Antidepressants and inflammatory bowel disease: a systematic review

Background A number of studies have suggested a link between the patient's psyche and the course of inflammatory bowel disease (IBD). Although pharmacotherapy with antidepressants has not been widely explored, some investigators have proposed that treating psychological co-morbidities with antidepressants may help to control disease activity. To date a systematic analysis of the available studies assessing the efficacy of antidepressants for the control of somatic symptoms in IBD patients has not been performed. Methods We searched electronic databases, without any language restriction. All relevant papers issued after 1990 were examined. Results 12 relevant publications were identified. All of them referred to non-randomised studies. Antidepressants reported in these publications included paroxetine, bupropion, amitriptyline, phenelzine, and mirtazapine. In 10 articles, paroxetine, bupropion, and phenelzine were suggested to be effective for treating both psychological and somatic symptoms in patients suffering from IBD. Amitriptyline was found ineffective for treating somatic symptoms of IBD. Mirtazapine was not recommended for IBD patients. Conclusion Although most of reviewed papers suggest a beneficial effect of treatment with antidepressants in patients with IBD, due to the lack of reliable data, it is impossible to judge the efficacy of antidepressants in IBD. Properly designed trials are justified and needed based upon the available uncontrolled data.


Background
Inflammatory bowel disease (IBD) is a group of relapsing incurable diseases of the gastrointestinal tract. There is ongoing active research to find a curative treatment and understand the aetiology of IBD in immunology [1], microbiology [2], molecular biology [3] and food science [4]. As yet, IBD is incompletely understood (or treated) and the individual patient's response to treatment is variable. Until globally effective treatment is found, there is a need to decrease the number of relapses of the disease, lengthen remission and improve quality of life and psychosocial functioning of patients.
The psychology of patients with IBD has been of great interest to many investigators [5][6][7][8][9][10][11][12]. A number of high quality studies have shown a link between the patient's psyche and the course of the disease [5,13,14]. However, when psychological treatment in the form of psychotherapy is given most randomized controlled trials in IBD patients have found it to be ineffective [15][16][17][18][19]. Thus, some investigators have proposed that treating psychological co-morbidities with antidepressants might be of more utility to control disease activity and lengthen remission, particularly in Crohn's disease patients [20][21][22][23]. This may be particularly likely because treatment with antidepressants has been found effective in irritable bowel syndrome (IBS) [24][25][26][27], a partly postinfectious disease that commonly co-exists with IBD [28,29]. Thus far, a systematic analysis of available studies assessing the efficacy of antidepressant therapy for the control of somatic symptoms in IBD patients has not been undertaken. Therefore, the purpose of this study is to examine whether the existing literature supports a role for antidepressants in managing inflammatory bowel disease.

Study selection
Inclusion criteria All forms of research publications, describing any study design published between 1990 and 2005, which examined the use of antidepressants in inflammatory bowel disease, were included in this review. Participants had to have a diagnosis of inflammatory bowel disease (either Crohn's disease or ulcerative colitis or not specified inflammatory disorder). Studies published before 1990 were not included, as the researchers were mostly interested in the newest antidepressants, introduced to the market in the 1990s.
Primary outcome measure Our primary outcome measure was the efficacy of antidepressants in maintaining or inducing remission of inflammatory bowel disease. Remission was defined as at least a 4-week period with disease activity at less than 150 points or a drop in a score of at least 70 points for Crohn's dis-ease and a score < 2 points or a drop in a score of at least 3 points for ulcerative colitis, measured on the Crohn's Disease Activity Index and the Simple Clinical Colitis Activity Index, respectively OR at least a 4-week period with a complete lack of IBD symptoms [30,31]. Therefore, the effectiveness of treatment with antidepressants in IBD patients was defined as the remission of the disease activity beyond the usual length of remission (different for a particular patient). The search terms used were: Inflammatory Bowel Diseases OR Inflammatory Bowel Disease OR Colitis, Ulcerative OR Ulcerative Colitis OR Crohn Disease OR Crohn* Disease OR Granulomatous Colitis OR Granulomatous Enteritis OR regional Ileitis OR terminal Ileitis OR Ileocolitis OR ibd AND Antidepressive Agents OR antidepress* OR Thymoanaleptics OR Thymoleptics OR ssri OR mirtazapine OR bupropion OR paroxetine OR selective serotonin reuptake inhibitor* OR selective norepinephrine serotonin reuptake inhibitor*. There was no language restriction. We searched for additional studies in the reference lists of identified articles. We also searched unpublished theses stored at the University of Adelaide and in the whole of Australia through the National Library of Australia. We additionally contacted selected experts (18 South Australian gastroenterologists).

