Psychiatry has enjoyed a particularly interesting relationship with the gastrointestinal (GI) illnesses since the brain–gut relationship was considered one of the core examples of how psychological stress could influence autonomic processes,¹ until increasing understanding regarding the pathophysiology underlying stomach and duodenal disorders diminished interest in this relationship. Still, it remains a fact that the brain and digestive tract are intimately connected and more recent—and more modest—research reveals strong evidence for direct and indirect influences of one on the other. Considering that depression can be a consequence of both physiological and psychological stress, it should be no surprise that depressive disorders very commonly co-occur with GI disorders. This chapter will consider several examples of the complex relationship between depressive disorders and GI disorders, including peptic ulcer disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and various diseases of the liver.

INTRODUCTION

Peptic ulcers are erosions of the GI lining that extend through the mucosa of the GI lumen. Ulcers can occur anywhere along the alimentary tract; however, they are most likely to occur in the stomach or in the proximal bulb of the duodenum: the “peptic” regions, so called because these are the areas that have the most contact with the corrosive digestive juices gastric acid and pepsin. This is why gastric and duodenal ulcers are collectively referred to as “peptic ulcers,” and as they are pathologically similar, they are usually considered together. The peptic lumen has adapted to protect against the effects of constant contact with acids and proteolytic enzymes through adaptations of the mucosal lining and its protective mucus layer; ulcers only occur when some pathological process disrupts this normal protection. Considered a disorder of the modern age,² the incidence of peptic ulcer disease rose dramatically in the 19th century, peaked in the first half of the 20th century, and then began to decline after the 1950s with advances in diagnosis and treatment. Despite these advances, they remain common, with an estimated prevalence of about 8% in the United States and an estimated cost of more than 3 billion dollars per year. The relationship of peptic ulcers to psychiatry is particularly interesting: thought to be a classic “psychosomatic” disease for much of the 20th century, research on the psychological aspect of ulcers was largely abandoned after it was discovered that the great majority were infectious in etiology. However, this understanding is incomplete and there is some renewed interest in the role of psychological stress and psychiatric disease, both as risk factors, perpetuating factors, and as possible complications of this disease.

EPIDEMIOLOGY

Epidemiological studies support an association between depression and peptic ulcer disease (Fig. 13-1, Box 13-1). A large epidemiological study in the United States demonstrated the association between mood and anxiety disorders and peptic ulcer disease: for the mood disorders, this association was strongest for chronic depressive disorder and persistent depressive disorder (dysthymia) (OR = 3.59).³ Alcohol and nicotine use explained some, but not all of this association. A large international epidemiological survey also found depression to be independently associated with peptic ulcer onset (OR = 1.3 for major depression or persistent depressive disorder [dysthymia]).⁴ This study had the advantage of only including episodes of depression that preceded ulcer onset.

Studies of patients with recurrent depression also show a high incidence of ulcers. For example, one large case–control study of patients with two or more episodes of major depression found that these patients were more likely to have peptic ulcers (OR = 4.31).⁵ However, another survey⁶ did not find an increased rate of peptic ulcers in persons who had had major depressive episodes in the past year. The discrepancy may be one of chronicity, as the second study did not select for recurrent depression.

PATHOPHYSIOLOGY

The majority of ulcers result from infection with Helicobacter pylori, which causes inflammation and disrupts the normal defensive and reparative processes of the mucosa. Nonsteroidal anti-inflammatory medications (NSAIDs), which impede the normal protective effects of prostaglandin, are the next most common cause. Much less common are ulcers due to other GI diseases (e.g., Crohn disease [CD]), other infections, medications, tumors, mechanical damage to the mucosa because of radiation or hiatal hernias, and hypersecretory states (e.g., Zollinger–Ellison syndrome). Ulcers can also be the result of severe insults to the body, such as a severe systemic illness, major surgery, severe head injury, or burns—such ulcers are referred to as “stress ulcers”—a term which occasionally causes confusion given the multiple meanings of the word “stress,” in this case referring to severe physical stress. The etiology of stress ulcers is not entirely understood, but thought to be due to splanchnic hypoperfusion: in life-threatening situations, the circulatory system typically shunts blood away from the GI system to muscles and other organs where the need is more pressing.

Up to 20% of peptic ulcers have no clear cause. It is assumed that in many of these cases the patients have undiagnosed H. pylori or are unaware that some medication they take has nonsteroidal anti-inflammatory properties. However, in some of these cases, emotional stress is thought to play a role.

