R E Clouse, P J Lustman

Transcription

1 1332 Reent advanes in linial pratie USE OF PSYCHOPHARMACOLOGICAL AGENTS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS See end of artile for authors affiliations Correspondene to: Professor R E Clouse, Division of Gastroenterology, Washington University Shool of Mediine, 660 South Eulid Ave, Campus Box 8124, St Louis, MO 63110, USA; rlouse@im.wustl.edu R E Clouse, P J Lustman Gut 2005; 54: doi: /gut INTRODUCTION In 1990 we asked liniians attending a symposium during the annual meeting of the Amerian Gastroenterologial Assoiation how many were using psyhopharmaologial agents, speifially antidepressants, to treat funtional gastrointestinal disorders. 1 Very few raised their hands. Over the subsequent 15 years, these agents inreasingly have beome used in the management of funtional gastrointestinal symptoms, despite a limited amount of sientifi information supporting this pratie. It is now estimated that at least 1 in 8 patients with irritable bowel syndrome (IBS) is offered an antidepressant. 2 3 Nearly every omprehensive urrent review of management strategies for IBS and other mainstream funtional gastrointestinal disorders mentions their use, and presribing among gastroenterologists has beome ommonplae In parallel with this hange, primary are physiians have beome suffiiently omfortable in using antidepressants for treating not only anxiety and depression but also a host of somati symptoms and syndromes that their use has nearly tripled in the past deade. 11 Enhaned appreiation for the relative importane of entral mehanisms (for example, signal proessing alterations) in many if not most patients with IBS and other painful funtional gastrointestinal disorders is an important fator responsible for presribing shifts among gastroenterologists more so than a new or improved understanding of the relationship of symptoms to anxiety or depression. 8 The omposite body of investigation over the past 15 years involving viseral stimulation, brain imaging, multidimensional linial studies, and treatment trials designed to answer mehanisti questions has led us loser to understanding the pathways by whih psyhopharmaologial agents may interrupt the symptomati proess in these ommon gastrointestinal disorders. Complemented by linial observations, improved reommendations for their use have evolved This review desribes the types of psyhopharmaologial agents used in funtional gastrointestinal disorders, new models for their potential benefits, a summary of the reported effiay, and pratial aspets surrounding treatment. The majority of the available information has been arued in patients with IBS, although findings are similar when other pain or disomfort based funtional gastrointestinal disorders have been studied. BACKGROUND Reounting observations instigating use of psyhopharmaologial agents in funtional gastrointestinal disorders remains a useful exerise beause their mehanism of effet remains unlear. The most onspiuous explanation for experimentation has been the high rate of psyhiatri illness in patients with these gastrointestinal disorders. Interview methods demonstrate that nearly 70% of patients seeking are at seondary or tertiary loations meet diagnosti riteria for a psyhiatri disorder, partiularly anxiety states and major depression. 14 These early observations have not hanged in reent years. However, approximately one third of subjets onspiuously do not meet riteria, and response to psyhopharmaologial agents, partiularly antidepressants, is neither prediated on the presene of an anxiety or depressive disorder nor onsistently dependent on the intended psyhiatri effets of the mediations. Suh findings indiate that the relevane of psyhiatri omorbidity is in its refletion of another underlying disorder or phenomenon that is responsive to psyhopharmaologial intervention. In this regard, several other observations have supported the use of psyhopharmaologial treatments (table 1), although none stands out as providing a singular dominant rationale for their need. Reent advanes have foused on the high degree of omorbidity with psyhiatri disorders and non-gastrointestinal funtional somati syndromes in larifying the role of psyhopharmaologial agents. 16 Although gastroenterologists have been slow to embrae the onept that funtional gastrointestinal disorders may be but one omponent of a broader polysymptomati proess with a unifying underlying mehanism, two lines of thought are developing that expand

2 Table 1 Observations supporting the testing of psyhopharmaologial agents for funtional gastrointestinal disorders High lifetime and urrent rates of anxiety disorders and depression High self reported distress Inreased sexual and physial abuse histories Response of other funtional syndromes to antidepressants Response of neuropathi pain syndromes to antidepressants the psyhopharmaologial rationale. One inorporates the prevalent omorbidity of medially unexplained somati syndromes with the funtional gastrointestinal disorders under the umbrella of somatisation This onstrut hypothesises that a entral neurophysiologial proess, separate from anxiety and depression, promotes distorted afferent signal proessing, reporting of various distint funtional syndromes, and endorsement of many medially unexplained symptoms aross multiple organ systems on symptom heklists. In support of this, high rates of somatisation disorder, an extreme example of somatisation defined by DSM-IV riteria, were deteted reently in two studies of female IBS patients seeking are at a university lini The rates (30 42% of patients meeting or nearly meeting riteria) were substantially