Targeting the gut-brain axis for therapeutic adherence in patients with inflammatory bowel disease: a review on the role of psychotherapy

Abstract

Purpose

Inflammatory Bowel Diseases (IBD) are disorders intensively studied in the literature as a model of gut-brain interactions within the so-called gut-brain axis. A non-negligible proportion of patients with IBD have psychological and psychiatric comorbidities and show non-low levels of depressive and anxiety symptoms. The remitting-recurrent course of IBD poses the need for therapeutic intervention that not only serves to induce clinical remission of the disease but also has an impact on maintenance. Therefore, therapeutic adherence is undoubtedly a cornerstone of managing these patients.

Material and methods

A literature search was conducted to identify studies with psychotherapy as an intervention and therapeutic adherence to IBD-specific therapy as one of the outcomes.

Results

Not many studies in the literature have specifically explored the role of psychotherapy in improving therapeutic adherence in patients with IBD. Most of the available trials have focused on cognitive-behavioral psychotherapeutic interventions and are directed toward basically oral therapies. Other studies focused on interventions delivered under telemedicine or mindfulness or hypnotherapy techniques.

Conclusions

This narrative review leans toward a probable beneficial effect of psychotherapy in therapeutic adherence although new and more organic studies need to be conducted to generate stronger evidence.

Keywords:

• Ulcerative colitis
• Crohn’s disease
• gut-brain axis
• psychotherapy

1. Introduction

Inflammatory Bowel Diseases (IBD), including Crohn’s Disease (CD), Ulcerative Colitis (UC), and Indeterminate Colitis are a group of inflammatory digestive diseases that may also have extra-intestinal manifestations, probably determined by multifactorial pathogenesis and not yet fully clarified [1,2]. IBD are systemic pathologies extensively studied in the context of the inter-relationships between brain and gut, based on hormonal, neurological, psychiatric, psychological, and microbiota-related connections [3]. Within this concept, psychotherapy has been widely proposed for adjunctive therapy in IBD [4–6].

IBD are epidemiologically relevant considering that about one million US people are affected and about two and a half million on the European continent [7]. The relapsing-remitting behavior of IBD places a need for treatment not only in the induction of remission but also in the maintenance of the latter [8,9]. This determines that adherence to IBD therapy is crucial, mainly because more than 30% of patients with IBD show poor adherence to treatment which can lead not only to disease flare-ups but also to the development of complications [10,11]. In general, the rate of therapeutic nonadherence varied greatly across studies, reaching as high as more than 70% in some settings [10]. The study of the therapeutic adherence of the IBD patient is critical because it directly impacts the natural history of the disease [12,13]. Patients with IBD showed a relatively higher rate of depressive and anxiety disorders than the general population [14]. In general, a prevalence of around 20% of anxiety disorders and 15% of depressive disorders has been traced in the population with IBD [14]. Depression affects therapeutic adherence negatively and an active disease is generally related to a higher prevalence of depressive and anxiety symptoms [15].

A European Crohn’s and Colitis Organisation (ECCO) paper pointed out that, before the diagnosis of IBD, there is a great prevalence of higher rates of anxiety and that the latter is a particularly frequent occurrence in patients with IBD, especially if they are in active disease. The same is true for depression. Reviewing the different psychological techniques, ECCO points out that cognitive-behavioral therapy has a short-term benefit on the quality of life in adults with IBD and hypnotherapy appears to reduce IBD-related symptoms, maintain clinical remission, and increase the quality of life in UC patients [4]. Little space, however, has been devoted studying therapeutic adherence to IBD therapy in the landscape of psychological techniques [6]. Psychotherapy has been posited as a strategy to regain therapy adherence already in other studies focused on several diseases such as chronic renal failure [16], bipolar disorder [17], and depressive disorders [18]. The aim of this review is to examine the available evidence on the effectiveness of psychotherapy techniques in inducing and maintaining therapeutic adherence in patients with IBD.

