Digestive and Liver Disease

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1 Digestive and Liver Disease 41 (2009) Contents lists available at ScienceDirect Digestive and Liver Disease journal homepage: Mini-Symposium Recent insights on central processing and psychological processes in functional gastrointestinal disorders L. Van Oudenhove a,b,, Q. Aziz c a Translational Research Center for Gastrointestinal Diseases (TARGID), Department of Pathophysiology, Gastroenterology Section, Leuven, Belgium b Department of Neurosciences, Psychiatry Division, University of Leuven, Leuven, Belgium c Wingate Institute for Neurogastroenterology, Queen Mary University of London, London, UK article info abstract Article history: Received 30 June 2009 Accepted 4 July 2009 Available online 8 August 2009 Keywords: Central nervous system Functional brain imaging Functional gastrointestinal disorders Psychology There is increasing evidence for a key role of psychological processes and their central nervous system substrates in functional gastrointestinal disorders, although the exact nature of the relationship remains only partially understood. However, progress in this key area of psychosomatic medicine is rapidly being made. In this review article, we will give an overview of recent advances in understanding the complex mechanisms by which psychological processes and functional gastrointestinal disorder symptoms reciprocally influence each other. Various lines of evidence from different branches of biomedical and psychological science will be discussed, particularly epidemiology, patho- and psychophysiology and functional brain imaging, focusing on the most recent and novel findings. We will conclude this paper with a paragraph on new insights into treatment Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction It is generally accepted that functional gastrointestinal disorders (FGID) are heterogeneous disorders; their pathophysiology is likely to be multifactorial and remains incompletely understood, but evidence for a key role of psychological processes is growing [1,2]. Evidence supporting the hypothesis that psychological processes influence gastrointestinal (GI) sensorimotor function and/or -symptom reporting is coming from various lines of research. First, most people have experienced changes in GI function during stress or emotional arousal, which may lead to symptoms and medical consultation. This folk psychology knowledge is reflected in medical literature as well as everyday language ( butterflies in my stomach, knot in my bowels and the like). Second, a large historical body of biomedical and psychological research suggests a close interaction between psychological processes and gastrointestinal function/symptoms. Third, recent epidemiological studies indicate that comorbidity with psychiatric disorders (mostly mood and anxiety disorders) as well as prevalence of severe psychosocial stressors (including a history of (childhood) sexual or physical abuse) is high in FGID [1,3 5]. Recent evidence has shown that this is not only true in tertiary care, but also in primary care [6] and non-help seeking community-based patients [3,7 11]. Fourth, psychophys- Corresponding author at: University Hospital Gasthuisberg, Herestraat 49, B Leuven, Belgium. Tel.: ; fax: address: lukas.vanoudenhove@med.kuleuven.be (L. Van Oudenhove). iological studies in Irritable Bowel Syndrome (IBS) showed that the hypersensitivity for rectal distension found in these patients is for an important part attributable to hypervigilance for visceral stimuli and a greater tendency to label visceral sensations as negative/painful rather than neurosensory sensitivity [12,13]. Furthermore, our group has shown that experimentally induced anxiety has a direct influence on gastric sensorimotor function in healthy humans [14]. Fifth, functional brain imaging evidence on rectal and esophageal sensation (reviewed in [15,16]), points towards a key influence of cognitive-affective processes on gastrointestinal sensation and its central nervous system (CNS) correlates in health and disease. It is indeed becoming increasingly clear from the somatic and, although to a lesser extent, visceral pain literature that cognitive-affective processes including arousal, attention, conditioning and negative affect strongly influence (visceral) pain perception through modulation of its neural correlates [16,17]. Finally, Damasio and other affective neuroscience researchers have shown that brain regions processing interoceptive-visceral information are also involved in generation and regulation of emotions as well as emotion cognition interactions [2,16,18], thereby elaborating on the James Lange theory of emotions, first formulated in the 1880s [19,20]. In summary, there is growing evidence for an influence of psychological processes on GI sensorimotor function and symptom reporting in FGID, including IBS and functional dyspepsia (FD). This has lead to a biopsychosocial conceptualisation of FGID, first formulated by Drossman in the previous international consensus report on FGID ( Rome II ) [21]. The biopsychosocial model of illness, con /$ Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi: /j.dld

