Irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders typically defy traditional diagnostic methods based on structural abnormalities, and has led to the emergence of the discipline of neurogastroenterology or the study of the “brain-gut axis,” which is based on dysregulation of neuroenteric pathways as a key pathophysiological feature of IBS. Centrally acting treatments can influence these pathways and improve the clinical manifestations of pain and bowel dysfunction associated with this disorder. To successfully implement these treatment strategies, it is important to recognize their dual effects on brain and gut, understanding the nature and severity of the GI symptoms and their psychosocial concomitants, and applying them within the context of the patient’s understanding of their value.
A more recent expansion in our understanding of irritable bowel syndrome (IBS) is leading to important therapeutic gains. The traditional concept of abnormal motility has been insufficient to explain the symptoms and pathogenesis of IBS and other functional GI disorders (FGIDs). We now recognize that visceral hypersensitivity (enhanced perception of peripheral signals), infection/inflammation, and psychological factors that alter brain-gut axis function are all operative in understanding these disorders. Modalities like brain imaging and brain-gut neurotransmitter research demonstrate a dysregulated brain-gut axis at peripheral, spinal, or supraspinal levels, all of which together contribute toward IBS and other FGID symptoms. For example, neurotransmitters like serotonin (5 HT), norepinephrine (NE), corticotrophin-releasing factor (CRF), and opioids, among others, modify both motility and sensation in the gut. This has made centrally acting treatments (psychotropic agents and behavioral treatments) a particularly attractive treatment strategy because of their modulation of 5-HT and NE pathways causing overarching effects on the brain-gut axis in addition to their use for managing associated psychological disturbances that are commonly associated with these disorders.
The use of psychotropic agents for FGIDs has grown significantly in the past 2 decades. Nowadays, at least every 1 in 8 patients with IBS is offered an antidepressant. A recent pharmacy database study from the United Kingdom has shown that patients prescribed ongoing therapy for presumed IBS are 2 to 4 times more likely to be prescribed central nervous system (CNS)-acting drugs than controls. These included antidepressants, anxiolytics, antipsychotics, and hypno-sedatives. In a study from Sweden, after anti-acids, antidepressants were the most commonly used drug category reported by IBS patients. In a recent survey of around 2000 IBS patients, about 31% reported antidepressant use. However, it still remains a challenging strategy because of insufficient understanding and the complex nature of these disorders, lack of well-designed drug studies, and variability among the treatment efficacy end points.
This article describes the rationale, mechanisms, efficacy, side-effects, practical aspects involving use of psychotropics, and behavioral treatments in IBS and other FGIDs with focus on some of the more recent work in this field.
Biopsychosocial construct of irritable bowel syndrome and role of psychological factors
In the biomedical model of medicine, IBS is often considered at the “functional” end of the “functional-organic” spectrum where a disorder is characterized by absence of detectable structural abnormalities using traditional diagnostic techniques, such as endoscopy or imaging. In the past 2 decades, there has been a surge in the research in the area of motility, brain imaging, and neurotransmitters, which has helped define the “brain-gut axis.” As a result, pathophysiological understanding of IBS has increased, leading to organification of a “functional” disorder. In fact, IBS can be best conceptualized with a biopsychosocial construct where an influence of central nervous system at spinal and supraspinal levels results in sensory and motor dysfunction of the GI tract. The trigger can be peripheral (eg, GI infection, abdominal surgery) or central (eg, history of abuse) but psychosocial factors often play an important role in perpetuation and clinical manifestation of this disorder through centrally mediated pathways. The influence of these factors becomes increasingly significant with increasing severity of these disorders.