2. Some interplays in psychopathological manifestations in inflammatory bowel diseases: the common denominator of the gut-brain axis

The interactions between the gut and brain, in the context of the definition of the gut-brain axis, summarize all bidirectional communications between these two organs so impairment of these could determine the formation of new psychological disorders in the IBD patient. Still, the latter can determine the onset of new gastrointestinal symptoms on the pre-existing IBD [19]. Although this review aims not to examine all the complex biomolecular interactions underlying the gut-brain axis, hormonal, neurological, and immunological factors, but also factors related to variations in the gut microbiota, have indeed been implicated [20]. A previous systematic review that examined data from 158317 patients found a non-negligible general prevalence of anxiety (20%) and depression (15%) in patients with IBD. Interestingly the prevalence of depressive symptoms was 16.5% in patients in remission compared with patients with active disease (40.7%), underlining that even IBD patients in remission are not spared by mood disorders [14].

In addition, sometimes the onset of new gastrointestinal symptoms in a patient with IBD is not always directly related to a reactivation of the underlying disease. Starting from the assumption that the assessment of IBD status also makes use of noninvasive evaluations [21], primarily based on the review of clinical symptoms, the latter does not always correlate proportionally with endoscopic and histologic IBD status [22,23]. The genesis of these new gastrointestinal symptoms may be related, in many patients with IBD, to the overlap of a possible associated functional gastrointestinal disease, such as irritable bowel syndrome (IBS) [19]. This overlap between IBD and IBS has as a common matrix the presence, in both diseases, as already exposed to IBD, of a higher rate of anxiety and depression compared to the general population. Also in IBS, a meta-analysis has in fact confirmed this finding [24]. Neuroimaging studies have, moreover, brought elements to support the interactions between brain and gut in the pathogenesis of functional gastrointestinal disorders highlighted as visceral hypersensitivity, common in these disorders, may be associated with the presence of functional dysfunction in some brain areas [25,26]. Jones et al. moreover, showed that anxiety-depressive disorders could present a few years before the diagnosis of functional gastrointestinal disorders [27].

The onset of mood and anxiety disorders in the IBD patient inevitably impacts therapeutic adherence. Among the various factors examined in the differences between adherent and nonadherent patients, not surprisingly, ample space was given to psychological factors [28–32]. There is evidence of how the coexistence of IBD and anxiety and mood disorders are a general risk factor for discontinuation of anti-TNF therapy within one year after the start [33]. In addition, other findings highlight how a worse mental state is inevitably correlated with a greater number of relapses and greater disease activity [30,34].

In general, a “vicious circle” has been hypothesized as an overall mechanism in which reduced mentalization by the IBD patient leads to reduced therapeutic adherence. It worsens the underlying IBD creating stress for the patients. However, the worsening of IBD can be bidirectionally created by the same stress. Thus, an inevitable sense of patient insecurity is formed [13].

3. The application of psychotherapy in inflammatory bowel diseases: what techniques and what space for therapeutic adherence?

The role of psychotherapy in the management of IBD has been repeatedly raised in the literature [6], however, although several studies have reported marked benefits in the application of this technique in the management of this condition (in terms of reducing bowel and systemic symptoms, pain, and fatigue, and reducing recurrences) [35–39], results provided by systematic reviews had instead gone in the opposite direction [40]. This is also because other studies have not, contrary to the above, pointed to such a clear benefit of psychotherapy [41–43].

Among the most widely used psychological techniques, these certainly include cognitive-behavioral therapy [44–49], stress management or relaxation techniques [35,36,43,50,51], social support [41] as well as techniques targeted to the individual (i.e., tailored) [52].

However, in the design of these studies, very little space has been reserved for outcomes related to therapeutic adherence. Most of the studies focused in fact on quality of life, reduction of anxious-depressive symptoms, as well as improvement of IBD-related symptoms and relapse rates [6].

Two trials focused on studying adolescent IBD patients’ adherence to oral therapy (mesalamine, 6-mercaptopurine/azathioprine) through the application of cognitive-behavioral technique.

This specific psychological technique focuses on the problem and the collaboration of the patient to obtain a cognitive restructuring and identification of those thoughts that are “inaccurate” or unnecessary and that are associated with the patient’s psychological distress. Furthermore, it aims at behavioral activation as an active technique by engaging the patient in the first person in implementing activities to provide the patient with reinforcement and personal fulfillment. The fulcrum of the method is, therefore, the problem-solving with which the patient solves the psychological problem with the awareness of the same and with the application of resolutive behaviors [53]. This technique has been extensively studied in managing anxiety and depression in young adults and adolescents [54,55].

