrate loading on brain neurotransmitter metabolism suggests an alternative hypothesis. Increasing the proportion of carbohydrate in the diet tends to increase the amount of tryptophan entering the brain and consequently raises the amounts of serotonin available for neurotransmissi’on. Since hypoactivity of serotoninergic pathways has been proposed as a mechanism mediating some forms of depression. the carbohydrate craver could be attempting to raise serotonin levels via this mechanism. Evidence that central serotonin levels can influence the proportions of carbohydrate and protein selected in the diet has been used to support this notion ’ A second body of data links allergy to depression. Ossofsky” 37and Nasr et a1.28have reported a high incidence of allergy in depressed patients, although a specific breakdown as to type of allergy was not addressed. In the study of Nasr et al. the incidence of allergy was about 33% in the depressed patients and 2% in a control group of schizophrenic patients. In Ossofsky’s studies the incidence of atopy was more than 70% in the depressed patients. The apparently high incidence of “allergy” in depression requires further study. Since tricyclic antidepressant medications are potent antihistamines,‘” a common histamine-mediated lpathway might be invoked in certain allergic-depressive patients. Little systematic study has been done of food sensitivity in depressed patients. The studies of Rix et al. “’ and Pearson et al.3’ attempted to determine the true incidence off food allergy in allergy clinic patients with psychologic complaints. Ten of their 18 subjects were diagnosed as having depressive neuroses. They were unable to confirm the presence of food allergy in the subjects ,with psychologic complaints that the subjects had attributed to foods. The lack of detail regarding the fo’od challenge methodology makes this study difticult to assess. SOMATIZATION
DISORDER
Perhaps the most commonly encountered type of patient with complaints of food sensitivity and behavioral symptoms will prompt a consideration of the somatization disorders. Patients with numerous unexplained physical symptoms present a special challenge to the physician. These patients require inordinate attention, time, and support. May” has pointed out the remarkable similarity between neurotic symptom? 34 and the allergic tension-fatigue syndrome.“’ This sim-
TABLE
to foods:
Relevance
I. Syndromes
to psychiatric
of multiple
245
disorders
somatic
complaints
Symptoms
Fatigue. sickly Food intolerance
Gastrointestinal symptoms (pain, nausea, vomiting, etc) Arthralgias Myalglas Cognitive deficits (memory, concentration, etc) Palpitations Insomnia Headache Depression Irritability Nasal symptoms Hives Eczem,l Deafness Blindness Loss of voice Convulsions Sexual indifference
Neurasthenia”
Allergic tension fatigue5’
Somatoform disordeP
+
t
+
+ +
+ +
+ +
+ + +
+ + +
+ + +
+ + + + + 0 0 0 0 0 0 0 0
+ + + + + + + + 0 0 0 0 0
+ 0 0 0 0 0 0 0 + + + + +
ilarity of symptom profiles raises the question of how to discriminate between symptoms that are being attributed to food sensitivity and those that stem from neuro5is. The new psychiatric nomenclature published in 1980 collects several disorders characterized by complaints, about physical symptoms under the rubric somatoform disorders.” These conditions include somatization disorder, conversion disorder, psychogenic pain disorder, and hypochondriasis. Specific diagnostic criteria for each of these conditions facilitates our undeistanding of the relationship between physical and paychologic complaints and how to discriminate between the two. It is of interest to trace the evolution of these concepts lover the past 100 years, since this evolution illustrates a variety of approaches to the problem of distinguishing between psychologic and physical conditions,‘7, 3X(Table I). In 1880 Charles Beard” published his (then) widely regarded monograph of neurasthenia, a condition characterized by fatigue, irritability, mental confusion, peculiar intolerances to various foods, and a variety of other somatic complaints. He noted that diet was a particularly important aspect of the treatment of patients with neurasthenia.