Psychosocial factors can play a vital role at any and all stages in the natural history of IBS, being responsible for predisposition, precipitation, and perpetuation of symptoms and illness behavior. In one series, up to three-fourths of patients with FGID seeking care at a tertiary care referral center meet diagnostic criteria for a psychiatric disorder, most commonly anxiety and depression, although in general the prevalence is much lower for patients seen in primary care or even general gastroenterology practice. A history of major stressful life events, such as sexual abuse, separation, and personal losses are common in IBS, particularly for patients with more severe symptoms who perpetuate the severity via maladaptive illness behavior (catastrophizing). Abuse, life stress, and poor or maladaptive coping can directly influence symptom severity, health-related quality of life (HRQOL), and response to treatment. Feelings of distress in response to the GI condition can have adverse effects on psychological state or health status independent of presence of a preexisting psychiatric diagnosis. Furthermore, a negative workup, incomplete understanding, and an unsatisfactory explanation from the physician lead to constant worry, fear, and anxiety and often perpetuates the symptom severity. Postinfectious (PI)-IBS provides an ideal example of psychological factors on IBS disease process. Psychosocial distress at the time of infection has been shown to be an independent predictor of later development of PI-IBS. Stress has been proposed to act by overarching effects on inflammation and the brain-gut axis in PI-IBS.
In addition, a subgroup of patients with IBS, particularly with more severe and refractory symptoms, report many non-GI symptoms, and some have hypothesized the existence of broader neurophysiological processes (eg, so called “somatization”) in up to 15% to 45% of patients with IBS. In effect, these patients have central dysregulation of pain regulatory pathways and often have comorbid problems such as fibromyalgia, chronic fatigue, or chronic generalized pain. This understanding has important implications on using centrally acting treatments, alone or in combination, to target this broader polysymptomatic process with FGIDs and even predicting response to these agents. These individuals may set lower thresholds for symptom reporting and often turn out to be “nonresponders” to a variety of different, especially peripherally based, pharmacologic interventions.
Rationale for the use of psychotropic agents and behavioral therapies
Most widely used psychotropic agents in IBS and other FGIDs are antidepressants, especially tricyclic antidepressants (TCAs). The rationale for the use of these agents in IBS is highlighted in Box 1 . In spite of significant heterogeneity in study designs and treatment end points, several reviews and meta-analyses have shown both pain reduction and global improvement as potential benefits of antidepressants in IBS and other FGIDs. A recent American College of Gastroenterology–funded meta-analysis showed significantly decreased relative risk of persistent IBS symptoms with antidepressant treatment. Others have estimated an overall improvement in IBS with an odds ratio of 2.6 to 4.2. On average, 3 to 4 patients needed to be treated with an antidepressant to improve 1 patient’s symptom. Up to 80% of patients with IBS appear to have moderate to greater physician-rated benefits in an open-label clinical practice, and adherence to antidepressants is higher than for other treatments. The peripheral effects of these agents on the gut may be of secondary importance considering that most patients treated with antidepressants have failed treatment with conventional gut-acting agents. In addition, studies on therapeutic effects of antidepressants on visceral hypersensitivity are mixed. Also, treatment satisfaction with TCAs or selective serotonin reuptake inhibitors (SSRIs) has not been consistently correlated with reduction in the pain ratings. Overall, the benefit with these agents, especially SSRIs seems to correlate more with improvement in global measures of well-being rather than improvements in pain ratings. This improvement in global distress is still therapeutic, as morbidity associated with FGIDs is linked to global distress in the form of social impairment, work absenteeism, and other functional limitations.
Central effects:
- 1.
Alters central pain perception: analgesia or antihyperalgesia.
- 2.
Therapeutic effects on mood: to manage general anxiety, hypervigilance, symptom-related anxiety, agoraphobia, and increased stress responsiveness.
- 3.
Treatment of associated psychiatric disorders: depression, posttraumatic stress disorder, somatization.
- 4.
Treatment of associated sleep disturbances.
- 1.
Peripheral effects:
- 1.
Peripheral analgesic effects: alters visceral afferent signaling.
- 2.
Effect in GI physiology (motility and secretion) via effects on cholinergic, noradrenergic, and serotonergic pathways.
- 3.
Smooth muscle effects on viscera, eg, gastric fundic relaxation.
- 1.
The concept of neuroplasticity with loss of cortical neurons in psychiatric trauma, and neurogenesis (ie, regrowth of neurons) with clinical treatment, also provides rationalization for the use of central treatments. Functional MRI studies have shown reduced neuron density in cortical brain regions involved in emotional and pain regulation in patients with pain disorder and with IBS. Notably, recent data suggest that antidepressant (and possibly psychological) treatments may restore lost neurons. Levels of brain-derived neurotrophic factor, a precursor of neurogenesis, increase with antidepressant treatment and correlate with longer periods of treatment and with the degree of recovery from depression. Furthermore, the longer patients are treated with antidepressants, the lower is the frequency of relapse or recurrence of the depression. These findings provide insight into neuronal growth regulation in key areas of the central pain matrix and provide new and important opportunities for research and patient care using antidepressants for treatment of IBS.