Psychological Factors and Peptic Ulcers

Psychological explanations for peptic ulcers have had a long and interesting history. After it became apparent that the 19th century model of acid hypersecretion could only explain a small fraction of occurrences and as no other cause was evident many looked for psychological explanations. These explanations were derived from psychoanalytic theory, invoking concepts of various conflicts and frustrated drives. Support for these theories mainly came from anecdotal cases and uncontrolled, correlative studies. This remained the dominant explanation for peptic ulcers throughout the 20th century until the 1970s when H. pylori bacilli were identified and cultured from the gastric epithelium around areas of inflammation.⁷ Subsequent studies demonstrated dramatic improvements following eradication of the bacteria and emergence of the disease after one of the investigators ingested the bacilli. These spelled the end of the psychosomatic theory of ulcer formation.⁸

Subsequently, some researchers studying the effects of stress on disease suggested that it was a mistake to entirely abandon psychological investigations, opining that, as with most chronic diseases, peptic ulcer disease would benefit from a biopsychosocial perspective. It was noted, for example, that a lack of central nervous influences on this and other GI diseases would be surprising, given the multiple intimate connections between the two organ systems, which include multiple points of contact between the autonomic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis. Instances were noted in which the risk of peptic ulcers increased dramatically following stressful mass events.⁹ Better controlled prospective studies then demonstrated a link between psychosocial factors and peptic ulcers.¹⁰ A good deal of this association likely reflects incorrect diagnoses and recall biases and much of this association may be accounted for by behaviors that are associated with both stress and ulcers, including smoking, sleeplessness, poor diet, alcohol use, and medication use (particularly NSAIDs). However, it appears that even when all these factors are accounted for, there remains a small but significant relationship between psychosocial stress and the incidence of peptic ulcers. Thus, studies controlling for these health risk behaviors still found an elevated risk of peptic ulcer in individuals experiencing high levels of stress (OR = 1.7–2.9).^11–13 As a whole, although each of these studies had methodological problems and none accounted for all possible confounders, the weight of evidence suggests some direct relationship between stress and peptic ulcer risk. These epidemiological data were also supported, in part, by animal models in which the induction of psychological stress increased the risk for ulcers, as well as the persistence and extent of ulceration in affected animals.¹⁴

The exact mechanism by which stress can contribute to ulcer formation is not known but remains a ripe area for speculation: as already noted, the GI system and the central nervous system are closely linked (Box 13-2). Most frequently implicated are neuroendocrine responses to stress mediated by the HPA axis as well as through the autonomic system.^15,16 For example, autonomic hyperactivity can decrease gastric emptying and perfusion,¹⁷ both of which can predispose to ulcer formation, and stress-related hypercortisolemia can delay wound healing.¹⁸ Various other mechanisms, such as decreased resistance to H. pylori due to glucocorticoid-mediated inhibition of the immune response, are possible as well.

This said, it must be appreciated that correlation is not causation, and the fact that there is a relationship between stress and ulcer formation says little about the nature of that relationship. For example, one study showed a significant decrease in anxiety following definitive peptic ulcer treatment by eradication of H. pylori,¹⁹ supporting the idea that psychological stress can be the result of peptic ulcers rather than the cause. Although this remains to be worked out, it seems reasonable to assume a complex and bidirectional relationship.

Depression and Peptic Ulcers

Given the above discussion on the relationship between stress and ulcers, one should expect there to be a high rate of depression in individuals with peptic ulcers, in that depression can be considered a disorder of chronic stress. Indeed, most animal models of depression are actually models of chronic mild stress.²⁰ Thus, the same strategies used for animal stress studies (e.g., forced swimming tests, chronic aversive stimuli) can also support a relationship between depression and peptic ulcer disease.²¹ Similar mechanisms of action have been suggested as well, including, most commonly, disruptions of the HPA axis.²¹

As noted above, epidemiological studies also support a relationship between depression and peptic ulcer disease, with national and world survey data showing increased risks of depression in patients suffering from peptic ulcer disease. However, the directionality of the relationship remains unclear and is, again, most likely bidirectional.

CLINICAL PRESENTATION, ASSESSMENT, AND DIFFERENTIAL DIAGNOSIS

Diagnosing major depression in patients with peptic ulcers presents the same dilemma encountered when diagnosing depression with other medical disorders (Box 13-3 to Box 13-4). Many of the symptoms associated with the ulcers, including the psychological distress caused by pain, loss of appetite, and occasional weakness can overlap with depression. That said, patients with peptic ulcers do not usually develop systemic symptoms and we would recommend an inclusive approach, in which patients who exhibit the full spectrum of symptoms associated with a major depressive disorder be treated as having such, even when alternative explanations for individual symptoms are possible.