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In particular, a fast was found to produce rapid improvement in some patients after 4 or 5 days. Beard’s suggestions were amplified by Mitchell,30 a member of the National Academy of Sciences. Mitchell proposed that patients with neurasthenia lacked the capacity to form these two substances, and his treatment was designed to increase their capacity to form them. Diet was a central aspect to his treatment. He advocated a single-food (diet of boiled skim milk in gradually increasing amounts. While diet was a central feature of both Beard and Mitchell’s systems, they cannot be considered the sole reason for improvement, since both used treatments with multiple modalities including psychotherapy, exercise, hot baths, and, perhaps most of all. intense interest and support by the physician. The term neurasthenia is seldom used today in this country, although it is still commonly used in Europe and the Soviet Union. What happened to neurasthenia (Table I)? Clearly, as originally formulated, neurasthenia encompassed a wide variety of physical and mental disorders. As early as the 1880s more distinct groupings within this rather heterogenous group were being made. Freud” pointed out the differences between the anxiety neuroses and neurasthenia. The hysteric invariably expressed (her) psychologic conflict in physical terms, so that one could always find an intense psychologic dysfunction underlying the somatic dysfunction of the hysteric patient. Psychologic underpinnings were not found in patients with neurasthenia. No primary (intrapsychic) or secondary (interpersonal) gain could be found to explain the development of symptoms in the patients with neurasthenia. Consequently, at this early juncture an important distrnction between hysteria as a predominantly psychologic illness and neurasthenia as a predominantly physiologic illness had been made. In I944 Allen”’ reported. on a large series of patients with a chief complaint of fatigue and weakness. He found that in only 20% of the cases could a physical condition be found to explain the complaints. The other 80% of cases were attributed to neurasthenia or “benign nervousness.” In rebuttal, Randolph”’ proposed that many patients diagnosed as neurasthenic were more accurately described as suffering from allergictension fatigue. Certainly the similarity in symptom constellations in the two disorders is striking. Both are characterized by fatigue, irritability, depression, difficulty concentrating, and a wide variety of physical complaints. The term neurasthenia is no longer used in this country and presumably patients with this diagnosis have been absorbed by other diagnostic entities such as somatization disorder, conversion disorder, dysthymic disorder. and the group of “cardiac neuroses.”
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Similarly, there is question as to whether allergictension fatigue exists as a distinct diagnostic entity. If it can be validated, subjects with this disorder may be found Im the group of patients now diagnosed to have one of the somatoform or anxiety disorders. Table I suggests that there may be considerable overlap among the three syndromes of multiple somatic complaints. While many of the symptoms are shared by the three syndromes. there are interesting differences in the symptoms. Both neurasthenia and the allergic tension-fatigue syndrome list affective symptoms such as depression and irritability as features while somatoform disorder does not. The allergic tension-fatigue syndrome is the only one of the three to specifically mention common allergic complaints such as hives, eczema, and nasal symptoms. Somatization di’sorder uses clearly “hysteric” symptoms such as blindness, deafness, and convulsions as criteria. These differences, as well as the other specific inclusion and exclusion criteria for somatoform disorder, may help clue the physician in to which of these closely related and overlapping conditions is present. Somatization disorder is characterized by a history of numerous physical complaints of several years’ duration beginning before the age of 30 years. The specific criteria for inclusion in this category are that the patient must report at least 14 (for women) or 12 (for men) symptoms selected from a list of 37 symptoms. It is most important in making this diagnosis that the quality of the patient’s responses, not just the response itself, be monitored. The criteria indicate that it is not necessary that the patient actually experience the symptom, only that they report it. Consequently, this category of illness taps a quality of suggestibility and complaint proneness in the patient.“’ In addition, patients with somatization disorder tend to have a high degree of sociopathic tendencies such as delinquency, fighting, rage attacks, and truancy.“> Early research into this condition by the Washington University group 51.1sindicated that this physical cornplaint-prone group represented a stable category of dysfunction. These patients did not go on to have significant physical illness that later “explained” their illness. They noted that this condition started early in life, usually in the teens or early 20s. Patients who met the criteria for multiple complaints after the age of 30 years were likely to have underlying physical illness. Another important aspect of this work is that patients with fewer than the required number of somatic complaints were diagnosed as having an “undiagnosed medical condition.” These patients tended to go on to show signs and symptoms of a medical condition alnd did not show the stable course of the group with somatization disorder. Since patients with numerous somatic complaints