higher than reported previously beause physiian interviewers and arefully exeuted hart review were used for establishing the diagnosis. Likewise, somatisation tendeny, as measured by somati symptom ratings on self report measures, is prevalent among patients with funtional gastrointestinal disorders and has proved to be an important independent preditor of a variety of linial and experimental harateristis assoiated with them, inluding sensitivity to balloon distension in the gut, linkage of abuse history to subsequent funtional gastrointestinal and nongastrointestinal symptoms, and likelihood of lingering IBS symptoms following gut infetion. The relevane of these observations to the average patient is highlighted by the remarkably high prevalene rates of multiple gastrointestinal and non-gastrointestinal funtional syndromes in patients with funtional gastrointestinal disorders. A minority of patients has a single funtional gastrointestinal disorder with no assoiated omorbidity. Another reent observation demonstrates that the exess anxiety and affetive disorders previously assoiated with IBS also segregate predominantly to the subgroup showing high degrees of somatisation. 17 Thus this group of self report based syndromes may be refletive of an underlying symptom reporting tendeny, being psyhoform rather than preisely representing the primary psyhiatri disorders. These intriguing possibilities may provide support for the modest dosages of psyhopharmaologial agents ommonly employed for funtional gastrointestinal disorders, as the response may differ ompared with management of primary affetive or anxiety disorders enountered in psyhiatri praties. 28 Management of somatisation, therefore, may represent another rationale for the use of psyhopharmaologial agents. Determining its importane to the individual patient with a funtional gastrointestinal disorder is an area of flourishing investigation. A seond line of thought links speifi medial and psyhiatri syndromes, inluding IBS, fibromyalgia, and New observations Psyhopharmaologial agents, partiularly antidepressants, ommonly are used today for patients with funtional gastrointestinal disorders Central nervous system neurophysiologial proesses, suh as somatisation, help explain the high prevalene of omorbid funtional somati syndromes and psyhiatri illnesses with funtional gastrointestinal disorders Suh entral proesses partiipate in global distress and morbidity assoiated with funtional gastrointestinal disorders and are responsive to psyhopharmaologial treatment Psyhopharmaologial agents have greater effet on global measures than speifi gastrointestinal symptoms migraine, as representing affetive spetrum disorders. 29 The disorders are not thought to be manifestations of depression; the term is meant to imply their responsiveness to antidepressant therapy or possibly their representation of a unique type of affetive disorder with heritable harateristis Again, a unifying entral neurophysiologial proess is speulated, a proess that differs potentially from somatisation and segregates this luster from somatisation disorder. Both lines of thought have merit in expanding previously narrow vistas of the rationale for psyhopharmaologial agents in funtional gastrointestinal disorders. Although treatment is seleted today using onventional linial indiators, inluding refratoriness of symptoms, severity of manifestations, and risk-benefit ratios, it seems likely that better haraterisation of the funtional gastrointestinal disorder patient within broader onstruts refleting ativity of these suspeted entral mehanisms will refine management algorithms. Funtional brain imaging eventually may omplement linial indiators (suh as medial histories of other funtional syndromes or self report symptom heklists) in further improving the identifiation of subjets most likely to benefit from psyhopharmaologial interventions. At a minimum, investigative use of these tehniques may refine the linially based seletion proess. Finally, better stratifiation of patients based on the extent and type of omorbidities may improve seletion of existing psyhopharmaologial agents as well as assist in the development of new mediations speifially direted at entral mehanisms behind funtional symptoms rather than being targeted primarily at anxiety and depression. PSYCHOPHARMACOLOGICAL AGENTS USED FOR FUNCTIONAL GASTROINTESTINAL DISORDERS As a result of the above observations and their pereived utility in linial pratie, anxiolytis and antidepressants are the psyhopharmaologial agents most ommonly used for funtional gastrointestinal disorders. Early reports desribed some suess with phenothiazines and related antipsyhoti agents Benefits were not related onspiuously to antipsyhoti effets of the drugs, side effets from long term use appeared unwarranted, and suh agents are no longer reommended. Contemporary antipsyhoti agents have not been tested. Anxiolytis, inluding benzodiazepines and buspirone, have also been used both for their anxiolyti properties and for effets that may be targeted more speifially at funtional gastrointestinal symptoms Clinial experiene suggests that benzodiazepines share many benefits observed from antidepressants but their 1333

