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Psychiatric Disorders in Patients with Esophageal Disease
Unexplained Chest Pain
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Psychiatric Disorders in Patients with Esophageal Disease
Ray E. Clouse, MD*
Psychiatric disorders may play an important role in the presentation of many medical diseases. Their importance in chest pain syndromes only recently has received widespread attention. Initially, psychiatric factors were considered relevant primarily in cases in which somatic explanations for chest pain could not be determined, presumably cases of "psychogenic" pain. Attention is now being given to the full spectrum of medicalpsychiatric interactions to better understand the psychiatric contrihution in many clinical disorders and to extract therapeutic implications. Esophageal diseases are well-recognized causes of chest pain. 60 In particular, gastroesophageal reflux and motor disorders involving the distal esophagus are both prevalent in patients with recurrent chest pain and no evidence of cardiac disease. 6 ..50. 56 As with many medical conditions, the role of coexistent psychiatric illness with esophageal disorders in the presentation of chest pain remains poorly understood. Technologic advances in measuring degrees and types of esophageal dysfunction (e.g., improved manometric techniques and 24-hour pH monitoring) have extended the focus hy investigators and clinicians on a search for physiologic explanations and somatic diagnoses for chest pain. However, these same advances have helped expose the incomplete association of measured physiologic almormalities with symptoms. Thus, the contribution of psychiatric factors to the overall manifestations of esophageal disease is gaining renewed interest. Despite the interest, few studies have systematically determined the coexistence of psychiatric disorders in patients with defined esophageal diseases. Additionally, ohservations of psychiatric interactions with medical illness were often anecdotal in earlier studies (prior to 1970), employing psychiatric methods that would not satisfy current scientific standards ..52 More recent reports have included control groups, blinded evaluations, and validated psychiatric instruments. Such studies will be the focus of this article.
*Associate
Professor of Medicine, Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine; and Associate Physician, Barnes Hospital, St. Louis, Missouri
Medical Clinics of North America-Vol. 75. No. 5, September 1991
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POTENTIAL ROLES OF PSYCHIATRIC ILLNESS IN PATIENTS WITH ESOPHAGEAL DISEASE Psychiatric disorders have potentially important roles in the occurrence and presentation of esophageal syndromes (Table 1). At one extreme, psychiatric illness could be causative of the esophageal disease; at the other, it may simply produce symptoms that occur in parallel with the esophageal symptoms, thereby confusing the clinical presentation. Determining that a somatic illness is actually a manifestation of psychiatric illness, especially if measurable abnormalities of organ function are present, is a difficult task. An unrecognized pathologic lesion in the target organ may be responsible. However, the neuroanatomic framework is available such that derangements in esophageal motor function, for example, could be produced by the central nervous system, including such phenomena as emotional change. 12 The evidence for or against an etiologic role of psychiatric illness will be offered for several esophageal diseases, particularly those associated with chest pain. Interactive roles are likely in all cases. PSYCHIATRIC DISORDERS IN SPECIFIC ESOPHAGEAL SYNDROMES Esophageal Motility Disorders
Achalasia. This disease of the distal esophagus and lower esophageal sphincter results from degeneration of the intramural neurons that control esophageal motility and lower sphincter relaxation. 81 Symptoms may first present at nearly any age, but the modal age range at diagnosis is 20 to 50 years.lI Dysphagia and regurgitation are the principal symptoms, and substernal chest pain is reported by 30% to 50% of patients. Initially, this disorder was considered one of smooth muscle dysfunction or spasm with prominent involvement of the lower sphincter. Later work confirmed the degenerative neural lesion in the esophageal myenteric plexus. 9 Table 1. Potential Roles of Psychiatric Illness in Patients with Esophageal Disease POTENTIAL ROLE
Causative Interactive Psychophysiologic effect Behavioral effect
Parallel symptom activity
EXA~lPLE
Psychiatric illness directly produces the esophageal manifestations Psychiatric illness alters normal esophageal motor or sensory function in presence of esophageal disease Psychiatric illness induces health-care-seeking behavior, alters medication compliance, or acts through other indirect behavioral mechanisms (e.g., enhanced cigarette smoking, increased alcohol consumption) that may interact with esophageal disease Symptoms of psychiatric illness (e. g., anorexia, fatigue, fear of eating) confound interpretation of the esophageal disease
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Achalasia is the only primary esophageal motility disorder for which the pathophysiology is thoroughly understood. Before the neural abnormalities were detected, a psychiatric contribution to (if not cause for) the development of esophageal muscle spasm, irregular contractions, and subsequent symptoms was considered likely. Wolf and AlmyB° studied 14 achalasic subjects by fluoroscopically monitoring barium transit during emotionally charged interviews. These authors noted that barium passage was markedly delayed in most subjects when the interview shifted to topics of intense emotional impact. In contrast, barium transit was most rapid when the subjects were relaxed. As a clinical parallel, the subjects often reported symptom exacerbations and remissions (prior to any treatment) in conjunction with variations in life situations and stresses. Several normal control subjects also demonstrated delayed barium transit (to lesser degrees) with noxious stimuli and with the stressful interview, but the manometric correlate of this delay in transit was not determined. The authors concluded that achalasia may represent a biologic reaction to stress (i.e., that psychiatric disorder is causative in this disease). Several other early uncontrolled studies favored a psychogenic cause for achalasia based on the investigators' determination of stressful life events or other psychic trauma preceding the onset of esophageal symptoms. 46, 79 In light of current understanding of the pathophysiology of achalasia, a causative role of psychiatric illness is not considered likely. The disease has continued to appear worldwide at a relatively constant rate without apparent epidemics or familial clustering, 11 and the neural lesion is acknowledged. There is no evidence or clinical suspicion that the disease is more common in psychiatric clinic populations. Prevalence data of psychiatric disorders in patients with achalasia are, for the most part, lacking. A study of subjects with nonspecific motor disturbances included three patients with achalasia in one of the control groups. 14 Psychiatric illness, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Version III (DSM-IIP), was uncommon in the control group in general, and none of the 15 diagnoses sought were present in the three achalasia patients (unpublished observations). A subsequent study evaluated recent psychologic symptoms in patients with esophageal motor disorders, and again a control group (n = 14) comprising patients with achalasia (n = 9) and other related disorders was included. 15 A multidimensional self-report measure (the Hopkins Symptom Checklist, SCL-90R2R) including nine primary symptom dimensions (e.g., depression, anxiety, somatization, psychoticism) and three global scales was employed. Subjects in this control group scored lowest on the SCL-90R of any study subjects, T -scores being less than 55 on 9 of the 12 scales. Thus, recent data to support a psychiatric etiology of this motor disorder are lacking. The early work by Wolf and Almy likely demonstrates esophageal responsiveness to stressful stimuli, responsiveness that subsequently has been confirmed using intraluminal manometric recording devices. 82 It seems logical that such psychophysiologic interactions could be more detrimental from a symptom-production standpoint in an organ with existing disease (e.g., achalasia) than in the normal subject, and the clinical and laboratory observations made in the earlier work would confirm this suspicion.