VOLUME NUMBER
Reactions to foods: Relevance to psychiatric
78 1. PART 2
frequently complain of food sensitivities, the distinction between food sensitivity and somatization disorder could be difficult. Forty-eight percent of the patients who met the criteria for somatization disorder complained of food intolerance.46 It would be interesting to determine the distribution of numbers of complaints in food-sensitive individuals and compare those who also meet DSM-III criteriajh for somatization disorder with those who do not. Conversion
disorder
Conversion disorder is diagnosed when there is a predominant physical complaint suggestive of a physical disorder but that is thought to be due to psychologic factors. Patients may develop physical complaints to help lresolve a conflictive problem, avoid some unpleasant or stressful situation, or elicit support from the environment. Individuals with this condition have been helped through suggestion, reassurance, and support. They ordinarily complain of only one symptom and classically show surprisingly little concern for the disability even though it would seem to be extremely disabling. Several featur’es of conversion disorder are helpful in distinguishing it from a true medical condition and, specifically, food sensitivity. True food-sensitive patients would generally lack a clear psychologic “meaning” to their symptoms, gain little by having them, and lack the inappropriate indifference of the patient with conversion disorder toward the condition. Hypochondriasis Hypochondriasis is a condition of unrealistic fear of having a serio’us illness. Patients misinterpret physical signs as abnormal or as indicative of life-threatening illness. They resist reassurance by their physician that no physical illness is present and tend to seek out d physician who will confirm their worst fears. The empha.sisin this condition is on the patient’s unrealistic fears of disorder. Brodsky” studied eight litigants who were seeking damages t‘or disabilities that they claimed were due to being “allergic to everything.” Standard medical evaluations had failed to reveal evidence of damage. Clearly, some patients may incorporate their physical problems into conscious or unconscious attempts to obtain compensation, sympathy, and support. The thorny problem presented by these patients is understanding the interplay between underlying physical factors and psychologic ones. A comprehensive approach to such patients is clearly indicated. Litigants pose special problems since their potential financial gains ma] be large and their sense of outrage at a poison environment intense.
disorders
247
ANXIETY DISORDERS Panic disorder Panic disorder is characterized by intense, recurrent episodles of apprehension or terror associated with fears of death or impending doom. These attacks are commonly associated with dyspnea, palpitations, chest pain or discomfort, choking or smothering sensations, dizziness, vertigo, hot and cold flashes, sweating, faintness, trembling or shaking, and fears of going crazy or dying. Panic disorder research suggests that there may be an underlying physical disorder associated with the condition. Reports of a high incidence of mitral valve prolapse in panic disorder”8 suggest some underlying biologic basis for this condition. In addition, all of the symptoms and signs of a typical panic attack can be reproduced by infusion of sodium lactate, suggesting that some derangement of lactate metabolism may be a mediating factor in the condition.” Anaphylactoid reactions to foods or chemicals could conceivably be ‘confused with this disorder since they share several features such as rapid onset and prominent cardiovascular and autonomic symptoms. However, since anaphylactoid reactions occur in close proximity to food exposure. the relationship to food ingestion is usually readily apparent. Generalized
anxiety
reaction
Generalized anxiety reaction is characterized by persistfznt anxiety for at least 1 month’s duration. The cardinal features are motor tension with fatigability, restlessness, autonomic reactivity such as sweating, palpitations, tachycardia, diarrhea, apprehensive expectations, and hypervigilance. The causes of this disorder are unknown. Some researchers consider anxiety reactions as manifestations of a breakdown in the individual’s capacity to psychologically cope with a stressful situation. and it is clear in some situations that either assisting the patient in coping with some stressful situation or altering the situation leads to successful treatment of the anxiety condition. Benzodiazepine anxiolytic agents are usually effective in controlling these disorders. Confusion over the relationship between cardiac symptoms and symptoms of anxiety is frequently encounte!red. Miles and Cobb”’ attempted to clarify the relationship between neurocirculatory asthenia and neurotic anxiety. They suggested that quantitative differences between the two types could be delineated, with a clearer suggestion of a metabolic or physiologic process present in neurocirculatory asthenia and a clearer suggestion of a psychogenic factor in anxiety. Patients with food complaints often mention anxiety symptoms as food related. In these cases a trial of