In the area of applications of behavioral techniques to the IBD patient, one experience with group behavioral interventions was provided by Hommel et al. [56] in adolescent patients. In this randomized controlled trial, the authors compared this intervention, spread over four weeks of family therapy, with usual care as a control. Adherence was measured in a multimodal manner by not adopting a single metric. Specifically, the authors developed a special ad hoc questionnaire for their study (i.e., Treatment Regimen Adherence Questionnaire, TRAQ) as well as using the pill count (i.e., a count expressed as doses removed from the bottle out of the total doses prescribed multiplied by one hundred). As a result, there was a significant improvement in adherence to mesalamine by 25% from baseline but not to 6-mercaptopurine/azathioprine. The intervention in this study was structured through 4 sessions of about 60–90 min in which only one, the last, was practiced with patients and parents together present while the others were practiced separately with patients and parents. The first session was educational and organizational. The patient was mainly informed about IBD and the side effects of drugs and discussed the barriers to therapeutic adherence and strategies to simplify the dosage. The second and third sessions, on the other hand, focused on behavioral modification, problem-solving, and adherence monitoring. Finally, the last session aimed to provide better communication strategies between family members, in negotiating and resolving intra-family conflicts.

In a previous study, Hommel et al. [52], while remaining in the field of adherence to oral therapy in adolescents with IBD, focused instead on applying a tailored and, therefore, individual psychological intervention. As in the previously described study, also in this other randomized controlled trial, the authors proposed a brief treatment of four sessions. The schedule of the sessions, in terms of topics, was the exact focus, during the sessions, respectively on educational and organizational intervention, behavioral intervention, adherence monitoring and problem-solving, and, finally, family functioning. Also, in this case, one of the main outcomes was therapeutic adherence measured on pill count. The intervention showed improved adherence to azathioprine and 6-mercaptopurine by about 4% and again by 25% towards mesalamine. However, all of these increases in adherence were not statistically significant.

Another study, always remaining in the cognitive-behavioral techniques, wanted to focus on a specific IBD (in detail, CD) targeting, instead, an adult population. A model proposed for this purpose was the “Project Management for Crohn’s Disease” framework proposed in a 2012 clinical trial by Keefer et al. [57]. The protocol excluded patients with active disease or apparent psychological distress. The duration of psychological intervention was more prolonged than in previous studies, with six weekly 60-minute individualized sessions. Adherence was not measured by pill count but by a questionnaire widely used in the literature, namely the Morisky scale [58]. This project was framed within the psychological therapy of “health behavior change” and “social learning theory” and fell within the scope of cognitive-behavioral techniques [57]. The study, however, did not show any particular impact of this psychological strategy on the improvement of therapeutic adherence but rather on symptomatic outcomes related to disease activity. The organization of the psychological sessions, as mentioned above in number six, was particularly articulated. In detail, the first session elaborated on a real project scope statement including potential barriers to the project by the patient. Following, the second session, monitoring the clinical symptomatologic state of the disease, the key stakeholders were identified, and a decision-making tree was elaborated to plan the activity of medical therapy. In the subsequent two sessions, time management and sleep hygiene care were carried on. The patient was trained to relax, encouraging the cessation of cigarette smoking and, as typical in cognitive-behavioral techniques on problem-solving. In the penultimate session, active behavior was targeted (i.e., reaching an exercise or dietary goal). Finally, in the last session, an emergency protocol was also developed in addition to reviewing the project’s scope, if required, and self-esteem for project completion [57].

The administration of cognitive therapy has also been tested in a telemedicine study (enrolling 11–18 years old IBD patients) providing promising results by a nonsignificant increase of the therapeutic adherence to mesalamine from 62% to 91%. The therapy was administered weekly for four times duration always superimposable to the studies already exposed previously (i.e., about 60–90 min), and conducted via Skype and webcam working [59].

