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Keywords:

  • antidepressant;
  • barostat;
  • dyspepsia;
  • noci-ception;
  • visceral sensitivity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

AbstractVisceral hypersensitivity may contribute to symptoms in functional dyspepsia. Selective serotonin reuptake inhibitors (SSRIs) may be beneficial in functional gastrointestinal disorders. The aim of this study was to determine whether the SSRI sertraline affects gastric sensitivity and compliance in healthy humans. Ten healthy humans completed a 6-week randomized, double-blind, crossover trial of sertraline (50 mg day−1) vs. placebo. After each 2-week treatment, fullness, pain and nausea were rated at increasing gastric barostat distending pressures. Sensation thresholds above minimal distending pressure (MDP) were determined with a tracking method. Somatic sensory testing was performed by hand immersion in ice water. No differences were found between sertraline and placebo for symptoms as a function of distending pressure (fullness, P = 0.72; pain, P = 0.79; nausea, P = 0.41), gastric compliance (P = 0.15), median and interquartile range thresholds for first sensation [4.1 (3.5–5.7) vs. 6.2 (3.3–10.0) mmHg above MDP, P = 0.19] and pain [15.2 (8.3–21.0) vs. 15.3 (10.3–19.8) mmHg above MDP, P = 0.85], and median tolerance times for hand ice water immersion [27 (19–99) vs. 29 (20–180) s, P = 0.73]. In conclusion, sertraline had no effect on gastric sensitivity or compliance, or somatic pain tolerance in healthy humans. Studies are needed to assess the effects of SSRIs on visceral sensation and clinical symptoms in patients with functional dyspepsia.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

The annual prevalence of chronic dyspepsia, which is defined as upper abdominal pain or discomfort, approximates to 25% in the general population.1 In many patients who seek medical care for persistent or recurrent dyspepsia, no evidence of organic disease is found and these patients are given a diagnosis of functional dyspepsia.1 Visceral hypersensitivity may contribute to symptoms in this disorder,2–6 which most likely represents a heterogeneous group of conditions whose pathophysiology remains incompletely understood. For the subgroup of patients with functional gastrointestinal disorders who exhibit visceral hypersensitivity, it remains to be established whether abnormalities reside at the end organ level, the sensory afferent pathways, or the central nervous system.7–9

At present, therapeutic options for patients with functional dyspepsia are limited.10 Antidepressant medications may be of benefit in treating functional gastrointestinal symptoms.11–17 Although the tricyclic compounds are the class of antidepressants best studied for this application, the selective serotonin reuptake inhibitors (SSRIs) are commonly used in clinical practice because of their lower incidence of side-effects. However, limited data exist on the effects of SSRIs on visceral sensation or on clinical symptoms in the functional gastrointestinal disorders.18–21 The precise mechanism of action of SSRIs in the treatment of depression is not fully understood, but chronic administration of these agents has been reported to downregulate the serotonin transmitter responsible for serotonin reuptake,22 as well as serotonergic receptors.23,24

We wished to test the hypothesis that visceral sensitivity can be affected by treatment with SSRIs. The principal aim of this study was to investigate the effect of the SSRI sertraline on gastric sensitivity to distension in healthy humans. To test the specificity of any potential effect of sertraline on visceral sensation, somatic pain sensitivity was also assessed.

General study design

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

The Committee on Human Research of the University of California, San Francisco approved the study. All subjects provided written informed consent before participation.

The study design is illustrated in Fig. 1. The University of California, San Francisco Investigational Drug Pharmacy prepared identical capsules of 50 mg sertraline (Pfizer Inc., New York, NY, USA) and placebo, and developed a randomization list using a random number generator and permuted blocks of size four or two to ensure balanced treatment allocation (half of subjects initially assigned to each treatment). Subjects were randomly assigned to treatment with sertraline (50 mg day−1) or placebo for 2 weeks, followed by a 2-week washout period, and then crossover to the alternative treatment for 2 weeks. Subjects and investigators were blinded to treatment allocation, and subjects were blinded to details of the barostat protocol. After treatment periods, capsule counts were performed to assess treatment adherence, and subjects underwent barostat studies and somatic sensory testing as described below. To assess the adequacy of blinding, subjects made a forced-choice guess regarding treatment order at study completion.

image

Figure 1. Study design. Subjects were randomly assigned in a double-blind fashion to treatment with sertraline (50 mg day−1) or placebo for 2 weeks, followed by a 2-week washout period, and then crossover to the alternate treatment for 2 weeks. Visceral and somatic sensory testing was performed at the end of each treatment period.