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Diffuse EsophageaZ Spasm and Nonspecific Motor Disorders. The role of psychiatric factors in the presentation of these motility disorders remains of greater interest for several reasons: (1) a pathologic esophageal lesion (e.g., a defined neural abnormality) is absent in most cases; (2) regression of manometric abnormalities to normal has been observed 41 , 43; and (3) the clinical impression persists that patients with these disorders are more distressed and generally emotionally upset than patients with other esophageal diseases. 14 , 62 In addition, satisfactory symptom management is often difficult, If understanding a psychiatric interaction would lead to improved treatment regimens, practitioners would be pleased. In this article, I will include diffuse esophageal spasm and the nonspecific disorders outlined in Table 2. The clinical syndromes of these manometric disorders are virtually identical 45 and will be addressed as the "esophageal spasm syndrome." As currently defined, diffuse esophageal spasm differs from the nonspecific disorders only in the presence of periodic simultaneous contraction sequences, 59 findings that may be absent on a brief manometric tracing. The overlap of the nonspecific disorders with diffuse esophageal spasm has been demonstrated in several ways, 11, 30, 49, 73 and for these reasons it seems justified to discuss these disorders as a group. A small subset of patients with diffuse esophageal spasm who have more severe manometric derangement may not be correctly represented by the group as a whole. In these cases, a neural lesion similar to that in achalasia may be responsible for the findings. Io Likewise, some subjects with typical findings of diffuse esophageal spasm at presentation subsequently have been diagnosed as having achalasia, 42, 75 but this evolution appears rare, Although segregation of patients with a histologic neural lesion from those with the motor "dysfunction" is difficult and failure to do so leaves a heterogeneous study population, the proportion of subjects with the achalasia-like disorder appears to be very small, Table 2. Diffuse Esophageal Spasm and Nonspecific Motor Disorders MANOMETRIC DISORDER
Diffuse esophageal spasm
Nonspecific motor disorders Vigorous contraction wave abnormalities
Hypertensive lower esophageal sphincter pressure
CHARACTERISTICS
COMMENT
Frequent simultaneous, nonperistaltic contraction sequences (following > 10% of recorded swallows)
Manometric features of the nonspecific motor disorders often also present
Increased contraction amplitude (the "nutcracker esophagus"), prolonged wave duration, increased frequency of multipeaked wave forms Increased basal (resting) pressure in the lower esophageal sphincter
Manometric features seen alone or in any combination
Can be an isolated finding but is usually found in conjunction with vigorous contraction wave abnormalities
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Patients with esophageal spasm syndrome usually present in adulthood, the mean age at diagnosis being 40 to 50 years. l l In most American reports, women are predominant. Chest pain is reported by 80% or more of subjects and is usually the most significant symptom. 11, 58 Because the pain is retrosternal and may have radiation patterns similar to that of angina pectoris, it is not surprising that many patients who present with chest pain and have cardiac disease excluded are ultimately thought to have this syndrome. In fact, diffuse esophageal spasm and the nonspecific motor disorders have been detected in 18% to 58% of chest pain subjects with negative cardiac evaluations. 6, ,32, 40, 54, 70 Associated psychologic symptoms (e.g., of anxiety or depression) have long been noted to accompany the esophageal symptoms in this syndrome. 14, 62 An association of psychiatric factors with the esophageal spasm syndrome was further suspected when a high prevalence of psychiatric illness was detected in chest pain patients who had no evidence of cardiac disease. 4 , 5, 26, 39 For example, Bass et al 4 found that 61% of such subjects met criteria for psychiatric diagnoses (most commonly panic disorder). Likewise, using DSM-III criteria, Katon et aP9 found that current psychiatric diagnoses were present in 79% of subjects without coronary artery disease versus 26% in controls. Anxiety and affective disorders were most common. Do psychiatric disorders detected in these studies represent causes of chest pain that are separate from the esophageal diseases? Are there three main categories in the noncardiac group: psychiatric (or "psychogenic"), esophageal, and undiagnosed?" 8 Or do these processes overlap? Several studies have systematically looked at psychopathology in patients with the esophageal spasm syndrome in whom cardiac disease had been excluded. 14, 18, 21, 62 In 1983, Clouse and Lustman 14 used a structured interview and DSM-lII criteria to determine the rates of psychiatric diagnoses in patients referred for manometry, The subjects with chest pain had completed unrevealing cardiac evaluations. Psychiatric diagnoses were made in 84% of patients with contraction wave abnormalities (see Table 2) and the esophageal spasm syndrome, whereas diagnoses were made in only 31 % to 33% of patients in two control groups. Rates of major depression (in 52% of spasm patients) and anxiety states (generalized anxiety disorder and panic disorder, in 36% of spasm patients) were most significantly different among groups. Of potential importance in the results of this study, only 8 of 13 patients with major depression had active psychiatric symptoms at the time of evaluation, and a current diagnosis was present in only seven of nine patients with the anxiety states, implying that the psychiatric and esophageal diseases might run different symptom courses. Subsequent to that report, Colgan et aPl studied 63 patients with anginal chest pain but without evidence of coronary artery disease. These authors used the Clinical Interview Schedule34 to determine psychiatric "caseness" and manometry, endoscopy, and 24-hour pH monitoring to determine esophageal disease. Only esophageal spasm and the nonspecific motor disorders were considered in the results. 65 Using these techniques, psychiatric cases were identified as 44% of the subjects versus 29% of a control group with documented coronary artery disease. The subject group
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was further separated, and psychiatric illness was diagnosed in 59% of patients with esophageal abnormalities as the presumed cause of chest pain versus 18% of those with left ventricular dysfunction (as the presumed cause of pain). The highest rate of psychiatric diagnosis (63%) was in the subgroup with motility disorders. These findings would further support the segregation of psychiatric illness with esophageal motor disorders of the types listed in Table 2. In an additional report, Richter et aF5 compared psychologic profiles on the Millon Behavioral Health Inventory in chest pain patients with highamplitude contraction wave abnormalities to profiles from control groups that included asymptomatic volunteers and patients with structural esophageal disease. 62 Once again, patients with the nonspecific motor disorder were psychologically different from controls with significant differences on several scales (somatic anxiety, gastrointestinal susceptibility; less Significant trends on depression scales). Psychologic differences (especially in anxiety and depression symptoms) between patients with nonspecific motor disorders and achalasia were confirmed in another study, but differences between motor disorder patients and chest pain patients without motility abnormalities were less apparent. 15 Evaluating recent psychologic symptoms has not been as rewarding in these disorders as determining lifetime psychiatric diagnoses (e. g., using a structured interview and diagnostic criteria). 14. 15 An additional piece of information must be considered in formulating conclusions about the role of psychiatric illness in these disorders. Two additional reports from the same group reproduced the high prevalence of DSM-III diagnoses in patients with contraction wave abnormalities. 17. 18 One of these studies included diabetic patients who had no csophageal symptoms l7 and the contraction wave abnormalities correlated with psychiatric illness, not neuropathy. Thus, the manometric findings may be associated with psychopathology independent of esophageal symptoms. Similar studies in psychiatric populations (involving patients without any potentially confounding neuropathies) have not been reported, but this information would be very useful. These findings also speak against any suspicion that the psychiatric illnesses result from the motor disorder, e. g., from debilitating symptoms. Likewise, appropriately symptomatic control groups were employed in the studies mentioned previously. 14. 15.62 The high rates of psychiatric diagnoses and their association with contraction abnormalities independent of symptoms raise the following question: Are diffuse esophageal spasm and nonspecific motility disorders caused by psychiatric factors? Simply because the pathophysiology of these disorders is poorly understood, investigators are justifiably unwilling to make this assumption and then see the story of achalasia repeated. In an attempt to answer the question, several groups have examined the esophageal motor response to acute stress (Table 3). The induced radiographic and manometric findings are not unlike the spontaneous abnormalities found in esophageal spasm and the related nonspecific disorders. The manometric changes reported by Young et al 82 and Anderson et aP are probably most reliable as the manometric techniques employed satisfY contemporary standards and the psychological methods were sound. In-
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Table 3. Esophageal Motor Response to Acute Stress \1EASURED AUTHOR (YEAR)
ESOPHAGEAL STRESSOR
RESPONSE
FINDINGS
Faulkner et al (1942)31
25 selected patients
Discussion of unpleasant topics
Changes on barium fluoroscopy and during esophagoscopy
Rubin et al (1962)63
5 healthy volunteers
Stress interview
Peristaltic performance using lowfidelity manometric methods
Stacher et al (1979)69*
22 healthy volunteers
Loud noises of varying frequency and intensity
Contraction wave parameters uSing highfidelity manometry
Young et al (1987)82*
25 healthy volunteers
Abnormal contractions in distal esophagus and delayed barium clearance in all (?) subjects; spasms during esophagoscopy Significantly more simultaneous contractions during emotionally charged periods on three subjects Spontaneous contractions induced above decibel and frequency threshold in all subjects (?startle) Increased contraction amplitude with all stressors; no consistent peristaltic change Increased contraction amplitude with both stressors, greater increment in NSMD patients; no consistent peristaltic change
Anderson et al (1989)3*
SUBJECTS
White noise, cold Contraction wave pressor test, and parameters and cognitive task peristaltic performance using highfidelity manometry 20 healthy White noise, Contraction wave volunteers cognitive task parameters and and 19 chest peristaltic pain performance using highpatientst fidelity manometry
Abbreviations: NSMD = nonspecific motor disorder. *Well-controlled experimental design; blinded response interpretation. tIncluded 10 patients with a nonspecific motor disorder (the nutcracker esophagus").
