1
Using Anti-Depressants
in the IBS Patient
Philip Schoenfeld, MD, MSEd, MSc (Epi)
Associate Professor of Medicine
Director, Training Program in GI Epidemiology
U. of Michigan School of Medicine
2
• Abdominal cramping/bloating & frequent loose,
watery stools with urgency or
hard, pellet-like stools with straining
• Associated nausea/dyspepsia/gerd sxs
are commonly present
• Has had multiple diagnostic tests-all normal
• Has tried fiber, lactose-free diet, elimination of
some foods
• Tried anti-spasmodic agents in low doses (e.g., Bentyl®
10 mg bid),laxative (Miralax® 17gm/day) or anti-
diarrheal (Imodium®) prescribed to use “as needed”
My “Average” Severe IBS Patient
4
• TCAs and SSRIs are more effective than placebo at
relieving global IBS symptoms, and appear to reduce
abdominal pain
• There are limited data on the safety and tolerability of
these agents in patients with IBS
• For IBS-D, use TCAs
• For IBS-C, use SSRIs
Antidepressants: ACG Recommendations
Brandt LJ et al. Am J Gastroenterol. 2009;104 Suppl 1:S1-35.
5
0
20
40
60
80
100
ITT n=201
Desipramine Placebo
TCA vs. Placebo for Moderate
to Severe FGIDs
Drossman DA et al. Gastroenterology. 2003;125:19-26.
Halpert, Am J Gastroenterol. 2005;100:664-669.
P=0.13
(12 weeks) %
Resp
on
ders
60
47
6
TCA vs. Placebo for
Moderate to Severe FGIDs
Drossman, Gastro 2003;125:19
*Halpert, Am J Gastroenterol 2005;100:664
60
73
47 49
0
20
40
60
80
100
ITT n=201 PP n=153
Desipramine Placebo
P=0.13
P=0.006
NNT=4
26% of pts d/c
Desipramine due
to side effects:
constipation,
fatigue
% R
esp
on
ders
(12 wks)
7
TCA vs. Placebo for
Moderate to Severe FGIDs
Drossman, Gastro 2003;125:19
*Halpert, Am J Gastroenterol 2005;100:664
Best response in patients with IBS-D!
60
73
47 49
0
20
40
60
80
100
ITT n=201 PP n=153
Desipramine Placebo
P=0.13
P=0.006
NNT=4
26% of pts d/c
Desipramine due
to side effects:
constipation,
fatigue
% R
esp
on
ders
(12 wks)
8
Meta-analysis: TCAs in IBS
Total events: 132 (treatment), 153 (control)
Test for heterogeneity: X2 = 10.92, df=8, (p=.21), I2 = 26.9%
Test for overall effect: Z=3.86 (p=.0001)
Ford AC et al. Am J Gastroenterol. 2009;104:1831-1843; quiz 1844.
Study
or sub-category
Treatment
n/N
Control
n/N RR (random)
95% CI
Weight
%
RR (random)
95% CI
Heefner 1978
Myren 1982
Nigam 1984
Boerner 1988
Bergmann 1991
Vij 1991
Drossman 2003
Talley 2008
Vahedi 2008
10/22
5/30
14/21
16/42
5/19
14/25
60/115
0/18
8/27
12/22
10/31
21/21
19/41
14/16
20/25
36/57
5/16
16/27
Subtotal (95% CI) 319 256 67.56 0.68 (0.56-0.83)
5.94
2.66
14.74
7.63
3.82
10.67
16.77
0.33
5.02
0.83 (0.46 to 1.51)
0.52 (0.20 to 1.33)
0.67 (0.49 to 0.90)
0.82 (0.50 to 1.36)
0.30 (0.14 to 0.65)
0.70 (0.47 to 1.04)
0.83 (0.63 to 1.08)
0.08 (0.00 to 1.36)
0.50 (0.26 to 0.97)
Tricyclic Antidepressants
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Efficacy of SSRIs in Relieving
Global IBS Symptoms*
*Significant heterogeneity among studies may limit conclusions. Study duration ranged from 6 weeks to 12 weeks.
Ford AC, et al. Gut. 2009;58:367-378.