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The dose of sertraline chosen is the initial dose recommended for treatment of depression and obsessive compulsive disorder.25 The duration of the treatment and washout periods were chosen based on the terminal elimination half-life of plasma sertraline (approximately 26 h) and the expected time to steady-state plasma levels (1 week with once-daily dosing).25

Study population

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Healthy volunteers were recruited by advertisement. Inclusion criteria consisted of being at least 18 years old, in good general health, and able to provide informed consent. Exclusion criteria, which were assessed by structured interview, included a history of chronic gastrointestinal illness or major abdominal surgery, neurological disease, diabetes, vasculopathy, other systemic or psychiatric illness, use of medications that may affect gastrointestinal motility or sensory perception, use of medications that may interact with sertraline, and pregnancy and breast-feeding. In addition, subjects were screened with the Beck Depression Inventory to ensure that no subject was depressed.

Barostat study

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Subjects fasted overnight before barostat studies but were instructed to take a treatment capsule on the morning of the study. Barostat bags of 1 L volume were fashioned from nonelastic polyethylene plastic and affixed to 18 French Salem Sump nasogastric tubes (Sherwood Medical, St. Louis, MO, USA). After applying a local anaesthetic spray to the throat (Hurricaine topical anaesthetic; Beutlich LP Pharmaceuticals, Waukegan, IL, USA), the barostat bag was passed orally so its proximal end was 40–45 cm from the incisors. After the subject acclimatized to the apparatus (20 min), the bag was inflated with 300 mL of air and the tubing was gently withdrawn until mild resistance was felt, in order to place the balloon in the gastric fundus. The tubing was secured with tape and connected to a barostat machine (Distender Series II; G & J Electronics Inc., Willowdale, Ontario, Canada). The operation of the barostat was controlled by a computer (Dell Inspiron 7000; Dell Computer Corp., Round Rock, TX, USA) using the Protocol Plus Deluxe software (G & J Electronics Inc). During the study period, the computer recorded barostat bag pressure, volume and corrected volume (accounting for air compressibility) every s. The barostat inflation rate was approximately 50 mL s−1. Therefore during each distension, a steady-state volume was generally achieved within 20 s.

Ascending method of limits: symptoms and volume as a function of pressure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

A series of ascending, intermittent, isobaric 60-s distensions was performed in 2 mmHg increments from 0–30 mmHg above MDP (ascending method of limits).27 This pressure range induces symptoms while still being tolerable in the majority of subjects. Distensions were separated by 60-s bag deflations to MDP. During each distension step, subjects were asked to rate the intensity of fullness (or bloating), pain (or discomfort), and nausea on 0–10 visual analogue scales (VAS). The corrected volume was continuously recorded during the distension series.

Double random staircase: pressure thresholds for symptoms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

A 1-h rest followed testing with the ascending method of limits. The double random staircase, a tracking method, was then used to determine the pressure thresholds for the first sensation of balloon inflation and for pain (or discomfort).27 Testing for these two threshold pressures was separated by 15 min. Distensions were delivered at unpredictable pressures until the threshold of interest was reached, as described below. During each distension, subjects rated the level of sensation using a panel (Deluxe Perception Panel; G & J Electronics Inc.) with seven buttons labelled ‘nothing’, ‘? inflated’, ‘barely inflated’, ‘more inflated’, ‘? pain or discomfort’, ‘barely painful or discomfort’, and ‘strong pain or discomfort.‘ The threshold for first sensation was defined as ‘barely inflated’ and for pain (or discomfort) as ‘barely painful or discomfort’. Two staircases of ascending, isobaric 60-s distensions separated by 60-s deflations to MDP were programmed into the barostat-controlling software, with increments of 2 and 3 mmHg, respectively. For each distension step, the software selected randomly either the first or second staircase, delivering the next step in the staircase if the threshold of interest had not been reached. When the threshold of interest was reached in a given staircase, the preceding step in the staircase was used the next time that staircase was randomly selected, with subsequent ascending distensions as described. In this manner, the threshold of interest was determined six times and an average was determined for each subject.