duced manometric changes in both normal subjects and in symptomatic patients with high-amplitude contractions were small (amplitude increases by 5% to 12% of baseline) but in the direction of worsening contraction wave abnormalities. 3,82 Possibly more sustained stress could produce greater change. In favor of this hypothesis, Keshavarzian et al41 found marked elevations of contraction amplitudes or other nonspecific motor abnormalities in 14 of 18 patients with chronic alcoholism who were undergoing
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alcohol withdrawal,41 although none of the subjects were symptomatic (e.g., with chest pain). After recovery, manometry returned to normal in five of six restudied subjects. Despite these intriguing findings from acute and subacute stress studies, convincing evidence, as from longitudinal evaluations, that psychiatric illness actually precipitates the motor disorders is lacking. The simultaneous contraction sequences typical of esophageal spasm were not provoked with stressful stimuli in the recent manometric studies. 3 . 82 Also, using the best psychiatric tools available today (structured interviews, diagnostic criteria), investigators have shown that approximately 20% of symptomatic subjects with these manometric findings do not meet criteria for any psychiatric diagnosis, and the psychiatric diagnoses themselves vary from study to study. 14. 18 Thus, a causative role of psychiatric illness at present must be considered unproven. Besides a potential causative role, other psychiatric interactions (see Table 1) may be operational in these disorders, particularly in affecting the clinical presentation. The importance of such interactions has not been systematically determined. The esophageal spasm syndrome shares many clinical features with irritable bowel syndrome, 13.'53.66 and only recently has the effect of health-ca re-seeking behavior been recognized in this intestinal disorder. 29. 68. 77 Psychopathology may precipitate a visit to the doctor for complaints (e.g., abdominal pain) that might otherwise be disregarded. If the same is true in esophageal spasm, then psychopathology may be overrepresented in the subset of patients who are actively seeking medical care (and are, thus, included in medical reports). As another form of interaction, the presence of an underlying motor disorder may enhance sensitivity to normal psychophysiologic esophageal responses, as was described for achalasia. These possibilities have not been fully explored. Finally, the mechanism by which chest pain and other esophageal symptoms are produced in diffuse esophageal spasm and nonspecific motor disorders remains poorly understood. In particular, the defining motor events may actually have little to do with symptoms (especially chest pain) in most cases. 16. 40. 41 One possibility is that the motor abnormalities are epiphenomena with chest symptoms arising from a nonesophageal site. However, the symptoms often sound distinctly esophageal, and chest pain can be reproduced with esophageal stimuli in 30% to 50% of patients. 19. 40 Recent attention has been given to the sensitivity of esophageal sensory receptors to intraluminal stimuli, particularly to balloon distention. 19,61 The relationship of abnormal sensitivity to balloon distention with psychiatric illness and stress has not yet been reported. It does appear that abnormal balloon sensitivity is only partially related to the nonspecific motor disorders19,61 and is unrelated to measures of recent psychologic distress, 19 Although an interaction of psychiatric illness with enhancement of visceral sensitivity is an attractive hypothesis to explain prior clinical and investigative observations, these early reports do not immediately favor such a simple solution, Gastroesophageal Reflux Disease Gastroesophageal reflux disease includes symptoms and resultant organ damage (esophageal, pharyngeal, laryngeal, pulmonary) from excessive
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reflux of gastric acid through the gastroesophageal junction or excessive acid exposure to the esophageal mucosa. A variety of mechanisms are responsible for the manifestations. :16 Principal symptoms are heartburn, chest pain, postural regurgitation of gastric contents, dysphagia, and a variety of other nonspecific symptoms, such as "lump" or tightness in throat. 72 Chest pain induced by reflux can be related to exercise and readily confused with angina pectoris. 64 When polled, as many as 64% of healthy adult Americans believe that excessive stress is a cause of heartburn. 57 Despite this widely held notion, little scientific information is available to support an association of reflux and emotional factors. Indirect evidence would indicate that some symptoms of reflux disease may be associated with specific psychiatric disorders. Chest pain is reported by as many as 85% of panic disorder patients 20 ; chest pain (72%) and lump in throat (28%) are both common in somatization disorder. 55 In a separate report, typical reflux symptoms were described by 42% of psychiatric patients with somatization disorder. 71 Similar symptoms were listed by only 5% of the healthy control subjects. Are the reflux-like symptoms reported by these patients and by stressed subjects actually related to gastroesophageal reflux, or do they occur through a separate mechanism? Nielzen et aPl reviewed the psychiatric features of 26 symptomatic patients who had been referred for evaluation of suspected gastroesophageal reflux. Subjects were then categorized as having reflux (endoscopic evidence of esophagitis or manometric evidence of provocable reflux) or hiatal hernia in one group, and neither in the other. A psychologic test of photograph interpretation Cmeta contrast" technique) was used to infer psychiatric symptoms. Of the seven psychologic characteristics determined by this technique, two scales (anxiety, depressive signs) were significantly more common in the group without objective evidence of reflux disease, and none were more common in those with documented reflux or hiatal hernia. Thus, the psychiatric factors segregated best with the subjects who had reflux symptoms but no objective evidence of reflux disease. The methods of measuring reflux in this study were, however, suboptimal. Preliminary data are available from two studies examining the effects of acute stress on reflux parameters. Cook and Collins 22 studied six healthy volunteers using a pH probe and stress in the form of dichotic listening with a superimposed intellectual task. Frequency and duration of reflux were quantitated following a standard meal, and the stress episodes were interspersed with control periods of relaxing music. Although the stressor was sufficient to raise heart rate and systolic blood pressure significantly, reflux parameters were not altered. Pulliam et aJ57 subsequently found that stressors (cognitive and manual tasks, delayed auditory feedback) did not significantly influence objective measures of acid reflux in 10 subjects with known symptomatic reflux disease. Twenty-four-hour pH monitoring devices were employed. These authors did show, however, that reflux symptoms were (subjectively) accentuated during stress in subjects with higher scores on multidimensional psychologic measures. Taken together, it appears that psychiatric factors may interact with reflux disease primarily by increasing reflux symptoms without affecting
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measured reflux parameters. The symptoms may either be (1) accentuated perception of reflux events or (2) symptoms produced by a mechanism that mimics reflux disease. The investigations employing 24-hour pH monitoring may help determine which of these mechanisms is of greatest significance in subjects with and without existing reflux disease. Other Esophageal Disorders
Globus Sensation. The globus sensation, or sense of a lump in the hypopharynx at the level of and immediately behind the cricoid cartilage, is not an uncommon complaint. The symptom represents up to 4% of referrals to otolaryngologists. 48 Globus sensation can rarely result from structural lesions in the hypopharynx, cervical esophagus, or neighboring structures in the neck. At times, the globus sensation may be representative of gastroesophageal reflux or other distal esophageal process. In most instances, however, the isolated symptom occurs in patients who have no recognized cervical or esophageal pathology. A consistent motor or sensory abnormality in the region of the cricopharyngeus muscle to explain the symptom has not been detected. 23 Globus sensation is a common symptom of patients with somatization disorder, being reported by nearly a third of patients. 55 Its association with other psychiatric diagnoses is not fully known. Several cases of globus sensation in association with panic attacks and major depression have been reported. 7 In a recent report, Deary et a}27 studied 121 globus patients using self-report inventories to estimate personality traits and psychiatric morbidity (e. g., Eysenck Personality Questionnaire, General Health Questionnaire [GHQ]). The patients were compared with appropriately symptomatic and matched controls. Female subjects showed low extraversion scores, high GHQ scores of psychiatric morbidity, and high levels of anxiety, depression, and somatic concern, and in some ways resembled a cohort of psychiatric outpatients. The smaller number of men in this study were no different from control subjects. The authors concluded that psychologic factors were likely important in this disorder-possibly of primary importance, especially in female subjects. Other investigators have found similar psychologic abnormalities in globus patients. 23 A psychophysiologic explanation for the symptom is lacking. Cook et a}24 have shown that the upper esophageal sphincter (the anatomic location of the globus sensation) is responsive to acute emotional stress in normal individuals. These same investigators subsequently showed that upper sphincter basal tone and reactivity to stress were similar in globus patients and asymptomatic subjects. 23 Thus, despite the psychologic differences between these groups, upper esophageal sphincter response to stress does not explain the origin of the symptom. Recent preliminary data indicate that the sensation can be more easily produced in globus patients than in asymptomatic controls with a balloon distention stimulus in the esophagus. 25 These data may indicate that esophageal sensory dysfunction is as relevant in globus sensation as it appears to be in non cardiac chest pain. 61 The relationship of this visceral sensory abnormality to psychiatric factors has not been explored. Esophageal Cancer. Specific psychiatric illnesses in relation to esoph-
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ageal cancer have not been systematically determined. An association with depression (as seen with pancreatic cancer) is not recognized for esophageal cancer, nor is recognized for nonpancreatic abdominal neoplasms. 33, 38 Epidemiologic studies have confirmed the close relationship of alcohol use and esophageal carcinoma,78 but this relationship has not been specifically studied from the psychiatric standpoint. Alcohol is not directly cancerinducing, but it may act as a promoter for carcinogens in the beverage or in other ingested foods. 78 Alcohol and tobacco act synergistically in the pathogenesis of esophageal cancer such that the risk of this tumor is increased by 18-fold in alcoholics drinking more than 80 g of ethanol per day and by 44-fold in this group if tobacco consumption exceeds 20 g.74 Because of the close association of esophageal cancer with alcohol and tobacco use, psychiatric illnesses (other than abuse and dependency) are likely prevalent in subjects with this tumor. However, at present, the principal relationship of psychiatric factors with esophageal cancer is considered one of a behavioral interaction leading to toxic effects of alcohol and tobacco consumption. Rumination Syndrome. Rumination is a rare syndrome that most commonly occurs in infants and mentally retarded children or adults. 67 In this syndrome, recently ingested food is regurgitated into the mouth, remasticated, and swallowed again or, occasionally, spit out. The event is effortless and not associated with unpleasant symptoms, such as nausea, heartburn, or abdominal pain. Structural lesions in the esophagus or stomach and primary motor disorders of the esophagus (including achalasia and esophageal spasm) are not present to explain rumination. Brief increments in abdominal pressure, presumably resulting from contraction of abdominal (and possibly diaphragmatic) muscles, coincide with swallowing and concomitant relaxation of the lower esophageal sphincter to produce the regurgitation events. I Two psycho logic hypotheses have been proposed to explain the syndrome in nonretarded children: (1) the behavior is self-stimulatory in response to emotional or physical separation from the mother; (2) the behavior is learned and maintained by the reward of parental attention. 76 The first psychological mechanism may also apply to mentally retarded children. In nonretarded adults, rumination is frequently associated with psychopathology, particularly depression and anxiety. I, 44 No primary abnormality of esophageal or gastrointestinal motility is present in rumination syndrome, and the disorder is consistent with a learned behavior, often apparently as a response to psychologic distress.