248
J. ALLERGY
Cravton
standard anxiolytic medication such as one of the benzodiazepine class of drugs would help discriminate between a generalized anxiety disorder and a foodrelated anxiety state. CHILDHOOD
PSYCHIATRIC
DISORDERS
Most studies of relationships between food sensitivity and childhood psychiatric disorders have been carried out with children who have what is currently termed “attention deficit disorder.” This term has replaced a number of popular terms that have not withstood tests of reliability and validity. Minimal brain dysfunction, hyperkinesis, and learning disability are among the terms formerly used for this group of patients. Attention defcit disorder is characterized by “developmentally inappropriate attention, impulsivity, and hyperactivity.” Inattention may be manifested by a frequent failure to complete tasks, failure to listen, easy distractibility, and difficulty concentrating on schoolwork or other tasks requiring sustained attention. Impulsivity is indicated by the child acting without thinking, shifting from one activity to another, difficulty organizing work, need for supervision, calling out in class, and difficulty awaiting turn in games or group situations. Hyperactivity is indicated by running about or climbing on things excessively, difficulty sitting still or fidgeting excessively, difficulty staying seated, moving about excessively during sleep, and always being “on the go” or “driven by a motor.” The condition begins before the age of 7 years and has lasted at least 6 months. Several articles suggest a relationship between food sensitivity and attention deficit disorder. One particularly intriguing report indicated that transcallosalevoked potential latencies dropped from more than 70 msec to under 20 iafter the institution of a hypoallergenic diet in presumably food-sensitive children with learning disabilities.” Methods of transcallosal potential latency me:asurement are open to question but, if replicated, this report would suggest that interhemispheric communication was dramatically slowed in some food-sensitive, learning-disabled children. Others have been unable to reproduce putative behavioral effects of foods in double-blind challenges. While it has been tempting to assert that the allergic problem “caused” the behavior dysfunction, this conclusion may not be warranted. A more complete explanation of the behavioral dysfunction may need to include an underlying predisposition to behavioral dysfunction based on psychologic or neurophysiologic factors that are (perhaps) aggravated by the allergic condition. For exam,ple, Kittler and Baldwin”’ have
CLIN. IMMUNOL. JULY 1986
reported that food allergy can aggravate the behavioral dysfunction of children with “minimal brain dysfunction.’ ’ Millman et al. ix reported that a combination of psychotherapy and allergy therapy improved the school performance and behavior of a series of learning-disabled children as assessed by several neuropsychologic assessment instruments. CEREBRAL ALLERGY Because of the widespread reports of food sensitivity producing behavioral effects, the question has been raised as to whether food could produce effects on the brain and behavior in the absence of effects on other body systems. Reasoning from analogy with asthma or hay fever, the contention is made that the brain can be singled out for organ-specific “cerebral allergy.” However, a review of the case histories of several workers in this field suggests that individuals with food sensitivity with only brain and behavioral dysfunction must be extremely rare. Virtually all of the several hundred appropriately complete case histories reviewed contained reference to both physical and mental signs and symptoms. Specifically, the patients reported by Randolph” in his article on psychiatric patients reported a variety of allergic symptoms such as rhinitis, hives, bronchitis, and asthma accompanying their psychologic complaints. In Davison’s initial report of “cerebral allergy,“” he summarized results from 87 patients. “In only four of these patients were symptoms of cerebral allergy present alone; in the other 83 cases, from one to seven other allergic manifestations were present. These were usually asthma, hay fever, urticaria, angioedema, eczema, and either gastrointestinal or genitourinary manifestations.” Seventy-two patients had a family history of allergy. Clarkes” surveyed 171 allergists and received case histories from them of behavioral or cerebral reactions to foods. Among the 24 patients presented in his report, all but two also had prominent allergic symptoms at the time of evaluation. It seems likely that occasional patients might have predominantly behavioral complaints but a careful history and physical examination would usually reveal additional physical signs and symptoms. If nearly all patients described as having central nervous system complaints on the basis of allergy in fact have other stigmata of allergic or hypersensitivity disease, the issue shifts somewhat to that of trying to determine whether the allergic condition actually caused the behavioral condition on a physiologic basis or whether the psychologic or behavioral dysfunction is a primarily psychologic reaction to being physically ill.
