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Patients with functional GI disorders (FGIDs) are commonplace in the gastroenterologist's practice. A number of these patients may be refractory to peripherally acting agents, yet respond to central neuromodulators. There are benefits and potential adverse effects to using TCAs, SSRIs, SNRIs, atypical antipsychotics, and miscellaneous central neuromodulators in these patients. These agents can benefit mood, pain, diarrhea, constipation, nausea, sleep, and depression. The mechanisms by which they work, the differences between classes and individual agents, and the various adverse effects are outlined. Dosing, augmentation strategies, and treatment scenarios specifically for painful FGIDs, FD with PDS, and chronic nausea and vomiting syndrome are outlined.Am J Gastroenterol advance online publication, 28 March 2017; doi:10.1038/ajg.2017.57.
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© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
Central neuromodulators can bene t the more challenging and
refractory functional gastrointestinal disorders (FGIDs) ( 1–5 ).
Rome IV considers FGIDs to be disorders of gut brain interaction.
e enteric nervous system (ENS) is hardwired to the CNS in a
way that neuroreceptors share similar neurotransmitters and psy-
chiatric drugs can be used to treat disorders of both the gut and
brain. Yet gastroenterologists are reluctant to use them because of
the stigma attached to them or because they feel ill prepared to
use them. Indeed a patient asked to take an “antidepressant” or
“atypical antipsychotic” may develop false perceptions of their
intended use: that they are depressed, “crazy”, or that the medi-
cation will alter their thinking and behavior.  e growing  eld
of neurogastroenterology now requires that we consider chang-
ing these names to that of neuromodulators or centrally targeted
agents to be more consistent with their actions on brain–gut
pathways.  is article is a primer to help gastroenterologists
understand how best to use central neuromodulators to optimize
patient care. We have made e orts to clarify how these agents can
be used speci cally for various symptom clusters or FGIDs.
ere are a number of ways in which central neuromodulators
can help patients with functional gastrointestinal disorders. First,
many patients with FGIDs experience co-morbid anxiety or other
types of psychological distress and these neuromodulators help
reduce psychological distress, anxiety, hyper vigilance, selec-
tive attention, and catastrophizing associated with the GI symp-
toms ( 6–8 ). Second, they treat associated psychiatric diagnoses,
like major depression ( 1 ).  ird, they can reduce pain by down
regulation of incoming visceral signals via gating mechanisms
( 9,10 ). Fourth, clinicians can take advantage of their e ects on GI
motor function i.e., selective serotonin reuptake inhibitors (SSRIs)
improve constipation by accelerating intestinal transit and tricy-
clic antidepressants (TCAs) improve diarrhea by slowing transit.
Fi h, providers can bene t from the action of several of these
neuromodulators to help address symptoms like nausea ( 11–13 ).
Sixth, over time, depression, anxiety, and other forms of chronic
emotional distress are believed to lead to a loss of cortical neuron
density and central neuromodulators may reverse this process via
neurogenesis ( 14 ). Longer treatment with central neuromodu-
lators leads to an increase in BDNF (brain-derived neurotropic
factor) and presumably increased neurogenesis ( 15 ).
Gastroenterologists, while not trained in the use of psycho-
pharmacological treatments, may want to consider their use
when treating patients with FGIDs, and this article provides
some guidelines. Nevertheless, none of the psychopharmaco-
logical treatments have undergone su cient trials by FDA to be
approved for painful FGIDs by FDA or other regulatory agencies.
Regulatory approval for these treatments has now lagged behind
the rationale for their use based on our growing knowledge of
neurogastroenterology and the results, including meta-analyses
of a limited number of available clinical studies targeted to these
disorders. However, many if not most other non-psychopharma-
cologic medications used to treat FGIDs are also utilized in an o
label manner, and are based on compelling clinical wisdom.  us
Central Neuromodulators for Treating Functional GI
Disorders: A Primer
W. H a r l e y S o b i n , M D 1 , omas W. Heinrich , MD, FAPM 2 and Douglas A. Drossman , MD, MACG 3
Patients with functional GI disorders (FGIDs) are commonplace in the gastroenterologist's practice. A number of
these patients may be refractory to peripherally acting agents, yet respond to central neuromodulators. There are
benefi ts and potential adverse effects to using TCAs, SSRIs, SNRIs, atypical antipsychotics, and miscellaneous
central neuromodulators in these patients. These agents can benefi t mood, pain, diarrhea, constipation, nausea,
sleep, and depression. The mechanisms by which they work, the differences between classes and individual agents,
and the various adverse effects are outlined. Dosing, augmentation strategies, and treatment scenarios specifi cally
for painful FGIDs, FD with PDS, and chronic nausea and vomiting syndrome are outlined.
