irritable bowel syndrome ( ibs ) is a multifactorial disorder in which psychosocial aspects interact with altered functioning to cause a disorder with high clinical and societal impact . serotonin is an important neurotransmitter in both the brain and gastrointestinal tract , where it plays a key role in the regulation of sensory and motor functions . this is exemplified by the variation in the reuptake of serotonin through genetic variations in the uptake process . 5-ht transporter ( sert , also called slc6a4 ) is central to fine - tuning brain 5-ht neurotransmission and is abundant in cortical and limbic areas , thereby affecting emotional aspects of behavior , the occurrence of anxiety , and other psychiatric disease . variation in the promoter region upstream of the 5-ht coding sequence ( sert - p ) or promoter is manifest as long polymorphic region ( 5httlpr ) and short variants of the region impact the response to antidepressant treatment . in addition , 5-httlpr genotype ( s allele ) is associated with higher pain sensory ratings during rectal distension in health and ibs , and 5-httlpr ( s / s genotype ) activates greater regional cerebral blood flow in specific brain regions ( left anterior cingulate cortex and right parahippocampal gyrus ) in response to 040  mmhg colorectal distention in humans . serotonergic psychoactive agents are frequently used in treatment of patients with functional gastrointestinal disorders ( fgids ) . the central effects of these agents are well established ; however , there are also gastrointestinal effects of these agents . the objectives of this paper are to review the pharmacodynamic effects of these agents on gastrointestinal functions , and to examine how these effects might be reflected in results of randomized , controlled trials with these agents . patients must have had one or more of the following symptoms for the past 3  months , with symptom onset at least 6  months prior to diagnosis : postprandial fullness , early satiety , epigastric burning , as well as no evidence of structural disease that is likely to explain symptoms ( including any condition detected by upper endoscopy ) . this is further classified as:(a)postprandial distress syndrome(b)epigastric pain syndrome postprandial distress syndrome epigastric pain syndrome in general , the pathophysiology of functional dyspepsia involves psychosocial factors , altered motility ( including gastric emptying and accommodation ) and altered sensation ; a subset of patients reports a prior episode of gastroenteritis . among serotonergic psychoactive agents proposed for treatment of functional dyspepsia , buspirone , a 5-ht1a receptor agonist , enhanced gastric relaxation , and paroxetine , a selective serotonin reuptake inhibitor ( ssri , 30  mg paroxetine daily for 4  days ) , accelerated orocecal transit in 10 healthy controls and 8 ibs patients , but there was no effect on whole gut transit time [ 6 , 7 ] . there is a third class of combined serotonin and norepinephrine reuptake inhibitors ( snri ) , of which a prototype is venlafaxine . in a detailed study of upper gastrointestinal functions ( gastric emptying accommodation and satiation ) in healthy participants , the effects of a spectrum of serotonergic psychoactive agents administered ( at standard starting doses to treat anxiety and depression ) for 11  days showed that paroxetine , 20  mg per day , accelerated orocecal transit of a solid meal ; buspirone , 10  mg p.o . twice daily , decreased postprandial aggregate symptom and nausea scores after a fully satiating liquid nutrient meal ; and venlafaxine - xr , 75  mg per day , enhanced gastric accommodation measured by spect imaging , a validated method to measure gastric volume [ 9 , 10 ] . examined the effects of buspirone on gastric functions and postprandial symptoms in 17 patients with functional dyspepsia in a double - blind , placebo - controlled , randomized trial . the study showed reduction in fullness , bloating , belching , and nausea , as well as overall dyspepsia severity score , and this was associated with increased postprandial accommodation , but there were no significant effects on gastric emptying or sensation thresholds in response to balloon distension in the stomach . on the other hand , the effects of venlafaxine , 75150  mg , compared to placebo were tested in functional dyspepsia , but this treatment was associated with considerable drop - outs secondary to adverse events ( such as nausea , palpitations , sweating , sleeping disorders , dizziness , visual impairment ) , and no overall clinical efficacy was demonstrated during treatment or follow - up . the effects of the tricyclic antidepressant ( tca ) , amitriptyline , on postprandial symptoms were tested in healthy volunteers and in patients with functional dyspepsia . in healthy volunteers , amitriptyline retards gastric emptying and reduces postprandial ( caloric drink challenge ) symptoms , especially nausea . a single - center , parallel - group study showed amitriptyline ( 12.550  mg for 8  weeks ) , compared to placebo , did not affect drinking capacity and postprandial symptoms evoked by the drink test in 38 functional dyspepsia patients . however , during the entire treatment , nausea symptom score was significantly reduced by amitriptyline compared with placebo . results of an nih - funded multicenter study of clinical efficacy are awaited . meanwhile , a small study from japan compared amitriptyline to no treatment in patients with functional dyspepsia who were famotidine and mosapride non - responders . on the other hand , a large multicenter study of amitriptyline in children with diverse fgids showed no benefit of the tca over placebo . the rome iii diagnostic criteria for ibs   are as follows : recurrent abdominal pain or discomfort at least 3  days per month in the last 3  months associated with 2 or more of the following : improvement with defecationonset associated with a change in frequency of stoolonset associated with a change in form ( appearance ) of stool improvement with defecation onset associated with a change in frequency of stool onset associated with a change in form ( appearance ) of stool in general , the pathophysiology of ibs involves psychosocial factors , altered motor function ( including motility and transit ) , altered sensation , and altered host genetic and intraluminal factor interactions [ 19 , 20 ] . many patients report a prior episode of gastroenteritis . in a detailed study of lower gastrointestinal functions ( colonic motility , compliance and sensation ) in healthy participants , buspirone had virtually no effects , whereas venlafaxine increased compliance , relaxed tone , reduced postprandial colonic contraction , and tended to increase thresholds for sensation of first perception and gas , while it also reduced pain sensation ratings in response to grades distensions . the main effect of the ssri , fluoxetine ( 20  mg a day for 6  weeks ) , was to reduce pain scores , especially in non - depressed ibs patients who were hypersensitive at baseline before drug administration , but no differences were seen in rectal sensation in the overall group . acute citalopram infusion increased colonic contractility , including induction of high amplitude propagated contractions , reduced colonic tone during fasting , as well as reduced the increase in tone after meal ingestion . while citalopram increased colonic compliance , it had no significant effect on sensation . in a separate , small cross - over , randomized , controlled trial of 23 patients with ibs , on the other hand , in a slightly smaller study , talley et al .   showed no benefit with citalopram on global ibs endpoints over placebo . in a large , multicenter , parallel- group , randomized , controlled trial , both paroxetine and psychotherapy improved health - related quality of life in severe ibs without any additional costs . in another placebo controlled trial of ibs patients , refractory to high - fiber diet , paroxetine improved overall well - being , but no improvement was seen in abdominal pain , bloating , or social functioning . another small study examining effects of fluoxetine in rome ii ibs - c patients showed decrease in abdominal discomfort , bloating , and improvements in stool frequency and consistency . no study has examined the efficacy of mirtazapine in symptoms or sensorimotor function in ibs . an interesting animal study highlights difficulty in correlating antinociceptive effects of drugs with different antidepressant classes across a range of neuropathic pain models , and suggests that antidepressants with both noradrenaline and 5-ht action might have more potent antinociceptive effects than ssris . the american college of gastroenterology task force report of 2009 suggested there are several effective treatments for ibs , such as fiber , peppermint oil , antidepressants , probiotics , and antispasmodics / smooth muscle relaxants . indeed , the estimated number needed to treat was as low as 4 for many classes of treatment , including antidepressants . there is always concern when meta - analyses include trials with different designs , different doses , diverse mechanisms , and small trials to reach conclusions that are often proposed in societal guidelines . it is wise to follow the counsel that meta - analyses should only be used for hypothesis generation . moreover , when multiple treatment comparison meta - analyses use indirect evidence from randomized controlled trials to compare the relative effectiveness of all included interventions , they are particularly vulnerable to potential biases that can affect the interpretation of these analyses . in fact , several systematic analyses have been published and reach different conclusions , and it is not surprising when one considers the different data sets that are included within each meta - analysis , whether they are commissioned by national societies , individual research groups , or the cochrane systematic reviews . three specific studies included in many of these meta - analyses illustrate the dangers of these analyses based on the unrepresentative nature of the results , or the use of secondary endpoints in individual trials that are used in drawing conclusions of class effects when the primary endpoints are not significant . for example , in a trial of fluoxetine ( an ssri ) in constipation - predominant ibs , there was an unrepresentative 10  % placebo response for discomfort and bloating , and , in a trial of 50 patients with diarrhea - predominant ibs , amitriptyline , 10  mg , was uncharacteristically efficacious , since 68  % of patients receiving this relatively low dose of amitriptyline showed complete response defined as loss of all symptoms , compared with only 28  % of those receiving placebo . in a third study of flexible dose of paroxetine , there was no significant difference in the primary endpoint , that is , the reduction of composite pain scores . on the other hand , meta - analyses often include the significant effects on clinical global impression scores to illustrate efficacy relative to placebo . for example , one meta - analysis   involved 13 studies that compared antidepressants to placebo for treatment of ibs with a total of 789 patients , 432 active therapy and 357 placebo . several analyses showed heterogeneity and even publication bias with funnel plot asymmetry , thus raising important flags that it is essential to cautiously interpret the results of meta - analyses . regrettably , there are few trials involving patients with ibs who were concomitantly suffering affective disorders . in those settings , in the systematic review of antidepressant agents in patients with ibs and comorbid depression , there were 4 studies of ssris , 4 of tcas , 1 of ssri vs. tca , and 1 of a serotonin  norepinephrine reuptake inhibitor ( duloxetine ) . it is important to note that most studies excluded patients with diagnosed depression and/or anxiety , and that none of the controlled studies used the primary outcome of assessment of the symptoms of manic - depressive disorder in the ibs patients . the two ssri studies ( citalopram and paroxetine ) reported a statistically significant , ~50  % , improvement in ibs symptoms [ 24 , 27 ] . paroxetine also provided an ~30  % improvement in scores on beck depression inventory ( also statistically significant ) . of two studies of fluoxetine , one ( reviewed above ) showed benefit on ibs symptoms , though the 10  % response to placebo for both pain and bloating seems uncharacteristically low . in addition , one of the tca studies found a significant improvement in depressive symptoms with desipramine , 150  mg / day , ( p  =  0.025 ) . in conclusion , the effects of antidepressants on the gastrointestinal tract may contribute to their potential efficacy in functional dyspepsia and ibs ; buspirone appears efficacious in functional dyspepsia . the recommendations of efficacy and number needed to treat from meta - analyses are suspect , and more prospective trials are needed . additionally , novel mechanisms such as effects on gut permeability and immune dysregulation in ibs need to be explored .
the effects of antidepressants on the gastrointestinal tract may contribute to their potential efficacy in functional dyspepsia and irritable bowel syndrome ; buspirone , a prototype 5-ht1a agonist , enhances gastric accommodation and reduces postprandial symptoms in response to a challenge meal . 
 paroxetine , a selective serotonin reuptake inhibitor , accelerates small bowel but not colonic transit , and this property may not be relevant to improve gut function in functional gastrointestinal disorders . 
 venlafaxine , a prototype serotonin norepinephrine reuptake inhibitor , enhances gastric accommodation , increases colonic compliance and reduces sensations to distension ; however , it is associated with adverse effects that reduce its applicability in treatment of functional gastrointestinal disorders . 
 tricyclic antidepressants reduce sensations in response to food , including nausea , and delay gastric emptying , especially in females . 
 buspirone appears efficacious in functional dyspepsia ; amitriptyline was not efficacious in a large trial of children with functional gastrointestinal disorders . 
 clinical trials of antidepressants for treatment of irritable bowel syndrome are generally small . 
 the recommendations of efficacy and number needed to treat from meta - analyses are suspect , and more prospective trials are needed in patients without diagnosed psychiatric diseases . 
 antidepressants appear to be more effective in the treatment of patients with anxiety or depression , but larger prospective trials assessing both clinical and pharmacodynamic effects on gut sensorimotor function are needed .