Statistical analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

In a previous study with a similar barostat protocol, the distending pressures required to achieve moderate pain in the proximal stomach of healthy volunteers was found to be 20 mmHg, with standard deviation of 1.7 mmHg.28 Power calculations determined that increases in this threshold pressures to at least 22 mmHg (10% increase) with sertraline treatment would be detected with power of 0.9 at a significance level of 0.05 based on a two-tailed paired t-test with a sample size of 10 subjects. This change was considered to be clinically relevant.

Pressure, volume, and corrected volume data were imported, and sensory data were entered into a spreadsheet program (Excel; Microsoft, Redmond, WA, USA). For every subject, the mean corrected volume duringthe last 40 s of every distension (steady state) was determined and used in the analysis of gastric compliance.

Data were imported into a commercial statistical program (SAS; SAS Institute, Cary, NC, USA) for analysis. For the ascending method of limits, the mean symptom scores and volume for the study population, and their standard errors, were calculated at every distending pressure with sertraline and placebo. Curves were generated for symptoms as a function of distending pressure and for gastric compliance (pressure–volume relationship). Median sensory thresholds and median somatic pain tolerance times for the study population were calculated for sertraline and placebo.

To compare symptom and compliance curves between sertraline and placebo, the difference between the dependent measure (symptom or volume) at every pressure during sertraline and placebo was calculated for every subject. These values were used to calculate a mean difference between sertraline and placebo throughout the entire pressure range tested for each subject. These individual subject mean differences were used to calculate a grand mean difference for the population. Student's t-test was used to test the null hypothesis that this grand mean difference was equal to zero (that is, that the sertraline and placebo curves were not different overall). Median sensory thresholds and somatic pain tolerance times were compared for sertraline and placebo with the Wilcoxon rank sum test. Statistical significance was set at α ≤ 0.05.

Treatment adherence and blinding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Capsule counts were exact in 15 of 20 treatment periods (75%), one dose was missed in three periods (15%), and one extra dose was taken in two periods (10%), reflecting excellent adherence to treatment. Five of 10 subjects correctly identified the treatment order, as would be expected by chance alone, suggesting that blinding of subjects to treatment allocation was successful.

Symptoms as a function of distending pressure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Figure 2 shows symptom scores as a function of distending pressure for fullness, pain and nausea with sertraline compared to placebo. Overall, no differences were found between symptom curves during sertraline compared to placebo treatment (fullness, P = 0.72; pain, P = 0.79; nausea, P = 0.41), as illustrated by respective mean scores at 22 mmHg above MDP of 4.0 ± 1.1 vs. 4.4 ± 0.8 for fullness, 3.3 ± 0.8 vs. 2.9 ± 0.7 for pain, and 2.1 ± 0.9 vs. 2.1 ± 0.9 for nausea.

image

Figure 2. Symptom scores as a function of gastric distending pressure. Overall, no differences were found with the ascending method of limits between symptom curves during sertraline compared to placebo treatment for (a) fullness, P = 0.72; (b) pain, P = 0.79; and (c) nausea, P = 0.41.

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Gastric compliance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Figure 3 shows gastric compliance with sertraline compared to placebo. Overall, no difference in gastric compliance was found between sertraline compared to placebo treatment (P = 0.15), as illustrated by respective volumes at 22 mmHg above MDP of 650 ± 31 vs. 690 ± 27 mL. This lack of effect of sertraline on gastric compliance suggests that its lack of effect on gastric sensitivity to isobaric distension cannot be explained by medication-induced changes in gastric wall properties.

image

Figure 3. Gastric compliance. Overall, no difference was found in gastric compliance during sertraline compared to placebo treatment (P = 0.15).

