The role of antidepressants in the management of irritable bowel syndrome (IBS)

Eamonn MM Quigley, MD, FRCP, FACP, FACG, FRCPI (1), Orla F Craig, MB, MRCPI (1), Timothy G Dinan, MD, PhD, DSc, FRCPsych (2)

(1) Alimentary Pharmabiotic Centre and Department of Medicine. University College Cork. Cork, Ireland.

(2) Alimentary Pharmabiotic Centre and Department of Psychiatry, University College Cork, Cork, Ireland.

Received: 02-05-11 Accepted: 30-05-11

Abstract

Irritable Bowel Syndrome (IBS) is a complex entity whose etiology is unknown and whose physiopathology is incompletely known. It occurs frequently, and many treatments for it have been described. The relation of psycho-social factors to the genesis and presentation of IBS has been studied with special attention. The approach to treating IBS patients requires contemplation of the patient’s symptoms and reactions to his or her illness and environment. Of the multiple treatments for IBS which have been described, antidepressants have received considerable attention although their clinical utility is still not clear. The objective of this work is to review the literature regarding the physiopathological basis of IBS, comorbidities with psychiatric disorders, and the clinical usefulness of antidepressants for treating irritable bowel syndrome.

Key words

Irritable bowel syndrome (IBS), antidepressants, treatment.

The functional gastrointestinal disorders (FGID) are symptom-based disorders that cannot be currently explained by definable structural or biochemical causes (1). These disorders are common: the presence of at least one functional GI disorder was identified in 70% of participants in a large US householder survey (2). Functional GI disorders are associated with significant impairment of quality of life and considerable economic burden on the healthcare system (3-5).

Although several classification systems exist for defining functional gastrointestinal disorders, the Rome criteria are the most commonly used for research purposes. The most recent iteration, the Rome III diagnostic criteria, was released in 2006 (6). It defines 28 distinct functional gastrointestinal disorders in 6 major domains. A Canadian householder survey using Rome II criteria found that functional bowel syndromes, including irritable bowel syndrome (IBS), the focus of this review, were the most prevalent, diagnosed in 41% of responders, followed by functional oesophageal syndromes, including functional heartburn, which were found in 28% (7). In addition, considerable overlap exists between the FGIDs, with 30% of those with IBS and 60% of those with functional heartburn also fulfilling criteria for the diagnosis of functional dyspepsia (8, 9). These findings have considerable implications for the assessment of the patient presenting with IBS. Community surveys in a variety of countries have indicated that approximately 10-20% of adults in the West have symptoms consistent with IBS (10, 11). Indeed, it is now evident that IBS is a global issue and has been identified at a similar frequency in Asia, Latin America and Africa (12).

Over the decades, various theories have been advanced to explain the pathogenesis of symptoms in the IBS patient, including dysmotility, visceral hypersensitivity and the psyche. While most would agree that the pathophysiology of some of the individual symptoms, in IBS, is reasonably well understood, the underlying cause of the disorder remains to be elucidated. Thus, a combination of visceral hypersensitivity, smooth muscle spasm and impairment of central pain processing (13, 14) likely contribute to pain, while altered intestinal motility underlies the disordered defecation experienced by some patients (15).The concept of the gut-brain axis, emphasizing the interactivity at sensory, motor and neuro-endocrine levels, between the brain and the gut has provided a useful paradigm to encompass these diverse factors. This axis has been extended, by some, to include interactions between the gut flora (or microbiota), the immune system (both mucosal and systemic), the gut and the brain (the gut-brain-immune-microbial axis). In this scenario, interactions between the flora (be it normal or disturbed) and the mucosal immune system (gut-, or mucosa-associated lymphoid tissue; GALT or MALT) lead to the release of peptides and other neuro-active substances which generate, both locally and systemically, the neuromuscular events that typify IBS and generate the patient’s symptoms. The advancement of this concept in IBS occurs at a time when considerable emphasis and research effort if being expended, with considerable success, at understanding the role of the microbiota in health and disease and in unlocking its therapeutic potential (16, 17).