3 Table 2 Common antidepressants and usual psyhiatri dosages Class Agent Proposed antidepressant mehanism Usual daily dosage (mg)* 1334 TCAs Tertiary amine Amitriptyline NE and 5-HT reuptake inhibition Imipramine NE and 5-HT reuptake inhibition Doxepin NE and 5-HT reuptake inhibition Trimipramine NE and 5-HT reuptake inhibition Clomipramine Mixed ation Seondary amine Nortriptyline NE reuptake inhibition Desipramine NE reuptake inhibition SSRIs Citalopram 5-HT reuptake inhibition Esitalopram 5-HT reuptake inhibition Fluoxetine 5-HT reuptake inhibition Paroxetine 5-HT reuptake inhibition Sertraline 5-HT reuptake inhibition Other newer antidepressants Bupropion Dopamine reuptake inhibition Duloxetine NE and 5-HT reuptake inhibition Nefazodone Pre- and postsynapti ativity Mirtazapine Pre- and postsynapti ativity Trazodone Mixed ation Venlafaxine NE and 5-HT reuptake inhibition TCAs, triyli antidepressants; SSRIs, seletive serotonin reuptake inhibitors; NE, norepinephrine; 5-HT, 5-hydroxytryptamine. *Dosage ranges for adults in good health not taking onfounding mediations; geriatri dosages may be required. Adapted from Rush AJ. Mood disorders: treatment of depression. In: Sadok BJ, Sadok VA. Kaplan and Sadok s omprehensive textbook of psyhiatry, 8th edn. Philadelphia: Lippinott Williams and Wilkins, 2005: pharmaokinetis and potential for dependeny make them undesirable but for short term symptom management. By far the greatest reported experiene has been with antidepressants, espeially the triyli antidepressants (TCAs) (table 2). 36 TCAs have broad effets on neurotransmitter physiology, a feature that potentially explains their non-antidepressant benefit in funtional gastrointestinal disorders as well as their expanded side effet profile. Diret omparisons of TCAs in managing funtional gastrointestinal symptoms are laking, and no agent appears onspiuously superior to another in open label observation. 28 More reent studies report outomes from seletive serotonin reuptake inhibitors (SSRIs) in funtional gastrointestinal syndromes Although one approah had been to reserve SSRIs for TCA failures, for patients with suspeted primary anxiety or affetive disorders that might be influening symptom presentation, or for patients with anxiety or depression symptoms that persist despite improvement in funtional gastrointestinal symptoms with TCAs, the agents are being used inreasingly for the initial antidepressant trial in suitable andidates Antidepressants that more losely share the neurotransmitter effets of TCAs and their analgesi effets, suh as duloxetine, are also being examined for their benefits in funtional gastrointestinal symptoms, and other newer antidepressants are being employed anedotally (table 2). Aeptability of antidepressants varies onsiderably from patient to patient when they are used for psyhiatri purposes, and the same holds true when they are presribed for funtional gastrointestinal disorders. Consequently, liniians are advised to familiarise themselves with several TCAs and non-tca antidepressants. Knowledge of reommended dosage ranges for managing psyhiatri disorders is important (table 2). Reahing this target is advised when the goal is management of a omorbid anxiety or depressive disorder; a low dose regimen initially employed for managing funtional gastrointestinal symptoms should be esalated to this therapeuti range in the unresponsive patient. Given the urrent limitations in understanding the pathogeneti mehanisms behind funtional gastrointestinal symptoms and the non-systemati often empirial use of psyhopharmaologial agents in symptom management, seletion of the speifi mediation is a rude proess. Interation of the side effet profile with presenting gastrointestinal symptoms often ditates the initial hoie. For example, TCAs with dominant antiholinergi properties may seem better hosen for IBS patients denying onstipation predominant patterns. 6 Suh onerns are not substantiated fully in linial pratie, and fears that side effets of psyhopharmaologial agents will exaerbate dysmotility symptoms may be overrated Instability in motility features, suh as bowel habit subtype within IBS populations, is partly responsible for this observation. 43 The bulk of additional information on psyhopharmaologial agents in funtional gastrointestinal disorders is related to antidepressants. Consequently, the remainder of this review will fous on antidepressant mehanisms, antidepressant effiay, and pratial aspets of antidepressant use in funtional gastrointestinal disorders. POTENTIAL BENEFITS OF ANTIDEPRESSANTS IN FUNCTIONAL GASTROINTESTINAL DISORDERS Antidepressants have a spetrum of ations that potentially ould help patients with funtional gastrointestinal disorders (table 3). Effets on gut motility, inluding transit, are Table 3 Antidepressant ations that ould influene symptom reporting in funtional gastrointestinal disorders Central ations Depression remission Anxiolysis Generalised effet on unexplained symptom reporting (antisomatisation effet) Sleep restoration Analgesia Modulation of viseral pain pereption (inonsistent findings) Peripheral ations Antiholinergi effets Altered gastrointestinal transit Gastri fundi relaxation Peripheral analgesi effet