2 782 L. Van Oudenhove, Q. Aziz / Digestive and Liver Disease 41 (2009) ceived by the late George Engel in 1977, postulates that all illnesses, but especially functional somatic disorders result from a complex reciprocal interaction between biological, psychological and social factors [22]. Each of these factors may be primarily predisposing, precipitating or perpetuating. Although the biopsychosocial model has certainly been important in emphasising the importance of psychosocial factors in virtually all illnesses, it also suffers from some conceptual weaknesses. More than 30 years after its birth, the nature of the interactions between the different factors in the model still remains highly unclear. In the present article, we will try to shed some light on the nature of these psychobiological mechanisms by reviewing the most recent evidence from the various sources briefly introduced above. More specifically, we will give an overview of novel findings on FGID from epidemiology, patho- and psychophysiology, functional brain imaging and treatment studies. 2. Epidemiology There is a bidirectional comorbidity between FGID and psychiatric disorders, especially mood and anxiety disorders, without these two groups of disorders being fully dependent on, and thus reducable to, each other [5] Comorbid psychiatric disorders in patients with FGID It has fairly long been established that comorbidity of mood and anxiety disorders in FGID patients is higher than in the general population [5], with rates up to 50% or even more, depending on the population studied, as reviewed before [2,23]. Moreover, this seems to be true not only in healthcare-seeking FGID patient samples, but also in community-based samples, indicating that psychiatric comorbidity in FGID may be more than merely a determinant of health care use [3,7 11]. Furthermore, psychological factors have been shown not to be independent determinants of help seeking in FGID [24]. Finally, FGID patients with psychiatric comorbidity are more likely to develop a psychiatric disorder before the onset of the FGID symptoms, which again suggests a role for psychiatric disorders in FGID development that goes beyond their mere influence on healthcare-seeking [25] Comorbid FGID in patients with psychiatric disorders Comorbidity in this direction has also been established more than 10 years ago, although in smaller studies by the same group, with IBS comorbidity rates of 19%, 27%, 46% and 59% in patients with schizophrenia, major depressive disorder, panic disorder and dysthymia, respectively [26]. All these comorbidity rates were significantly higher than in a control group. More recent studies, however, have strengthened this line of evidence. Hillilä et al. showed, in a population-based sample, that prevalence of IBS was 54% in depressed patients, compared to 29% in non-depressed controls [27]. Karling et al. confirmed high levels of IBS symptoms in depressed patients; IBS symptom levels in patients with recurrent depression currently in remission did not differ from controls [28]. A Japanese group found comorbid IBS in 36% of a large panic disorder patient sample. Patients with the diarrheapredominant subtype of IBS and agoraphobia avoided significantly more situations due to fear of a panic attack than non-ibs patients with agoraphobia. IBS with agoraphobia and avoidant behaviour due to fear of IBS symptoms was associated with significantly higher depression scores and a greater number of situations avoided owing to fear of panic attacks [29]. Lydiard confirmed a significant association between panic disorder and all FGID, including IBS (26% vs. 11%) and FD (25% vs. 3%) [30]. Finally, Masand et al. reported a significant association between the anxiety disorder obsessivecompulsive disorder (OCD) and IBS (comorbid IBS in 35% of the OCD group vs. 2.5% in controls) [31]. Recently, a significant association between binge-eating disorder on the one hand and other psychiatric disorders (including mood and anxiety disorders) and functional somatic syndromes (including IBS and fibromyalgia) has been reported [32] Abuse history in FGID patients In a landmark study on this topic, Drossman et al. reported a 44% prevalence of sexual or physical abuse in FGID patients, which was significantly higher than in a control group with organic GI disorders. Both types of abuse frequently occurred together and were associated with increased symptom reporting and history of surgeries [33]. Many research on this important topic has been performed since this initial report, confirming the high prevalences as well as the association with FGID, other functional somatic syndromes, personality traits as neuroticism and psychiatric disorders, including depression and anxiety disorders, in consulting as well as population samples [34 42]. Neuroticism, somatisation, dissociation and psychiatric comorbidity have all been proposed as potential mediators of the relationship between abuse history and FGID, although some controversy remains [4,41,43,44]. This issue has recently been the subject of a systematic review [45]. 