Data extraction
The systematic review identified no randomized controlled trials, cohort prospective studies nor case-controlled studies. Nevertheless, we located an open-label study, case reports, reviews, a guideline, a discussion, and a letter. The quality of the selected studies was assessed using the Cochrane Reviewers' Handbook [32]. However, because all the identified studies were non-randomised we also used the appendix to this manual prepared by the Cochrane Non-Randomised Studies Methods Group [33]. The standard components of the quality assessment are: sample size, allocation concealment, clear description of treatment, representative source of subjects, use of diag-nostic criteria or inclusion criteria, outcome measures described and the use of validated instruments. The Cochrane Non-Randomised Studies Methods Group has not specified the components of the quality assessment for non-randomised trials as yet. We therefore needed to create our own criteria. As our systematic review identified mainly case reports, reviews and one open-label study, we focused in assessing their quality on: length of a treatment, follow-up, clear description of a treatment, description of participants, and the use of validated instruments. We are aware of the various limitations of these studies. However, because no other published data exists in this field it is important to sum up the up-to-date literature as it may inform and facilitate future randomised trials in this area.

Data synthesis
As statistical data were accessible only for one study, and even then were limited, we could not conduct a metaanalysis.

Description of studies
We identified a total of 106 articles from the electronic databases, most of which were not directly related to the entered keywords. Only 12 publications met the inclusion criteria. During hand searches of journals, and during searches of reference lists of identified articles and unpublished theses we found no new articles that would match our inclusion criteria. The contact with selected experts also failed to identify new papers.
In order of design quality articles that met the inclusion criteria were: one non-randomised open-label trial, six case reports, three reviews, one guideline, one discussion paper, and one letter referring to previous studies. The total number of IBD patients described was only 20; eight participants were described in the open-label study and 12 in case reports. Antidepressants described included: paroxetine, bupropion, amitriptyline, phenelzine and mirtazapine. Paroxetine was used in three studies in 12 participants. Bupropion was used in two studies in six participants, and was recommended for use in IBD patients in two reviews, one discussion paper and one letter. Amitriptyline was used in one study in one participant. Phenelzine was used in one study in one participant. Mirtazapine was not recommended in one review (Table 1).

Positive impact of antidepressants on inflammatory bowel disease activity
Five research studies indicated a positive impact of the treatment with antidepressants on the inflammatory bowel disease activity. Four out of these five studies were case reports. One study out of the five was an open-label trial. There were 16 patients treated with antidepressants in these five studies. All of them benefited from this treatment. Among 16 patients treated with antidepressants, there were four females, two males, and in 10 the gender was not specified. Among these patients, seven suffered from Crohn's disease, one from ulcerative colitis, and 8 from unspecified inflammatory bowel disorder. All patients were adults. Examined antidepressants were: paroxetine (two studies), bupropion (two studies), and phenelzine (one study).
Two reviews, one discussion paper, and one letter also endorsed a positive impact of the treatment with antidepressants on the inflammatory bowel disease activity, despite the lack of provision of any new patient data. In all four of these papers bupropion was recommended for use in inflammatory bowel disease patients. In one paper, mirtazapine was not recommended for use in inflammatory bowel disease (See: Discussion for explanation).