Am J Gastroenterol advance online publication, 28 March 2017; doi: 10.1038/ajg.2017.57
1 United Hospital System , Kenosha , Wisconsin , USA ;
2 Department of Psychiatry, Medical College of Wisconsin , Milwaukee , Wisconsin , USA ;
3 Center for Education
and Practice of Biopsychosocial Care and Drossman Gastroenterology , Chapel Hill , North Carolina , USA . Correspondence: W. Harley Sobin, MD, United Hospital
System , 6308 8th Avenue, Suite 202 , Kenosha , Wisconsin 53143-5031 , USA . E-mail:
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017
the recommendations made are derived from the available studies
using these central neuromodulating agents for FGIDs (clinical
trials and case series), as well as a larger number of studies relating
to the treatment of chronic somatic pain, or of psychiatric disor-
ders, and personal experience over several decades with their use.
e purpose of this article is to provide expert recommendations
for the choice of central neuromodulators for FGIDs rather than
provide detailed systematic reviews. However, general evidence
is provided via the largest clinical analysis of the use of central
neuromodulators in functional gastrointestinal disorders.  is
meta-analysis by Ford et al. ( 16 ) analyzed almost 1,100 IBS
patients treated with antidepressants. Looking at TCAs there was
improvement in 57% receiving medication while placebo treated
patients improved 36% of the time. With SSRIs there was improve-
ment in 55% but only 33% receiving placebo.  e number needed
to see improvement in one patient with both classes of drugs was
4. But the bene t was associated with increased side e ects.  ere
were adverse side e ects in 31% of those treated with antidepres-
sants but only 16% of those treated with placebo. What follows
is information where selected medications are recommended for
selected conditions, and systematic reviews at that level of discus-
sion are not available.
Central neuromodulators involve a number of neuroreceptors,
and neurotransmitter transporters ( 17 ).  e key monoamine
neurotransmitters released by neurons include serotonin, nor-
epinephrine, and dopamine. Transporters function to allow for
reuptake of the monoamines back into the neurons a er neuro-
transmission occurs thereby terminating their action and allow-
ing the neurotransmitters to be reutilized. If the action of the
transporters is inhibited there is a subsequent rise in the level of
these monoamines outside of neurons. A key element of many
neuromodulators is to inhibit transporter reuptake of monoam-
ines, thus maintaining neurotransmitter action in the synaptic
cle . For example, the resulting increase of serotonin levels in the
central nervous system by serotonin reuptake inhibitors is thought
to play a role in the treatment of major depression and a variety of
anxiety disorders, although the exact mechanism of this response
has not yet been fully elucidated. Medications that increase both
serotonin and norepinephrine levels have also been shown to help
promote analgesia and treat painful conditions such as  bromy-
algia and neuropathic pain.  ose agents that increase dopamine
levels have a tendency to have a more stimulating e ect on the
patient thereby decreasing sedation.
Several of the key transporters and neuroreceptors are noted
below. A more detailed listing is in Table 1A .
SERT (serotonin transporter) removes serotonin from the synap-
tic cle . SERT inhibition leads to increased levels of serotonin.
Increasing the levels of serotonin has been associated with the
bene cial e ect of treating depression, but is also associated with
the adverse e ects of nausea, and diarrhea. SERT inhibition is
potent in all SSRIs, serotonin and norepinephrine reuptake inhib-
itors (SNRIs), and, to a lesser extent, all TCAs.
NET (norepinephrine transporter) removes norepinephrine from
the synaptic cle . NET inhibition has been linked to the promo-
tion of analgesia and the treatment of depression. Increased nor-
epinephrine may also contribute to a sense of activation and other
sympathomimetic e ects. It is mildly constipating. It is present in
all SNRIs and TCAs, but, of note, is absent in SSRIs.
Table 1A . Action of central neuromodulators on different transporters and receptors
Transporter or receptor Stimulate or inhibit Action Clinical Adverse effects Drug class
SERT (t) Inhibit serotonin
Increase serotonin AD Antianxiety Nausea diarrhea SSRI SNRI TCA
NET (t) Inhibit norepinephrine
Increase norepinephrine AD and analgesic Dry mouth sweats
DAT (t) Inhibit dopamine
Increase dopamine Increase activation Nausea Buproprion, sertraline
D2 Receptor antagonist Decrease dopamine Antipsychotic Antiemetic EPS galactorrhea All antipsychotics
5HT1 Receptor agonist Stimulate 5HT1 AD and improves gastric
5HT2A Receptor antagonist Increase dopamine in
striatum +pituitary
Antipsychotic without EPS
or galactorhea
Atypical antipsychotics
5HT3 Receptor antagonist Inhibit 5HT3 Less nausea, diarrhea,
Mirtazapine, olanzapine,
AD, Antidepressant, DAT, dopamine transporter; NET, norepinephrine transporter; SERT, serotonin transporter; SNRI, serotonin and norepinephrine reuptake inhibitor;
SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
Treating Functional GI Disorders: A Primer
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
DAT (dopamine transporter) removes dopamine from the synap-
tic cle . DAT inhibition increases dopamine levels.  is increase
can be associated with activation and treatment of depression,
but has also been linked to the adverse e ect of nausea. Of note,
excess dopamine might lead to psychosis.
D2 receptor
Inhibition of this receptor is thought to be responsible for the
antipsychotic e cacy of most of the antipsychotic medications. In
addition, inhibition of the D2 receptor may also improve nausea
and is part of the mechanism of action of metoclopramide and
domperidone. D2 receptor antagonism is also responsible for the
extrapyramidal side e ects experienced by some patients treated
with this class of medications.