In addition to diagnosing depression in this population, it is important to look for other common comorbid psychiatric disorders that can worsen the course of both diseases. Of most concern are alcohol and nicotine use disorders, as both are also risk factors for peptic ulcer disease. In addition, anxiety disorders, particularly panic disorder, may be comorbid as well.

COURSE AND NATURAL HISTORY

Typically, ulcers can be eradicated with appropriate pharmacotherapy (antimicrobial therapy for H. pylori infection and proton pump inhibitors), and refractory ulcers are rare; in such cases nonadherence or some other underlying pathology (such as hypersecretory states) should be suspected. In the case of NSAID-related ulcers, cessation of the NSAID should obviously be added to the standard anti-ulcer regimen.

There is some evidence to suggest that depression can worsen the course of peptic ulcer disease and one study of 75 patients with duodenal ulcers found that those who were depressed spent more time than psychologically well ulcer patients experiencing ulcer-related symptoms over an approximately 3-year follow-up period.²² Some of that difference may have been mediated by having greater life or socioeconomic stress.

Although not studied sufficiently in this particular disorder, we know that comorbid medical illnesses invariably worsen the course of major depressive episodes,²³ arguing for early and aggressive treatment of depressive symptoms.

TREATMENT

Given the data that depression is frequently associated with peptic ulcers, and that the presence of depression might worsen the course of the disease, it is reasonable to hope that treatment of depression would improve the course of peptic ulcer disease (Box 13-5). However, investigations of that proposition have been disappointing. Studies of psychotherapy, including cognitive therapy and stress management approaches, have generally not shown any effect on the course of peptic ulcer disease. Similarly, antidepressant pharmacotherapy has little role in ulcer treatment per se. It has been occasionally noted that some antidepressants, particularly tricyclic antidepressants (TCAs), have some effect as anti-ulcer agents, largely owing to their potency as antihistamines. In addition, fluoxetine may have anti-ulcer effects although the mechanism is not as clear.²⁴ At any rate, both agents are inferior to current ulcer treatments and in practice are rarely used for that purpose.

For patients with comorbid peptic ulcer disease and depression, it remains important to treat their depression as well as their ulcers. Although improvement of psychiatric symptoms following primary treatment of peptic ulcers has been reported, both disorders should be treated independently. Studies examining the treatment of depression with comorbid peptic ulcer disease are largely lacking but it makes sense to assume that the standard treatments for depression, both in terms of psychotherapy and pharmacology, are indicated here as well. This approach is somewhat tempered by the concern that selective serotonin reuptake inhibitors (SSRIs) may cause GI bleeding through inhibition of platelet function,²⁵ particularly in the elderly.²⁶ Some have questioned the prevalence of this adverse effect, and at least one endoscopic study of patients with a variety of upper GI diseases found no adverse effects in individuals who were taking SSRIs for at least a month.²⁷ That said, in patients with active peptic ulcer disease, particularly elderly patients, non-SSRI antidepressants should be considered. In such patients for whom SSRIs are preferred (e.g., because of a good response in the past), careful monitoring for GI bleeding is indicated and adjunctive acid-suppressing agents should be considered.

SUMMARY

Peptic ulcer disease has had a particularly dramatic relationship with psychiatry. Considered to be a psychosomatic disorder for most of the 20th century, research on the psychological aspects of peptic ulcer disease virtually ceased after the discovery that most cases of the disease were infectious in origin. The last decade and a half, however, has seen some modest but meaningful recrudescence of interest in the role that psychosocial factors, particularly psychological stress, could play in the onset and course of the disease. The weight of evidence supports a direct relationship between stress and ulcers, perhaps mediated by the HPA axis or autonomic regulation of the gut. It therefore follows that psychiatric disorders associated with chronic stress, including depression, are associated with peptic ulcer disease and may represent independent risk factors for it. Further research is needed to better elucidate the mechanisms connecting the disorders, and, perhaps, improve treatments for both.

INTRODUCTION

IBS is the most common of the “functional bowel disorders,” so named because they are defined by their effect on bowel functioning rather than any consistent pathological finding. IBS’s primary feature is chronic abdominal bowel pain that is relieved by defecation. Other features include changes in the appearance and frequently of stool as well as feelings of bloating, urgency, incomplete evacuation, and flatulence. IBS is usually divided into two types depending on whether it is associated with diarrhea or constipation. These symptoms are found in many GI disorders and the diagnosis often rests more on the lack of systemic symptoms (fever, weight loss) or other symptoms that would imply a specific underlying condition (e.g., GI bleeding). Multiple studies have failed to elucidate a consistent underlying pathology or pathophysiological mechanism for this disorder, and it is commonly associated with other non-GI functional disorders, such as chronic headaches, fibromyalgia, and other forms of chronic pain. It is also frequently associated with a number of psychiatric disorders.