THERAPEUTIC IMPLICATIONS An important outcome of unraveling the interactions of psychiatric factors with esophageal illness, or any medical illness, is a better understanding of therapeutic options. In some conditions, for example, therapy directed at psychiatric disorders, even if psychiatric symptoms seem minimal, may be an appropriate front-line approach; in others, this approach could be tangential and even wasteful. The esophageal diseases or syn-
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dromes with greatest psychiatric interaction, especially those for which a primary, causative role of psychiatric illness remains a possibility, are certainly those with greatest potential for improvement with psychiatric therapies. Behavioral modification is effective in stopping the learned behavior of rumination syndrome. 76 Therapies that reduce anxiety and depression symptoms in patients with achalasia or gastroesophageal reflux may reduce symptoms of these esophageal diseases, but improvement in objective disease parameters would not be expected. Likewise, altering the behavior that led to alcohol and tobacco abuse would have no recognized effect on the course of esophageal cancer. These comments probably seem obvious to the clinician. But what of esophageal spasm, the nonspecific motor disorders, and globus sensation-esophageal disorders with uncertain relationships to psychiatric illness? The clinical and investigative observations regarding psychopathology associated with these disorders are leading to further treatment trials as the pathophysiology is being determined. Several anecdotal reports have shown responsiveness of the esophageal spasm syndrome to psychotherapeutic intervention. A controlled trial of trazodone hydrochloride (Desyrel) in symptomatic patients with nonspecific motor disorders has also been reported. IS Subjects treated with 100 to 150 mg/day of trazodone rated significantly less distress related to esophageal symptoms and a greater sense of well-being after 6 weeks when compared with placebo-treated subjects. The occurrence of esophageal symptoms also improved but had not reached statistical significance at 6 weeks. Manometric parameters did not change despite symptom improvement, and changes in psychologic parameters were small. When all clinical responders were compared with nonresponders (irrespective of treatment group), the only significant psychometric change was a reduction in somatization. A recent report also examined the uncontrolled response of globus sensation to antidepressant therapy. 7 Three adult women were treated with imipramine, phenelzine, or tranylcypromine, and all had dramatic improvement. Other reports of antidepressant therapy in this syndrome have not appeared. Psychopharmacologic trials for somatic syndromes are not unique to the esophagus, and the efficacy of antidepressants, in particular, for other syndromes with strong associations to psychiatric illness are being explored. 35, 37
SUMMARY Psychiatric disorders have potentially important roles in the manifestations of esophageal disease, A primary causative role for psychiatric factors in the common motility disorders associated with chest pain (esophageal spasm and the nonspecific motor disorders) remains unproven, but psychiatric disorders appear particularly prevalent in this group. In most other esophageal diseases, psychiatric factors interact through recognized psychophysiologic or behavioral mechanisms to affect the clinical presentation.
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Recognizing the possible levels of interaction has significant therapeutic implications.
REFERENCES 1. Amarnath RP, Abell TL, Malagelada JR: The rumination syndrome in adults: A characteristic manometric pattern. Ann Intern Med 105:513-51S, 19S6 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3. Washington, DC, American Psychiatric Association, 19S0 3. Anderson KO, Dalton CB, Bradley LA, et al: Stress induces alteration of esophageal pressures in healthy volunteers and non-cardiac chest pain patients. Dig Dis Sci 34:S391, 19S9 4. Bass C, Wade C: Chest pain with normal coronary arteries: A comparative study of psychiatric and social morbidity. Psychol Med 14:51-61, 19S4 5. Beitman BD, Mukerji V, Lamberti JW, et al: Panic disorder in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 63:1399-1403, 19S9 6. Brand DC, Martin D, Pope CE: Esophageal manometries in patients with angina-like chest pain. Dig Dis Sci 22:300-304, 1977 7. Brown SR, Schwartz JM, Summergrad P, et al: Globus hystericus syndrome responsive to antidepressants. Am J Psychiatry 143:917-91S, 19S6 S. Camey RM, Freedland KE, Sapira JD, et al: Panic disorder and depression in patients with chest pain not due to coronary artery disease. Am J Cardiol 65:1048, 1990 9. Cassella RR, Brown AL Jr, Sayre GP, et al: Achalasia of the esophagus: pathologic and etiologic considerations. Ann Surg 160:474, 1964 10. Cassella RR, Ellis FH Jr, Brown AL Jr: Diffuse spasm of the lower part of the esophagus: Fine structure of esophageal smooth muscle and nerve. JAMA 191:379-3S2, 1965 11. Clouse RE: Motor disorders of the esophagus. In Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, ed 4. Philadelphia, WB Saunders, 19S9 12. Clouse RE: Anxiety and gastrointestinal illness. Psychiatr Clin North Am 11:399-417, 19S5 13. Clouse RE, Eckert TC: Gastrointestinal symptoms of patients with esophageal contraction abnormalities. Dig Dis Sci 31:236-240, 19S6 14. Clouse RE, Lustman PJ: Psychiatric illness and contraction abnormalities of the esophagus. N Engl J Med 309:1337-1342, 19S3 15. Clouse RE, Lustman PJ: Value of recent psychological symptoms in identifying patients with esophageal contraction abnormalities. Psychosom Med 51:570-576, 19S9 16. Clouse RE, Staiano A, Landau DW, et al: Manometric findings during spontaneous chest pain in patients with presumed esophageal "spasms." Gastroenterology S5:395-402, 19S3 17. Clouse RE, Lustman pJ, Reidel W: Correlation of esophageal motility abnormalities with neuropsychiatric status in diabetics. Gastroenterology 90:1146-1154, 19S6 IS. Clouse RE, Lustman pJ, Eckert TC, et al: Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities: A double-blind, placebo-controlled trial. Gastroenterology 92: 1027-1036, 19S7 19. Clouse RE, McCord GS, Lustman PI. et al: Clinical correlates of abnormal sensitivity to intraesophageal balloon distension. Dig Dis Sci, in press 20. Cohen M, White P: Life situations, emotions, and neurocirculatory asthenia (anxiety neurosis, effort syndrome). Am J Hum Genet 3:126, 1951 21. Colgan SM, Schofield PM, Whorwell pJ, et al: Angina-like chest pain: A joint medical and psychiatric investigation. Postgrad Med J 64:743-746, 19S5 22. Cook IJ, Collins SM: Does acute emotional stress influence frequency or duration of gastroesophageal reflux in human subjects? Gastroenterology 90:A13S0, 19S6 23. Cook IJ, Dent J, Collins SM: Upper esophageal sphincter tone and reactivity to stress in patients with a history of globus sensation. Dig Dis Sci 34:672-676, 19S9 24. Cook rJ, Dent I. Shannon S, et al: Measurement of upper esophageal sphincter pressure: Effect of acute emotional stress. Gastroenterology 93:526-532, 19S7
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25. Cook 1J, Shaker R, Dodds WJ, et al: Role of mechanical and chemical stimulation of the esophagus in globus sensation. Gastroenterology 96:A99, 1989 26. Connier LE, Katon W, Russo J, et al: Chest pain with negative cardiac diagnostic studies: relationship to psychiatric illness. J "'erv Mental Dis 176:351-358, 1988 27. Deary IJ, Wilson JA, Mitchell L, et al: Covert psychiatric disturbances in patients with globus pharyngitis. Br J Med Psychol 62:381-389, 1989 28. Derogatis LR, Rickels K, Rock AF: The SCL-90 and the MMPI: A step in the validation of a new self-report scale. Br J Psychiatry 128:280-289, 1976 29. Drossman DA, McKee DC, Sandler RS, et al: Psychosocial factors in the irritable bowel syndrome: A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology 95:701-708, 1987 30. Eypasch EP, Stein HJ, DeMeester TR, et al: A new technique to define and clarify esophageal motor disorders. Am J Surg 159:144-151, 1990 31. Faulkner WB, Rudenbaugh FH, O'Neill JR: InRuence of the emotions upon esophageal function: Comparison of esophagoscopic and roentgenologic findings. Radiology 37:443447, 1942 32. Ferguson SC, Hodges K, Hersh T, et al: Esophageal manometry in patients with chest pain and normal coronary arteriograms. Am J Gastroenterol 75:124-127, 1981 33. Fras I, Litin EM, Pearson JS: Comparison of psychiatric symptoms in carcinoma of the pancreas with those in some other intra-abdominal neoplasms. Am J Psychiatry 123:1553-1562, 1967 34. Goldberg DP, Cooper B, Eastwood MR, et al: A standardized psychiatric interview for use in community surveys. Br J Prev Soc Med 24:18-23, 1970 35. Greenbaum DS, Mayle JE, Vanegeren LE, et al: Effects of desipramine on irritable bowel syndrome compared with atropine and placebo. Dig Dis Sci 32:257-266, 1987 36. Holloway HH, Dent J: Pathophysiology of gastroesophageal reRux: Lower esophageal sphincter dysfunction in