4 probably of seondary importane in many patients, onsidering that most patients who are andidates for antidepressants already have failed onventional treatments Although reognised for their analgesia in management of neuropathi pain, impressive effets of antidepressants on viseral hypersensitivity have not been demonstrated Meta-analyses and systemati reviews identify both global improvement and pain redution as potential benefits of antidepressants in IBS and other funtional gastrointestinal disorders However, a reent well designed trial of desipramine in women with painful funtional bowel disorders found that treatment satisfation realised by TCA treatment was not related signifiantly to a redution in pain ratings. 41 Similarly, longitudinal evaluation of paroxetine (an SSRI) in IBS demonstrated improved funtional outomes, yet no distint advantage of the antidepressant in pain relief. 37 These findings were orroborated in a subsequent double blind plaebo ontrolled trial of paroxetine in IBS patients who failed to respond to fibre supplementation alone. 38 The fat that antidepressants are more onsistent in improving global measures than speifi gastrointestinal symptoms has raised some onerns. 2 Do antidepressants provide purely a band-aid approah to management or are mehanisms of ation more diretly targeted at the underlying pathophysiology? A reent advane towards understanding fators responsible for global well being in various A B GI symptoms Other fators GI symptoms? Other fators Global distress Global distress Primary effet Seondary effet Antidepressant ation Figure 1 New paradigms for understanding global impairment in funtional gastrointestinal disorders and the potential effets of antidepressants. Fators other than gastrointestinal (GI) symptoms alone (for example, somatisation, other underlying neurophysiologial mehanisms) may (A) oexist with funtional gastrointestinal disorders or (B) underlie the presentation of funtional gastrointestinal symptoms and have important independent effets on global well being. Antidepressants ould blok the independent effets of other fators on global well being or influene both the manifestation of funtional gastrointestinal symptoms (for example, pain) and global well being through somewhat separate mehanisms. (Dual ations may be more representative of triyli antidepressants than seletive serotonin reuptake inhibitors.) The effet of antidepressants on global well being is not mediated through an ation on gastrointestinal symptoms alone. gastrointestinal disorders addresses this point. Preliminary data from patients with funtional and non-funtional gastrointestinal disorders attending a university based lini revealed disrepanies in the ontribution of priniple gastrointestinal symptoms towards global well being. 52 In patients with non-funtional disorders, priniple gastrointestinal symptoms were strong preditors of pretreatment global well being, and symptom hanges with treatment orrelated well with hanges in global measures. In ontrast, priniple gastrointestinal symptoms in patients with funtional gastrointestinal disorders were poor preditors of global well being at baseline, and hanges in their ratings were only weak preditors of hanges in well being following treatment with TCAs. Drossman et al also found that treatment indued hanges in abdominal pain in patients with painful funtional bowel disorders did not ontribute signifiantly to treatment satisfation. 41 Most reently, Spiegel et al showed that non-gastrointestinal symptoms rather than traditionally eliited gastrointestinal symptoms were the strongest preditors of health related quality of life in patients with IBS. 53 These authors disouraged a fous on physiologial features suh as stool harateristis and subtypes of IBS in favour of gauging global symptom severity in planning management. Consequently, antidepressants may address mehanisms more speifially related to global distress than to orretion of gut physiologial abnormalities or individual gastrointestinal omplaints, mehanisms presumably of more importane in funtional gastrointestinal disorders than has been appreiated (fig 1). The relevane of this lies in the fat that morbidity assoiated with funtional gastrointestinal disorders is linked to soial impairment, work absenteeism, and other funtional limitations morbidity often resulting from the degree of global distress. Although gut events (for example, infetion, inflammation, noxious stimuli) presumably are responsible for the initiation and possibly perpetuation of the syndromes, they beome overshadowed by antidepressant responsive features in many subjets. EFFICACY OF ANTIDEPRESSANTS IN FUNCTIONAL GASTROINTESTINAL DISORDERS A small number of plaebo ontrolled antidepressant trials has been reported One limiting fator restriting the body of information has been the lak of pharmaeutial industry support for large sale or multientre investigations. Metaanalyses of existing trials aknowledge the limited quality of many investigations. Three separate meta-analyses, either restrited to IBS or enompassing all funtional gastrointestinal disorders, onluded that antidepressants demonstrate Reent treatment advanes Suess with antidepressants is best measured in terms of global well being, improved quality of life, and treatment satisfation. Ative depression symptoms interfere with outome, represent either primary psyhiatri omorbidity or neurophysiologial proesses underlying funtional gastrointestinal disorders, and may need speifi attention. Many antidepressant side effets reflet these same symptom promoting mehanisms and an be attenuated with low initial dosages and slow inrementation, espeially in patients with prominent features of somatisation. 1335