EPIDEMIOLOGY

The majority of people with IBS do not seek medical attention,²⁸ making epidemiological studies difficult to interpret, but it is thought to be very common and affects perhaps 10% to 15% of the general population (Fig. 13-1).²⁹ Interestingly, whereas the disorder is more often seen in women in the United States and other western countries, in Asian countries it is more commonly found in men.

As noted above, psychiatric comorbidity is common, although exact reports vary widely, with estimates ranging from approximately half of patients with IBS to nearly all.³⁰ Among psychiatric disorders, depressive disorders are the most common, followed by anxiety disorders (Box 13-6). Patients with IBS are two to five times more likely to suffer depression or anxiety (odds ratio 2.7–4.6)^31–38 than those without. Directionality of the relationship between depression and IBS is understandably hard to establish–frequently the depressive symptoms precede the GI symptoms; however, the opposite is reported as well.²⁹

Despite the reports that depression is very frequently associated with IBS, this may be population-specific and apply mainly to those patients seeking medical care, particularly in tertiary medical centers. Most community samples suggest that the rates of comorbid psychopathology are much lower in persons with IBS who do not regularly seek medical attention.

Certain risk factors shared by IBS and depression may help explain the relationship; of particular note is the observation that patients with IBS often have a history of physical or sexual abuse or other early life traumas.^39–42

PATHOPHYSIOLOGY

There is a great deal of speculation regarding the underlying pathology behind IBS; however, the disorder has defied simple explanations; this likely reflects the heterogeneous nature of this disorder (Box 13-2). Theories include altered stress responses (similar to those described above for peptic ulcer disease), autonomic hypersensitivity, inflammatory processes, and abnormal serotonin signaling. Altered stress responses have been noted in some studies, for example, increased corticotropin response to corticotropin-releasing factor, as well as changes in the HPA axis.⁴³ Similarly, abnormal sympathetic and parasympathetic activity has been reported in some IBS patients.⁴⁴ In addition, hypersensitivity to pain likely plays a role. For example, distention of the rectum or gut, even within a normal range, is felt more intensely and perceived to be painful at a lower threshold by patients with IBS.⁴⁵ A role of inflammatory processes seems likely for at least some forms of the disorder; this is supported by the fact that patients with IBS often previously had some sort of GI infection, and biopsies have shown increases in inflammatory cell types (e.g., T-cells, mast cells).⁴⁶ These observations have led to the characterization of a “post infectious” subtype of IBS. A role for serotonin has been suggested as well. From a psychiatric perspective, it is notable that 90% of all serotonin in the body is located in the enterochromaffin cells of the GI tract, where it acts as a hormone regulating gastric motility, and the normal functioning of serotonin in this system has been reported to be disrupted.^47,48

It should be stressed, however, that all these theories lack empirical support and no consistent pathology underlying IBS has been demonstrated. They are, of course, not mutually exclusive and it is likely that IBS is a heterogeneous disorder that results from multiple physiological disturbances.

Given this lack of a clear pathology, the many speculations about the role of depression in IBS are equally preliminary. Nonetheless, numerous pathophysiologic links between depression and IBS have been suggested. Depression can affect the perception of pain, and make individuals overly sensitive to normal stimuli, and depression’s effect on the pain threshold may be the mediating factor between depression and IBS.³⁴ However, there may be more direct links. As noted above, dysregulation of the autonomic nervous system, serotonin, and the HPA axis have all been speculated to underlie IBS and these are also thought to be important in the pathophysiology of mood disorders as well. Many connections between the brain and GI system have led some investigators to refer to a “brain–gut” axis.⁴⁹ Theories range from those that suggest that depression and IBS are distinct disorders sharing underlying mechanisms to some who propose that IBS is a forme fruste of depression. More confident statements regarding the many possible relationships await a better understanding of the pathophysiology of the depressive disorders

CLINICAL PRESENTATION

The main features of IBS are distinct from the primary symptoms of depression as the disorder is defined by recurrent abdominal pain or discomfort and changes in the frequency or appearance of stool (Box 13-2 and Table 13-1). However, a number of systemic symptoms can be associated with IBS, particularly in its more severe forms, including fatigue, insomnia, and sexual dysfunction and these overlap with symptoms of depression. As with the discussion of peptic ulcers, in cases of possible overlap it is usually best to take an inclusive approach, diagnosing both IBS and depression in cases in which patients meet both criteria.