gastroesophageal reRux disease. Gastroenterol Clin North Am 19:.517-.53.5, 1990 37. Hudson JI, Hudson MS, Pliner LF, et al: Fibromyalgia and major affective disorder: A controlled phenomenology and family history study. Am J Psychiatry 142:441-446, 198.5 38. Joffe RT, Adsett CA: Depression and carcinoma of the pancreas. Can J Psychiatry 30:117118, 198.5 39. Katon W, Hall ML, Russo J, et al: Chest pain: Relationship of psychiatric illness to coronary arteriographic results. Am J Med 84:1-9, 1988 40. Katz PO, Dalton CB, Hichter JE, et al: Esophageal testing of patients with noncardiac chest pain or dysphagia: Hesults of three years' experience with 1161 patients. Ann Intern Med 106:.593-.597, 1987 41. Keshavarzian A, Iber FL, Ferguson Y: Esophageal manometry and radionuclide emptying in chronic alcoholics. Gastroenterology 92:6.51-6.57, 1987 42. Kramer P, Harris LD, Donaldson HM Jr: Transition from symptomatic diffuse spasm to cardiospasm. Gut 8:11.5-119, 1969 43. Landau D, Clouse HE: Hepeated esophageal manometries in patients with the nutcracker esophagus. Gastroenterology 82:A1111, 1982 44. Levine DF, Wingate DL, Pfeffer JM, et al: Habitual rumination: A benign disorder. Br Med J 287:2.5.5-2.56, 1983 45. McCord GS, Staiano A, Clouse HE: Achalasia, diffuse spasm, and nonspecific motor disorders. Balliere's Gastroenterol, in press 46. McMahon JM, Braceland FJ, Moersch HJ: The psychosomatic aspects of cardiospasm. Ann Intern Med 34:608-631, 19.51 47. Millon T, Green CJ, Meagher HB: Millon Behavioral Health Inventory Manual, ed 3. Minneapolis, National Computer Systems, 1982 48. Moloy pJ, Charter H: The globus symptom: Incidence, therapeutic response, and age and sex relationships. Arch OtoI108:740-744, 1982 49. Narducci F, Bassotti G, Gaburri M, et al: Transition from nutcracker esophagus to diffuse esophageal spasm. Am J Gastroenterol 80:242-244, 198.5 .50. Nevens F, Janssens J, Piessens J, et al: Prospective study on prevalence of esophageal chest pain in patients referred on an elective basis to a cardiac unit for suspected myocardial ischemia. Dig Dis Sci 36:229-235, 1991 .51. Nielzen S, Pettersson KI, Hegnell G, et al: The role of psychiatric factors in symptoms of hiatus hernia or gastric reRux. Acta Psychiatr Scand 73:214-220, 1986
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52. North CS, Clouse RE, Spitznagel E, et al: The relation of ulcerative colitis to psychiatric factors: a review of findings and methods. Am J Psychiatry 147:974-981, 1990 53. Obrecht WF, Richter JE, Kerr RM, et al: Is the nutcracker esophagus part of the spectrum of the irritable bowel syndrome? Gastroenterology 84:A1262, 1983 54. Patterson OR: Diffuse esophageal spasm in patients with undiagnosed chest pain. J Clin Gastroenterol 4:415-417, 1982 55. Perley MJ, Guze SB: Hysteria-the stability and usefulness of clinical criteria. N Engl J Med 266:421-426, 1962 56. Peters L, Maas L, Petty 0, et al: Spontaneous non-cardiac chest pain: Evaluation by 24hour ambulatory esophageal motility and pH monitoring. Gastroenterology 94:878-886, 1988 57. Pulliam TJ, Bradley LA, Dalton CB, et al: Role of psychological stress in gastroesophageal reflux disease (GERD). Gastroenterology 96:A401, 1989 58. Reidel WL, Clouse RE: Variations in clinical presentation of patients with esophageal contraction abnormalities. Dig Dis Sci 30:1065-1071, 1985 59. Richter JE, Castell DO: Diffuse esopahgeal spasm: A reappraisal. Ann Intern Med 100:242-245, 1984 60. Richter JE, Castell DO: Chest pain of esophageal origin. Dig Dis 7:39-50, 1989 61. Richter JE, Barish CF, Castell DO: Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 91:845-862, 1986 62. Richter JE, Obrecht WF, Bradley LA, et al: Psychological comparison of patients with nutcracker esophagus and irritable bowel syndrome. Dig Dis Sci 31:131-138, 1986 63. Rubin J, Nagler R, Spiro H, et al: Measuring the effects of emotions on esophageal motility. Psychosom Med 24:170-176, 1962 64. Schofield PM, Bennett OH, Whorwell PJ, et al: Exertional gastroesophageal reflux: A mechanism for symptoms in patients with angina pectoris and normal coronary angiograms. Br Med J 294:1459-1461, 1987 65. Schofield PM, Brooks NH, Colgan S, et al: Left ventricular function and oesophageal function in patients with angina pectoris and normal coronary angiograms. Br Heart J 58:218-224, 1987 66. Schuster MM: Esophageal spasm and psychiatric disorder. N Engl J Med 309:1382-1383, 1983 67. Singh NN: Rumination. Int Rev Res Ment Retard 10:139-182, 1981 68. Smith RC, Greenbaum DS, Vancouver JB, et al: Psychosocial factors are associated with health care seeking rather than diagnosis in irritable bowel syndrome. Gastroenterology 98:293-301, 1990 69. Stacher G, Schmierer G, Landgraf M: Tertiary esophageal contractions evoked by acoustical stimuli. Gastroenterology 77:49-54, 1979 70. Svennson 0, Stenport G, Tibbling L, et al: Esophageal function and coronary angiogram in patients with disabling chest pain. Acta Med Scand 204:173-178, 1978 71. Talley NJ, Phillips SF, Bruce B, et al: Relation among personality and symptoms in non ulcer dyspepsia and the irritable bowel syndrome. Gastroenterology 99:327-333, 1990 72. Traube M: The spectrum of the symptoms and presentations of gastroesophageal reflux disease. Gastroenterol Clin North Am 19:609-616, 1990 73. Traube M, Aaronson RM, McCallum RW: Transition from peristaltic esophageal contractions to diffuse esophageal spasm. Arch Intern Med 146:1844-1846, 1986 74. Tuyns AJ, Pequignot G, Jensen OM: Le cancer de l'oesophage en Ille-et-Vilaine en fonction des niveaux de consommation d' alcool et de tabac. Bulletin du Cancer 64:4560, 1977 75. Vantrappen G, Janssens J, Hellemans J, et al: Achalasia, diffuse esophageal spasm, and related motility disorders. Gastroenterology 76:450-457, 1979 76. Whitehead WE, Schuster MM: Rumination syndrome, vomiting, aerophagia, and belching. In Whitehead WE, Schuster MM (eds): Gastrointestinal Disorders: Behavioral and Physiological Basis for Treatment. Orlando, Academic Press, 1985, pp 67-90 77. Whitehead WE, Bosmajian L, Zonderman AB, et al: Symptoms of psychologic distress associated with irritable bowel syndrome. Gastroenterology 95:709-714, 1988 78. Wienbeck M, Berges W: Oesophageal lesions in the alcoholic. Clin Gastroenterol 10:375388, 1981 79. Winkelstein A: Psychogenic factors in cardiospasm. Am J Surg 12:135-138, 1931
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80. Wolf S, Almy TP: Experimental observations on cardiospasm in man. Gastroenterology 13:401-421, 1949 81. Wong RKH, Johnson LF: Achalasia. In Castell DO, Johnson LF (eds): Esophageal Function in Health and Disease. New York, EIsevier Biomedical, 1983, pp 99-123 82. Young LD, Richter JE, Anderson KO, et al: The effects of psychological and environmental stressors on peristaltic esophageal contractions in healthy volunteers. Psychophysiology 24:132-141, 1987
Address reprint requests to Ray E. Clouse, MD Digestive Disease Clinical Center One Barnes Hospital Plaza St. Louis, MO 63110
0025-712.5/91 $0.00 + .20
Psychiatric Disorders in Patients with Esophageal Disease
Ray E. Clouse, MD*
Psychiatric disorders may play an important role in the presentation of many medical diseases. Their importance in chest pain syndromes only recently has received widespread attention. Initially, psychiatric factors were considered relevant primarily in cases in which somatic explanations for chest pain could not be determined, presumably cases of "psychogenic" pain. Attention is now being given to the full spectrum of medicalpsychiatric interactions to better understand the psychiatric contrihution in many clinical disorders and to extract therapeutic implications. Esophageal diseases are well-recognized causes of chest pain. 60 In particular, gastroesophageal reflux and motor disorders involving the distal esophagus are both prevalent in patients with recurrent chest pain and no evidence of cardiac disease. 6 ..50. 56 As with many medical conditions, the role of coexistent psychiatric illness with esophageal disorders in the presentation of chest pain remains poorly understood. Technologic advances in measuring degrees and types of esophageal dysfunction (e.g., improved manometric techniques and 24-hour pH monitoring) have extended the focus hy investigators and clinicians on a search for physiologic explanations and somatic diagnoses for chest pain. However, these same advances have helped expose the incomplete association of measured physiologic almormalities with symptoms. Thus, the contribution of psychiatric factors to the overall manifestations of esophageal disease is gaining renewed interest. Despite the interest, few studies have systematically determined the coexistence of psychiatric disorders in patients with defined esophageal diseases. Additionally, ohservations of psychiatric interactions with medical illness were often anecdotal in earlier studies (prior to 1970), employing psychiatric methods that would not satisfy current scientific standards ..52 More recent reports have included control groups, blinded evaluations, and validated psychiatric instruments. Such studies will be the focus of this article.