A considerable need for evidence is required for assessing and achieving therapeutic adherence in those cases in which the patient with IBD has a concomitant major psychiatric problem. A Hungarian report showed an improvement in adherence with the application of a “low-intensity evidence-based cognitive-behavioral therapy”. In detail, this technique integrated psychological education, motivation, behavioral activation, cognitive restructuring, family counseling, and problem-solving training through twenty-five sessions. In this report, the patient was a 21-year-old male suffering from active CD and a contextual mood dysregulation disorder. Well, therapeutic adherence was improved in conjunction with the improvement of psychiatric symptoms [60]. This technique is, in addition, defined as "low intensity" because it tends to limit the number of sessions (i.e., to concentrate on therapy in a maximum of six or eight sessions). The duration is generally shorter than traditional cognitive behavioral therapy (i.e., about 30 min). It is a technique that adopts with great relevance self-help materials (such as books, websites, and the like). Face-to-face interventions are not mutual, but telematic interventions are also encouraged as well as simple e-mail correspondence [60].

More recently, in 2019, a protocol for mindfulness-based cognitive therapy targeted to adolescents and young adults with simultaneous IBD and high levels of depressive symptoms was proposed and included therapeutic adherence in its secondary outcomes [61]. This technique has already shown promising efficacy in chronic diseases [62], and according to the hypothesis raised in the protocol study by the authors, it could improve therapeutic adherence, always acting on the improvement of the levels of anxious-depressive symptoms.

The results of this trial were encouraging in this regard [45]. The main topics covered in the eight sessions were respectively: awareness and automatic pilot, living in our heads, gathering the scattered mind, recognizing aversion, allowing/letting be, thoughts are not facts, “how can I best take care of myself?” and maintaining and extending new learning.

Mindfulness-based cognitive therapy has shown the ability to modify some functional neurological brain structures in the context of the experience-induced neuroplasticity concept suggesting a possible role of such modifications in improving psychological symptoms [61,63].

A further study examined the application of gut-directed hypnotherapy. Still, the effects were more in favor of prolonging the state of clinical remission in patients with UC rather than enhancing therapeutic adherence. However, this trial had in it aims the evaluation of the latter [64].

Hypnotherapy is a type of psychotherapeutic hypnosis that uses metaphors to convey post-hypnotic suggestions to improve gastrointestinal health, which has already been studied in other gastrointestinal disorders such as IBS, functional dyspepsia, delayed gastric emptying and for the relapse prevention of peptic ulcer [65–70].

During hypnosis, suggestions are typically statements made by the therapist in which he affirms that the patient, for example, will have no more pain, will have normalization of evacuations, and the like. The metaphors often used are the river, the warmth of the hands, or even drugs. The river generally represents the flow of the gastrointestinal tract, the warmth of hands the calm and control, and the use of drugs, of course, the pharmacological therapeutic action on the symptomatic gastrointestinal disorder [66]. Table 1 summarizes the main available evidence on the application of psychotherapy in improving adherence to IBD-specific therapy.

Table 1. Clinical trials that evaluated therapeutic adherence to therapy for inflammatory bowel diseases provided by psychological techniques.

Study, year and reference	Design	Intervention	Main adherence assessment	Main results
Hommel et al., (2011) [52]	RCT	Individually tailored behavioral treatment (four sessions of 60–75 minutes)	Pill count	Adherence to azathioprine/6-mercaptopurine and mesalamine increased by 4% and 25%, respectively, in the intervention group compared with the control.
Hommel et al., (2012) [56]	RCT	Family-Based Group Behavioral treatment (four sessions of 60–90 minutes)	Treatment regimen adherence questionnaire (designed ad hoc), pill count	Significant improvement of 25% in adherence toward mesalamine in the intervention group compared with the control.
Hommel et al (2013)., [59]	nRCT	Telehealth behavioral treatment (four weekly Skype sessions of 60–90 minutes)	Pill count	Nonsignificant 29% increase in mesalamine adherence.
Keefer et al (2012)., [57]	RCT	“Project Management” (six sessions of 60 minutes), Crohn’s disease targeted	Morisky adherence scale	No impact on medication adherence
Ewais et al (2021)., [45]	RCT	Mindfulness-based cognitive therapy (eight weekly sessions of 60 minutes)	Morisky adherence scale	Improvement in medication adherence
Keefer et al (2013)., [64]	RCT	Gut-directed hypnotherapy (seven weekly sessions of 40 minutes), ulcerative colitis targeted	Morisky adherence scale	No impact on medication adherence

RCT: randomized controlled trial; nRCT: nonrandomized nor controlled trial.