5HT1 receptor
Stimulation of this receptor is thought to play a role in the
treatment of anxiety and depression. It has also been shown to
improve gastric compliance and accommodation. Buspirone is
an example ( 18 ). Sumatriptan is a well-known 5HT1 agonist that
is not a central neuromodulator, but helps to relax the gastric
5HT3 receptor
Stimulation of this receptor has been linked to increased levels of
pain, nausea and diarrhea. A number of central neuromodulators
inhibit 5HT3. Several antiemetic drugs: ondansetron, dolasetron,
and granisetron relieve nausea by inhibiting 5HT3. Alosetron
blocks pain and reduces diarrhea by inhibiting 5HT3.  e neuro-
modulators mirtazapine ( 19,20 ) and olanzapine, which both
inhibit 5HT3, have been used to treat chronic nausea.
A number of central neuromodulators act on receptors leading
to undesirable side e ects (more detailed in Table 1B ):
M1 receptor
Antagonism of the muscarinic receptor is responsible for anti-
cholinergic side e ects, such as dry mouth and constipation.
ere is M1 inhibition with all TCAs and also paroxetine, an SSRI.
While most SSRIs cause diarrhea, paroxetine is the SSRI most
likely to cause constipation, due to its M1 inhibition. All TCAs are
associated with constipation.
H1 receptor
H1 inhibition is associated with sedation and weight gain. H1
inhibition occurs with all TCAs and a number of atypical anti-
What follows is general information about the use of the various
classes of neuromodulators followed by clinical recommenda-
tions for the gastroenterologist.  is includes tables of the dif-
ferent neuromodulators used in GI with dosages ( Tabl e 2 ) and
a listing of which neuromodulators to choose for di erent
symptom complexes in patients with FGIDs ( Tabl e 3 ). In addi-
tion, for each medication type we summarize the information
by o ering our clinical recommendations. Finally, we provide in
the Appendix hierarchical treatment algorithms to address pre-
dominant symptoms of pain, dyspepsia, and nausea/vomiting.
However, when using unfamiliar medications or treatments in
combination (i.e., augmentation), psychiatric consultation should
be considered.
TCAs are central neuromodulators that have been used for many
decades in psychiatry to treat depression, but newer agents have
largely supplanted their use. Currently the TCAs are prescribed
in low dosages (e.g., 25–75 mg/day in the medical setting vs.
200–300 mg/day in the psychiatric setting) to treat various pain-
ful conditions or to act as a sleep aid. With regard to GI practice,
TCAs are used most frequently to treat IBS-D. However, they can
be used for many other painful FGIDs including centrally medi-
ated abdominal pain syndrome (CAPS-formerly FAPS), func-
tional chest pain, anorectal pain, and functional dyspepsia.  e
bene cial e ects of TCAs have been linked to their inhibition
of SERT and NET.  ere may be adverse e ects due to inhibi-
tion of M1, H1, alpha 1 adrenergic (leading to postural hypoten-
sion), and cardiac fast sodium channel receptors (in high doses
may cause arrhythmias). TCAs are more e ective than SSRIs in
reducing pain ( 10,21,22 ).  e anticholinergic properties of this
class of medications may be a bene t in patients experiencing
diarrhea.  e H1 inhibition may bene t those patients su ering
from insomnia.
Table 1B . Central neuromodulators-receptor actions with undesirable side effects
Receptor Action Adverse effect Drug class
M1 Antagonist Anticholinergic Dry mouth, constipation All TCAs, paroxetine
H1 Antagonist Antihistaminic Lethargy, weight gain All TCAs, many antipsychotics
Alpha 1 adrenergic Antagonist Decrease adrenergic tone Postural hypotension All TCAs some antipsychotics
Cardiac fast sodium channels Antagonist Slow cardiac conduction Cardiac arrhythmia All TCAs
TCA, tricyclic antidepressant.
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017
As a result of TCA’s propensity to cause sedation and ortho-
stasis they should be administered at night.  e initial dose and
titration schedule of the various TCAs is similar, however, tertiary
amines (amitriptyline and imipramine) have more side e ects
because of their greater antagonism of cholinergic, adrenergic, and
histamine receptors. Dosing can start at 25 mg, going up to 50 mg
a er a week if well tolerated by the patient and if needed increased
to 75 mg. If there is insu cient bene t a er a month at this low
dose, the TCA dose can be further increased. Doses up to 150 mg
have been studied in functional GI disorders ( 23 ). In patients with
FGIDs, most early side e ects reported by patients, other than
the expected anticholinergic side e ects, correlate more with the
patient’s underlying level of anxiety than the TCA blood levels or
the number of pills taken ( 24 ).
Patients should be informed that anticholinergic side e ects
occur early in the treatment course. However, the patient should
be encouraged to adhere to the treatment course because it might
take a month to experience the full bene t of the medication and
side e ects tend to become more tolerable over time.
It should be noted that TCAs, due to their inhibition of cardiac
fast sodium channels leading to a prolongation of the refractory
period of the cardiac action potential, are classi ed as class 1A
antiarrhythmic agents.  ey may, therefore, pose a proarrhyth-
mic risk in certain patients.  ey should be avoided in patients
at risk for a cardiac arrhythmia, including those with a history
of myocardial infarction, le bundle branch block, bifascicular
block, or patients with a prolonged QT interval.  erefore a
baseline ECG should be checked prior to initiation of a TCA in
patients at risk for cardiac conduction abnormalities and in all
pediatric patients.