3. Patho- and psychophysiological research In this paragraph, we will discuss findings on the relationship between psychosocial factors, GI sensorimotor function and FGID symptoms and the putative pathophysiological mechanisms underlying this link The relationship between psychosocial factors and GI sensorimotor function We recently showed that experimentally induced anxiety in healthy volunteers was associated with impaired gastric compliance and accommodation [14]. In a subsequent study in FD patients, we found negative correlations between state anxiety levels during a barostat test on the one hand and gastric sensitivity and compliance on the other, but this was limited to the subgroup of patients characterised by gastric hypersensitivity [46]. These results are largely in line with research regarding the role of hypervigilance in the visceral hypersensitivity found in at least a subgroup of FGID patients. The UCLA group were the first to show evidence for two distinct perceptual alterations in IBS, namely hypervigilance for visceral stimuli (higher tendency to label a visceral sensation as discomfort ) and true, unbiased visceral hypersensitivity, using two different psychophysical tasks [12]. A recent interesting study by Dorn et al., applying sensory decision theory to a barostat study in a large IBS sample, suggests that hypervigilance may be a more important mechanism than neurosensory sensitivity [13]. The same group draws somewhat similar conclusions from an epidemiological study on comorbidity with a high number of somatic disorders (both functional and non-functional) in IBS, which was found to be higher than in controls and IBD patients, but without specific associations with any disease. The authors conclude that IBS results from biased symptom perception [47]. The relationship between abuse history and GI sensitivity has also been studied, but with mixed results. An older, small study in IBS found no association between abuse history and rectal sensitivity [48], whereas in a more recent, large study by the same group, a history of sexual or physical abuse was associated with rectal

3 L. Van Oudenhove, Q. Aziz / Digestive and Liver Disease 41 (2009) hyposensitivity [49]. In a large recent study in FD from the Leuven group, sexual, but not physical abuse was significantly related to gastric hypersensitivity, and the effect was found to be more pronounced in the subgroup with severe sexual abuse [42]. In a recent small Brazilian study in IBS, depression levels were found to be negatively correlated with rectal pain threshold, but only in the alternating subtype of IBS [50]. In another large study from the Netherlands, no relationship between rectal sensitivity on the one hand and a number of psychosocial factors, including anxiety, depression, somatisation, vigilance, pain coping, dysfunctional cognitions and psychoneuroticism was found [51] The relationship between GI sensorimotor function, psychosocial factors and FGID status/symptoms In a very interesting large prospective study in primary care on predictors of post-infectious IBS status, Spence et al. found that perceived stress, anxiety, somatisation and negative illness beliefs at the time of infection were all significantly associated with developing post-infectious IBS. Moreover, patients with IBS were also significantly more likely to remain active in the face of their acute symptoms until they felt forced to rest (all-or-nothing behaviour) and significantly less likely to initially rest in response to their acute illness. The authors intepret these findings as being in line with a cognitive-behavioural model of IBS [52]. Posserud et al. recently studied a large sample of IBS patients, in whom rectal hypersensitivity was associated with the symptoms pain and bloating in multivariate analysis. Although rectal hypersensitivity was related to higher anxiety levels in univariate analysis, anxiety was not found to be an independent correlate of rectal sensitivity in multivariate analysis [53]. Van Oudenhove et al. reported on the first study in which the relative contribution of gastric sensorimotor function, psychosocial factors and somatisation on FD symptoms and weight loss was investigated. Gastric sensitivity, depression and somatisation significantly correlated with FD symptom severity in univariate analysis. However, in multivariate analysis, only somatisation and, to a lesser extent, depression, were significant determinants of FD symptoms. The effect of depression was partially mediated by somatisation. The effect of somatisation (and the variance explained) was found to be stronger in hypersensitive patients. Gastric sensitivity (borderline significant), childhood sexual abuse history and somatisation were found to be independent determinants of weight loss; the effect of depression was fully mediated by somatisation. The role of gastric sensorimotor (especially gastric accommodation) was more important in