5 Study (1 author) (QS) Treatment (n/n) Control (n/n) Peto OR (95% Cl random) 1336 Trimipramine Myren 1982 Myren 1984 Tripathi Subtotal (95% CI) Amitryptyline Mertz Rajagopalan Steinhart (3) (4) (3) (3) (2) (3) Subtotal (95% CI) Subtotal high quality studies (95% CI) Desipramine Drossman Grenbaum Heffner Subtotal (95% CI) (5) (2) (2) 21/31 273/329 7/25 301/385 5/7 7/11 11/14 23/32 25/30 48/71 4/25 77/126 2/7 3/11 5/14 10/32 16/21 7/21 64/107 15/22 12/14 91/143 27/57 5/24 10/17 42/98 Subtotal high quality studies (95% CI) 61/107 7/21 Mianserin Tanum (3) 18/25 2/22 Doxepin Vlj (2) 11/21 5/23 Fluoxetine Kuiken (4) 10/19 9/21 Total (95% CI) 454/ /322 Subtotal high quality studies (95% CI) 391/ /225 effiay on at least one outome measure, typially a global rating or pain. The most reent meta-analysis by Lesbros-Pantoflikova et al found a signifiant effet of antidepressants in IBS on overall improvement, with an odds ratio of 2.6 (onfidene interval (CI) ). 50 When the analysis was restrited to higher quality studies, the odds ratio was 1.9 (CI ) in favour of antidepressants (fig 2). Odds ratios are greater for antidepressants when other funtional gastrointestinal disorders are inluded in the evaluation but many of these additional studies are of low quality. 49 The number needed to treat (NNT) estimate for antidepressant effiay in funtional gastrointestinal disorders has been as low as 3.2; as many as 80% of IBS patients appear to have moderate or greater physiian rated benefits in open label linial pratie, and adherene to antidepressants is higher than for other treatments Although umulative findings from mixed quality trials, meta-analyses, and linial experiene almost uniformly support the value of antidepressants, important reent advanes ome from examining a well onstruted two entre trial of the TCA desipramine in women with painful funtional bowel disorders. 41 The large number of partiipants had riteria defined IBS or funtional abdominal pain ( ) 4.8 ( ) 5.2 ( ) 2.4 ( ) 1.7 ( ) 15.4 ( ) 3.7 ( ) 1.4 ( ) 2.6 ( ) 1.9 ( ) Figure 2 Effets of antidepressants on global improvement in patients with irritable bowel syndrome (IBS). Odds ratio (OR) and assoiated 95% onfidene interval (CI ) for eah study are plotted on a logarithmi sale. Box sizes are proportional to the study s weight in the analysis, based on study size and variane. Diamonds represents the point estimate and 95% CI for the pooled data. Open boxes represent low quality studies (quality sore,3); losed boxes represent high quality studies (quality sore.3). Open diamonds represent the point estimate of all studies (high and low quality); losed diamonds represent the point estimate of high quality studies only. Quality sore (QS): double blind study (yes 1, no 0); suffiient number of subjets (yes 1, no 0); rossover (0) or parallel design (1); adequate definition of IBS symptoms (yes 1, no 0); presene (1) or absene (0) of intention to treat analysis. Modified from Lesbros-Pantoflikova and olleagues. 50 Citations for the individual studies listed in the figure are provided in the original report. 50 syndrome and were offered up to 150 mg desipramine per day in a plaebo ontrolled study. In the intention to treat analysis, desipramine was not signifiantly superior to plaebo, although there was a 13% margin in treatment satisfation (p = 0.13). Inlusion of patients with funtional abdominal pain syndrome, a rare and more refratory funtional gastrointestinal disorder, may have attenuated the response to the TCA. Of note, 28% of subjets in the desipramine arm failed to omplete the trial, most ommonly beause of side effets. An additional 12% of subjets had undetetable blood levels of desipramine, suggesting that they did not take the mediation. When a post ho analysis was performed in subjets who atually adhered to the study protool, the agent was indeed effetive with a 24% margin over plaebo (p,0.01). This study demonstrates the limitations imposed by side effets and possibly the stigmata assoiated with the use of psyhopharmaologial agents for somati symptoms. It undersores the importane of a preemptive plan towards side effet redution and eduation regarding use of antidepressants for their ability to reverse global impairments assoiated with funtional gastrointestinal disorders independent of traditional psyhiatri effets (anxiolyti, antidepressant). 42

6 Funtional GI disorder diagnosis Yes Initiate very low dose TCA regimen Consider nonpharmaologial therapy for intolerane or poor response Initiate ontemporary antidepressant at usual dose Monitor symptom response and add low dose TCA for persistent GI symptoms* Moderate to severe or refratory symptoms High degree of somatisation suspeted? Ative anxiety or affetive disorder present or No Initiate low dose TCA regimen Monitor symptom response and add ontemporary antidepressant for persistent psyhiatri symptoms No evidene for ative anxiety or affetive disorder Initiate low dose TCA regimen Figure 3 An algorithm for the appropriate initiation of antidepressants in seleted patients with funtional gastrointestinal disorders. High degrees of somatisation an be deteted by patient endorsement of many symptoms on a review of systems heklist or from features of somatisation disorder in the medial history. Contemporary antidepressants inlude the seletive serotonin reuptake inhibitors (SSRIs). *Monitoring for toxiity with triyli antidepressant (TCA) levels is required if the TCA is used in onjuntion with mediations that interfere with normal ytohrome p450 ativity, suh as SSRIs. Modified from Clouse. 12 Patient harateristis that indiate a high degree of somatisation History of multiple funtional disorders and drug sensitivities. Positive response to at least seven symptoms on a 15 item sreening tool for somatisation (find this tool at psy.psyhiatryonline.org/gi/ontent/full/39/3/263).* Features of somatisation disorder (ompliated medial history beginning before the age of 30; history of pain related to at least four sites or funtions; two gastrointestinal symptoms; one sexual symptom; and one symptom suggestive of a neurologial ondition, none of whih are feigned or an be explained adequately by the medial evaluation).à Endorsement of many symptoms on a review of systems heklist (.15 on a omprehensive heklist exeeds the mean for funtional gastrointestinal patients and has a high speifiity for a funtional diagnosis).