TCAs should be considered  rst line for treating pain in patients
with IBS, CAPS, or other painful FGIDs.  ey should be pre-
scribed in moderate dosages (25 mg building up to 75 or 100 mg).
Because secondary amine TCAs (e.g., desipramine, nor triptyline)
have less anticholinergic and antihistaminic side e ects when
compared with tertiary amine TCAs (amitriptyline, imipra-
mine), they are favored to allow for higher dosages to manage the
pain. All TCAs can also be helpful in reducing diarrhea such as
with IBS-D though this e ect is greater with the tertiary amines.
SSRIs are not primary agents for treating pain but may be used in
patients with painful FGIDs already receiving a TCA but who are
poorly controlled due to associated anxiety symptoms ( 3 ).  ey
may also bene t patients with FGIDs and comorbid panic disor-
der, generalized anxiety disorder, depression, social anxiety, spe-
ci c phobias, or a somatic symptom disorder. Patients who exhibit
selective attention to their symptoms or who are hyper vigilant to
worsening symptoms may also bene t from an SSRI.
SSRIs may be used, in lieu of a TCA, to manage a patient who
has IBS-C when pain is not a dominant feature. SSRIs are more
likely to cause diarrhea while TCAs tend to be constipating. When
pain is dominant, one would choose a TCA or SNRI over an SSRI.
Nevertheless, unlike studies on chronic abdominal pain or dys-
pepsia, SSRIs were found e ective in small controlled studies of
patients with functional chest pain using sertraline 50 mg ( 25 ),
paroxetine 10–50 mg ( 26 ), and citalopram 20 mg ( 27 ).
When choosing between SSRIs, the medications sertraline,
citalopram, and escitalopram tend to have the fewest pharmaco-
kinetic drug–drug interactions as they exhibit minimal e ects on
the cytochrome P450 enzyme system. Fluoxetine and paroxetine,
however, have an increased risk of pharmacokinetic drug inter-
actions through their strong inhibition of the P450 isoenzymes
1A2 and 2D6 ( 28 ). In addition,  uoxetine, and its active metabolite
Table 2 . Central neuromodulators-dosage
Generic Rx name Brand Rx name Dosage
Amitriptyline Elavil 25–150 mg qd
Desipramine Norpramin 25–150 mg qd
Imipramine Tofranil 25–150 mg qd
Nortriptyline Pamelor 25–150 mg qd
Citalopram Celexa 10–40 mg qd
Escitalopram Lexapro 5–20 mg qd
Fluoxetine Prozac 10–40 mg qd
Paroxetine Paxil 10–40 mg qd
Sertraline Zoloft 50–150 mg qd
Duloxetine Cymbalta 30–90 mg qd
Minacipran Savella 50–100 mg bid
Venlafaxine Effexor 75–225 mg qd
Buproprion Wellbutrin 100–150 mg bid
Buspirone Buspar 15–45 mg bid
Mirtazapine Remeron 7.5–45 mg qd
Trazodone Desyrel 75–150 mg qd
Aripiprazole Abilify 2.5–5 mg qd
Brexipiprazole Rexulti 1–1.5 mg qd
Lurasidone Latuda NS*
Olanzapine Zyprexa 2.5–10 mg qd
Quetiapine Seroquel 25–200 mg qd
Ziprasidone Geodon NS*
SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin
reuptake inhibitor; TCA, tricyclic antidepressant.
*NS—drugs not prescribed by gastroenterologists.
Treating Functional GI Disorders: A Primer
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
SSRI’s are not  rst line treatments for painful FGIDs. How-
ever they can provide bene t when anxiety related symptoms
(symptom related anxiety, symptom hyper vigilance, obsessive
behaviors, social phobia, or agoraphobia) are dominant. If pain
is also present, SSRI’s in low dose can be added to a TCA. SSRI’s
can also help to improve constipation. Escitalopram may be
the preferred SSRI based on tolerability and fewest drug inter-
actions, with citalopram as a preferred alternative.
SNRIs are agents indicated for treating painful somatic syn-
dromes including diabetic neuropathy,  bromyalgia and chronic
musculoskeletal pain.  eir value for visceral pain has not been
adequately studied, but they are commonly used for this purpose
o label with empiric bene t ( 29–31 ) eir value relates to a lower
side e ect burden than the TCA’s with similar pain reduction ( 32 ).
SNRIs can be prescribed as primary agents for treating painful
FGIDs.  ey may also be utilized in patients with painful FGIDs
who failed an initial trial of a TCA or experienced intolerable side
e ects from the TCA that precluded them from reaching a poten-
tially therapeutic dose. SNRIs are used to treat centrally mediated
abdominal pain (CAPS), formerly functional abdominal pain
(FAPS) ( 33,34 ), functional chest pain, and IBS and other FGIDs
with associated abdominal wall pain or  bromyalgia. SNRIs can
also be used in IBS-C.  ey are less constipating than TCAs and
bring more pain relief than SSRIs. Dosing: duloxetine 30–90 mg
qd, and milnacipran-50–100 mg bid. Although another SNRI,
nor uoxetine, have an additive half-life of 10–12 days, making
SSRI discontinuation syndrome (discussed later) a rarity in
patients taking this medication.  us, uoxetine can be a useful
medication for patients who may miss doses of this central neuro-
modulator. In contrast, paroxetine has a short half-life of less than
a day and is commonly implicated in cases of discontinuation
syndrome when stopped abruptly. Citalopram, escitalopram, and
sertraline all exhibit half-lives of longer than a day, but still require
a gradual taper to avoid the uncomfortable symptoms of SSRI
discontinuation syndrome.