Rationale for the use of psychotropic agents and behavioral therapies
Most widely used psychotropic agents in IBS and other FGIDs are antidepressants, especially tricyclic antidepressants (TCAs). The rationale for the use of these agents in IBS is highlighted in Box 1 . In spite of significant heterogeneity in study designs and treatment end points, several reviews and meta-analyses have shown both pain reduction and global improvement as potential benefits of antidepressants in IBS and other FGIDs. A recent American College of Gastroenterology–funded meta-analysis showed significantly decreased relative risk of persistent IBS symptoms with antidepressant treatment. Others have estimated an overall improvement in IBS with an odds ratio of 2.6 to 4.2. On average, 3 to 4 patients needed to be treated with an antidepressant to improve 1 patient’s symptom. Up to 80% of patients with IBS appear to have moderate to greater physician-rated benefits in an open-label clinical practice, and adherence to antidepressants is higher than for other treatments. The peripheral effects of these agents on the gut may be of secondary importance considering that most patients treated with antidepressants have failed treatment with conventional gut-acting agents. In addition, studies on therapeutic effects of antidepressants on visceral hypersensitivity are mixed. Also, treatment satisfaction with TCAs or selective serotonin reuptake inhibitors (SSRIs) has not been consistently correlated with reduction in the pain ratings. Overall, the benefit with these agents, especially SSRIs seems to correlate more with improvement in global measures of well-being rather than improvements in pain ratings. This improvement in global distress is still therapeutic, as morbidity associated with FGIDs is linked to global distress in the form of social impairment, work absenteeism, and other functional limitations.
Central effects:
- 1.
Alters central pain perception: analgesia or antihyperalgesia.
- 2.
Therapeutic effects on mood: to manage general anxiety, hypervigilance, symptom-related anxiety, agoraphobia, and increased stress responsiveness.
- 3.
Treatment of associated psychiatric disorders: depression, posttraumatic stress disorder, somatization.
- 4.
Treatment of associated sleep disturbances.
- 1.
Peripheral effects:
- 1.
Peripheral analgesic effects: alters visceral afferent signaling.
- 2.
Effect in GI physiology (motility and secretion) via effects on cholinergic, noradrenergic, and serotonergic pathways.
- 3.
Smooth muscle effects on viscera, eg, gastric fundic relaxation.
- 1.
The concept of neuroplasticity with loss of cortical neurons in psychiatric trauma, and neurogenesis (ie, regrowth of neurons) with clinical treatment, also provides rationalization for the use of central treatments. Functional MRI studies have shown reduced neuron density in cortical brain regions involved in emotional and pain regulation in patients with pain disorder and with IBS. Notably, recent data suggest that antidepressant (and possibly psychological) treatments may restore lost neurons. Levels of brain-derived neurotrophic factor, a precursor of neurogenesis, increase with antidepressant treatment and correlate with longer periods of treatment and with the degree of recovery from depression. Furthermore, the longer patients are treated with antidepressants, the lower is the frequency of relapse or recurrence of the depression. These findings provide insight into neuronal growth regulation in key areas of the central pain matrix and provide new and important opportunities for research and patient care using antidepressants for treatment of IBS.
Psychotropic agents
Four major classes of psychotropic agents of interest and investigation in IBS are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and atypical antipsychotics. Among these, TCAs and SSRIs have been most widely studied. However, other agents, especially SNRIs, are gaining popularity for treatment for other chronic pain conditions such as fibromyalgia and are likely to be further explored in IBS and other FGIDs.