Negative impact or no impact of antidepressants on inflammatory bowel disease activity
One study, a case report, suggested a potential negative impact of an antidepressant on inflammatory bowel disease. Three patients were described, and the antidepressant used was paroxetine. Prior to paroxetine patients had not been diagnosed with inflammatory bowel disease. Following treatment with paroxetine for depression, patients developed chronic diarrhoea and were subsequently diagnosed with inflammatory bowel disease, Crohn's disease in two patients and non-specified inflammatory bowel disorder in one patient. There was no control group in the study however, and the significance of this observation seems unclear.
Another case report found no impact of antidepressants on inflammatory bowel disease. One adult, male participant was described, and the antidepressant used was transdermal amitriptyline gel. Amitriptyline did not help the patient with pain nor fully treat the depression, however, the patient noticed his mood improved.

Quality of studies
We set five quality criteria for analysis: length of treatment with antidepressant, follow-up, clear description of treatment, description of participants, and validated instruments (See: Table 2).
Five studies met all or four out of five of the quality criteria. One article met three out of five of the quality criteria. Six publications met only one out of five of the quality criteria. The study by Kast et al. (2001) met all the quality criteria chosen in this systematic review. The next best study was by Walker et al. (1996). However, the weakness of this study lay in the fact that the authors did not specify the IBD type and did not use a disease activity index. The    (1999) also matched the majority of the quality criteria, however, the researchers did not use a validated instrument to measure the inflammatory bowel disease activity, and they focused only on pain and depression, as their intention was to treat these disorders, rather than to influence the IBD activity. Eirund et al.'s (1998) study addressed four out of five quality criteria, however, these researchers also failed to use an inflammatory bowel disease activity index. The study by Kast (1998) also met four criteria out of five, but again, the researchers did not use a validated instrument to measure the inflammatory bowel disease activity. Kane et al.'s (2003) study addressed three out of five criteria. The researchers did not provide the information about the length of treatment nor did they describe patients' characteristics and further follow-up. The non-experimental papers [34][35][36][37][38] and the study by Torras et al. (2003) did not match the quality criteria. Moreover, although their recommendations were of interest and may help in understanding the problem, they added no new data.