DEPRESSION, ANXIETY AND PSYCHOLOGICAL FACTORS IN IBS

From its earliest descriptions, IBS, or spastic colon as it was formerly known, has been linked with psychiatric co-morbidity. In their seminal report, Chaudhary and Truelove reported that 80% of their patients exhibited "psychological factors" as either initiating or exacerbating influences in IBS (18). Later studies in secondary and tertiary care identified a very high prevalence of psychiatric co-morbidity, most commonly anxiety and depression, among those who consulted for IBS, leading to the impression that IBS symptoms originated in the psyche (19). For example, one group with a long-standing interest in IBS identified an associated co-morbid psychiatric condition, such as anxiety, mood or panic disorder, in up to 60% of those attending their gastroenterology outpatient clinics with a functional compliant (20). However, like so many other aspects of this disorder, perception here has been distorted by the location of study. Thus, while IBS, as seen in the clinic and, especially in the specialist’s office, is often accompanied by a variety of psychological disorders, this association is much weaker among IBS subjects identified in the community, i.e. among those who suffer from IBS-type symptoms and can satisfy criteria for the diagnosis of IBS yet do not seek medical or specialist attention (19). Psychopathology has come to viewed, accordingly, not as a fundamental prerequisite for the development of IBS, but, rather, as a co-factor which, if present, will modify the individual’s response to IBS symptomatology and significantly influence its presentation, natural history, impact and response to therapy. Thus IBS subjects with psychological com-morbidity (or individuals with anxiety or depression who also have IBS) (20) are more likely to exhibit health-care seeking behaviour, suffer more severe symptoms, experience a more negative impact on quality of life and endure an inferior outcome (19, 21-23).

Over the years, IBS and other functional gastrointestinal disorders have been associated with a wide variety of intestinal and extra-intestinal symptoms and syndromes. Thus, recent community surveys have confirmed how frequently IBS, functional dyspepsia (FD) and gastroesophageal reflux disease (and non-erosive reflux disease (NERD), in particular) overlap (24); a phenomenon that may complicate clinical trials, as well as diagnostic and therapeutic strategies. IBS patients commonly complain of fatigue and tiredness; these appear to be real entities in IBS, yet have been scarcely acknowledged in the assessment of IBS activity or response to therapy. Urinary and gynecological symptoms are also common; the basis for these associations is less clear (25-29). Though IBS patients with gastrointestinal and non-gastrointestinal co-morbidity are more likely to also exhibit anxiety and depression (26), a careful review of the available literature concluded that the frequent co-existence, in referral populations, of IBS and such conditions as fibromyalgia, chronic fatigue syndrome and pelvic pain could not be explained on the basis of anxiety or depression as a common denominator (30).

ANTI-DEPRESSANTS IN IBS

For the gastroenterologist who will, by definition, encounter the IBS patient in a secondary or tertiary care context, the issue of employing antidepressant medications will arise in one of two contexts:

1. Treating co-morbid depression and related disorders

2. Employing antidepressants to manage the symptoms of IBS in a patient who does not have psychiatric co-morbidity

TREATING CO-MORBID DEPRESSION AND RELATED DISORDERS

The first context is a source of some anxiety for the gastroenterologist who, typically, has no advanced training in the recognition and management of depression, anxiety and other psychiatric disorders. Depression associated with and identified among IBS subjects is usually regarded as quite distinct from major depressive symptoms; it should be noted, however, that a systematic review concluded that patients with IBS were two to four times more likely to have a history of suicidal behaviour, even in the absence of depression (31). In an important study that compared the prevalence of suicidal ideation among IBS subjects in tertiary, secondary and primary care settings, Miller and colleagues found that 38% of tertiary care subjects had contemplated suicide because of their symptoms compared with 16% and 4% in the secondary and primary care groups, respectively. Five of the tertiary care patients had actually attempted suicide because of their gastrointestinal symptoms. Importantly, these high levels of suicidal ideation could not be entirely explained on the basis of co-morbid depression, suggesting that despair related to IBS symptoms, per se, may be sufficient to lead patients to contemplate this drastic step (32). The clinician needs to be alert, therefore, not only to the possible existence of significant co-morbid depression and anxiety, but also to the potential for severe and chronic GI symptoms to impact so severely on the patient and society (33). If the gastroenterologist is in doubt or has concerns, formal psychiatric consultation should be considered.

Unfortunately, there are few studies of the impact of anti-depressants on either gastrointestinal symptoms or depression in the patient with a major depressive disorder and IBS. As pointed out in a recent systematic review, most studies of antidepressants in IBS deliberately excluded patients with a major depressive disorder (34). For more severe forms of depression and anxiety, in general, most psychiatrists regard serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venalfaxine, as more potent than selective serotonin reuptake inhibitors (SSRIs). However, there is little or no data on the impact of SNRIs on core IBS symptoms, per se. Likewise, there is little data on monamine oxidase inhibitors (MAOIs) in IBS and, given their potential for side-effects and serious drug interaction, they are best avoided.