*Associate
Professor of Medicine, Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine; and Associate Physician, Barnes Hospital, St. Louis, Missouri
Medical Clinics of North America-Vol. 75. No. 5, September 1991
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POTENTIAL ROLES OF PSYCHIATRIC ILLNESS IN PATIENTS WITH ESOPHAGEAL DISEASE Psychiatric disorders have potentially important roles in the occurrence and presentation of esophageal syndromes (Table 1). At one extreme, psychiatric illness could be causative of the esophageal disease; at the other, it may simply produce symptoms that occur in parallel with the esophageal symptoms, thereby confusing the clinical presentation. Determining that a somatic illness is actually a manifestation of psychiatric illness, especially if measurable abnormalities of organ function are present, is a difficult task. An unrecognized pathologic lesion in the target organ may be responsible. However, the neuroanatomic framework is available such that derangements in esophageal motor function, for example, could be produced by the central nervous system, including such phenomena as emotional change. 12 The evidence for or against an etiologic role of psychiatric illness will be offered for several esophageal diseases, particularly those associated with chest pain. Interactive roles are likely in all cases. PSYCHIATRIC DISORDERS IN SPECIFIC ESOPHAGEAL SYNDROMES Esophageal Motility Disorders
Achalasia. This disease of the distal esophagus and lower esophageal sphincter results from degeneration of the intramural neurons that control esophageal motility and lower sphincter relaxation. 81 Symptoms may first present at nearly any age, but the modal age range at diagnosis is 20 to 50 years.lI Dysphagia and regurgitation are the principal symptoms, and substernal chest pain is reported by 30% to 50% of patients. Initially, this disorder was considered one of smooth muscle dysfunction or spasm with prominent involvement of the lower sphincter. Later work confirmed the degenerative neural lesion in the esophageal myenteric plexus. 9 Table 1. Potential Roles of Psychiatric Illness in Patients with Esophageal Disease POTENTIAL ROLE
Causative Interactive Psychophysiologic effect Behavioral effect
Parallel symptom activity
EXA~lPLE
Psychiatric illness directly produces the esophageal manifestations Psychiatric illness alters normal esophageal motor or sensory function in presence of esophageal disease Psychiatric illness induces health-care-seeking behavior, alters medication compliance, or acts through other indirect behavioral mechanisms (e.g., enhanced cigarette smoking, increased alcohol consumption) that may interact with esophageal disease Symptoms of psychiatric illness (e. g., anorexia, fatigue, fear of eating) confound interpretation of the esophageal disease
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Achalasia is the only primary esophageal motility disorder for which the pathophysiology is thoroughly understood. Before the neural abnormalities were detected, a psychiatric contribution to (if not cause for) the development of esophageal muscle spasm, irregular contractions, and subsequent symptoms was considered likely. Wolf and AlmyB° studied 14 achalasic subjects by fluoroscopically monitoring barium transit during emotionally charged interviews. These authors noted that barium passage was markedly delayed in most subjects when the interview shifted to topics of intense emotional impact. In contrast, barium transit was most rapid when the subjects were relaxed. As a clinical parallel, the subjects often reported symptom exacerbations and remissions (prior to any treatment) in conjunction with variations in life situations and stresses. Several normal control subjects also demonstrated delayed barium transit (to lesser degrees) with noxious stimuli and with the stressful interview, but the manometric correlate of this delay in transit was not determined. The authors concluded that achalasia may represent a biologic reaction to stress (i.e., that psychiatric disorder is causative in this disease). Several other early uncontrolled studies favored a psychogenic cause for achalasia based on the investigators' determination of stressful life events or other psychic trauma preceding the onset of esophageal symptoms. 46, 79 In light of current understanding of the pathophysiology of achalasia, a causative role of psychiatric illness is not considered likely. The disease has continued to appear worldwide at a relatively constant rate without apparent epidemics or familial clustering, 11 and the neural lesion is acknowledged. There is no evidence or clinical suspicion that the disease is more common in psychiatric clinic populations. Prevalence data of psychiatric disorders in patients with achalasia are, for the most part, lacking. A study of subjects with nonspecific motor disturbances included three patients with achalasia in one of the control groups. 14 Psychiatric illness, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Version III (DSM-IIP), was uncommon in the control group in general, and none of the 15 diagnoses sought were present in the three achalasia patients (unpublished observations). A subsequent study evaluated recent psychologic symptoms in patients with esophageal motor disorders, and again a control group (n = 14) comprising patients with achalasia (n = 9) and other related disorders was included. 15 A multidimensional self-report measure (the Hopkins Symptom Checklist, SCL-90R2R) including nine primary symptom dimensions (e.g., depression, anxiety, somatization, psychoticism) and three global scales was employed. Subjects in this control group scored lowest on the SCL-90R of any study subjects, T -scores being less than 55 on 9 of the 12 scales. Thus, recent data to support a psychiatric etiology of this motor disorder are lacking. The early work by Wolf and Almy likely demonstrates esophageal responsiveness to stressful stimuli, responsiveness that subsequently has been confirmed using intraluminal manometric recording devices. 82 It seems logical that such psychophysiologic interactions could be more detrimental from a symptom-production standpoint in an organ with existing disease (e.g., achalasia) than in the normal subject, and the clinical and laboratory observations made in the earlier work would confirm this suspicion.
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Diffuse EsophageaZ Spasm and Nonspecific Motor Disorders. The role of psychiatric factors in the presentation of these motility disorders remains of greater interest for several reasons: (1) a pathologic esophageal lesion (e.g., a defined neural abnormality) is absent in most cases; (2) regression of manometric abnormalities to normal has been observed 41 , 43; and (3) the clinical impression persists that patients with these disorders are more distressed and generally emotionally upset than patients with other esophageal diseases. 14 , 62 In addition, satisfactory symptom management is often difficult, If understanding a psychiatric interaction would lead to improved treatment regimens, practitioners would be pleased. In this article, I will include diffuse esophageal spasm and the nonspecific disorders outlined in Table 2. The clinical syndromes of these manometric disorders are virtually identical 45 and will be addressed as the "esophageal spasm syndrome." As currently defined, diffuse esophageal spasm differs from the nonspecific disorders only in the presence of periodic simultaneous contraction sequences, 59 findings that may be absent on a brief manometric tracing. The overlap of the nonspecific disorders with diffuse esophageal spasm has been demonstrated in several ways, 11, 30, 49, 73 and for these reasons it seems justified to discuss these disorders as a group. A small subset of patients with diffuse esophageal spasm who have more severe manometric derangement may not be correctly represented by the group as a whole. In these cases, a neural lesion similar to that in achalasia may be responsible for the findings. Io Likewise, some subjects with typical findings of diffuse esophageal spasm at presentation subsequently have been diagnosed as having achalasia, 42, 75 but this evolution appears rare, Although segregation of patients with a histologic neural lesion from those with the motor "dysfunction" is difficult and failure to do so leaves a heterogeneous study population, the proportion of subjects with the achalasia-like disorder appears to be very small, Table 2. Diffuse Esophageal Spasm and Nonspecific Motor Disorders MANOMETRIC DISORDER
Diffuse esophageal spasm
Nonspecific motor disorders Vigorous contraction wave abnormalities
Hypertensive lower esophageal sphincter pressure
CHARACTERISTICS
COMMENT
Frequent simultaneous, nonperistaltic contraction sequences (following > 10% of recorded swallows)
Manometric features of the nonspecific motor disorders often also present
Increased contraction amplitude (the "nutcracker esophagus"), prolonged wave duration, increased frequency of multipeaked wave forms Increased basal (resting) pressure in the lower esophageal sphincter
Manometric features seen alone or in any combination
Can be an isolated finding but is usually found in conjunction with vigorous contraction wave abnormalities
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Patients with esophageal spasm syndrome usually present in adulthood, the mean age at diagnosis being 40 to 50 years. l l In most American reports, women are predominant. Chest pain is reported by 80% or more of subjects and is usually the most significant symptom. 11, 58 Because the pain is retrosternal and may have radiation patterns similar to that of angina pectoris, it is not surprising that many patients who present with chest pain and have cardiac disease excluded are ultimately thought to have this syndrome. In fact, diffuse esophageal spasm and the nonspecific motor disorders have been detected in 18% to 58% of chest pain subjects with negative cardiac evaluations. 6, ,32, 40, 54, 70 Associated psychologic symptoms (e.g., of anxiety or depression) have long been noted to accompany the esophageal symptoms in this syndrome. 14, 62 An association of psychiatric factors with the esophageal spasm syndrome was further suspected when a high prevalence of psychiatric illness was detected in chest pain patients who had no evidence of cardiac disease. 4 , 5, 26, 39 For example, Bass et al 4 found that 61% of such subjects met criteria for psychiatric diagnoses (most commonly panic disorder). Likewise, using DSM-III criteria, Katon et aP9 found that current psychiatric diagnoses were present in 79% of subjects without coronary artery disease versus 26% in controls. Anxiety and affective disorders were most common. Do psychiatric disorders detected in these studies represent causes of chest pain that are separate from the esophageal diseases? Are there three main categories in the noncardiac group: psychiatric (or "psychogenic"), esophageal, and undiagnosed?" 8 Or do these processes overlap? Several studies have systematically looked at psychopathology in patients with the esophageal spasm syndrome in whom cardiac disease had been excluded. 14, 18, 21, 62 In 1983, Clouse and Lustman 14 used a structured interview and DSM-lII criteria to determine the rates of psychiatric diagnoses in patients referred for manometry, The subjects with chest pain had completed unrevealing cardiac evaluations. Psychiatric diagnoses were made in 84% of patients with contraction wave abnormalities (see Table 2) and the esophageal spasm syndrome, whereas diagnoses were made in only 31 % to 33% of patients in two control groups. Rates of major depression (in 52% of spasm patients) and anxiety states (generalized anxiety disorder and panic disorder, in 36% of spasm patients) were most significantly different among groups. Of potential importance in the results of this study, only 8 of 13 patients with major depression had active psychiatric symptoms at the time of evaluation, and a current diagnosis was present in only seven of nine patients with the anxiety states, implying that the psychiatric and esophageal diseases might run different symptom courses. Subsequent to that report, Colgan et aPl studied 63 patients with anginal chest pain but without evidence of coronary artery disease. These authors used the Clinical Interview Schedule34 to determine psychiatric "caseness" and manometry, endoscopy, and 24-hour pH monitoring to determine esophageal disease. Only esophageal spasm and the nonspecific motor disorders were considered in the results. 65 Using these techniques, psychiatric cases were identified as 44% of the subjects versus 29% of a control group with documented coronary artery disease. The subject group