Tricyclic Antidepressants
The tricyclic antidepressants (TCAs) are the most rigorously studied class of psychotropic agents used in IBS. The results of some of the recent randomized controlled trials (RCTs) are summarized in Table 1 . The reason for marginal intention-to-treat effects in our large study was because one-fourth of the patients dropped out from the treatment arm, primarily because of side effects. However, a per protocol post hoc analysis showed a 20% effect size margin. Clouse and colleagues reported managing 138 patients with IBS with antidepressants in whom TCAs were used 130 times, newer agents 39 times, and anxiolytics 47 times. Improvement occurred in 89% and complete remission in 61% of patients. For the most part, despite methodological problems in designing good studies with antidepressants, there is evidence of treatment benefit with TCAs, providing patients are able to stay on medication.
| Citation | Drug | Sample | Study Design | Outcome |
|---|---|---|---|---|
| Drossman et al, 2003 | Desipramine | Women; moderate to severe IBS (n = 431) | 12 weeks Multicenter, comparator-controlled RCT | Per-protocol analysis: desipramine superior to placebo; intention-to-treat analysis: not significant. With dosages up to 150 mg, there is no relationship between total dose or plasma level and the clinical response. |
| Otaka et al, 2005 | Amitriptyline | Refractory Functional Dyspepsia (n = 14) | 4 weeks Double-blind RCT | Amitriptyline showed 66.7% efficacy in famotidine-failed group and 75.0% efficacy in the mosapride-failed group. |
| Morgan et al, 2005 | Amitriptyline | Women with severe IBS (n = 19) | 4 weeks RCT | During stress, amitriptyline reduced pain-related cerebral activations in the perigenual ACC and the left posterior parietal cortex. |
| Vahedi et al, 2008 | Amitriptyline | IBS-D (n = 50) | 8 weeks Double-blind RCT | Lower incidence of loose stool and feeling of incomplete defecation. Increased report of “loss of all symptoms” compared with placebo (68% vs 28%). |
| Bahar et al, 2008 | Amitriptyline | Adolescent IBS (n = 33) | 13 weeks Double-blind RCT | Improved overall quality of life. Reduction in IBS diarrhea. Improved abdominal pain. |
| Abdul-Baki et al, 2009 | Imipramine | IBS (n = 107) | 12 weeks RCT | Higher global symptom relief. Improvements in SF-36 scales. |
TCAs reduce pain sensitivity in chronic neuropathic animal models, more effectively than SSRIs. In animal studies, they reduce the frequency of nerve impulses evoked by noxious distension in the colon. The analgesic properties are also likely contributed by alpha-adrenergic, sodium channel blockade, and N-methyl D-aspartate (NMDA) antagonistlike action. Their effect on visceral perception has been mixed. A recent study showed that TCAs do not have significant effects on gastric motor function or satiation post nutrient challenge in healthy individuals. In another recent proof on concept study, amitriptyline appeared to decrease stress-induced rectal hypersensitivity in patients with IBS, thus providing mechanistic insights of potential disease-modifying actions of TCAs.
The lack of substantive data on peripheral analgesic properties of TCAs in humans suggests that the more pronounced effects are on central pain modulation. In functional MRI studies, the mid cingulate cortex (MCC) is activated during painful rectal distensions in patients with IBS. This activation is associated with poor clinical status in severe IBS and there is reduced activation with clinical improvement. Those with IBS and abuse report more pain, greater MCC activation, and reduced activity of anterior cingulate cortex (ACC), which is implicated in pain inhibition and arousal. Furthermore, amitriptyline reduced brain activation during pain in the perigenual (limbic) ACC and parietal association cortex during stress.
Side effects depend on the class of TCAs but for the most part include sedation, anticholinergic (constipation, tachycardia, urinary retention, and xerostomia), and CNS side effects (insomnia, agitation, nightmares). TCAs can slow both small bowel and colonic transit. However, the side-effect profiles vary because of differences in the postsynaptic receptor affinities. In general, secondary amine TCAs (eg, desipramine, nortriptyline) are better tolerated than tertiary amine TCAs (eg, amitriptyline, imipramine) because of their lower antihistaminic and anticholinergic properties.