` *Kruenke K, Spitzer RL, degruy FV III, et al. A symptom heklist to sreen for somatoform disorders in primary are. Psyhosomatis 1998;39: ÀPseudoneurologial symptoms inlude paralysis, loss of oordination, imbalane, loalised weakness, et. Amerian Psyhiatri Assoiation. 20 `See Brown and olleagues. 22 INITIATING ANTIDEPRESSANT THERAPY Antidepressants are indiated for patients who meet riteria for a funtional gastrointestinal disorder and who fail onventional low risk interventions, inluding reassurane and pharmaologial and non-pharmaologial therapies (for example, diet, fibre) direted at speifi gut symptoms. 6 Suffiient interferene with global well being and funtional apaity is also expeted suh that the risk/benefit ratio is aeptable. The liniian should feel onfident in offering an antidepressant in this situation. Although andidate seletion is not prediated on the presene or absene of anxiety or depression, the initiation protool an be affeted by the degree of omorbidity and omplexity of funtional omplaints expressed by the patient (that is, the degree of suspeted somatisation) (fig 3). Patients with high degrees of somatisation by linial evaluation tolerate mediation side effets poorly, and the effetiveness of the intervention ultimately is impaired. 17 Beause there is some evidene that unexplained somati omplaints, even in patients with high degrees of somatisation, will respond to antidepressants, an initial trial is warranted. 54 However, the trial should begin with a very low dose of the antidepressant (for example, 10 mg/day of a TCA) and dose esalation should be slow. A systemati review found that TCAs are more suessful than SSRIs aross the 1337

7 1338 spetrum of unexplained somati symptoms and syndromes, further supporting the initial trial with a TCA even in this situation. 55 They also have an analgesi advantage that may have value A moderately low daily dose of a TCA (25 50 mg per day) is the reasonable initiation step for patients in whom lower degrees of somatisation are evident. This approah is partiularly warranted in subjets without any onspiuous symptoms of an ative anxiety or depressive disorder. The hoie of initial antidepressant in the subset of patients exhibiting signifiant anxiety and depression symptoms remains debated. Beause these symptoms may represent further manifestations of the neurophysiology behind funtional gastrointestinal symptoms, as mentioned above, an initial trial with a TCA at low daily dosage (for example, esalated to mg/day) is not unreasonable, as long as monitoring of psyhiatri symptoms is inluded in the management plan. Alternatively, an SSRI or other ontemporary antidepressant may be initiated primarily and outome on the funtional gastrointestinal symptoms monitored (fig 3). An important linial error is failure to esalate antidepressant dosages when patients respond inadequately to the initial intervention. Consensus reommendations for inreasing dosages are unavailable, but most suggest TCA inrements by mg/day at 5 7 day intervals. Patients who tolerate the mediations yet see limited initial benefits should be instruted to ontinue inrementing the dosage well into the psyhiatri dosing range (table 2) before delaring the trial a failure. In most instanes, SSRIs and other ontemporary antidepressants are presribed aording to reommended psyhiatri starting dosages from the outset, but daily dosages of these agents should also be esalated appropriately in non-responders. Unsatisfatory response after four weeks at the full psyhiatri or maximum tolerated dose indiates a hange in mediation or approah. FACTORS AFFECTING OUTCOME Patients resisting psyhopharmaologial therapy, those who fail to take the presribed mediations, and subjets with intolerable side effets obviously do poorly. Aeptane is enhaned by eduating the patient of potential side effets of antidepressants and aknowledging that their primary benefits often are independent of anxiolyti or antidepressant effets of the drugs. Offering plausible mehanisti explanations to the patient in the presene of a relative or signifiant other may also enhane treatment adherene. This tehnique an avoid unfounded assumptions when dialogues ontinue beyond the offie visit that the physiian simply suspets anxiety or depression. Comparing antidepressants with other mediations that have benefits extending beyond their original indiations an be helpful (for example, to aspirin when used for heart disease versus fever or arthritis), although most patients today are familiar with off label presribing. Despite the long list of potential adverse effets from antidepressants, a high level of dislosure is reommended. Trust in the presribing physiian will inrease, and the patient will be in a better position to ompare advantages and disadvantages of therapy at follow up visits. Who has a good outome from antidepressants? This is not predited easily from linial harateristis, and presently no biologial marker is used for seleting optimal andidates. With IBS patients, pain or diarrhoea predominane may predit a better response to TCAs ompared with a onstipation predominant pattern Disriminating harateristis in other funtional gastrointestinal disorders have not been identified. One might predit that subjets with more diffuse funtional symptom presentations (that is, those with higher degrees of somatisation) might be better andidates beause a greater entral ontribution to global impairment is suspeted. Contrast this with the patient with little omorbidity and presumably a simpler form of gastrointestinal disorder. 