normosensitives, whereas the role of abuse history and somatisation (and the variance explained) was more important in hypersensitives [54] Potential mechanisms mediating the link between psychiatric disorders and FGID The most obvious candidate physiological mechanisms to be involved in this link is the serotonin (5-HT) neurotransmission system in both the enteric and central nervous systems and the closely linked autonomic nervous system (ANS), stress-hormone system and immune system, besides brain mechanisms discussed in the paragraph on functional brain imaging studies below. Selected topics will be discussed here, with emphasis on the presentation of recent studies; the reader is referred to a recent editorial by Van Oudenhove on this subject for further discussion [55] The autonomic nervous system Autonomic dysfunction has been described in both mood and anxiety disorders, mostly a relative hyperfunction of the sympathetic branch and/or a relative hypofunction of the parasympathetic branch (low vagal tone) [56,57]. Evidence for a similar dysfunction in FGID is growing, providing a putative link between both groups of disorders. Autonomic dysfunction in FGID, whether or not during psychological stress, GI balloon distension or feeding, has been demonstrated in older studies [58,59], but a number of recent studies, some of which used new methodology, add significantly to the evidence [60 63]. A recent Polish report links these autonomic disturbances directly to GI physiological abnormalities as measured by EGG [64]. In another study, differences in ANS activity between healthy volunteers and IBS patients were mainly found during rectal distension. Autonomic function correlated significantly with anxiety and depression scores in the diarrhea-predominant subgroup, and with depression scores only in the alternating subgroup [65]. Finally, vagal dysfunction, as measured by heart rate variability, is related to pain and predominant bowel pattern in female IBS patients [66]. The Bergen group has recently started looking at the therapeutic potential of manipulation ANS activity, mainly in FD. First, they showed that neither vagal stimulation (mental relaxation with deep breathing) nor acute stress stimulation (serial subtraction task) was able to influence gastric accommodation in FD. Cholinergic blockade, however, did improve accommodation in the subgroup of FD patients with impaired accommodation [67]. Second, they found that vagal stimulation by sham-feeding improved postprandial gastric motor function in FD, which was inversely correlated to pain scores [68]. Finally, breathing exercises with vagal biofeedback increased drinking capacity and improved quality of life in FD, but did not improve baseline vagal tone, although after the treatment period, RSA during breathing exercises was significantly correlated to drinking capacity [69]. A more comprehensive program of relaxation training, including breathing exercises, was also recently found to provide long-term benefit (1 year) in IBS, including a reduction of symptom severity and medical consumption as well as an improvement in quality of life [70] The stress-hormone system: HPA-axis Hypothalamo pituitary adrenal axis (HPA-axis) abnormalities have been reported in at least a subset of patients with depression and anxiety disorders [71]. Depression, for example, may be characterised by a corticotropin-release factor (CRF) hyperdrive in subcortical brain regions [71]. CRF, both centrally and peripherally, has been shown to influence GI function in animals and human research [72,73], mainly through activation of the (sympathetic) ANS. A recent study has also shown that peripheral CRF injection in healthy humans induces rectal hypersensitivity during repetitive rectal distension, a phenomenon observed in IBS patients without injection of CRF [74]. Several papers reported on HPA-axis function in FGID, with mixed results. Bohmelt et al. mainly found hypofunction in a mixed FD-IBS group, both at baseline and after stimulation using CRF [75]. Dinan et al., on the contrary, reported higher baseline cortisol levels (although measured at noon), as well as an increased response to CRF in a large IBS sample. Furthermore, this hyperactivity was shown to correlate with proinflammatory cytokine levels [76]. The results from a recent UCLA-based study were somewhat in between the two former results. Basal ACTH levels were significantly blunted, while basal and stimulated plasma cortisol levels were higher in IBS patients. Basal cortisol levels prior to sigmoidoscopy positively correlated with anxiety symptoms, but not IBS symptoms [77]. Another study confirmed the finding of higher cortisol levels prior to rectal distension in IBS subjects (compared to controls and compared to a day without GI investigation), with no further increase during the actual distension. This points to a key role of anticipatory stress [78]. Elsenbruch et al., however, found no difference in autonomic neuroendocrine and neuroimmune responses to a public speech stress

