Specificity and Specification: Two Continuing Problems in Psychosomatic Research1 HERBERT WEINER, MD, DR MED (HON)

INTRODUCTION

Hopefully, you realize how honored I am to be asked on this special occasion to give a lecture in memory of Dr. Edward Weiss, who was Professor of Clinical Medicine at Temple University. He was an early American advocate and pioneer of that more comprehensive form of medicine which we call psychosomatic. He was also one of our founding fathers. He and O. S. English wrote the first American textbook on psychosomatic medicine (1). Because of the elegance of its style, it was a pleasure to read. Comprehensive coverage was given to diseases of every organ system. Not for another 22 years did any book appear that attempted such a complete survey; we are indebted to Professor Dr. Thure von Uexkiill for accomplishing this second feat (2). Scholarly books of such quality matter. They point the way to the future. Reviews of the state of knowledge in a field illu-

From the Department of Psychiatry & Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California. Address reprint requests to: Herbert Weiner, M.D., Department of Psychiatry & Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90024. Received for publication January 17, 1992; revision received June 15, 1992 The Edward Weiss Memorial Lecture given at the Fiftieth Anniversary Meeting of the American Psychosomatic Society, April 2, 1992, New York City.

Psychosomatic Medicine 54:567-587 (1992) 0033-3174/92/5405-0567103 00/0 Copyright © 1992 by the American Psychosomatic Soc

minate the gaps in its fabric; they highlight what still needs to be accomplished. Both books also defined the operations of psychosomatic medicine. Their authors called for the integration of social and psychological factors into others known to contribute to the etiology, pathogenesis, treatment, progression, and prognosis of disease and illness. By implication, such ambitious efforts also seek to contribute to a definition of health that is missing from traditional medicine. We have so far failed to complete this comprehensive program despite much progress in the past 50 years. Perhaps we should not blame ourselves too severely for our failure. The conceptual and empirical problems that need to be solved before we put the Humpty-Dumpty of reductionistic medicine back together again are staggering. One continuing challenge is to identify the questions which require an answer before further progress is to be made. The purpose of this lecture is to extend the inquiry begun by Weiss and English, in order to achieve our main aim: The development of an organismic, integrated biology of human health, illness, and disease. Before accomplishing this goal many gaps in our knowledge need to be filled in as new data appear and old problems reappear. I have identified a limited series of topics, some of which I have previously discussed (3, 4): The main subject matter of this lecture is the relevance and likely importance of the biolog567

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ical fact of the diversity of every person and of each disease.

SPECIFIC CONFLICTS, STRESSFUL EXPERIENCES, AND OUTCOMES

This essay will try to highlight the continuing problem of not taking variation into account in psychosomatic research and theory. The need to do so arose because of the obvious fact that one must specify with rigor the population of patients under study. In the course of discussing this problem, some words like "specific" and "specification" will be used. The former is a loaded one, due to past disagreement between those, who like Alexander (5) believed that every disease was characterized by a specific psychological conflict, and other investigators who have held to more general concepts, such as dependency (6), or the shared, personal characteristics of patients such as introversion, neuroticism, helplessness and hopelessness (7), alexithymia (8), or a (general) predisposition to illness and disease (9). In my opinion, the argument is overdone: A synthesis of the two points of view is required; they do not refer to the same areas of discourse, nor are they necessarily or mutually contradictory. No a priori reason exists for believing that patients with sub-forms of the same or different diseases are psychologically the same. Nonetheless, they may also share some common characteristics which sensitize them to certain life experiences, and/or make them less versatile in adapting to challenges and changes in their lives (10). In some areas of psychological functioning specificity (of conflicts) are present, 568

but in other areas the patient has limited capacities to be aware of, and communicate feelings; has an enhanced need for (social) support; and/or reduced adaptive skills in the face of changes in the environment or challenges. This suggestion would reconcile many observations on the psychology of patients with a variety of diseases. In fact some data exist to support this point of view: They describe significant correlation between dependency2 and diminished adaptive tools (6). However, shared characteristics of patients even with the same disease do not help if one wishes to answer two seminal questions: Why does a particular person fall ill with one disease (or its sub-form) and not another? And are patients with the various sub-forms of a particular disease marked by different psychological and physiological features? It is increasingly apparent that there is no single way that most diseases come about (11). Diseases such as diabetes mellitus, peptic ulcer, essential hypertension, rheumatoid arthritis, malignant tumors, several neurological diseases, and perhaps schizophrenia and bipolar disease are not due to the Mendelian inheritance of genes. They are multifactorial genetic