Selective Serotonin Reuptake Inhibitors
The main action of selective serotonin reuptake inhibitors (SSRIs) is to selectively inhibit the re-uptake of 5HT and block the 5HT transporter protein at the level of presynaptic nerve endings, increasing synaptic concentration of 5HT. These agents have effects on animal somatic pain models, although weaker than the TCAs. Activation of opioid descending spinal pathways is another proposed mechanism of action. Data on visceral pain perception with SSRIs is mixed and central nociceptive effects of SSRIs have not been studied. Table 2 summarizes some of the recent RCTs on use of SSRIs in FGIDs.
| Citation | Drug | Sample | Study Design | Outcome |
|---|---|---|---|---|
| Creed et al, 2003 | Paroxetine | Severe IBS (n = 257) | 3 months Multicenter Parallel RCT | Improved physical component of SF-36 (QOL) scale. Decreased health care costs at 1-year follow-up. Decreased severity and number of days in pain. |
| Kuiken et al, 2003 | Fluoxetine | IBS (n = 40) | 6 weeks Double-blind placebo-controlled RCT | Improved abdominal pain score (53% vs 26%) showing trends toward significance. Patients on fluoxetine were more likely to continue with the drug (84% vs 37%). Significant reduction in abdominal pain in patients with gut hypersensitivity. |
| Tabas et al, 2004 | Paroxetine | IBS (n = 110) | 12 weeks Double-blind placebo-controlled RCT | Improved overall well-being. Increased desire to continue medication. Less IBS-related anxiety. Decreased food avoidance. Benefit seen in nondepressed. |
| Vahedi et al, 2005 | Fluoxetine | IBS-C (n = 44) | 12 weeks Double-blind RCT | Decreased abdominal discomfort and bloating. Increased frequency of bowel movements and decreased stool consistency. Insignificant reduction in the mean number of symptoms per patient. |
| Tack et al, 2006 | Citalopram | IBS patients (n = 23) | 6 weeks Double-blind placebo-controlled RCT | Improved abdominal pain and bloating. Less impact of symptoms on daily life and improved overall well-being. Effects independent of psychologic and colonic sensory-motor function. |
| Talley et al, 2008 | Imipramine and Citalopram | IBS patients (n = 51) | 12 week Multicenter double-blind parallel-group RCT | Imipramine improved bowel symptom severity rating for interference and distress. Imipramine improved depression and SF-36 (mental component) score. Neither imipramine nor citalopram significantly improved Rome III global IBS end point (adequate relief). |
| Masand et al, 2009 | Paroxetine (controlled release) | IBS patients (n = 72) | 12 week Double-blind RCT | No significant differences in composite pain scores (primary outcomes). Higher proportion of responders in treatment group per clinical global improvement scale (secondary outcome). |
| Ladabaum et al, 2010 | Citalopram | Nondepressed IBS patients (n = 54) | 4 weeks Double-blind RCT | Not superior to placebo in achieving global relief, specific symptom, or QOL improvement. |
SSRIs can be used to augment the overall benefit of TCAs through their effect on anxiety, or in sufficient dosages in treating psychiatric comorbidities. Although they are reported to show analgesic effect in neuropathic pain, back pain, and migraines, the studies do not show an independent effect of SSRIs on GI pain.
In summary, SSRIs may help in treating FGIDs because (1) they improve global well-being and some GI-specific symptoms (independent of the effects on depression); (2) they have anxiolytic properties and can target social phobia, agoraphobia, and symptom-related anxiety; (3) they may augment the analgesic effects of other agents (TCAs); and (4) they treat psychiatric comorbidities. In contrast to the dose ranging needed with TCAs, SSRIs do not require much dose readjustment because of selective receptor affinity for 5HT. Thus, diarrhea may be a side effect, and SSRIs may benefit patients with constipation. Within the SSRI class, paroxetine has more muscarinic effect and may be useful for those with predominant diarrhea. Fluoxetine has a longer half-life and fewer withdrawal effects and may be selected if poor compliance is an issue. Side effects include agitation, hostility, and suicidality.
Serotonin-Norepinephrine Reuptake Inhibitors
The serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine, duloxetine, and desvenlafaxine, may potentially be as effective as the TCAs, owing to their dual blockade of reuptake of NE and 5HT receptors. Currently these agents are gaining increased use for other somatic painful conditions such as fibromyalgia.