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Sensory pressure thresholds

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

Consistent with the lack of effect of sertraline on symptoms assessed by the ascending method of limits, the sensory thresholds determined with a tracking method did not differ between sertraline and placebo. Median and interquartile range thresholds for first sensation were 4.1 (3.5–5.7) vs. 6.2 (3.3–10.0) mmHg above MDP with sertraline and placebo, respectively (P = 0.19). Median and interquartile range thresholds for pain were 15.2 (8.3–21.0) vs. 15.3 (10.3–19.8) mmHg above MDP with sertraline and placebo, respectively (P = 0.85).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References

In this randomized, double-blind, crossover study in healthy humans, the SSRI sertraline had no effect compared with placebo on gastric sensitivity during isobaric distension. Gastric compliance did not increase with sertraline, suggesting that the lack of effect of sertraline on symptoms cannot be attributed to achieving larger gastric volumes at a given distending pressure, which could increase isobaric distension-induced symptoms and thus counteract an antinociceptive drug effect. In addition, sertraline had no effect on somatic pain tolerance.

Our finding that an SSRI had no effect on visceral sensitivity in healthy humans is consistent with the results of a preliminary report of the SSRI citalopram on colonic sensitivity.19 In healthy humans, citalopram induced colonic relaxation, and thus an increase in the volume threshold for discomfort, but no change in the pressure threshold for discomfort. Another preliminary investigation with acute citalopram administration did report a decrease in oesophageal sensitivity in healthy subjects.21 The reasons for the different preliminary results in the colon and oesophagus remain to be elucidated. It is conceivable that the lack of change in the colonic pressure threshold for discomfort may be related to the increase in colonic compliance induced by citalopram. When compliance is increased, any given distending pressure is associated with a larger volume and thus greater tension; this increase in tension at any given pressure could potentially counteract an analgesic effect, resulting in an apparent lack of change in the pressure threshold for discomfort.

While we must consider the possibility that our study may have failed to detect a true effect of sertraline on gastric sensitivity in healthy humans, this seems unlikely for several reasons. Although the sample size was small, the study was powered to detect reasonable differences in sensory parameters between sertraline and placebo treatments, and the curves of symptoms as a function of distending pressure during sertraline or placebo treatment are essentially superimposed (Fig. 2). The sertraline dose that was administered is a clinically relevant dose (the initial treatment dose for depression and obsessive-compulsive disorder25), and the trial duration seems adequate for healthy volunteers given that a steady-state plasma sertraline level is expected after 1 week with once-daily dosing25 and that the beneficial effects of antidepressants in functional gastrointestinal disorders are often observed after shorter treatment duration than in depression.12 While the effects of antidepressants in functional gastrointestinal disorders are often observed with lower drug doses than needed to treat depression,12,16,17,29 it is nonetheless possible that our negative findings could relate to the specific medication dose we studied. Finally, in crossover studies, a carry-over effect can obscure differences between treatments. However, given that the terminal elimination half-life of sertraline is approximately 26 h,25 a 2-week washout period between treatments should be adequate for drug clearance. Chronic administration of SSRIs may downregulate the serotonin transmitter and serotonergic receptors,22–24 and this effect may take weeks to reverse. However, a pronounced crossover effect in our study would be unlikely given that those subjects who received sertraline in the first treatment period underwent sensory testing following placebo treatment 4 weeks after the last sertraline dose (the 2-week washout and the second 2-week treatment period).