Dosing: citalopram 10–40 mg, escitalopram 5–20 mg,  uoxetine
10–40 mg, paroxetine 10–40 mg, sertraline 25–150 mg.
Even though SSRIs are  rst line pharmacologic agents for the
treatment of anxiety disorders they have the potential, when the
drug is  rst started, to induce restlessness and exacerbate anxi-
ety. To minimize these potential anxiogenic adverse e ects they
are typically initiated at half of the usual starting dose.  e dose
may then be gradually increased a er about 1 week to the regular
starting dose.  e bene cial e ect of the SSRI is usually delayed
3–4 weeks, which may represent a problem for those patients
with signi cant anxiety that is complicating treatment and
causing signi cant functional impairment. In such cases, a useful
strategy is to schedule a long-acting benzodiazepine to tempo-
rarily “bridge” this lag-time and provide symptomatic relief for
the patient’s anxiety symptoms.  e benzodiazepine should then
be tapered o a er about 4 weeks of SSRI treatment. Clonazepam
at a scheduled dose of 0.25–0.5 mg bid is o en utilized in this
“bridging” period.  e longer half-life of clonazepam helps pre-
vent break-through anxiety and allows for an easier taper o the
Table 3 . Choosing and avoiding central neuromodulators for FGIDs based on associated symptoms
Symptom/syndrome Choose Avoid
a TCA, SNRI, quetiapine Narcotics
Chronic nausea and vomiting syndrome Mirtazapine, olanzapine, TCA SSRI, SNRI, buproprion, topirimate
Functional bloating TCA, buspirone, SSRI
Functional chest pain Trazodone, venlafaxine, SSRI, TCA
Functional constipation SSRI (not paroxetine), SNRI TCA, paroxetine
Functional diarrhea TCA, SNRI, paroxetine
Functional Dyspepsia (PDS) Buspirone, mirtazapine, TCA
Globus SSRI
Hyper vigilance SSRI, SNRI, short-term clonazepam Long term use of benzodiazepines
IBS-C SSRI (not paroxetine), SNRI TCA, paroxetine
IBS-D TCA, SNRI, paroxetine Other SSRIs
Insomnia Quetiapine, mirtazapine, trazodone Buproprion, sertraline, fl uoxetine
Lethargy Buproprion, sertraline, fl uoxetine TCA, mirtazapine, olanzapine, paroxetine, quetiapine, trazodone
CAPS, centrally mediated abdominal pain; FAPS, functional abdominal pain; FGID, functional gastrointestinal disorder; PDS, postprandial distress syndrome; SNRI,
serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
a Centrally mediated abdominal pain syndrome, previously FAPS.
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017
weight gain compared to quetiapine. Although studied extensively
in psychiatry the evidence for using these drugs to treat FGIDs is
still empiric.
Olanzapine has been used in oncology, anesthesiology, and now
gastroenterology to treat chronic nausea due to its 5HT3 and D2
inhibition.  ere is a full description of its use in the section on
Central Neuromodulators and Nausea.
Atypical agents, in particular quetiapine in low dosage (e.g.,
25–100 mg qhs), are used to augment the pain bene t of TCAs
or SNRIs. Quetiapine has the added bene t of producing normal
restorative sleep and anxiolysis. If weight gain or excessive seda-
tion occurs and can’t be managed by dose titration, a less sedating
atypical agent (e.g., aripiprazole or brexpiprazole) can be substi-
tuted to augment the pain bene t and achieve anxiety reduction.
When nausea is a dominant feature olanzapine can be considered.
Buspirone is a 5HT1A agonist. It is a non-benzodiazepine anti-anxiety
neuromodulator that also acts to improve gastric compliance ( 18 ).
By enhancing gastric fundic relaxation it is useful in patients with
functional dyspepsia with post-prandial distress syndrome ( 18 ).  e
usual dose in treating functional dyspepsia is 15–45 mg bid.
Trazodone blocks 5HT2 receptors and serotonin reuptake. It has
been found useful in gastroenterology treating functional chest
pain ( 39 ). e usual dose is 75–150 mg HS. It is most o en utilized
in psychiatry to treat insomnia.
Mirtazapine is a selective alpha-2 adrenergic agonist that also
blocks 5HT2, 5HT3, and H1 receptors. Due to its receptor pro le
it is a powerful agent in gastroenterology for managing chronic
nausea, dyspepsia, and weight loss ( 19 ). In addition, its antihis-
taminergic properties make it a useful medication for addressing
insomnia.  e usual e ective dose is 15–45 mg qhs.