2 The word "dependency" might well be dropped, not only because it stems from outdated theory, but also because of its pejorative meaning—being dependent is equated with being "infantile." Furthermore, the referents of the behaviors alluded to, overlook the fact that humans are social animals—they are attached to each other in several different ways (described by John Bowlby in Attachment and Loss, Vol. I. Attachment. London, Hogarth, 1969). Furthermore, the label of dependency does not specify what function this trait performs. In all studies of the role of human relationships in health and disease the precise quality of the attachment behavior should be specified.

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disorders. Several or many genes, not one, endow a risk factor for such diseases. Their phenotypic expression is the endproduct of both genetic and environmental factors. But these combined factors are not necessarily uniform, not only because environmental and developmental factors differ but because sub-forms of each one of these diseases occur. It is, therefore, quite legitimate to identify the genetic and environmental risk factors in each form of the disease under study, once these sub-forms have clearly been characterized. Then one may ask whether psychobiological heterogeneity exists: If so, one source of diversity would be identified. Specification of these sub-forms is proposed. And, in this endeavor general concepts about psychosocial factors in disease do not seem to help: One such concept is "stress." Therefore, I have chosen to discuss seemingly unrelated topics to support this proposal. In the case of peptic ulcer, it is now possible to identify 29 different sub-forms of the disease. Given this fact, we may need to specify the particular form of (stressful) experiences and personal (phenotypic) characteristics in each of the sub-forms. The second topic of this essay is a group of disorders known as the functional bowel disorders: This conglomerate is heterogeneous. An urgent need is felt to classify them before they are specifically related to "obvious" but unidentified stressful experiences. Finally, the topic of neoplasia is discussed. Given its many forms, stage-wise progression, and the known general and specific mechanisms characteristic of each, the question is raised how specific stressful experiences and their attendant psychological changes could interact with them. Psychosomatic Medicine 54:567-587 (1992)

The Generality of the Concept of Stress Stress research and theory have profoundly influenced psychosomatic clinical and experimental research. But as explicated by Selye (12) "stress" was another general concept. He defined it as, "the non-specific response to any demand made upon it (the body)." Missing from his definition was the observation that "stressors" also have behavioral and psychological as well as physical consequences. For example, different animals have a variety of behavioral strategies for survival in dealing with the threat (i.e., the stressful experience) of predators; these behavioral responses must be appropriate to the threat or challenge if they are to succeed; were they random or indiscriminate (nonspecific), survival would not be assured. When the threat to survival is an infection, the appropriate response is immunological. If the threat to reproductive success is competition among males for mates, the appropriate response is to fight the rival, or submit to him, or flee from him to find another mating partner. Perturbing an organism is a standard way of producing integrated behavioral, psychological, and physiological responses, and also, but not inevitably, disease. However, Selye did not systematically study the behavior of his rats; they were in fact rendered incapable of making the appropriate behavioral responses in order to protect themselves against the various "stressors" that he applied. It took many years before Hinkle (13) pointed out that if animals made general or indiscriminate responses to each and every challenge, danger, threat, problem, or task, they would not survive. And Mason (14) demonstrated that patterns of 569

