This article revisits the links between psychopathology and functional gastrointestinal disorders such as irritable bowel syndrome (IBS), discusses the rational use of antidepressants as well as non-pharmacological approaches to the management of IBS, and suggests guidelines for the treatment of IBS based on an interdisciplinary perspective from the present state of knowledge. Relevant published literature on psychiatric disorders, especially somatization disorder, in the context of IBS, and literature providing direction for management is reviewed, and new directions are provided from findings in the literature. IBS is a heterogeneous syndrome with various potential mechanisms responsible for its clinical presentations. IBS is typically complicated with psychiatric issues, unexplained symptoms, and functional syndromes in other organ systems. Most IBS patients have multiple complaints without demonstrated cause, and that these symptoms can involve systems other than the intestine, e.g. bones and joints (fibromyalgia, temporomandibular joint syndrome), heart (non-cardiac chest pain), vascular (post-menopausal syndrome), and brain (anxiety, depression). Most IBS patients do not have psychiatric illness per se, but a range of psychoform (psychological complaints in the absence of psychiatric disorder) symptoms that accompany their somatoform (physical symptoms in the absence of medical disorder) complaints. It is not correct to label IBS patients as psychiatric patients (except those more difficult patients with true somatization disorder). One mode of treatment is unlikely to be universally effective or to resolve most symptoms. The techniques of psychotherapy or cognitive-behavioral therapy can allow IBS patients to cope more readily with their illness. Specific episodes of depressive or anxiety disorders can be managed as appropriate for those conditions. Medications designed to improve anxiety or depression are not uniformly useful for psychiatric complaints in IBS, because the psychoform symptoms that sound similar to those seen in psychiatric disorders may not have the same significance in patients with IBS.

Functional medical disorders, by definition, lack objective physical, metabolic, or neurological explanations for their symptom presentations. Diagnosis of these disorders, like diagnosis of psychiatric disorders, is based entirely on subjective complaints. This may have contributed to longstanding conceptualizations of functional disorders as fundamentally psychiatric or psychological in origin, cloaking this class of disorders with a negative stigma. Although irritable bowel syndrome (IBS) may be considered an archetype among the functional gastrointestinal disorders, a wide variety of medical syndromes and disorders in many medical subspecialties are also characterized by lack of objective indicators and subjective determination of diagnosis. Non-ulcer dyspepsia, premenstrual syndrome, chronic pain syndromes, tension headaches, fibromyalgia, chronic fatigue syndrome, interstitial cystitis, reflex sympathetic dystrophy, temporomandibular joint syndrome, and various chemical and food sensitivities are examples of functional disorders in many organ systems.

Despite longstanding assumptions about psychiatric origins of functional disorders, few gastroenterologists as recently as 15 years ago used psychopharmacologic agents to treat functional gastrointestinal disorders. Clouse and Lustman[1] observed that recognition of the utility of antidepressant agents for functional disorders, especially IBS, precipitated a rise in the use of antidepressants in treatment of functional gastrointestinal disorders. Now, in 2007, the treatment of these disorders with antidepressants by gastroenterologists is quite common, and as many as one in eight patients with these disorders are offered psychopharmacological agents.

Recently increasing application of psychopha-rmacotherapy for functional gastrointestinal disorders has further confused clinicians trying to manage these poorly understood functional syndromes with historical biases toward assumptions of psychiatric origins. The use and effectiveness of antidepressants may further solidify long-held beliefs that functional gastrointestinal disorders are really psychiatric. The well-known association of psychiatric illness and functional gastrointestinal disorders further contributes to assumptions of psychopathology inherent in these disorders.

This article revisits the linkes between psychopathology and functional gastrointestinal disorders such as IBS and will discusses the rational use of antidepressants as well as non-pharmacological approaches such as psychotherapy and psychoeducational/behavioral approaches in the management of IBS. This article will also suggests guidelines for the treatment of IBS from an interdisciplinary (psychology, psychiatry, and gastrointestinal/internal medicine) perspective based on the present state of knowledge.