Buspirone may be used for post-prandial distress syndrome
variant of functional dyspepsia in doses up to 30–45 mg bid,
and to also help with mild anxiety reduction. Mirtazapine
15–45 mg can be used for functional dyspepsia (alone or in
combination with buspirone) or to treat nausea and reduced
appetite associated with weight loss or sleep disturbance. Tra-
zodone 75–150 mg qhs can be considered for functional chest
pain or to treat sleep disturbance.
Among their other e ects on various receptors mirtazapine and
olanzapine are both potent 5HT3 inhibitors with long half-lives
that allow for once daily dosing to manage nausea.  ese drugs
venlafaxine, is dosed for depression at 75–225 mg, it acts primar-
ily as an SSRI at lower doses, and needs to be prescribed at higher
doses (150 mg or more per day) to achieve adequate noradren-
ergic bene t via NET inhibition for treating pain.  is is not the
case with duloxetine, which acts as an SNRI throughout the dose
Venlafaxine has also been studied in treating functional dyspep-
sia ( 35 ). However, the SNRIs tend, in general, to have a higher fre-
quency of nausea, especially venlafaxine. Milnacipran is indicated
for  bromyalgia and other chronic somatic pain syndromes. It is
an SNRI but is not marketed for depression and is titrated up to
doses of 50–100 mg bid.  is may encourage acceptance by some
patients who are concerned about using “a psychiatric drug”.
SNRI’s are used as  rst line treatment for pain management with
fewer side e ects than TCA’s and can be used in patients with
constipation. Nausea may occur but can be minimized when
taken with meals. Duloxetine has been favored in dosages of
30–60 or up to 90 mg/day but venlafaxine can be used in higher
dosages (>150 mg/day). As an alternative milnacipran can also
be considered for pain, titrating the dose up to 50–100 mg bid.
e second-generation antipsychotics, such as quetiapine, ari-
piprazole, or olanzapine, are o en called atypical antipsychotics,
because they don’t present the same risk of extrapyramidal side
e ects (such as dystonic reactions or parkinsonism) when com-
pared to the older (typical) antipsychotics like haloperidol.  e
multiple atypical antipsychotics have varied clinical indications.
All are approved for schizophrenia while some have additional
indications for bipolar disorder and treatment resistant depres-
sion. Many of these agents have also been used for various “o -
label” psychiatric indications such as treatment refractory anxiety,
personality disorders, and insomnia although the evidence for
such use is limited ( 36 ).
ese agents are also used in gastroenterology as second line aug-
menting agents for various FGIDs. Quetiapine has been used as an
augmenting agent in patients with painful IBS or CAPS who did not
respond to treatment a er 4 or more weeks with TCAs or SNRIs
and have adjunctive bene t for reducing symptom related anxiety
and normalizing sleep architecture ( 37 ). Low doses, 25–100 mg are
given nightly, but can be increased to 200 mg for patients with severe
anxiety, sleep disturbance, or pain. It helps relieve pain by inhibiting
NET. D2 inhibition helps relieve nausea ( 38 ).
Quetiapine has a very low rate of associated extrapyramidal side
e ects and hyperprolactinemia, but it has an intermediate risk of
metabolic e ects (obesity, hyperlipidemia, and diabetes).
For patients who develop too much weight gain or lethargy on
quetiapine, from personal experience aripiprazole 2.5–5 mg or
brexpiprazole at 1–1.5 mg can be substituted as pain augmenting
agents and to help reduce the anxiety component of FGID pain.
ese agents have a reduced propensity to cause sedation and
Treating Functional GI Disorders: A Primer
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
can be very e ective in patients who have functional dyspepsia
( 19,20 ) and chronic nausea vomiting syndrome. Generic mir-
tazapine also has the bene t of being inexpensive, helps with
sleep, anxiety, and depression. A typical starting dose can be
7.5 mg with a usual therapeutic dose of 15–45 mg (rarely 60 mg)
given at nighttime.  e major side e ect is daytime sedation and
weight gain. Mirtazapine has been used extensively in oncology
for managing nausea associated with chemotherapy ( 11,12 ) and
also in anesthesiology. Some patients, however, are intolerant of
even low doses.
Olanzapine has also been used in managing challenging nausea
in anesthesiology and oncology ( 13 ). It is generally used as a second
line drug for chronic nausea vomiting syndrome. Olanzapine, due
its dopamine antagonism, may be used in patients who initially
respond to mirtazapine and then have break-through nausea, or
in patients who fail to respond to mirtazapine. Olanzapine may
also be less sedating for those patients who  nd mirtazapine overly
sedating. Typical starting dose of 2.5 mg with a therapeutic dose of
5–10 mg. Olanzapine may lead to adverse metabolic consequences,
including weight gain, hyperlipidemia, and diabetes, along with a
potential for neurological adverse e ects including akathisia and
dystonic reactions.  ese e ects are unusual at the lower doses
recommended in the treatment of FGIDs.
For patients who have only occasional, or intermittent nausea
we recommend ondansetron 4.0–8.0 mg or promethazine 12.5
to 25 mg up to q6h. For patients requiring long term control
of nausea or vomiting mirtazapine 15 to 45 mg qhs should be
considered, with olanzapine 2.5 to 10 mg qd as a second line
drug, If mirtazapine is not tolerated due to lethargy, or proves
ine ective, consider substituting olanzapine.