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Definitive diagnosis is complicated by the heterogeneity of the functional disorders. There has been, however, some effort to identify more homogeneous subgroups based on tighter diagnostic criteria for IBS (e.g., the Rome Criteria III; Table 13-1) and on clinical features, including IBS diarrhea predominant, IBS constipation predominant, and postinfectious IBS. Much of the diagnostic workup for IBS involves ruling out other potential causes for abdominal pain, for which the list is long, but usually suggested by such “alarm” symptoms as fever, weight loss, or GI bleeding.²⁹

When depression is comorbid, it is likely similar to that seen in depressed patients without IBS, with the addition of some amplification of the IBS symptoms. As noted above, it is a common comorbid condition, but not invariably associated. Thus, although one should investigate for mood disorders in IBS patients, we cannot assume their presence. A comprehensive diagnostic workup for depression and psychopathology is always indicated; as noted above it is usually best to take an inclusive approach toward symptoms consistent with a major depressive episode when considering such a diagnosis.

TREATMENT

Primary treatment of IBS usually involves symptomatic treatment of the diarrhea or constipation. A recent review comparing various approaches found no benefit with bulking agents (i.e., fiber supplements) but did see some with antispasmodics (such as cimetropium/dicyclomine, peppermint oil, pinaverium, and trimebutine).⁵⁰ Education is a critical component of care for these illnesses to reinforce reassurance about the nature of the disease as well as good dietary and hygiene practices.

Many patients with IBS receive anxiolytics and antidepressants.³¹ Even absent comorbid depression, antidepressants can be helpful for IBS patients: SSRIs have been shown to improve overall symptoms and TCAs may be preferentially effective for abdominal pain.⁵⁰ The use of TCAs is limited by their many side effects, particularly anticholinergic side effects. In patients without comorbid depression, lower doses can be used to take advantage of the anticholinergic effects without their becoming intolerable. In depressed patients, SSRIs may be the initial drug of choice. Among the SSRIs, paroxetine is particularly anticholinergic; although often a downside of this drug, it may be an advantage for patients with diarrhea-predominant IBS.^51,52 Non-SSRIs, such as the SNRI duloxetine, are likely to be helpful as well although to date their support is mainly through open-label studies.⁵³ Indeed, although data are lacking, it is reasonable to assume that the standard antidepressants that show efficacy for depression in other situations will be useful in this context.

A variety of psychotherapies have been used for IBS—both for the disorder itself and for the comorbid depression, including CBT, psychodynamic psychotherapy, various relaxation therapies, and hypnosis. All have at least some positive clinical trials²⁹; however when taken as a whole the effects of such therapies, particularly for IBS absent depression, have been equivocal.⁵⁴ Some of these disappointing results can be attributed to methodological problems with many of the studies, and more rigorous studies have shown significant improvement of IBS symptoms with CBT,^55,56 including self-administered CBT.⁵⁷ The CBT used emphasizes such techniques as self-monitoring, cognitive reappraisal, worry control, and problem-solving training.

CBT is, of course, an effective treatment for depression, including depression that is comorbid with IBS. Whether the improvement in IBS symptoms from psychotherapeutic treatments is related to treatment of underlying depression is unclear, but the mechanism of effect is thought to relate to more nonspecific factors, such as general stress reduction.⁵⁸ However, there may be more specific effects—one interesting study examined response to CBT in IBS patients using positron emission tomography (PET) and found that improvement was related to areas of the brain associated with attention to fear stimuli, danger orientation, and vigilance (e.g., anterior cingulated cortex and amygdale).⁵⁹

EPIDEMIOLOGY

Patients with IBD have a high incidence of psychiatric comorbidity, predominantly depressive and anxiety symptoms, as well as major depressive disorder. Compared with the general population, IBD patients are twice as likely to have a depressive disorder (Fig. 13-1).⁶⁰ However, persistent depressive disorder (dysthymia) does not appear to be more prevalent in individuals with IBD than the general population.⁶⁰ The prevalence of depression and/or anxiety in IBD is estimated at 15% to 35% during remission and up to 60% for depression and 80% for anxiety during relapse.⁶¹ Symptoms of IBD, which include abdominal pain, diarrhea, fatigue, malnutrition, weight loss, anemia, joint pain, anemia, hematochezia, and skin lesions,⁶² can cause considerable psychiatric distress and lead to a significant decrement in quality of life.⁶³