4 784 L. Van Oudenhove, Q. Aziz / Digestive and Liver Disease 41 (2009) test between IBS patients and controls, despite higher anxiety state in patients [79]. Thus, results have been varying, from hyperfunction to hypofunction, and the complexity of the HPA-axis with various feedback mechanisms renders the interpretation of the results even more difficult. More specifically, it is hard to determine at which level of the HPA-axis the primary dysfunction is situated. Moreover, key candidate moderators, most notably abuse history, have not been included in HPA-axis studies in FGID so far The immune system An interesting recent French study showed that IBS was characterised by higher counts of mast cells in the gut lamina propria compared to controls and that fatigue and depression ratings correlated with mast cell counts [80]. Evidence for a lowgrade inflammatory state in both FGID and depression is indeed growing [76,81]. Liebregts et al. found that patients with diarrheapredominant IBS display enhanced proinflammatory cytokine release, and this was associated with symptoms and anxiety. More specifically, LPS-induced TNF-alpha production was associated with anxiety [82]. A study from the UNC group reported no relationship between psychological status and small intestinal bacterial overgrowth in IBS [83]. 4. Functional brain imaging studies We have reviewed the basic neuroanatomy of the brain-gut axis and older brain imaging results before [2,15,84], so we will focus on the discussion of recent results here Healthy volunteers Van Oudenhove et al. were the first to describe an extensive pattern of cortical deactivations during visceral distension leading to discomfort/pain. Deactivations were found in medial parietal (posterior cingulate, precuneus), medial temporal (amygdala, hippocampus) and medial prefrontal areas [the latter including subgenual anterior cingulate cortex (sacc)]. Some of these areas may be (visceral) sensation-specific, for example amygdala deactivation has been reported as an adaptive response to somatic pain before and the sacc is known to be involved in visceromotor responses. However, the complete pattern is strikingly consistent with attenuation of activity in the brain s default network induced by an attention-demanding stimulus. This had never been demonstrated for an interoceptive stimulus before [85]. Coen et al. recently studied the neural mechanisms underlying the effect of attention on esophageal sensation in male healthy volunteers using fmri. They found that the reduction in pain ratings during distraction from the esophageal stimulus were paralleled by a reduction in neural activity in the right midcingulate cortex (MCC) as well as the right dorsolateral and ventrolateral prefrontal cortex (DLPFC and VLPFC), but not in the primary or secondary somatosensory cortex (SI/SII) [86]. This is in line with a sensory-discriminative visceral pain-processing function for the somatosensory cortex, whereas the right MCC and prefrontal areas may serve as cognitive pain modulatory areas Irritable bowel syndrome Price et al. were the first to study the neural correlates of placebo analgesia in IBS. In their interesting fmri study, administration of rectal placebo jelly was found to be associated with significantly lower pain ratings during rectal distension compared to distension without placebo, at equal distending pressures. This was paralleled by significant attenuation in almost all regions of the visceral pain neuromatrix, including thalamus, SI/SII, insula and ACC, similar to the effect of lowering the stimulus intensity. These changes, however, also seemed to be partly due to non-placebo related processes such as habituation, especially in SI/SII [87]. Ringel et al. studied the effect of abuse history on brain activity in IBS and healthy controls, more specifically in cingulate subregions. In IBS patients and controls taken together, abuse history was associated with higher activation in MCC and posterior cingulate cortex (PCC) during rectal distension. Within the IBS group, an association was found between abuse history and higher pain reports as well as higher activation in the same areas, and lower activation in the sacc [88]. Three of the most interesting recent brain imaging papers on IBS have come from the UCLA group. In a first paper, they showed that IBS patients are more anxious than controls during certain expectation of rectal distension, this was associated with a lack of deactivation in key arousal network areas, most notably the dorsal brainstem including the noradrenergic locus coeruleus. Controls also showed deactivations in homeostatic-afferent processing network/visceral pain neuromatrix regions, contrary to IBS patients, but most of these differences did not reach significance in group comparison. Furthermore, deactivation in the dorsal brainstem found in IBS patients was found to correlate with activation in the pacc and VLPFC, key antinociceptive areas, during the actual rectal distension. These results suggest a key role for arousal/anticipation and their neural correlates in symptom generation in IBS [89]. In a second