Side effects of central neuromodulators
e more common side e ects of central neuromodulators are descri-
bed below and have been extensively outlined previously ( 17,40,41 ).
Nausea and vomiting . e newer atypical antipsychotics aripipra-
zole, lurasidone, and ziprasidone may be commonly associated
with nausea and occasionally vomiting, while the atypical agents
previously discussed, quetiapine and olanzapine, more commonly
help improve nausea and vomiting but may produce weight gain
and metabolic syndrome. If a patient on the newer neuromodula-
tors has moderate to severe nausea or vomiting it is reasonable to
switch to olanzapine or quetiapine.
Bupropion, an antidepressant, and topirimate, an antiepi leptic
medication, have both been employed to prevent weight gain but
have been associated with increased rates of nausea. Finally, most
SSRIs and SNRIs can be associated with nausea, particularly early
in the course of treatment.  is adverse e ect may be mitigated
by recommending that the patient take the medication with food.
Alteration of bowel movements . Most all SSRIs can cause diar-
rhea. Paroxetine, however, has more anticholinergic e ects, so
diarrhea is not an expected side e ect and can be considered
for patients with IBS-D. All TCAs are constipating although
the tertiary amine agents (e.g., amitriptyline, imipramine)
are more constipating than the secondary amine agents (e.g.,
amitriptyline, imipramine). Some atypical antipsychotics (e.g.,
olanzapine) can be constipating due to greater anticholinergic
Alteration of energy levels . A number of neuromodulators can
cause excess sedation.  ese include all TCAs, paroxetine, mir-
tazapine, olanzapine, and quetiapine. Other neuromodulators
tend to be more activating.  ese include  uoxetine, sertraline,
and bupropion.
Sexual dysfunction . Sexual dysfunction is a common adverse ef-
fect associated with medications that inhibit SERT. Paroxetine has
been found to have a higher incidence than comparable central
neuromodulators. TCAs are unlikely to cause sexual dysfunction,
in the low doses usually used to treat FGIDs. Of the various cen-
tral neuromodulators, bupropion and mirtazapine are least likely
to cause sexual dysfunction. Trazodone has been linked to rare
cases of priapism.
Unmasking a bipolar disorder . Some patients who present with
depression may actually have an occult bipolar illness, and start-
ing a central neuromodulator may cause some patients to “cycle
into a hypomanic or manic episode, thereby exposing an underly-
ing bipolar disorder.  is switch from depression to mania usually
occurs fairly abruptly within the  rst couple of weeks of central
neuromodulator use.  is is unlikely to occur while using low-
dose TCAs for the treatment of a FGID, but may become more
common with higher dose SSRIs or SNRIs. If, a er the initiation
of a central neuromodulator, a patient were to start developing
signs of mania or hypomania (excess energy, rapid speech, eu-
phoria, impulsivity, and insomnia) the central neuromodulator
should be discontinued and the patient referred to a psychiatrist
for an evaluation for an underlying bipolar disorder.
GI bleeding . SSRIs may predispose to GI bleeding.  ey block
serotonin reuptake by platelets, thereby inhibiting serotonin-
mediated platelet aggregation. Two di erent studies addressed
this issue.  e earlier one, by Loke ( 42 ), found an increased odds
ratio of GI bleeding of 2.36 in patients on SSRIs alone or 6.33 if
they were on SSRIs and NSAIDS. A more recent review, by Anglin
( 43 ) found a smaller increased risk, 1.66 if on SSRIs or 4.25 if on
SSRIs and NSAIDS. Richter found that use of SSRIs within 24 h of
PEG placement was associated with a fourfold-increased risk of
post procedural GI bleeding ( 44 ).
NSAIDs should be avoided in patients on SSRIs. If the combina-
tion is necessary, PPIs are recommended. It is generally not practi-
cal to stop SSRIs prior to GI procedures. In many cases it would
require stopping them days in advance due to the long half-lives
and the potential of active metabolites.  e abrupt discontinua-
tion could also be associated with antidepressant discontinuation
syndrome. For patients who are at very high risk of GI bleeding
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017
alternative central neuromodulators, such as mirtazapine or
bupropion, may be preferable.
Serotonin syndrome . Serotonin syndrome ( 45 ) represents the
constellation of symptoms associated with serotonin toxicity.
Symptoms of serotonin syndrome may include fever, muscle
rigidity, tremors, confusion, tachycardia, seizures, and pupillary
It is most commonly implicated when two or more serotoni nergic
medications are administered to a patient, although it has been
reported when a high dose of a single serotonergic medication is
prescribed. Notably agents high in serotonin e ect (e.g., SSRI) when
compared to agents low in serotonin e ect (e.g., TCAs) are more
likely to cause the syndrome.  e onset of symptoms and signs o en
occurs soon a er dose escalation of a serotonergic medication or
the addition of another medication that increases serotonin levels.