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was further separated, and psychiatric illness was diagnosed in 59% of patients with esophageal abnormalities as the presumed cause of chest pain versus 18% of those with left ventricular dysfunction (as the presumed cause of pain). The highest rate of psychiatric diagnosis (63%) was in the subgroup with motility disorders. These findings would further support the segregation of psychiatric illness with esophageal motor disorders of the types listed in Table 2. In an additional report, Richter et aF5 compared psychologic profiles on the Millon Behavioral Health Inventory in chest pain patients with highamplitude contraction wave abnormalities to profiles from control groups that included asymptomatic volunteers and patients with structural esophageal disease. 62 Once again, patients with the nonspecific motor disorder were psychologically different from controls with significant differences on several scales (somatic anxiety, gastrointestinal susceptibility; less Significant trends on depression scales). Psychologic differences (especially in anxiety and depression symptoms) between patients with nonspecific motor disorders and achalasia were confirmed in another study, but differences between motor disorder patients and chest pain patients without motility abnormalities were less apparent. 15 Evaluating recent psychologic symptoms has not been as rewarding in these disorders as determining lifetime psychiatric diagnoses (e. g., using a structured interview and diagnostic criteria). 14. 15 An additional piece of information must be considered in formulating conclusions about the role of psychiatric illness in these disorders. Two additional reports from the same group reproduced the high prevalence of DSM-III diagnoses in patients with contraction wave abnormalities. 17. 18 One of these studies included diabetic patients who had no csophageal symptoms l7 and the contraction wave abnormalities correlated with psychiatric illness, not neuropathy. Thus, the manometric findings may be associated with psychopathology independent of esophageal symptoms. Similar studies in psychiatric populations (involving patients without any potentially confounding neuropathies) have not been reported, but this information would be very useful. These findings also speak against any suspicion that the psychiatric illnesses result from the motor disorder, e. g., from debilitating symptoms. Likewise, appropriately symptomatic control groups were employed in the studies mentioned previously. 14. 15.62 The high rates of psychiatric diagnoses and their association with contraction abnormalities independent of symptoms raise the following question: Are diffuse esophageal spasm and nonspecific motility disorders caused by psychiatric factors? Simply because the pathophysiology of these disorders is poorly understood, investigators are justifiably unwilling to make this assumption and then see the story of achalasia repeated. In an attempt to answer the question, several groups have examined the esophageal motor response to acute stress (Table 3). The induced radiographic and manometric findings are not unlike the spontaneous abnormalities found in esophageal spasm and the related nonspecific disorders. The manometric changes reported by Young et al 82 and Anderson et aP are probably most reliable as the manometric techniques employed satisfY contemporary standards and the psychological methods were sound. In-
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Table 3. Esophageal Motor Response to Acute Stress \1EASURED AUTHOR (YEAR)
ESOPHAGEAL STRESSOR
RESPONSE
FINDINGS
Faulkner et al (1942)31
25 selected patients
Discussion of unpleasant topics
Changes on barium fluoroscopy and during esophagoscopy
Rubin et al (1962)63
5 healthy volunteers
Stress interview
Peristaltic performance using lowfidelity manometric methods
Stacher et al (1979)69*
22 healthy volunteers
Loud noises of varying frequency and intensity
Contraction wave parameters uSing highfidelity manometry
Young et al (1987)82*
25 healthy volunteers
Abnormal contractions in distal esophagus and delayed barium clearance in all (?) subjects; spasms during esophagoscopy Significantly more simultaneous contractions during emotionally charged periods on three subjects Spontaneous contractions induced above decibel and frequency threshold in all subjects (?startle) Increased contraction amplitude with all stressors; no consistent peristaltic change Increased contraction amplitude with both stressors, greater increment in NSMD patients; no consistent peristaltic change
Anderson et al (1989)3*
SUBJECTS
White noise, cold Contraction wave pressor test, and parameters and cognitive task peristaltic performance using highfidelity manometry 20 healthy White noise, Contraction wave volunteers cognitive task parameters and and 19 chest peristaltic pain performance using highpatientst fidelity manometry
Abbreviations: NSMD = nonspecific motor disorder. *Well-controlled experimental design; blinded response interpretation. tIncluded 10 patients with a nonspecific motor disorder (the nutcracker esophagus").
duced manometric changes in both normal subjects and in symptomatic patients with high-amplitude contractions were small (amplitude increases by 5% to 12% of baseline) but in the direction of worsening contraction wave abnormalities. 3,82 Possibly more sustained stress could produce greater change. In favor of this hypothesis, Keshavarzian et al41 found marked elevations of contraction amplitudes or other nonspecific motor abnormalities in 14 of 18 patients with chronic alcoholism who were undergoing
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alcohol withdrawal,41 although none of the subjects were symptomatic (e.g., with chest pain). After recovery, manometry returned to normal in five of six restudied subjects. Despite these intriguing findings from acute and subacute stress studies, convincing evidence, as from longitudinal evaluations, that psychiatric illness actually precipitates the motor disorders is lacking. The simultaneous contraction sequences typical of esophageal spasm were not provoked with stressful stimuli in the recent manometric studies. 3 . 82 Also, using the best psychiatric tools available today (structured interviews, diagnostic criteria), investigators have shown that approximately 20% of symptomatic subjects with these manometric findings do not meet criteria for any psychiatric diagnosis, and the psychiatric diagnoses themselves vary from study to study. 14. 18 Thus, a causative role of psychiatric illness at present must be considered unproven. Besides a potential causative role, other psychiatric interactions (see Table 1) may be operational in these disorders, particularly in affecting the clinical presentation. The importance of such interactions has not been systematically determined. The esophageal spasm syndrome shares many clinical features with irritable bowel syndrome, 13.'53.66 and only recently has the effect of health-ca re-seeking behavior been recognized in this intestinal disorder. 29. 68. 77 Psychopathology may precipitate a visit to the doctor for complaints (e.g., abdominal pain) that might otherwise be disregarded. If the same is true in esophageal spasm, then psychopathology may be overrepresented in the subset of patients who are actively seeking medical care (and are, thus, included in medical reports). As another form of interaction, the presence of an underlying motor disorder may enhance sensitivity to normal psychophysiologic esophageal responses, as was described for achalasia. These possibilities have not been fully explored. Finally, the mechanism by which chest pain and other esophageal symptoms are produced in diffuse esophageal spasm and nonspecific motor disorders remains poorly understood. In particular, the defining motor events may actually have little to do with symptoms (especially chest pain) in most cases. 16. 40. 41 One possibility is that the motor abnormalities are epiphenomena with chest symptoms arising from a nonesophageal site. However, the symptoms often sound distinctly esophageal, and chest pain can be reproduced with esophageal stimuli in 30% to 50% of patients. 19. 40 Recent attention has been given to the sensitivity of esophageal sensory receptors to intraluminal stimuli, particularly to balloon distention. 19,61 The relationship of abnormal sensitivity to balloon distention with psychiatric illness and stress has not yet been reported. It does appear that abnormal balloon sensitivity is only partially related to the nonspecific motor disorders19,61 and is unrelated to measures of recent psychologic distress, 19 Although an interaction of psychiatric illness with enhancement of visceral sensitivity is an attractive hypothesis to explain prior clinical and investigative observations, these early reports do not immediately favor such a simple solution, Gastroesophageal Reflux Disease Gastroesophageal reflux disease includes symptoms and resultant organ damage (esophageal, pharyngeal, laryngeal, pulmonary) from excessive