EMPLOYING ANTIDEPRESSANTS TO MANAGE THE SYMPTOMS OF IBS IN A PATIENT WHO DOES NOT HAVE PSYCHIATRIC CO-MORBIDITY

Drug therapy, of any kind, should never be seen as the sole therapeutic approach in IBS. The Rome III process emphasizes the importance of the therapeutic relationship in the management of functional gastrointestinal disorders (35). A non- judgmental interview, together with an explanation of why symptoms occur, reassurance that the condition is not life-threatening and education regarding healthy lifestyle behaviours, may be important therapeutic tools. While invasive investigations to rule out organic pathology will be required in some, for many, a positive diagnosis based on symptom patterns can be made and the much more extensive and invasive "diagnosis by exclusion" route avoided. Indeed, inappropriate or repeated tests suggest physician uncertainty to the patient and may lead to fear on the part of the patient and serve to perpetuate a cycle of ineffective management (33).

Initially, a variety of agents, ranging from phenobarbitones to benzodiazepines were employed in the management of IBS, either on the assumption that there was a psychological basis for all IBS symptoms, or to address anxiety which had been identified as an exacerbating factor in a given patient. For obvious reasons, these approaches have been abandoned. The use of anti-depressants may have also originated from an assumption of a high prevalence of co-morbid depression but was also stimulated by the recognition that antidepressants had the potential to modulate pain perception (36); a symptom that is highly predictive of disease impact, as well as related medical costs and quality of life impairment (33).

What works?

A recent meta-analysis examined the role of antidepressants in the management of IBS and demonstrated benefits for both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) over placebo in the treatment of IBS (37). In comparison to placebo, antidepressants resulted in a 30 to 35% reduction in IBS symptoms. Tricyclic antidepressants and selective serotonin reuptake inhibitors appeared to be equally effective (37). Data on the safety and tolerability of these agents in IBS was found to be limited. TCAs are usually used at low doses (typically the equivalent of 10-50 mg amitriptyline daily) in the treatment of IBS on the assumption that symptomatic improvements relate more to peripheral than central effects as well as to avoid adverse events. It must be conceded that this practice has little basis in objective data. In contrast to TCAs, the same dose as of an SSRI as that used for mood disorders is recommended (38). SSRIs generally have a lower side effect profile than TCAs and should be considered in the treatment of IBS when psychological symptoms or coexistent somatic pain syndromes are present, or in those patients who have not responded to laxatives or antispasmodics (39). It is the experience of this author that some IBS patients are exquisitely intolerant of low-dose TCAs, experiencing somnolence and mood changes with doses of amitriptyline as low as 10 mg daily. While citalopram and escitalopram generally have less side effects and drug interactions than the other SSRIs, paroxetine can be considered in the treatment of constipation-predominant IBS (IBS-C) due to its effects on gut transit. Data on the use of serotonin and norepinephrine reuptake inhibitors (SNRIs) in the treatment of IBS is not currently available; venlafaxine, has been studied in the related disorder, functional dyspepsia, without significant benefit (40). New agents directed at corticotrophin releasing factor (CRF) and the CRF₁ receptor, in particular, offer promise given the frequency with which stress provokes symptoms in IBS (41).

How do antidepressants work in IBS?

If one accepts that antidepressants have a beneficial effect in IBS, the intriguing question is how do they work? Are these benefits exerted centrally or peripherally and, if there are peripheral, enteric, effects, what are these? Most conventional antidepressants work by acting on monoamine transporters, primarily 5HT and norepinephrine (NE) (42). Serotonergically-mediated mechanisms have attracted particular attention given the importance of serotonin as a neurotransmitter in the enteric and central nervous systems as well as in the pathogenesis of depression and anxiety (43). The fact that the gut contains a far greater concentration of 5HT than the brain lends support to the concept of a peripheral action. However, the issue will only be resolved with the arrival of a monoamine reuptake inhibitor that does not cross the blood brain barrier. Illustrating the dual central and peripheral roles of serotonin in IBS, dietary manipulations to either deplete or artificially increase tryptophan levels in the blood have been shown to affect both anxiety and gastrointestinal symptoms (44).

As well as an effect on monoamines, TCAs exert a powerful anti-muscarinic effect which may be of relevance; this effect is shared with the SSRI paroxetine (45). If, as is assumed, gut muscle "spasm" is a major factor in the genesis of pain in IBS, these anti-muscarinic effects will be of benefit.