Discussion
This systematic review is the first structured attempt to explore the hypothesis that the clinical course of IBD may be influenced by specifically treating psychological comorbidities with antidepressants. Despite widespread acknowledgement that IBD is not a "6 week illness" [39] the psychological dimension of the illness has been largely ignored in standard treatment paradigms. Unfortunately, because of the paucity of published data -both quantitative and qualitative -this review is unable to provide a definitive answer on whether IBD can be improved by antidepressant therapy. However, it has highlighted a significant "evidence gap" in the literature, supporting our premise that psychological co-morbidities in patients with inflammatory bowel disease are often unrecognised and in general remain under-treated and underresearched.
While we acknowledge the poor methodological quality of the collected studies, they do however indicate that antidepressants appeared not only to help certain individual patients with IBD cope with their emotional problems, but also improved their quality of life. The published observations also hold out the intriguing possibility that antidepressant therapy may have specifically influenced the course of their inflammatory disease. This novel therapeutic possibility warrants further consideration.
To date, researchers with an interest in the impact of a patient's psyche on disease activity in IBD have conducted little formal research on the use of antidepressants in this condition, with most published data being uncontrolled and anecdotal. Only 12 relevant articles were identified, and five of these did not include new data. However, the three case reports [20][21][22], two reviews [35,38], and a discussion paper [37] did explore the potential for influencing disease activity in IBD with antidepressants from a novel perspective. Kast [21] presented a medical history of a depressed and anxious patient with Crohn's disease who was treated with phenelzine and subsequently achieved remission from IBD. In further reports, Kast and Altschuler [22] describe two additional patients who achieved long-lasting remission of Crohn's disease whilst using bupropion. These investigators hypothesize that this may have resulted from decreased tumor necrosis factor-alpha (TNFα), which is known to play a vital role in Crohn's disease. Both phenelzine and bupropion increase intracellular cAMP [40] which, in turn, decreases TNFα. As phenelzine may cause a hypertensive crisis, bupropion is suggested to be a safer therapeutic option. Interestingly, phenelzine and other monoamine oxidase inhibitors have also been noted to induce remission of rheumatoid arthritis, a disease in which -as in Crohn's disease -TNFα has a central role [41]. Kast [35], compared the use of bupropion and mirtazapine in patients with Crohn's disease. He speculated that both these antidepressants have the potential to affect inflammatory responses: bupropion by lowering TNFα and mirtazapine by increasing its level. Therefore, according to his hypothesis [35], there are theoretical reasons for recommending bupropion and cautioning against mirtazapine when treating depression in patients with Crohn's disease. Although Kast's explanations appear logical and are supported by other investigators [20], their practical effectiveness needs to be experimentally confirmed in appropriate clinical studies.
The largest study in this systematic review, which most closely matched the standard quality criteria, (See: Data extraction) was that by Walker, Gelfand et al. (1996). Whilst comparing IBD patients with and without current psychological disorders, the investigators noticed that depressed patients (n = 8) who were given paroxetine in an open label design showed significant improvement in relation to functional disability. The researchers had expected an improvement only in depression, however, patients' scores on SF-12 also improved in the area of "physical limitations, occupational role, emotional role, social function, pain, mental health, vitality, and health perception, with higher scores associated with increased quality of life" [23]. Although the importance of this result seems unquestionable, significant weaknesses of the study need to be acknowledged. These include the small sample size, open label design and the fact that the investigators did not differentiate between patients with Crohn's disease and ulcerative colitis. However, given the potential importance of this observation, larger studies addressing these methodological issues are clearly needed.
In discussing the possible effects of antidepressant therapy on IBD as revealed by this systematic review, we acknowledge that all the analysed studies were characterized by various limitations. Specifically these limitations included: lack of randomisation or control groups, potential lack of relevance to ulcerative colitis as most data pertain to Crohn's disease, non homogenous participants, failure to consistently apply standardised instruments, and lack of routine follow-up tests. Similarly, because of the uncontrolled nature of the observations, all studies are open to selection, performance, attrition and detection bias. Moreover, seven of 12 publications were from the same group, and four of these were discussions that did not contain any new data.
The fact that there is little good quality data in this area does not mean it is unworthy of further study. Our present state of knowledge regarding the interaction between psychological co-morbidities and IBD resembles that of our knowledge of the pathogenesis of irritable bowel syndrome twenty years ago. At that stage, IBS was thought to be predominantly a psychological condition, whereas we now have clear-cut, well accepted evidence of pathological abnormalities in the gut [42]. Currently IBD is generally thought to be purely inflammatory, but clinical observations in individual patients make it hard to dismiss the potential role of psychological factors [43]. Moreover, it is well accepted that IBS frequently co-exists in patients with IBD [28,29] and that both patient groups suffer similar impairment in physical and psychological domains [28], making rigid distinctions between psychological versus inflammatory mechanisms more difficult to uphold. As antidepressants are widely used in IBS [24][25][26][27]44] and because doctors already empirically treat depression, anxiety and pain in IBD using guidelines for IBS [34,43], creating informed discussion and hopefully prompting further research in this area is therefore likely to improve our understanding of IBD and patient care.

Conclusion
Based on our findings, it is not possible to state that antidepressants have an impact on the course of inflammatory bowel disease. While they appeared to have a positive effect in 16 patients in five studies, because studies were neither randomised nor blinded, it can still be argued that the outcome may be due to chance. This systematic review therefore provides insufficient evidence to conclude that antidepressants are efficacious for the treatment of psychological co-morbidities or somatic complaints, which do not respond to conventional therapy in IBD patients. However, the data certainly do not rule out efficacy, and warrant further properly designed randomised controlled trials.