17 However, patients with higher degrees of somatisation are more sensitive to mediation side effets, diminishing the effiay of the intervention. Consequently, the good responder typially an only be identified post ho following the therapeuti trial. Little information is available regarding the long term outome in patients with funtional gastrointestinal disorders who initially are managed suessfully with antidepressants. In open label TCA treatment of patients with funtional hest pain who were unresponsive to antireflux therapy, 81% had at least a moderate initial response to a TCA. 58 Of these, more than two thirds had sustained improvement (defined as at least six months of treatment satisfation). During maintenane therapy, 41% were suessfully treated ontinuously or for symptom relapses over an average of 2.6 years; 29% disontinued suessful treatment after.0.5 years with sustained benefits; and the remaining 29% eventually disontinued suessful treatment for side effets or unertain reasons. Other maintenane treatment data are laking. Reommending at least six months of antidepressants for the suessfully managed patient seems prudent, and very long treatment ourses are ommon. 2 6 Who responds poorly to antidepressants? Poorer outomes are predited for patients with objetive delays in gastrointestinal motility or either speifi gastrointestinal symptoms or omorbid medial onditions that ould be exaerbated by antidepressant side effets, although therapeuti trials are not neessarily ontraindiated Of the antidepressants, TCAs are most likely to interat negatively. Patients with multiple mediation sensitivities and other features of somatisation disorder also tolerate antidepressants poorly, even in very low dosages Substituting nonpharmaologial interventions (for example, psyhotherapy, other psyhologial and behavioural therapies) for the psyhopharmaologial approah should be onsidered earlier in this group. Ative depression symptoms were shown in early TCA trials and onfirmed in the more reent desipramine study of women with funtional bowel disorders to redue antidepressant effiay. This irony an be explained away through several mehanisms. Firstly, the daily dosages used for treating funtional gastrointestinal symptoms, partiularly with TCAs, often fall below the usual reommendations for depression management. Esalating dosages into the psyhiatri therapeuti range when depression symptoms are evident may re-establish the effiay of antidepressants, although the benefits of this approah have not been doumented. The manoeuvre seems reasonable, if only to redue the diffuse effets omorbid depression has on medial illnesses in general. 60 A seond possibility is that depression symptom reporting heralds a more signifiant degree of entral dysfuntion ommon aross funtional disorders, a theme reiterated throughout this review, and thereby predits greater resistane to antidepressants. To this

8 Table 4 Relative ourrene of ommon side effets of seleted antidepressants Drug lass or drug Antiholinergi` Side effet* point, North et al found that a reent history of depression (urrent or within the past one year) was one of the best linial preditors of somatisation disorder in a study of IBS patients attending a university lini. 17 Thus the presene of depression symptoms requires more areful monitoring of treatment response, as suggested in the initiation algorithm of fig 3. SIDE EFFECTS OF ANTIDEPRESSANT THERAPY FOR FUNCTIONAL GASTROINTESTINAL DISORDERS Side effets of antidepressants are signifiant and ommon, emphasising the importane of suffiient morbidity from the funtional gastrointestinal disorder to establish patient andiday. The NNT for serious side effets from TCA treatment of neuropathi pain has been alulated at 22 and for minor side effets at Rates of side effets may be even higher when TCAs are used for funtional gastrointestinal disorders, despite low daily dosages Cliniians using antidepressants should beome very familiar with side effet profiles of the one or two TCA and non-tca antidepressants that they hoose to presribe. Although some side effets are peuliar to speifi antidepressants, typial side effets and their relative frequenies by antidepressant lass are shown in table 4. Early side effets most ommonly interfering with suessful TCA treatment inlude sedation, other CNS side effets (sleep disturbane, nervousness, agitation, nightmares), and antiholinergi side effets (xerostomia, tahyardia, palpitations, urinary dysfuntion, visual disturbanes). Weight gain and sexual dysfuntion are ommon patient omplaints when antidepressants are ontinued for maintenane therapy A host of other potential adverse effets are possible, and mediation interations are signifiant onsiderations. 66 TCAs are metabolised by the ytohrome P450 (2D6) system. Mediations that interfere with their metabolism, suh as SSRIs, an indue supra-therapeuti TCA blood levels even when low dose TCA regimens are used. 67 Combinations antidepressant regimens also inrease the risk of the unommon serotonin syndrome. 68 Reent observations that SSRI use an preipitate hostile behaviours and possibly suiide in adolesents and young adults are relevant. 