How should the lack of effect of sertraline on gastric sensitivity in healthy humans be interpreted with respect to the therapeutic potential of SSRIs in functional dyspepsia? A recent investigation found that sertraline may improve symptoms in functional chest pain,18 and preliminary findings suggest that citalopram may be of benefit in the irritable bowel syndrome.20 Notably, although there is evidence that tricyclic antidepressants are useful in treating functional gastrointestinal disorders,11–17 these medications do not appear to affect visceral sensory responses to distension at a given pressure in healthy humans.30,31 Thus, SSRIs may prove to be useful for treating symptoms in patients with functional dyspepsia even if they do not affect visceral sensitivity in healthy volunteers. Such a therapeutic benefit could be based on at least two mechanisms. Firstly, if abnormal visceral sensation causes some functional symptoms, this abnormal sensation in patients (in contrast to ‘normal sensation’ in healthy volunteers) might be affected by SSRIs. Secondly, these agents may be of clinical benefit in functional dyspepsia even in the absence of a direct effect on visceral sensitivity as assessed in the laboratory. The same level of sensation during a patient's daily life, for instance, could be interpreted as less noxious with SSRI treatment compared with the untreated state. As discussed below, existing evidence suggests that the second mechanism might apply with respect to the effect of antidepressants in functional gastrointestinal diseases.

In a crossover study of the tricyclic antidepressant amitriptyline compared with placebo in patients with functional dyspepsia, 7/7 patients reported significantly less severe gastrointestinal symptoms with amitriptyline compared to placebo.14 However, this was not associated with changes in perception of gastric distension, leading the authors to suggest that increased tolerance to aversive sensations may play a role in amitriptyline's therapeutic effect. Preliminary findings suggest that citalopram may improve symptoms and global wellbeing more than placebo in the irritable bowel syndrome, even though acute intravenous administration of citalopram at study entry had no effect on colonic sensitivity.20 Thus, available evidence suggests that the beneficial effects of antidepressants in functional gastrointestinal syndromes may be independent of any direct effect on visceral sensitivity perse, and may relate to changes in the interpretation of symptoms or the importance ascribed to them at the level of the central nervous system.

In conclusion, in this study, the SSRI sertraline had no effect on gastric sensitivity in healthy humans. This finding does not rule out the possibility that SSRIs might affect abnormalities in visceral sensation in functional dyspepsia. Furthermore, a therapeutic effect of SSRIs in functional dyspepsia may exist in the absence of a direct effect on visceral sensitivity. Emerging evidence suggests the SSRIs may be useful in treating functional chest pain and symptoms of the irritable bowel syndrome. Further studies are needed to assess the efficacy of SSRIs in the treatment of functional dyspepsia.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. General study design
  6. Study population
  7. Barostat study
  8. Intra-abdominal pressure
  9. Ascending method of limits: symptoms and volume as a function of pressure
  10. Double random staircase: pressure thresholds for symptoms
  11. Somatic sensory testing
  12. Statistical analysis
  13. Results
  14. Study population
  15. Treatment adherence and blinding
  16. Minimal distending pressure
  17. Symptoms as a function of distending pressure
  18. Gastric compliance
  19. Sensory pressure thresholds
  20. Somatic pain tolerance
  21. Discussion
  22. Acknowledgments
  23. References
  • 1
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  • 2
    Mearin F, Cucala M, Azpiroz F, Malagelada JR. The origin of symptoms on the brain-gut axis in functional dyspepsia. Gastroenterology 1991; 101: 9991006.
  • 3
    Lemann M, Dederding JP, Flourie B, Franchisseur C, Rambaud JC, Jian R. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. The irritable stomach syndrome. Dig Dis Sci 1991; 36: 124954.
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    Bradette M, Pare P, Douville P, Morin A. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone. Dig Dis Sci 1991; 36: 528.
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    Mertz H, Fullerton S, Naliboff B, Mayer EA. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 1998; 42: 81422.
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    Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121: 52635.
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    Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 1994; 107: 27193.
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    Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112: 6472.
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    Mertz H, Morgan V, Tanner G et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000; 118: 8428.
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    Fisher RS, Parkman HP. Management of nonulcer dyspepsia. N Eng J Med 1998; 339: 137681.
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    Clouse RE. Antidepressants for functional gastrointestinal syndromes. Dig Dis Sci 1994; 39: 235263.
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    Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther 1994; 8: 40916.
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    Prakash C, Lustman PJ, Freedland KE, Clouse RE. Tricyclic antidepressants for functional nausea and vomiting: clinical outcome in 37 patients. Dig Dis Sci 1998; 43: 19516.
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    Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol 1998; 93: 1605.
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