paper by the same group, Labus et al. used functional connectivity analysis on PET data to show that the brain areas activated during actual and anticipated rectal distension are organised in distinct though overlapping functional networks. The homeostatic-afferent network mainly consists of thalamus, MCC and insula, while the emotion-arousal network mainly includes pacc, sacc, amygdala and dorsal pons including the noradrenergic locus coeruleus. Although not formally tested in the article, the cortical-modulatory network is hypothesised to mainly consist of prefrontal and parietal regions. Moreover, this paper shows that sex-related differences in effective connectivity within these networks mainly exist in the emotion-arousal network and, to a lesser extent, the cortical-modulatory network, with stronger connections in women, especially during expectation. This indicates that differences in emotional-arousal driven cortical modulation of visceral sensory signals, rather than differences in afferent signalling or processing themselves, contribute sex-based differences in autonomic and behavioural responses to rectal distension in IBS [90]. A third innovative pilot study from UCLA investigated psychological and neural predictors of treatment response to the 5-HT 3 antagonist alosetron in IBS. Less distensioninduced activation of the bilateral orbitofrontal cortex as well as lower levels of interpersonal sensitivity at baseline predicted better response to alosetron. The effect of interpersonal sensitivity was shown to be mediated by OFC activity, which in turn correlated positively with amygdala activation [91]. In a somewhat overlooked short report in Neurology, Davis et al. described prominent cortical thinning (i.e. structural abnormalities) in IBS patients compared to controls. The abnormalities were located in the right perigenual (p)acc (BA 32) and bilateral insula as well as the anterior/medial thalamus, all key areas involved in pain, attention and homeostasis/interoception. Whether this may be predisposing to or caused by the disease remain to be elucidated [92] Functional dyspepsia The Leuven group was the first to study brain responses to gastric balloon distension in FD. The only study published until today showed a lack of activation in the pacc and insula in mostly hypersensitive FD patients [93].

5 L. Van Oudenhove, Q. Aziz / Digestive and Liver Disease 41 (2009) Treatment studies Treatments shown to be effective in mood and anxiety disorders, antidepressant drugs (AD) and psychotherapy, are also increasingly being used in the treatment of FGID. This may provide another source of evidence supporting a link between psychopathology and FGID. However, it remains largely unclear whether the mechanisms underlying the antidepressant or anxiolytic affect of AD are the same as those involved in their effect on GI symptoms [94]. AD may work in FGID through a peripheral effect on the serotonergic system in the ENS or through a central mechanism distinct from the antidepressant one, for example modulation of descending antinociceptive pathways Antidepressant drug treatment Two relatively recent systematic reviews of the topic show that results of trials have been heterogeneous, but generally suggest a rather modest advantage, if any, of AD over placebo. Abdominal pain/discomfort seems to be the symptom most reactive to AD treatment, with no sufficient evidence for an effect on global symptom ratings. Most of the trials included were of rather low quality and used tricyclic agents (TCA) rather than the newer selective serotonin reuptake inhibitors (SSRI), for which the evidence was inconclusive due to an insufficient number of trials [94,95]. A number of studies have been published since then and will briefly be reviewed below. A small, randomised, double-blind, placebo-controlled crossover study by the Leuven group showed a significant effect of the SSRI citalopram (20/40 mg) on global symptom ratings, abdominal pain, bloating and quality of life in IBS. This effect was independent of changes in anxiety, depression and somatisation scores [96]. A similar study design and small sample size was recently used by a Lebanese group to study the effect of the combination of flupentixol melitracen in pain predominant FD. This combination of a low-dose typical antipsychotic and tetracyclic antidepressant is fairly widely used for psychosomatic symptoms in some parts of Europe, although without much evidence. A significant improvement in subjective global symptom relief as well as Nepean Dyspepsia Index scores was found when compared to placebo [97]. Vahedi et al. studied the effect of low-dose amitriptyline (10 mg), a TCA, in 50 diarrheapredominant IBS patients. Amitriptyline is another widely used drug in the treatment of IBS, for which there was not much firm evidence. After 2 months treatment, significantly more patients in the active arm reported complete response; the number of symptoms, as well as the symptoms of loose stools and feeling of incomplete defecation were also significantly reduced [98]. Two negative studies