Psychiatric disorders are prevalent in medical practice, especially in primary care, where as many as one-third of patients may suffer from one or more current diagnosable psychiatric disorders, especially depressive and anxiety disorders[2-5]. Among patients with functional gastrointestinal disorders, the rates of associated psychiatric disorders are even higher. In the case of IBS, 50%-90% of those seeking treatment have been found to also have comorbid lifetime psychiatric disorders, especially depressive and anxiety disorders[6]. Somatization disorder (SD) is also highly relevant to functional gastrointestinal disease. This is not only because of documented prevalence rates of somatization disorder in 15% to 48% among IBS patient samples[7-12], but also because of implications introduced by the presence of somatization disorder for classification and understanding of IBS and probably also other functional disorders as well.

Abnormal cytokine production has been found in association with IBS[13], major depression[14,15], and somatization disorder[16]. These findings suggest a potential unifying mechanism connecting events in the nervous system (central or enteric) with IBS symptoms (e.g. fatigue, myalgia, sleep disturbance). The cytokine findings, however, have not been consistently reproducible, nor have they been correlated well with individual symptoms.

Somatization disorder, a well-validated psychiatric disorder, is the anchor of the diagnostic category of somatoform disorders[17]. Somatization disorder shares many clinical features with IBS. Like other psychiatric disorders and functional disorders, somatization disorder lacks biological markers and is diagnosed based on subjectively reported symptoms[18]. The diagnosis of somatization disorder is defined by patient report of multiple subjective symptoms across multiple organ systems, often collected over time and across settings, because patients usually do not divulge all their symptoms at once to one interviewer[11,19]. Qualifying symptoms for the diagnosis are formally defined as physical complaints that on the surface seem to represent medically based problems, but upon sufficient medical investigation defy full medical explanation[20]. Thus, the term “somatoform” means, literally, symptoms resembling physical illness. Although somatoform symptoms have historically been considered to represent physical expression of psychological distress[21-23], these notions are not demonstrated by empirical research, and somatization disorder and somatoform symptoms are defined without assumption of psychological mechanisms.

Somatization disorder patients complain of many medically unexplained gastrointestinal and other bodily symptoms, such as neurological, sexual, and pain symptoms, as well as psychiatric symptoms. The line between IBS and somatization disorder is further blurred by the frequent occurrence of other comorbid functional disorders in patients with IBS[24]. Multivariate analyses suggest that comorbid functional syndromes are distinct disorders and not necessarily manifestations of one common disorder (e.g., somatization disorder), having features in common that lead to symptom reporting. Although the specific prevalence of IBS and other functional gastrointestinal disorders in patients with somatization disorder is not known, analysis of a large population study database indicated that virtually all individuals diagnosed with somatization disorder and few of those without somatization disorder acknowledged two or more medically unexplained gastrointestinal symptoms[25].

Patients with somatization disorder often do not confine their medically unexplained symptoms to the physical domains. Most also complain of many symptoms of many psychiatric disorders they do not actually have. Patients with somatization disorder have been demonstrated to report as many as, or more, symptoms of major depression, anxiety disorders, and schizophrenia than patients who actually suffer from these disorders[26-28]. These well documented psychiatric symptoms in these patients who do not have the psychiatric disorders associated with the symptoms they report have been termed “psychoform,” in parallel to the term “somatoform” referring to symptoms suggesting bodily illness that is not present[19,29,30].

Consistent with these symptom-reporting patterns, the medical histories of patients with somatization disorder typically reflect multiple medical and psychiatric diagnoses, often including various functional disorders[19]. The more functional disorders a patient has, the more likely is the diagnosis of somatization disorder[11]. When IBS or other functional disorders occur in patients with somatoform disorders, the gastrointestinal complaints are counted toward the diagnosis of SD because of the lack of objective indicators of medical illness[20]. Patients with somatization disorder may also have many complaints of allergic reactions and medication intolerances, consult multiple physicians in many specialties, have histories of multiple failed treatments, and generally follow a difficult course of treatment and patient-physician interactions[19]. Patients with somatization disorder typically exhibit a pattern of symptom expression recurrently throughout most of their lives, regardless of their current mood state, unlike patients with depressive disorders, who often have medically unexplained complaints during depressive episodes but not at other times[20]. No psychopharmacologic agent has been demonstrated to be effective in alleviating somatization disorder[19,31], although some patients may benefit from the usual treatments for established comorbid psychiatric illnesses that are commonly associated with this disorder, such as major depression[19,32].