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hormonal responses are specifically attuned to the experiences which incite them. In the last few years, we have learned just how specific such responses may be. Merely varying one parameter (the frequency) of electric shocks applied to rats produces different forms of analgesia, separate effects on natural killer (NK) cell numbers, and the rate of progression of injected tumor cells (15). In rats, different forms of life-threatening physiological challenges—for example, hypoglycemia and hypoxia—are followed by the release of arginine vasopressin but not oxytocin. Both peptides, however, are released by blood loss. On the other hand, restraining or exposing rats to cold, or forcing them to swim only raises oxytocin levels (16). These two examples illustrate an important principle: The need to specify rigorously the stressful experience and its parameters. The matter is truly complex. The behavioral responses of many animals to naturally occurring threat and danger do not consist only of fighting or fleeing; instead they are both more diverse and specific to the individual and species. Some animals use diversionary tactics to mislead the predator or foe. Animals of the same species even deceive each other. The responses depend on the context in which the predator and prey find themselves: Some animals only signal to their conspecifics when predators are about; when alone, no signal is emitted (17). The context determines the behavior. The social status in the hierarchy (18) in which a stressful experience occurs is also associated with the quality and quantity of the physiological responses. Another critical factor in determining the degree of physiological changes and anatomical damage is the animal's ability to 570

anticipate, to respond to the experience, and to avoid punishment for doing so (19). Although I have emphasized the specificity of psychobiological responses, we still do not know whether the specific and general physiological responses are mobilized to all challenges, tasks, and dangers which face organisms. In one case, that of immunological responses of bacterial (and viral) antigens, both a specific antibody is formed, and a general response—the acute phase reaction—occur. (Is it possible that other response systems follow this model?) Because Selye arranged his experimental procedures so that his animals were incapable of any kind of adaptive, behavioral response—an unnatural event—he produced the well-known triad of anatomical lesions including gastric erosion in rats (20). He placed the burden of their pathogenesis on the corticosteroids; his pathogenetic concept was linear. However, many factors play a role in gastric erosion formation in rats; they include the gender, the age, the prior experiences of animals, serum pepsinogen levels, and whether stressful experience is, or is not, expected or avoidable (19). Furthermore, each of the injurious ("nocuous") procedures used by Selye had the same disease outcome; therefore, they did not specify the lesion. The same conclusion can be reached for a specific human experience and its possible disease outcomes. Bereavement has been cited as the context in which a variety of diseases may manifest themselves (21). Therefore, it cannot be that the (stressful) experience specifies the disease, other factors must do so. In the language of molecular biology, the experience plays an "elective," rather than an "instructive" role (22). One may conclude that general conPsychosomatic Medicine 54:567-587 (1992)

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cepts such as "stress" do not help our understanding. The experience and its context must be precisely described. But the fact remains that the experience does not determine the specific disease outcome, if indeed any ensues (except perhaps in the case of direct injury to a body part). This conclusion should come as no surprise: A particular bacterium (or even virus) may incite a number of different inflammations in a variety of body systems, or none at all. To summarize: In research on human beings, specific constellations of psychological sensitivities and "weaknesses" should be described. The stressful experience and its parameters must be specified. The response to it should be recorded. But the disease, when it occurs, is determined by other factors, some of which will now be discussed. The complexity of this specification is heightened by the fact that so many diseases are heterogeneous—sub-forms exist. A disease is not a species as Sydenham believed but more like a genus, or class.

THE HETEROGENEITY OF DISEASE AND THE NEED FOR THE SPECIFICATION OF ITS SUBFORMS: PEPTIC ULCER

An historical account of research in psychosomatic medicine might conclude that many of the past controversies about the contexts in which disease manifests itself, the contingencies with which persons have to contend at its onset, and the psychological differences between sick persons, came about because of a failure to recognize that most (if not all) diseases, defined anatomically, are heterogeneous in nature. Although the anatomical lesion Psychosomatic Medicine 54:567-587 (1992)