Study (Year, Drug, Dose) Treatment
n/N
Control
n/N RR (Random) 95% CI
Kuiken (2003, fluoxetine 20 daily) 9/19 12/21
Tabas (2004, paroxetine 10-40 daily) 25/44 36/46
Vahedi (2005, fluoxetine 20 daily) 6/22 19/22
Tack (2006, citalopram 20-40 daily) 5/11 11/12
Talley (2008, citalopram 40 daily) 5/17 5/16
Subtotal (95% CI) 113 117
RR=0.62
(95% CI=0.45-0.87)
0.2 0.5 1 2 5
Favors Treatment Favors Control
0.1 10
Total events: 50 treatments; 83 controls
Test for heterogeneity: Chi2 = 6.46, df = 4, (P=.17), I2 = 38.1%
Test for overall effect: Z = 2.74 (P=.006)
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If I prescribe anti-depressants, then
am I implying that the patient is simply
depressed or anxious and that her IBS
symptoms are “just in her head”?
11
IBS is associated with Symptoms of Dysmotility
and Hypersensitivity
Symptoms of
hypersensitivity
may be the result of
changes in the way
the ENS
communicates
with the CNS.
Symptoms of dysmotility are a result of impaired coordination of the muscles and nerves in the GI tract.
Visceral Sensitivity
Motility Secretion
ENS= Enteric Nervous System
Mayer EA, Raybould HE
Gastroenterology 1990; 99:1688
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Why use Tri-cyclic anti-depressants
(TCA) for IBS-D and use SSRI for IBS-C?
Can I use SSRI for IBS-C?
Can I use TCA for IBS-C?
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Are TCAs, SSRIs, and SNRIs
Different in IBS?
TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;
SNRI=serotonin-norepinephrine reuptake inhibitor (eg, desvenlafaxine, venlafaxine, duloxetine)
Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.
TCAs SSRIs SNRIs
Peripheral pain
modulation ++ ? ++
Central
antinociception +++ + +++
Anxiolysis + +++ +
Motility ++ + ?
Visceral pain +++ ? ?
Sleep ++ — ?
Psychiatric
comorbidities ++ +++ +++
Potential benefits: A comparison
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Are TCAs, SSRIs, and SNRIs
Different in IBS?
TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;
SNRI=serotonin-norepinephrine reuptake inhibitor
Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.
TCAs SSRIs SNRIs
Adverse effects
Sedation
Constipation
Dry mouth/eyes
Weight gain
Hypotension
Sexual dysfunction
Insomnia
Diarrhea
Night sweats
Weight loss
Agitation
Sexual dysfunction
Nausea
Agitation
Dizziness
Fatigue
Liver dysfunction
Time to action
Few days to 2 weeks
(low doses)
2-6 weeks (high doses)
3-6 weeks 3-6 weeks
Efficacy Good Moderate Not adequately studied
Dose adjustments Common Usually not needed Common
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Available Antidepressants
and Dosages for IBS
TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;
SNRI=serotonin-norepinephrine reuptake inhibitor
Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.
TCAs SSRIs SNRIs
Agents
Amitriptyline
Imipramine
Doxepin
Desipramine
Nortriptyline
Fluoxetine
Sertraline
Paroxetine
Citalopram
Duloxetine
Venlafaxine
Desvenlafaxine
Dose range 10-200 mg 10-100 mg
50-400 mg (desvenlafaxine)
30-90 mg (duloxetine)
75-224 mg (venlafaxine)
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• For IBS-C, I start with citalopram (Celexa®) 10 mg daily
• For IBS-D, I start with nortiptyline (Pamelor®) 10-25mg
qhs. I choose the initial dosage based on weight of
the patient
How Do I Use Anti-depressants?
(Experience-Based Medicine)
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• Psychological therapies, including cognitive therapy,
dynamic psychotherapy, and hypnotherapy, but not
relaxation therapy, are more effective than usual care in
relieving global symptoms of IBS (Grade 1B)
Psychological Therapies:
ACG Recommendations
Brandt LJ et al. Am J Gastroenterol. 2009;104 Suppl 1:S1-35.
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• 20 studies (various psychological therapies),
1278 patients
• Significant heterogeneity and funnel plot asymmetry
Psychological Therapy for IBS:
Meta-analysis
Ford AC et al. BMJ. 2008;337:a2313.
Improvement:
Psychological therapy
(%)
Improvement: “Usual
management” or
control therapy (%)
RR symptoms remain
(95% CI)
49.1 27.5 0.67
(0.57-0.79)
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• If concurrent nausea: consider ondansetron (Zofran®)
as a scheduled dose (not on-demand)
• Use other meds for neuropathic pain: gabapentin
(Neurontin®) 300mg daily and escalate dose as
tolerated
• If using anti-spasmodics, use higher doses of
dicyclomine (Bentyl®) or hyoscyine (Levsin®) or
consider Librax® (chlordiazepoxide & clinidium bromide)
• The importance of a therapeutic patient-physician
relationship shouldn’t be underestimated
What else can be done?
(Experience-based medicine)