Clinicians and researchers have observed that patients with IBS or other functional gastrointestinal disorders tend to have additional functional disorders in various other organ systems, multiple somatoform symptoms distributed across most physical categories (e.g., unexplained pain; neurological symptoms such as paralysis, imbalance, and weakness; and sexual complaints), and complaints of multiple drug allergies and sensitivities. The previously mentioned comorbid psychopathology, especially depressive and anxiety syndromes, are consistent with these patients’ patterns of complaints of many types, including psychiatric. Many of these patients also engage in unusually frequent health care visits, undergo multiple diagnostic tests and surgical procedures, use many over-the-counter and prescription medications, and become refractory to treatment[33]. Treatment of refractory functional gastrointestinal disorders has been described as difficult and frustrating[33-35].

It is perhaps more than just coincidental that these characteristics of patients with IBS and other functional gastrointestinal disorders have many features in common with the classic features of patients with somatization disorder described earlier in this article. It has been previously hypothesized that the psychiatric comorbidity in IBS patients may reflect the inclusion of somatization disorder in IBS samples[36,37]. North and colleagues[11,19] further hypothesized that other clinical perceptions of IBS patients may be colored by prominent characteristics of the somatization disorder patients within their ranks. Indeed, examination of IBS patients segregated by the presence or absence of somatization disorder demonstrated that IBS patients had more abnormal illness behavior and psychiatric symptoms compared to patients with IBS alone, and patients with IBS alone were similar to a comparison group of ulcerative colitis patients on these characteristics[11,12]. Additionally, IBS patients with somatization disorder had significantly more gastrointestinal and other symptoms, psychiatric disorders, physicians consulted, telephone calls to physicians, urgent care visits, medication changes, missed work days, benzodiazepine use, poor treatment outcomes, and treatment dissatisfaction compared to their counterparts without somatization disorder[11]. These findings suggest one important point that IBS may be a heterogeneous concept, namely through its frequent association with somatization disorder.

The dimensional construct of somatization outside the context of the disorder based on its name reflects a need for further explication of medically unexplained symptoms in diverse settings. Outside of somatization disorder, the concept of somatization conceptualized as a process or a behavior is poorly understood. Somatoform syndromes not meeting full criteria for somatization disorder are recognized in formal diagnostic nomenclature[20], representing a residual category for persistent somatoform presentations lasting at least six months that do not meet somatization disorder criteria (undifferentiated somatoform disorder) and a category for unexplained physical complaints of less than six months’ duration (somatoform disorder not otherwise specified). However, these diagnoses are not diagnostically validated. Thus, the field does not really know what do to with medically unexplained symptoms that are not part of somatization disorder. The symptom of low mood which we call “depression” is not synonymous with the diagnosis of major depression; depressed mood also occurs in dysthymic disorder and even in normal people and does not necessarily reflect the same processes as those occurring when this symptom is part of a major depressive episode. Similarly, “somatization” behavior outside of somatization disorder may be a very different phenomenon from behavior bearing the same name that defines somatization disorder.

Outside diagnostic constructs that characterize longstanding trait-related phenomena, the concept of somatization has come to represent state-dependent behavior in the context of psychological stress. Thus, the term “somatization” has accumulated a baggage of assumptions of psychological processes beyond the defining lack of medical explanation for the symptoms of the disorder bearing its name. It is likely that features of “somatization” observed in functional medical disorders are actually contaminated with characteristics of unrecognized cases of somatization disorder among the patients. Among patients presenting with medically unexplained symptoms who also have psychiatric illness, the likelihood of having a somatoform disorder is remarkably high[2]. Because we do not know the etiology of medically unexplained symptoms outside validated somatoform disorders, “somatization” is a loaded term implying processes that may not apply, and thus terminology less burdened by assumptions such as “complaints without nonpsychiatric illness” may provide a more careful way to discuss these symptoms.

Many patients do not respond adequately to reassurance or education because of temperament, character, or learning style. They may not respond to dietary and nutritional advice, as there is no specific dietary component that can be identified consistently in IBS patients[41]. Finally, patients may not respond to medications for gastrointestinal symptoms, either because the symptom does not derive from the intestine itself, or because non-gastrointestinal symptoms are dominant and not influenced by drugs directed at gastrointestinal function. For these groups of patients, psychotropic medications may be helpful. The mainstay of psychopharmacotherapy in functional gastrointestinal disease is antidepressant medication. Antidepressants are not just for treatment of depression. These medications are also useful in the treatment of anxiety disorders, pain syndromes, and functional disorders, even in patients without depression.