may look alike, it can come about in different ways. Why it took so long for biomedical scientists to recognize this fact is puzzling: Since Darwin, the concept of variation is basic to all of biology. Variation in individuals and in their diseases is not only genetically determined. Many factors conduce to variable phenotypic expression. Each person is a product of the historical period in which he/she lives; the social, cultural, family, and educational environment in which he/she was raised; the adequacy of nutrition; and unique experiences. The variability of some diseases is astonishing: It is now recognized that at least 29 forms of human peptic ulcer disease exist, defined genetically (22), and by their pathophysiologies (23). Even this number may be too low. A minimum of 100 forms of malignant disease are recognized—their initiating factors are far from uniform. Either two or four forms of diabetes mellitus have been described. And there exist 400 different genetic variants of glucose-6-phosphate dehydrogenase, of which only 5% are phenotypically expressed (24). The point is particularly clear in several diseases, including peptic ulcer, which have long been of interest to psychosomatic investigators. Rare forms of peptic ulcer have been described—gastrinomas, or systemic mastocytosis—in which social and psychological factors are not known to play any role. The common and more familiar forms of this disease are characterized by variations in pepsinogen-I (PGI) and PG-II levels. To make the matter even more complex, patients at risk for, and with the disease characterized by hyperpepsinogenemia-I can further be specified separately by normal or increased 571

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levels of gastric acid secretion, or postprandial hypergastrinemia (22). About 50% of patients with duodenal ulcer have raised levels of PG-I (in the top 2%-5% of the distribution), the others do not (25-27). The elevations are present prior to disease onset. They are inherited as an autosomal dominant trait (28, 29). Pepsinogen-I is a generic name for a family of 5 isoforms (30, 31), which are coded by three genes on chromosome 11 (two of the variants are due to post-translational modification) (32). Duodenal ulcer, as mentioned, also occurs in the presence of normal pepsinogen levels, whose exact inheritance is not known. Patients with the normopepsinogenemic type of duodenal ulcer can further be separated into those who empty their stomachs more rapidly, and those who do not (22, 33). Other patients with duodenal ulcer have elevated PG-II levels; two forms of the enzyme precursor have been identified. These enzyme precursors are coded by a gene residing on chromosome 6 (26). Fairly conclusive evidence has been obtained that elevations of PG-I (>130 ;ug/ litpr) increases the odds ratio to 5.6 for acquiring the disease. When PG-II levels are in excess of 30 /ig/liter the odds ratio is also raised for duodenal ulcer, but more particularly for gastric ulcer (34). The genes coding for PG-I and PG-II are not evenly distributed in different populations: Japanese-Americans living in Hawaii are more frequently prone to gastric ulcer than are other Americans, because excessive PG-II levels occur in them more frequently than do the PG-I isoforms (34, 35). If such an uneven distribution in populations of these particular risk factors is found to occur, it might begin to explain the remarkable discrepancies and varia572

bility in incidence and prevalence of duodenal ulcer in various countries (36, 37). As mentioned, only about 50% of all patients with duodenal ulcer have elevated PG-I levels. A considerable proportion of the residual variance has been assumed to be of a social and/or psychological nature. Some proof of this contention was obtained (22, 38), before the issue of the genetic and pathophysiologic heterogeneity of the disease was recognized. These observations suggested that the psychological characteristics of peptic ulcer patients were not uniform (25). Three groups have recently investigated the question of the psychobiological heterogeneity of patients (39-43). The conclusions are limited because these studies are not comparable and because patients were studied after disease onset. These studies did not support the hypothesis that patients before and after disease onset are psychologically heterogeneous in terms of PG-I, or PG-II levels. Therefore, one may not conclude that the psychobiological heterogeneity of patients with peptic ulcer exists. Yet the question is potentially of more than theoretical interest; it has implications for comprehensive treatment and for prognosis (e.g., which patients are likely to have a chronic course, or are liable to complications of the disease?). On the other hand, the hypothesis of the psychobiological heterogeneity of peptic ulcer disease may be wrong. Alternative possibilities suggest themselves: a) Psychological risk factors with a specific constellation may occur only with one or another of the sub-forms of the disease under discussion; b) The patients with the various genetically defined sub-forms may share some common characteristics either in the form of their personal conflicts, or relationships to others, their psyPsychosomatic Medicine 54:567-587 (1992)