69 The phenomenon may have generalisation aross antidepressant lasses and an our in adults. Central nervous systemà Cardiovasular Other Drowsiness Insomnia/ agitation Orthostati hypotension Cardia arrhythmia Gastrointestinal distress TCAs Tertiary amines Seondary amines SSRIs Other newer antidepressants Bupropion Duloxetine Nefazodone Mirtazapine Trazodone Venlafaxine Weight gain (.6 kg) *Relative ourrene of side effets among agents listed: ranked from 0 (absent or rare) to 4 (relatively ommon). ÀA redution of seizure threshold an our with all antidepressants and is most pronouned with bupropion. `Inludes dry mouth, blurred vision, urinary hesitany, onstipation. Modified from Lustman PJ, Clouse RE, Alrakawi A, et al. Treatment of major depression in adults with diabetes: a primary are perspetive. Clin Diabetes 1997;15: Details of reent US Food and Drug Administration releases on this topi an be found at antidepressants/default.htm. Inreased awareness of withdrawal syndromes, inluding the potential for suiide, is also ourring Gradual introdution and withdrawal of antidepressants is reommended with forewarning of these potential adverse affets, espeially in young subjets. Although gradual introdution is already ommonplae in antidepressant management of funtional gastrointestinal disorders, many liniians are unaware of the importane of tapered withdrawal over two to four weeks depending on the antidepressant and daily dose at the time the deision for disontinuation is made. 66 Detailed assessment of side effet reporting when antidepressants are used for funtional gastrointestinal disorders has fuelled further the interest in entral proesses potentially underlying these disorders. Many side effets eventually attributed to the antidepressant and leading to its disontinuation are present at baseline, before the antidepressant is initiated. This observation has been made previously in some patients with major depression 74 but the dropout rate with antidepressant therapy in funtional gastrointestinal disorders appears to exeed that seen in depression, even in the fae of medial illness In funtional gastrointestinal disorders, higher degrees of somatisation predit worsening of existent symptoms or new side effets and subsequent antidepressant intolerane. 73 Thus the same neurophysiologial proesses suspeted as explaining the omorbidities assoiated with funtional gastrointestinal disorders, underlying many of the physiologial phenomena that haraterise these disorders, and responsible for a large portion of the assoiated global distress, may also define the propensity for side effets from psyhopharmaologial interventions. Awareness of this is helpful in management. Very gradual introdution of the antidepressant and use of agents with lowest side effet profiles is reommended for patients with multiple funtional omorbidities, diffusely positive system review, ompliated histories of symptoms poorly explained by the degree of objetive findings, histories of multiple mediation sensitivities, or other indiators of high degrees of somatisation. Within the TCA lass, the seondary amines may be better tolerated (for example, nortriptyline, desipramine). 1339

9 1340 Counselling the patient regarding the distintion between favourable effets and side effets, your intention to slowly inrement the dose to limit side effets while benefiial effets take hold, and your sensitivity to the patient s side effet predisposition may be helpful. Likewise, desribing the gradual benefits that might our over four weeks or more of treatment may improve adherene. If suspiions regarding mehanisms of side effets in many patients with funtional gastrointestinal disorders are orret, then this is one unusual situation in whih a mediation has the therapeuti potential to negate its own initial side effets. 74 NEW DIRECTIONS IN PSYCHOPHARMACOLOGICAL TREATMENT OF FUNCTIONAL GASTROINTESTINAL DISORDERS Optimal use of psyhopharmaologial agents in funtional gastrointestinal disorders undoubtedly has not been realised. Continued definition of the response mehanism is required and should enhane development or testing of new agents targeted more speifially to these disorders. Early attempts are being made to use funtional brain imaging for this purpose. 76 In the interim, better identifiation of response preditors should improve initial andidate seletion and redue dependene on therapeuti trials. Some interest in studying ombination therapy with both TCAs and other antidepressants is surfaing, espeially in the subset with ative anxiety or depression symptoms Preliminary data suggest that addition of a low dose TCA to a daily SSRI regimen in patients being managed with the latter for psyhiatri symptoms may improve funtional gastrointestinal symptoms, the TCA response being prediated by the degree of psyhiatri symptom ontrol. 67 Overall, investigation of psyhopharmaologial agents for funtional gastrointestinal disorders will likely inrease, as they may take a more primary position in management algorithms. 30 For the reasons outlined in this review, it is unlikely that onerns about limited diret effets of antidepressants on funtional gastrointestinal symptoms will deter this effort.... Authors affiliations R E Clouse, Division of Gastroenterology, and Department of Psyhiatry, Washington University Shool of Mediine, St Louis, Missouri, USA P J Lustman, Department of Psyhiatry, Washington University Shool of Mediine, St Louis, Missouri, USA, and Department of Veterans Affairs Medial Center, St Louis, Missouri, USA Conflit of interest: None delared. REFERENCES 1 Clouse RE. Esophageal spasm syndrome. Presented at the annual meeting of the Amerian Gastroenterologial Assoiation, San Antonio, May, Talley NJ. Antidepressants in IBS: are we deluding ourselves? Am J Gastroenterol 2004;99: Whitehead WE, Levy RL, Von Korff M, et al. The usual medial are for irritable bowel syndrome. Aliment Pharmaol Ther 2004;20: Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med 2001;52: Camilleri M, Heading RC, Thompson WG. Consensus report: linial perspetives, mehanisms, diagnosis and management of irritable bowel syndrome. Aliment Pharmaol Ther 2002;16: Mertz HR. 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