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SUMMARY
Reactions
AND CONCLUSIONS
There is some evidence in the literature that adverse reactions to foods can contribute to behavioral dysfunction. In view of what is known about food and behavior, this suggestion is entirely plausible. However. clear demonstrations of adverse behavioral reactions to foods have not been reported. The major methodologic problems are those of defining suitable baseline conditions and dealing with large ranges in dose, time course, and severity of reactions among putatively food-sensitive individuals. These problems, although l,arge, are surmountable. Another problem for studies in this area is nomenclature. The imprecision with which terms are used undoubtedly will diminish as the various mechanisms by which food can affect individuals are delineated. Until these issues are clarified, we are confronted with a group of patients who are convinced that their symptoms are somehow related to the food that they eat. Somta basic guidelines may help in the initial screening of these patients. (1) If a history of behavioral dysfunction related to food intolerance occurs in the context of otlher signs of allergy or hypersensitivity. it seems prudent to evaluate and treat the allergic or hypersensitivity condition and note the effect of that treatment on behavior. (2) If the food complaints occur in the context of marked suggestibility and large numbers af unexplained complaints are registered without any evidlence of allergy or hypersensitivity, a diagnosis of somatization disorder should be entertained. (31 If food complaints occur in a patient who does not meet the criteria for somatization disorder, a working diagnosis of undiagnosed medical condition should be entertained. A simple initial approach of a diet and behavior diary followed by an open trial with elimination and challenge with suspected foods may be useful in determining whether further studies are warranted (4) If food complaints occur in a context of clear psychologic conflict and an absence of objective signs of allergy or hypersensitivity. a diagnosis of conversion disorder should be entertained. Such patients are often helped by support, reassurance, and suggestion. (5) :Some patients report that the mere sight of a food
to foods:
Relevance
to psychiatric
disorders
249
These various issues will finally be resolved when the mechanisms mediating these reactions are understood and reliable dia,gnostic tests and effective treatments are developed. REFERENCES 1. Anderson GH, Johnston JL: Nutrient control of bram neurotransmitter synthesis and function. Can J Physiol Pharmacol 61271, 1983 2. Wurtman RJ: Food consumption. neurotransmitter synthesis and human behavior. Expenentia 44:356. 1983 3. Mandell M. Rose GJ: May emotional reactions be precipitated by &ergens. Conn Med 32:300, 1968 4. Ader R, Cohen N: Behaviorally conditioned immunosuppression. Psychosom Med 37:333. 1977 5. Bartrop RW. Luckhurst E, Lazarus L, Kiloh LG. Penny R: Depressed lymphocyte function after bereavement. Lancct i:834, 1977 6. Keller SE. Weiss JM, Schleifer SJ. Miller NE. Stein M: Suppression of immunity by stress: effect ot a graded series of stressorr on lymphocyte stimulation in the rat. Science 213:1397, 1981 7. Dohan FC, Grasberger JC: Relapsed schizophremch: earlier disc’harge from hospital after cereal-free milk-free diet. Am J Psychiatry 130:685, 1973 8. Dohan FC, Harper EH, Clark MH, Bodrigue RB. Zigas V: Is schizophrenia rare if grain is rare? Biol Psychiatry 19:385, 19x4 9. Dohan FC: Cereals and schizophrenia: data and hypothesis. Acta Psychiatr Stand 42:125. 1966 10. Singh MM. Kay SR: Wheat gluten as a pathogemc factor in schizophrenia. Science I91 :40 I, I976 II Rice JR. Ham CH, Gore WE: Another look at gluten in schizophrenia. Am J Psychiatry 135:1417. 