have been published recently as well. Talley et al. found no advantage of 50 mg imipramine (TCA) or 40 mg citalopram (SSRI) over placebo on global IBS endpoints [99]. Van Kerkhoven et al. recently reported the results of a high quality randomised, double-blind, placebo-controlled study investigating the effects of the AD venlafaxine (2 weeks 75 mg, 4 weeks 150 mg, and 2 weeks 75 mg once daily) on FD symptoms in 160 patients [100]. Their main finding was the lack of difference between placebo and venlafaxine on several dyspepsia symptom outcome measures (complete remission percentage being the most important one), at any point during follow-up. The fact that (absence of) anxiety, rather than treatment, is an independent predictor of being symptom-free is another interesting finding, adding support to the hypothesis that anxiety plays a crucial role in FD. For further comment on this interesting study, see [101] Psychotherapeutic treatment Various forms of psychotherapy (mainly cognitive-behavioural therapy (CBT) as well as psychoanalytic interpersonal therapy) and, to a somewhat lesser extent, hypnotherapy, relaxation and biofeedback, have been shown to be effective treatments in IBS, reducing individual symptoms including abdominal pain as well as psychological distress, as shown in two fairly recent systematic reviews/meta-analyses [95,102]. Lackner et al., in their metaanalysis, found an odds ratio of 12 and a number needed to treat of 2, with efficacy defined as response (i.e. 50% reduction in symptoms) [102]. Two recent studies from the same group mainly confirmed efficacy for self-administered CBT [103], but not for group CBT in IBS [104]. Another study found CBT in addition to mebeverine to be cost-effective in IBS, but not beyond 3 months [105]. Cheng et al. confirmed efficacy of a new psychotherapy, flexible coping psychotherapy, specifically designed for enhancing coping flexibility of FD patients, in a randomised, controlled trial [106]. A 2007 Cochrane review concluded that the quality of the included trials was inadequate to allow any conclusion about the efficacy of hypnotherapy for IBS [107]. The positive results of a comprehensive program of relaxation training have already been discussed above [70]. Lackner et al. recently published an interesting study giving insight into the mechanisms by which CBT may work in IBS, indicating that CBT has a direct effect on global IBS symptom improvement independent of its effects on psychological distress [108] Combination treatment Haag et al. showed that in a refractory FD group, intensified medical therapy (including sensorimotor function testing and subsequent targeted pharmacotherapy) plus psychological therapy (relaxation or CBT) was superior to standard medical therapy on the long term (12 months), both in terms of FD symptoms and quality of life. Comorbid anxiety and depression only improved in the group with added CBT [109]. 6. Summary Progress is being made in elucidating the mechanism by which psychological processes and functional gastrointestinal disorder symptoms influence each other: Epidemiology shows a bidirectional comorbidity between mood and anxiety disorders on the one hand, and FGID on the other; high prevalence of sexual and physical abuse may play a role in this comorbidity. Patho- and psychophysiology establishes the link between psychological processes on the one hand and GI sensorimotor function and symptoms on the other, in patients with FGID; autonomic as well as psychoneuroendocrine and psychoneuroimmunological branches of the brain-gut axis may be the mediators of this link. Functional brain imaging in health and FGID show a tight interaction between the neural mechanisms underlying psychological processes and visceral sensation. Treatment studies show that several treatment modalities shown to be effective in mood and anxiety disorders, including antidepressant drugs and psychotherapy, may also be promising option in FGID; their exact mechanism of action, however, remains to be elucidated. Conflict of interest None declared.

6 786 L. Van Oudenhove, Q. Aziz / Digestive and Liver Disease 41 (2009) List of abbreviations FGID, functional gastrointestinal disorders; GI, gastrointestinal; IBS, Irritable Bowel Syndrome; CNS, central nervous system; FD, functional dyspepsia; OCD, obsessive-compulsive disorder; 5-HT, 5-hydroxytryptamine (serotonin); ANS, autonomic nervous system; EGG, electrogastrogram; HPA-axis, hypothalamo pituitary adrenal axis; CRF, corticotrophinreleasing factor; ACTH, adrenocorticotropic hormone; LPS, lipopolysaccharide; TNF, tumor necrosis factor; (s/p)acc, (sub/pregenual) anterior cingulate cortex; fmri, functional magnetic resonance imaging; MCC, midcingulate cortex; DL/VLPFC, dorso/ventrolateral prefrontal cortex; SI/SII, primary/secondary somatosensory cortex; PCC, posterior cingulate cortex; OFC, orbitofrontal cortex; AD, antidepressant drugs; ENS, enteric nervous system; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; CBT, cognitive-behavioural therapy. 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