Evidence for the utility of antidepressant medication in functional gastrointestinal disease has emerged from an increasing volume of literature providing empirical support. Randomized clinical trials, however, provide little evidence that antidepressant therapy is superior to placebo as treatment for IBS[1]. Most of the available studies are of low or moderate quality and do not demonstrate any clear-cut advantage of antidepressant therapy. Another difficulty in assessing clinical trials of antidepressants for IBS is that most IBS patients do not require psychopharmacologic interventions because their symptoms are mild, infrequent, and only periodically troublesome. Short-term treatments, including over-the-counter preparations (e.g., laxatives, anti-diarrhea medicines, and anti-spasmodics), dietary modifications such as increased fiber, and behavioral management and encouragement, may be sufficient to manage most IBS symptoms. Antidepressant therapy is generally reserved for patients with more chronic and severe IBS.

In a meta-analysis reviewing twelve randomized placebo-controlled clinical trials, Jackson and colleagues[42] concluded that antidepressants appear to be effective in the treatment of functional gastrointestinal disorders with a reported odds ratio exceeding 4.0. Unfortunately, however, three patients needed to be treated to improve one individual’s symptoms. A Cochrane database systematic review, selecting only two studies using a dichotomous endpoint for pain relief, four using such an endpoint for global relief, and two using a continuous outcome for pain, concluded there was no evidence of an effect[43]. In a comprehensive review of all agents for IBS, Jailwala et al[44] concluded from seven double-blinded placebo-controlled and randomized studies that the evidence for global improvement using psychotropic agents is “based on a small number of studies of suboptimal quality”. In their recent comprehensive review of antidepressants for functional gastrointestinal disorders, Clouse and Lustman[1] similarly cautioned that methodological issues may have biased many of the conclusions of these studies. Many of the studies they reviewed were older and subject to criticisms of methodological designs not meeting current research standards for clinical trials.

Most studies reviewed by Clouse and Lustman used tricyclic antidepressants (primarily amitriptyline) rather than the newer antidepressant classes such as SSRIs. Studies concluding antidepressant effectiveness often used outcome measures combining IBS target symptoms with quality of life items and indicators of depression and anxiety. The studies using narrower targets for outcome measures, such as principal IBS symptoms, found fewer treatment advantages for antidepressant medications. Studies of antidepressant medications for functional gastrointestinal disease have also suffered from use of fixed dose protocols, an issue that is especially relevant for tricyclic antidepressant medications with their wide dosage range. In many of these studies, nonpsychiatric physicians (gastroenterologists and primary care providers) administered the antidepressant agents, further reducing the likelihood of demonstrating benefit from antidepressant medication. In clinical practice, doses are tailored to the patient rather than fixed, and patients are heterogeneous. Though the accumulated research suggests some beneficial effects of psychotropic medications with this population, it is difficult to make a clear judgment about their role with this population. At present, it is safest to conclude that clinical experience suggesting benefit of antidepressant medications in functional gastrointestinal disease is more persuasive than evidence from carefully executed randomized clinical trials.

IBS is a heterogeneous syndrome with many potential mechanisms responsible for its clinical presentations[53]. These mechanisms appear to relate to abnormal gut motility, parallel abnormalities of enteric and/or central nervous system functioning, and even immune dysregulation. In the majority of patients, IBS is complicated by psychiatric issues and unexplained symptoms and functional syndromes in other organ systems[1]. For these reasons, one mode of treatment is unlikely to be universally effective or to resolve most symptoms.

It has become clear in recent years that the majority of IBS patients have multiple complaints without demonstrated cause, and that these symptoms can affect systems other than the intestine, e.g. bones and joints (fibromyalgia, temporomandibular joint syndrome), heart (non-cardiac chest pain), vascular (post-menopausal syndrome), and brain (anxiety, depression). Viewed in this light, most IBS patients do not have psychiatric illness per se, but a range of psychoform complaints that accompany their somatoform ones. It is not correct to label them as psychiatric patients (except those more difficult patients with true somatization disorder), but it appears to be valid to utilize the techniques of psychotherapy or cognitive-behavioral therapy to allow them to cope more readily with their illness. Specific episodes of depressive or anxiety disorder can be managed as appropriate for those conditions. It is not surprising, therefore, that drugs designed to improve anxiety or depression are not uniformly useful for psychiatric complaints in IBS, because the psychoform symptoms that sound similar to those seen in psychiatric disorders may not have the same significance in patients with IBS.