1978 12. Hemmings WA, Williams EW: Transport of large breakdown products of dietary protein through the gut wall. Gut 19:715. I978 13 Ziobdrou C, Streaty RA, Klee WA: Opioid peptldes derived from food proteins. The exorphins. J Biol Chem 254:2446. I970 14 Jansson B, Kristjansson E, Nilsson L: Schizophrenic psychotic picture decreased in a patient given gluten-free diet. Lakartidningen 8 I :448, I984 15 Torr:y E, McGuire M, O’Hare A, Walsh D. Spellman MP: Endemic psychosis in western Ireland. Am J Psychiatry 141:966, 1984 16 Cooke WT, Johnson AF, Wolff AL: Vital staining and electron microscopy of the intramuscular nerve endings in the neuropathy of adult coeliac disease. Brain X9:663. 1966 17 Cooke WT. Smith WT: Neurological disorders associated with adult coeliac disease. Brain 89:683, 1966 18 Crqton JW, Meltzer HY: Degeneration and regeneration of motor neurons in psychotic patients. Biol Psychiatry 14:803. 1979 19 Craqton JW. Stalberg E. Hilton-Brown P: The motor unit in psychiatric patients: a single fiber EMG study. J Neural Neurosurg Psychiatry 40:455, 1977 20 Ashkenazi A, Krasilowsky D, Levin S. et al: Immunologic action of psychotic patients to fractions of gluten. Am J Psychiatry 10:1306, 1979 21 Potkin SC?, Weinberger D, Kleinman J, et al: Wheat gluten challenge in schizophrenic patients. Am J Psychiatry 138: 1208, 1981
Cravton
J. ALLERGY
22. Storms LH, Clopton JM, Wright C: Effects of gluten on achizophrenia. Arch Gen Psychiatry 39:323, 1982 23. Osborne M. Crayton JW, Javaid J, Davis JM: Lack of effect of a gluten free diet on neuroleptic blood levels in schizophrenic patients. Biol Psychiatry 17:627, 1982 24 Dcnman AhZ: The relevance of immunopathology to research into schizophrenia. In Hemmings J, editor: Biochemistry of schizophrenia and addiction. Lancaster, 1980. MTP Press 25. Kinnell HG. Kirkwood E. Lewis C: Food antibodies in schizophrenia. PsyLhol Mcd 12:85. 1982 26. Ossofsky HJ Endogenous depression in infancy and childhood. Compr Psychiatry 15: I 9, I974 27. Oslofsky HJ Affective and atopic disorders and cyclic AMP. Compr Psychiatry I7:335. 1976 2X. Nasr S. Altman EB. Meltzer HY: Concordance of atopic and atfcctive disorders. J Affect Dis 3:291, 1981 29. Richelson E: Pharmacology of antidepressants in use in the United States J Clin Psychiatry 43:4, 1982 30. Rix KJB, Pearson DJ. Bentley SJ: A psychiatric study of patients with supposed food allergy. Br J Psychiatry 145:121. I984 ?I Pearson DJ, Rix KJ, Bentley SJ: Food allergy: how much in the mind’? A clinical and psychiatric study of suspected food hypersensitivity. Lancet 1: 1259, 1983 32. May CD: Food sensitivity: facts and fancies. Nutr Rev 42:72. I984 33. Marks IM: Research in neurosis: a selective review. I Causes and courses. Psycho1 Med 3:436, 1973 34. Marks IM: Research in neurosis: a selective review. 2. Treatment. Psycho1 Med 4:89. 1974 3.i. Randolph T: Fatigue and weakness of allergic origin (allergic toxemia) to be differentiated from nervous fatigue or neurasthenia. Ann Allergy 3-4:418, 1945-1946 36. DSM-III Diagnostic and statistical manual of mental disorder\. ed 3. M’ashington. DC, 1980, American Psychiatric Association 37. Chatel JC. Peele R: A centennial review of neurasthenia. Am J Psychiatry l-6:1404, 1970 3X. Veith I: Hysteria: the history of a disease. Chicago, 196.5. University of Chicago Press 39 Beard CM: A practical treatise on nervous exhaustion (neurasthema. New York. 1880. William Ward
Summary Dean D. Metcalfe,
IMMUNOL. JULY 1986
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and recommendations M.D. Bethesda, Md.
From the Mast Cell Physiology Section, Laboratory of Clinical Investigation, Natronal Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 20892 Reprint requests: Dean D. Metcalfe, Head, Mast Cell Physiology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. National Institutes of Health, Bethesda, MD 20892.
250
CLIN
The abundance of mast cells and their release of potent chemical mediators as a result of immunologically mediated activation in mammalian skin, gastrointestinal, and pulmonary tissues are in large part responsible for these tissues being the primary sites of allergic reactions. The accessibility of the skin to