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chological characteristics, and/or diminished adaptive capabilities (41, 43); c) The fact that one may specify genetically different sub-forms of a disease does not necessarily mean that the gene-variants are phenotypically expressed, as illustrated in glucose-6-phosphate dehydrogenase deficiency (24); or d) The phenotypic expression of a genetically defined variant may have nothing to do with the genotype. It may result from differences in peisonal, social, and educational experiences; in age, gender, and socioeconomic status; or in exposure to stressful experiences, which may or may not, alter the genotype. There exist no data that would definitively allow one to decide the correctness of these four alternative hypotheses. Although it is premature to conclude that psychobiological diversity is present in peptic ulcer, the following section will present evidence for such heterogeneity in patients with essential hypertension (44-51).

Evidence for Psychobiological Heterogeneity in Essential Hypertension The importance of psychobiological heterogeneity is particularly clear in essential hypertension where patients can be divided into those with high, medium, and low plasma renin activity (PRA) levels. (Admittedly, such a classification is not proof that PRA levels are not the result of the disease.) Yet these three subforms of the disease have a different natural history and outcome, and are not evenly distributed in various ethnic groups (44). Furthermore, members of each group differed from each other on Psychosomatic Medicine 54:567-587 (1992)

measures of specific psychological characteristics (45, 46). Because these results were obtained in patients with established essential hypertension, an ideal study would enroll subjects at risk for the various sub-forms. Such a strategy is, however, not feasible in the case of essential hypertension, because the sub-groups cannot be identified reliably before its onset. An alternative design is to study patients with borderline hypertension (47-50). In 30% of such patients, the cardiac output was 2 standard deviations beyond the mean for normal, age-matched subjects. In this sub-group, the total peripheral resistance was inappropriately normal at rest, and PRA and plasma norepinephrine (NE) concentrations were elevated. The increased PRA did not seem to maintain the heightened blood pressure levels through its effect on angiotensin II and aldosterone production and secretion. The increased heart rate, cardiac output, and PRA could be reduced to normal levels with propranolol, but the plasma NE concentration and blood pressure continued to remain elevated. Therefore, the enhanced PRA was a result of increased sympathetic activity, but it was not the primary pathogenetic factor in raising the blood pressure (50, 51). The physiologic heterogeneity of patients with borderline hypertension is also reflected in their psychological heterogeneity. Those patients with high PRA and increased plasma NE levels differed on a number of psychological measures from borderline hypertensive male patients with normal PRA levels and from 20 men with normal blood pressure levels: They were described as controlled, guilt-ridden, submissive people with relatively high levels of unexpressed, or unexpressable anger, while the patients with normal PRA levels were able to do so. 573

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The Functional Bowel Disorders (FBD) Whereas, it is possible to identify subgroups of patients at risk for peptic ulcer, or suffering from essential hypertension and rheumatoid arthritis (52) by identifiable criteria, no such sub-division is as yet possible for FBD. Therefore, a proposal is put forward as to one way of classifying this supposedly heterogeneous group of disorders, in order systematically to study and compare the setting in which the members of each group develop the disorder, or recurrences of complaints occur. One might ask: What is the psychological make-up of such (different) persons? What determines an acute from a chronic form of FBD? What psycho-physiological mechanisms are set off by personal experiences? Do they differ? Can different specific treatments be developed for each group? The FBD continue to be a major puzzle in medicine; a source of disability, and of absenteeism from work; a burden to its victims, and to the medical care system. The clinical and human problem they present is enormous: About 50% of the entire population of western industrial nations suffer from FBD but only about one-third to one-tenth ever consult a physician (53). Those that do, may or may not differ in some way from those who do not, or they may not have the same illness. To add to an already confusing topic, the names given to the putative sub-forms of FBD change constantly (e.g., the symptoms of what is now called by some "nonulcer dyspepsia" (54) go by six other names (55)). Serious doubts exist that the sub-forms of FBD, named after the presumptive site of origin of symptoms in the gut, really constitute separate disorders (i.e., are the esophageal and colonic forms different?). 574