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reflux of gastric acid through the gastroesophageal junction or excessive acid exposure to the esophageal mucosa. A variety of mechanisms are responsible for the manifestations. :16 Principal symptoms are heartburn, chest pain, postural regurgitation of gastric contents, dysphagia, and a variety of other nonspecific symptoms, such as "lump" or tightness in throat. 72 Chest pain induced by reflux can be related to exercise and readily confused with angina pectoris. 64 When polled, as many as 64% of healthy adult Americans believe that excessive stress is a cause of heartburn. 57 Despite this widely held notion, little scientific information is available to support an association of reflux and emotional factors. Indirect evidence would indicate that some symptoms of reflux disease may be associated with specific psychiatric disorders. Chest pain is reported by as many as 85% of panic disorder patients 20 ; chest pain (72%) and lump in throat (28%) are both common in somatization disorder. 55 In a separate report, typical reflux symptoms were described by 42% of psychiatric patients with somatization disorder. 71 Similar symptoms were listed by only 5% of the healthy control subjects. Are the reflux-like symptoms reported by these patients and by stressed subjects actually related to gastroesophageal reflux, or do they occur through a separate mechanism? Nielzen et aPl reviewed the psychiatric features of 26 symptomatic patients who had been referred for evaluation of suspected gastroesophageal reflux. Subjects were then categorized as having reflux (endoscopic evidence of esophagitis or manometric evidence of provocable reflux) or hiatal hernia in one group, and neither in the other. A psychologic test of photograph interpretation Cmeta contrast" technique) was used to infer psychiatric symptoms. Of the seven psychologic characteristics determined by this technique, two scales (anxiety, depressive signs) were significantly more common in the group without objective evidence of reflux disease, and none were more common in those with documented reflux or hiatal hernia. Thus, the psychiatric factors segregated best with the subjects who had reflux symptoms but no objective evidence of reflux disease. The methods of measuring reflux in this study were, however, suboptimal. Preliminary data are available from two studies examining the effects of acute stress on reflux parameters. Cook and Collins 22 studied six healthy volunteers using a pH probe and stress in the form of dichotic listening with a superimposed intellectual task. Frequency and duration of reflux were quantitated following a standard meal, and the stress episodes were interspersed with control periods of relaxing music. Although the stressor was sufficient to raise heart rate and systolic blood pressure significantly, reflux parameters were not altered. Pulliam et aJ57 subsequently found that stressors (cognitive and manual tasks, delayed auditory feedback) did not significantly influence objective measures of acid reflux in 10 subjects with known symptomatic reflux disease. Twenty-four-hour pH monitoring devices were employed. These authors did show, however, that reflux symptoms were (subjectively) accentuated during stress in subjects with higher scores on multidimensional psychologic measures. Taken together, it appears that psychiatric factors may interact with reflux disease primarily by increasing reflux symptoms without affecting
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measured reflux parameters. The symptoms may either be (1) accentuated perception of reflux events or (2) symptoms produced by a mechanism that mimics reflux disease. The investigations employing 24-hour pH monitoring may help determine which of these mechanisms is of greatest significance in subjects with and without existing reflux disease. Other Esophageal Disorders
Globus Sensation. The globus sensation, or sense of a lump in the hypopharynx at the level of and immediately behind the cricoid cartilage, is not an uncommon complaint. The symptom represents up to 4% of referrals to otolaryngologists. 48 Globus sensation can rarely result from structural lesions in the hypopharynx, cervical esophagus, or neighboring structures in the neck. At times, the globus sensation may be representative of gastroesophageal reflux or other distal esophageal process. In most instances, however, the isolated symptom occurs in patients who have no recognized cervical or esophageal pathology. A consistent motor or sensory abnormality in the region of the cricopharyngeus muscle to explain the symptom has not been detected. 23 Globus sensation is a common symptom of patients with somatization disorder, being reported by nearly a third of patients. 55 Its association with other psychiatric diagnoses is not fully known. Several cases of globus sensation in association with panic attacks and major depression have been reported. 7 In a recent report, Deary et a}27 studied 121 globus patients using self-report inventories to estimate personality traits and psychiatric morbidity (e. g., Eysenck Personality Questionnaire, General Health Questionnaire [GHQ]). The patients were compared with appropriately symptomatic and matched controls. Female subjects showed low extraversion scores, high GHQ scores of psychiatric morbidity, and high levels of anxiety, depression, and somatic concern, and in some ways resembled a cohort of psychiatric outpatients. The smaller number of men in this study were no different from control subjects. The authors concluded that psychologic factors were likely important in this disorder-possibly of primary importance, especially in female subjects. Other investigators have found similar psychologic abnormalities in globus patients. 23 A psychophysiologic explanation for the symptom is lacking. Cook et a}24 have shown that the upper esophageal sphincter (the anatomic location of the globus sensation) is responsive to acute emotional stress in normal individuals. These same investigators subsequently showed that upper sphincter basal tone and reactivity to stress were similar in globus patients and asymptomatic subjects. 23 Thus, despite the psychologic differences between these groups, upper esophageal sphincter response to stress does not explain the origin of the symptom. Recent preliminary data indicate that the sensation can be more easily produced in globus patients than in asymptomatic controls with a balloon distention stimulus in the esophagus. 25 These data may indicate that esophageal sensory dysfunction is as relevant in globus sensation as it appears to be in non cardiac chest pain. 61 The relationship of this visceral sensory abnormality to psychiatric factors has not been explored. Esophageal Cancer. Specific psychiatric illnesses in relation to esoph-
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ageal cancer have not been systematically determined. An association with depression (as seen with pancreatic cancer) is not recognized for esophageal cancer, nor is recognized for nonpancreatic abdominal neoplasms. 33, 38 Epidemiologic studies have confirmed the close relationship of alcohol use and esophageal carcinoma,78 but this relationship has not been specifically studied from the psychiatric standpoint. Alcohol is not directly cancerinducing, but it may act as a promoter for carcinogens in the beverage or in other ingested foods. 78 Alcohol and tobacco act synergistically in the pathogenesis of esophageal cancer such that the risk of this tumor is increased by 18-fold in alcoholics drinking more than 80 g of ethanol per day and by 44-fold in this group if tobacco consumption exceeds 20 g.74 Because of the close association of esophageal cancer with alcohol and tobacco use, psychiatric illnesses (other than abuse and dependency) are likely prevalent in subjects with this tumor. However, at present, the principal relationship of psychiatric factors with esophageal cancer is considered one of a behavioral interaction leading to toxic effects of alcohol and tobacco consumption. Rumination Syndrome. Rumination is a rare syndrome that most commonly occurs in infants and mentally retarded children or adults. 67 In this syndrome, recently ingested food is regurgitated into the mouth, remasticated, and swallowed again or, occasionally, spit out. The event is effortless and not associated with unpleasant symptoms, such as nausea, heartburn, or abdominal pain. Structural lesions in the esophagus or stomach and primary motor disorders of the esophagus (including achalasia and esophageal spasm) are not present to explain rumination. Brief increments in abdominal pressure, presumably resulting from contraction of abdominal (and possibly diaphragmatic) muscles, coincide with swallowing and concomitant relaxation of the lower esophageal sphincter to produce the regurgitation events. I Two psycho logic hypotheses have been proposed to explain the syndrome in nonretarded children: (1) the behavior is self-stimulatory in response to emotional or physical separation from the mother; (2) the behavior is learned and maintained by the reward of parental attention. 76 The first psychological mechanism may also apply to mentally retarded children. In nonretarded adults, rumination is frequently associated with psychopathology, particularly depression and anxiety. I, 44 No primary abnormality of esophageal or gastrointestinal motility is present in rumination syndrome, and the disorder is consistent with a learned behavior, often apparently as a response to psychologic distress.
THERAPEUTIC IMPLICATIONS An important outcome of unraveling the interactions of psychiatric factors with esophageal illness, or any medical illness, is a better understanding of therapeutic options. In some conditions, for example, therapy directed at psychiatric disorders, even if psychiatric symptoms seem minimal, may be an appropriate front-line approach; in others, this approach could be tangential and even wasteful. The esophageal diseases or syn-
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dromes with greatest psychiatric interaction, especially those for which a primary, causative role of psychiatric illness remains a possibility, are certainly those with greatest potential for improvement with psychiatric therapies. Behavioral modification is effective in stopping the learned behavior of rumination syndrome. 76 Therapies that reduce anxiety and depression symptoms in patients with achalasia or gastroesophageal reflux may reduce symptoms of these esophageal diseases, but improvement in objective disease parameters would not be expected. Likewise, altering the behavior that led to alcohol and tobacco abuse would have no recognized effect on the course of esophageal cancer. These comments probably seem obvious to the clinician. But what of esophageal spasm, the nonspecific motor disorders, and globus sensation-esophageal disorders with uncertain relationships to psychiatric illness? The clinical and investigative observations regarding psychopathology associated with these disorders are leading to further treatment trials as the pathophysiology is being determined. Several anecdotal reports have shown responsiveness of the esophageal spasm syndrome to psychotherapeutic intervention. A controlled trial of trazodone hydrochloride (Desyrel) in symptomatic patients with nonspecific motor disorders has also been reported. IS Subjects treated with 100 to 150 mg/day of trazodone rated significantly less distress related to esophageal symptoms and a greater sense of well-being after 6 weeks when compared with placebo-treated subjects. The occurrence of esophageal symptoms also improved but had not reached statistical significance at 6 weeks. Manometric parameters did not change despite symptom improvement, and changes in psychologic parameters were small. When all clinical responders were compared with nonresponders (irrespective of treatment group), the only significant psychometric change was a reduction in somatization. A recent report also examined the uncontrolled response of globus sensation to antidepressant therapy. 7 Three adult women were treated with imipramine, phenelzine, or tranylcypromine, and all had dramatic improvement. Other reports of antidepressant therapy in this syndrome have not appeared. Psychopharmacologic trials for somatic syndromes are not unique to the esophagus, and the efficacy of antidepressants, in particular, for other syndromes with strong associations to psychiatric illness are being explored. 35, 37
SUMMARY Psychiatric disorders have potentially important roles in the manifestations of esophageal disease, A primary causative role for psychiatric factors in the common motility disorders associated with chest pain (esophageal spasm and the nonspecific motor disorders) remains unproven, but psychiatric disorders appear particularly prevalent in this group. In most other esophageal diseases, psychiatric factors interact through recognized psychophysiologic or behavioral mechanisms to affect the clinical presentation.
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Recognizing the possible levels of interaction has significant therapeutic implications.
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Address reprint requests to Ray E. Clouse, MD Digestive Disease Clinical Center One Barnes Hospital Plaza St. Louis, MO 63110