The atypical antidepressant mirtazepine blocks alpha-2 adrenoceptors, as well as 5HT₂ and 5HT₃ receptors. It is, in general, well tolerated in patients with functional bowel symptoms and, given its 5HT₃ blocking capacity, may be especially useful in treating nausea, a symptom that my occur among IBS patients with overlapping FD (46).

While the anti-nociceptive effects of TCAs on somatic and visceral pain have been extensively described (47), studies on TCAs and SSRIs in animal models of IBS have provided conflicting information. Thus while some studies showed effects of antidepressants on gut motility and visceral sensation (48-50), others showed none (51). In human studies, TCAs prolonged both orocecal and whole gut transit in a cohort of patients with diarrhoea-predominant IBS (IBS-D) and healthy controls (52, 53), while the SSRI, paroxetine, accelerated orocecal transit (53). This would appear to make TCAs an attractive option for diarrhea-predominant IBS, particularly in those where pain is a predominant feature, whereas SSRIs may be more suitable for those with constipation-predominant IBS. Interestingly, in the aforementioned studies, the effects on transit preceded any effects on mood, indicating a true dissociation between central and peripheral effects. In contrast, a study among human volunteers, which compared an SSRI with a SNRI and buspirone, a serotonin 5HT_1A receptor agonist, failed to document any effects on gastric emptying or colonic transit for any of these agents. Small bowel transit of a solid meal was accelerated by paroxetine while venlafaxine-XR increased the postprandial change in gastric volume (54). Others, also in healthy volunteers, demonstrated that citalopram increased motility, high amplitude propagating contractions and compliance but decreased the tonic meal response in the colon (55), effects that could be of benefit in constipation. In other studies, neither fluoxetine (56) nor citalopram (57) were shown to influence visceral sensation in IBS. Not surprisingly, given the methodological challenges that such studies present, there have been few investigations of the central nervous system effect of antidepressants in IBS. One study employing functional magnetic resonance imaging (fMRI) showed that low-dose amitriptyline reduced rectal pain-related activation of the anterior cingulate cortex (58); similar responses were demonstrated in association with symptomatic remission in another longitudinal study (59). Given the divergent nature of these various mechanistic studies, it should come as no surprise that, despite the conclusions of meta-analyses and systematic reviews, individual studies of antidepressants continue to provide contradictory results in IBS (56, 60-63).

Who will respond to antidepressants?

These variable responses to antidepressant therapy in IBS could reflect the heterogeneity that is an ever-present feature of IBS patient populations and a factor that has bedevilled studies of all pharmacological agents in IBS. Can responders to antidepressants be identified? Information is limited on this issue. As already alluded to, positive responses are not necessarily dependent on the presence of anxiety or depression. In a study that failed to demonstrate overall benefit with the TCA desipramine, those with moderate (rather than severe) symptoms, a history of abuse but not of depression and who had diarrhea-predominant symptoms were more likely to respond to this agent (62). In another study, however, a history of abuse had no impact on the response to paroxetine (64). Whether gender-related differences in serotonin metabolism (65) will influence responses is unknown; most studies have been insufficiently powered to permit comparisons between males and females.

CONCLUSIONS

Given the high levels of co-morbid depression seen among patients seen in a secondary or tertiary care setting, many patients with IBS will require antidepressant therapy. However, it is also clear that patients without co-morbid symptoms may also respond to such a strategy. The presence of depressive symptoms is not, therefore, a requirement for therapeutic benefit in IBS.

Though antidepressants have been used on a largely empirical basis for decades in the management of IBS, the scientific and clinical evidence to support their use remains frustratingly incomplete. The mechanism(s) of action of these agents in IBS remains unclear and, while selective effects on gut transit may favour a tricyclic or an SSRI in a given clinical scenario, there is little to guide the clinician in deciding when to employ these agents or which one to choose. From a safety perspective SSRIs with a short half-life, such as escitalopram, are more appropriate than longer half-life drugs such as fluoxetine. Furthermore, SSRIs should not be discontinued abruptly as they may be associated with a withdrawal syndrome (45).

Overall, TCAs and SSRIs agents seem to work in IBS but studies with individual agents are consistent only in their inconsistence. Many factors can be invoked to explain why some report positive and others negative results, including patient selection, dose (62), study design and size; only large, well-designed, controlled trials will ultimately establish the place of antidepressants in the management of IBS.

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