Duloxetine
This is the only SNRI agent that has been studied for the treatment of IBS. In a 12-week open-label study of 15 nondepressed patients with IBS, duloxetine (60 mg daily dosage) appeared to be effective for pain, severity of illness, quality of life, loose stool, work and family disability, and anxiety. Seven patients withdrew from the study reporting adverse effects, most notably constipation. It lacks activity at muscarinic, histamine, and adrenergic sites, thus avoids side effects seen with TCAs. Most common side effects are nausea, dry mouth, and constipation. It can also rarely cause nonspecific elevation of liver enzymes.
Venlafaxine
This agent inhibits both 5HT and NE reuptake and can increases stimulated pain threshold. However, higher dosages are needed to achieve pain benefit. It is also a mild inhibitor of dopamine reuptake. It can improve postprandial accommodation of the proximal stomach and may be used for treating functional dyspepsia. However, a recent multicenter RCT did not identify any benefit in functional dyspepsia. It has also been shown to decrease the sensitivity of colon to rectal distension. Nausea is a side effect to consider. Venlafaxine can be started at 37.5 mg or 75 mg and titrated up to achieve maximum effect.
Desvenlafaxine
Desvenlafaxine is related to venlafaxine in molecular structure and has recently been released for treatment of depression. Its benefit for painful GI conditions has not yet been studied.
Milnacipran
Milnacipran also belongs to the SNRI class and is currently used in the treatment of fibromyalgia. This agent can also potentially be used in pain-related chronic GI conditions such as IBS.
Atypical Antipsychotics
Atypical antipsychotics have gained wide acceptance for treatment of bipolar disorder and schizophrenia because of their efficacy and low toxicity. They can also be beneficial in lower dosages for patients with FGIDs because of their analgesic properties (alone or in synergism with antidepressants ) and their sedative and anxiolytic effects. They can enhance a more normal sleep architecture. Recently, we have used a low-dose atypical antipsychotic agent (eg, quetiapine 25–100 mg) with dopaminergic actions for augmenting treatment in our patients with FGIDs. Preliminary data from our clinic show that about 50% of patients with severe IBS and functional abdominal pain syndrome, who previously failed antidepressants and who are prescribed quetiapine with an antidepressant, stay on it, and most of those who do stay on it achieve some benefit. Olanzapine, another drug of this class, has shown promise for treating nausea and vomiting in patients with cancer.
Behavioral therapies
The forms of behavioral therapies studied in IBS include cognitive behavior therapy (CBT), relaxation training, psychodynamic interpersonal therapy (PIT), hypnotherapy, mindfulness meditation, and multicomponent psychotherapies. The rationale for their use is summarized in Box 2 .
- 1.
To establish a rational model of illness: reframe maladaptive beliefs
- 2.
To reduce overresponsiveness to stress, eg, stress and autonomic reactivity
- 3.
To reduce or modify maladaptive psychological responses: catastrophizing, symptom-specific anxiety, shame/guilt
- 4.
To reduce or modify maladaptive behaviors, eg, agoraphobia, seeking diagnostic studies
Cognitive Behavior Therapy
Cognitive behavior therapy (CBT) is based on social learning theory, which recognizes that behavior is shaped as a result of its social consequences. It focuses on ways to increase or decrease thoughts and behaviors. With treatment of the IBS, it typically consists of 3 components: cognitive change where patients learn to recognize the relationship between their beliefs and symptoms, addressing thoughts, behaviors, and responses that result from their experiences, and changing behavior by teaching relaxation and stress-management strategies. The specific content of the therapy is based on a biopsychosocial assessment of the patient’s background and current difficulties. For example, if a history of sexual abuse interferes with adaptation to the disorder, factors related to the abuse will be discussed. Several studies have looked at CBT for IBS ( Table 3 ), but with significant heterogeneity. Various ways to implement CBT (group, individual, therapist based, Internet based) have been assessed. In 2 recent separate analyses, early response (4 weeks) and maladaptive coping have been shown to be predictive of sustained response. It has been shown that CBT has a direct effect on global IBS symptom improvement, independent of its effects on distress, and symptom improvements are not moderated by variables reflecting the mental well-being of patients with IBS. Symptom benefit with CBT may be mediated through changes in neural activity of cortical-limbic regions that subserve hypervigilance and emotion regulation.
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