4. Which subgroups of inflammatory bowel diseases are at greatest risk for adherence: possible targets for psychotherapy?

Adherence to IBD therapy, as already exposed, is a serious problem that requires close attention from the clinician since it is associated with poorer symptom control, increased treatment costs, and an increased risk of relapse and colorectal cancer [71,72]. Treatment adherence, in contrast, is strongly associated with induction and maintenance of remission, prevention of relapses, greater symptom control, reduced risk of colorectal cancer, improved quality of life, and lower recurrence rates [71]. Although there are neither many nor definitive studies on which subgroups are more receptive to psychotherapy or in which it is more effective, there is evidence on which IBD subgroups are associated with lower therapeutic adherence. Salehi et al., highlighted that patients with higher perceived stress and a positive inclination to seek help were those in whom psychotherapy receptivity was the highest [73]. Several efforts have been made to identify IBD subgroups at risk for lower therapeutic adherence to target those populations deserving greater attention. One of the most focused factors was the recent diagnosis of IBD [74–76]. However, also the chronic nature of the disease and, consequently, the need to take drugs for a very long period would significantly cause reduced adherence [10,74,77,78]. Regarding drug intake, oral therapy was associated with substantially higher adherence than rectal therapy [74,75]. Moreover, concerning biologic therapies, one study [79] showed that drugs administered in hospital settings were associated with higher adherence than self-administered injections. The complexity of the therapeutic regimen related to a high frequency of administration, sometimes also associated with the need to take other drugs for possible comorbidities emerged as a predictor of poor adherence [71,80–82].

While disease-related factors such as activity, duration of treatment, the complexity of treatment regimen, and remission have a debated role, different studies [30,33,71,82–85], as also previously stated, showed that psychiatric comorbidities, particularly anxiety and mood disorders, are an important risk factor for nonadherence. A study [33] with 1135 IBD patients who initiated anti-TNF therapy, 15.7% of whom met diagnostic criteria for an anxiety or mood disorder, showed that psychiatric comorbidities significantly increased the risk of drug discontinuation within the first year after initiation of therapy; the reason for this would most be likely that people with anxiety and mood disorders are more likely to report a variety of somatic complaints that can be attributed to the newly taken medication. This eventuality would explain its discontinuation within the time frame indicated by the study. Despite all these variables considered, in many studies, non-adherence to therapy is often unintentional, for example, due to forgetfulness [74,85–87].

Finally, the greatest impact on nonadherence is also probably due to psychosocial factors such as negative attitudes toward treatment, doubts about the benefits and necessity of taking the medications, concerns or previous experience of adverse effects, worsening of health-related quality of life following therapy, negative beliefs about how much IBD medications affect emotional well-being, psychological distress and treatment-related constraints [71,76,77,88–90].

Gender appears to be another discriminating factor in therapeutic adherence in IBD patients. It seems that there are even real gender differences in symptoms, course, complications, adherence to treatment, and the presence of comorbidities such as psychiatric and psychosocial disorders in IBD which should be investigated to make therapy and medical support as tailored as possible [91]. In general, moreover, it appears that in IBD management, the female sex is more affected by nonadherence [78,87,92,93]. Finally, inadequate physician-patient communication has often been found to be an important cause of reduced treatment adherence [94,95], which is why improving the physician-patient relationship is a useful strategy for increasing treatment adherence [96,97].

5. Conclusion

Therapeutic adherence is a relevant clinical and health economics issue in managing patients with IBD. Considerable efforts have been made in the literature to study the potential application of psychotherapeutic techniques, especially cognitive-behavioral techniques, in improving various IBD-related outcomes (from the improvement of gastrointestinal symptoms to quality of life). However, very little space has been given to the study of this technique in the improvement of therapeutic adherence to IBD therapy. Very few studies have been conducted, most of them not on large samples and not with the same way of assessing adherence. There is a strong need for new studies on this potential application, especially extended to therapies not necessarily administered orally, such as biological therapies administered intravenously and subcutaneously. Even less space has been provided for this role in the context of patients with IBD and known psychiatric comorbidities. Psychotherapy can be considered a complementary technique in the management of IBD whose potential is yet to be fully understood and studied.

Author contributions

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature, and have been involved in writing the review article or revised it for intellectual content

Acknowledgments

None.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.