In the European literature, the FBD is a name for symptoms and disturbances which emanate from every part of the alimentary tract—from the mouth to the anus (56-58). Eighty percent of patients with the irritable colon syndrome experience swallowing difficulties, and 56% of those with "esophageal" symptoms complain of constipation, diarrhea, and lower abdominal pain. More general disturbances of motor function of the gut (e.g., a lower esophageal sphincter pressure) are observable even when colonic symptoms predominate. Often, other altered bodily functions and systems also manifest themselves with symptoms of the FBD: About onethird of all patients with functional musculoskeletal symptoms (fibromyalgia) suffer from the FBD (59, 60). Many FBD patients hyperventilate, are anxious or depressed, and sleep poorly (55, 56). In addition, they complain of headaches. For investigative, clinical, and therapeutic reasons, progress in this confused area of practice and research cannot occur unless homogeneous sub-forms are constituted. Such advances cannot take place by giving a descriptive, nonspecific name to a disorder, and then proclaiming it to be an "entity." The proposal that follows is that there may be three (or more?) types of FBD: A motoric, a sensory, and a combined sensorimotor form (61, 62). Motoric Disturbances in FBD. The disturbances in colonic motility in the ("irritable") colonic form of FBD were first described by Almy and his coworkers (63, 64). In the esophageal disorder, high amplitude propagated contractions, nonspecific spasm, non-propagated diffuse spasm, or achalasia have been recorded (65-67). In a majority of instances (64%), there is no correlation between the sympPsychosomatic Medicine 54:567-587 (1992)

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torn of chest pain and the motility disor- can be recorded. This statement is based ders (66). Furthermore, only 28% of all on the fact that: a) lower esophageal patients with symptoms referable to the sphincter pressure is decreased in most esophagus have any recordable motility patients with FBD (75); b) jejunal motility disorder (65, 67). Another 20% have an is diminished (76); c) the transit time of a excess of gastric acid in the esophagus, solid meal from the mouth to the cecum presumably due to its regurgitation from in patients with diarrhea is reduced (77); the stomach. Four percent have both a and d) the migratory motor complex is motility disturbance of, and excessive gas- abolished more frequently and permatric acid in, the esophagus (66). Therefore, nently by "stressful" perturbations (78). some other factor(s) must account for Therefore, the production of symptoms symptoms. such as pain in the chest and the abdoMotility disturbances in the esophagus men, or dysphagia, is complex. They may may or may not be associated with occur with normal patterns of gut motilchanges in lower esophageal sphincter ity. Conversely, various disturbances of tone. A variety of drugs and hormones motility (tetanus or diffuse spasm of the such as alcohol, nicotine, progesterone, esophagus) may be recorded, but the suband anti-cholinergics reduce the tone. ject does not notice, or complain of pain. Use of such drugs needs to be taken into Sensory Alterations in FBD. For the reaaccount before further investigations are sons just stated, a new line of approach is carried out. needed (61, 62, 78) to account for sympWhen symptoms are believed to ema- toms in the face of the low incidence nate from the stomach (non-ulcer dyspep- (25%) of motility alterations in FBD (67), sia [NUD]), correlations have been made and the fact that various provocative tests with a variety of motility disturbances. (instilling acid into the esophagus, or They occurred in only one-half of 70 pa- drugs designed to alter motility) did not tients (68, 69). In other studies of patients regularly incite pain (67, 79). In NUD only with NUD, the cumulative number of ac- one-half of all patients had any kind of tual contractions in patients experimen- motility disorder. The stimulation of gastally exposed to a stressful stimulus, tric acid secretion by pentagastrin regusometimes rises, or else it falls as it does larly produced pain in such patients, but the acid output was less than in peptic in normal subjects (55). In the colonic form of FBD, some con- ulcer patients (55, 80). Therefore, it was sensus about the motility disturbances concluded (61, 62) that the perception of has been achieved (70-73). Meals may or sensations (especially pain in the gut) are may not promote changes in either direc- altered in FBD. tion (74], or pain. However, the findings In the esophageal form of FBD, inflation are not always consistent, and the corre- of the organ with small volumes (