It is important to recognize that central neuromodulators are not
the only medications that increase serotonin levels.  e triptans,
tramadol, ondansetron, and the antibiotic linezolid have also been
implicated in cases of serotonin syndrome. If signs or symptoms of
serotonin syndrome develop, all medications with serotoninergic
properties should be discontinued and restarted later in lower dose
or with another medication, or if symptoms are mild, can be reduced
and observed for resolution of side e ects.
Hepatotoxicity . Central neuromodulators are generally well tol-
erated in patients with liver disease unless there is advanced cir-
rhosis. However, most patients with stable NAFLD or hepatitis
C should have little risk of liver toxicity. In patients with decom-
pensated cirrhosis all sedating drugs need be avoided, and dos-
ing frequently has to be decreased. Idiosyncratic drug reactions
have occasionally been reported with many di erent central
neuromodulators. Duloxetine is one of the more common, with
7/899 of the cases of severe hepatotoxic drug reactions reported
in the latest DILI network publication ( 46 ). However, central
neuromodulators are more likely to cause liver injury due to the
propensity of certain agents to cause weight gain and metabolic
syndrome, thereby worsening NAFLD.
e abrupt discontinuation of serotonergic central neuromodu-
lators (principally SSRIs and SNRIs) may be associated with an
antidepressant discontinuation syndrome.  e syndrome consists
of a variety of somatic complaints including nausea, headache,
and paresthesias. It is more common in agents with a shorter half-
life (such as paroxetine) and gradual taper of serotonergic central
neuromodulators is o en warranted to avoid this unpleasant syn-
drome. If discontinuing the central neuromodulator is planned,
it is advisable that the neuromodulator be tapered o slowly over
4-weeks (25% per week). However, if the patient has been on
the central neuromodulator for less than 4 weeks it is usually not
necessary to taper the neuromodulator.
Short-term use of clonazepam at a dose of 0.25–0.5 mg bid may
enhance tolerance of SSRIs and SNRIs. In tapering the medicine
it is best to discontinue the morning dose for a week then discon-
tinue the evening dose.
is article reviews the use of central neuromodulators in patients
with refractory FGIDs having symptoms of pain, nausea and vomit-
ing and comorbid anxiety and depression.  ey are to be considered
when patients have been treated with peripherally acting drugs but
still remain symptomatic. Central neuromodulators can be considered
as second line therapy or can be used to augment the e ect of peri-
pheral agents. Furthermore, these agents are also used to treat anxiety
and depression and thus may achieve dual purpose for patients with
co-morbid psychological distress.  us augmentation may include
combining peripheral and central agents, combining two central
agents or combining medications with psychological intervention
such as CBT. Since these recommendations are directed toward treat-
ment of medical symptoms, we suggest that when there are major
psychiatric co-morbidities present, that the clinician also consult with
a psychiatrist for optimal choice of medications and dosing,
Because many gastroenterologists feel ill prepared to prescribe
and manage central neuromodulators, our goal was to elucidate
their rational use in treating various FGIDs based on their domi-
nant symptom complex (pain, nausea/vomiting). Although not the
topic of this article, their use can also apply when treating patients
with other structural disorders such as painful IBD, or cancer
because of their central e ect.
ere are limited well-designed studies on the use of many of
these drugs in treating functional GI disorders. While there are
many well-designed studies and meta-analyses addressing anti-
depressants for FGIDs, they do not always address the dominant
symptoms relative to global response measures. Furthermore, few
studies address the use of SNRI’s, non-TCA or SSRI antidepres-
sants, or the newer antipsychotics.  e large meta-analysis by Ford
( 16 ) is supportive of the use of antidepressants in IBS. However,
the greatest database of knowledge on the value of central neuro-
modulators is based on studies done in patients with other painful
conditions like migraines,  bromyalgia, and chronic pain in general.
In some cases, the bene t with mirtazapine and olanzapine is
based on studies in oncology patients.
With these caveats, we have provided information to aid the
clinician on the use of these agents by combining review of
literature and personal experience. Clearly further studies are
much needed. For the time being we hope we have made use
of these medications more logical and accessible to clinicians
ultimately to bene t our patients.
Guarantor of the article: W. Harley Sobin, MD.
Speci c author contributions: W. Harley Sobin: conceived the
publication, performed literature review, and wrote the manuscript.
omas W. Heinrich: consulted the manuscript. Douglas A. Drossman:
consulted and wrote the manuscript.
Financial support: None.
Potential competing interests: None.
Treating Functional GI Disorders: A Primer
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
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Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017
e following are examples of treatments using neuromodulators for common functional gastrointestinal diagnoses.  ey are based on
review of the literature and clinical experience.  ey do not preclude the use of the many gastrointestinal-targeted agents, but they may
augment or substitute for the GI targeted agents if further optimization of the clinical response is needed. Two options are provided for
each scenario as starting treatment; in some cases, they may be combined in lower doses to augment the clinical e ect. Further clinical
trials are needed to con rm these recommendations and determine optimal dosing.
FGID with predominant pain (IBS, CAPS, FD, functional chest pain, Levator ani syndrome, Biliary pain)
Week 1 initial dose Week 2 optimal dose Weeks 6–8 ( 1 ) enhanced dose
TCA ( 2 ) Nortriptyline or desipramine ( 3 ) 25 mg 50 mg 75–150 mg or switch to SNRI or add quetiapine ( 4 )
(25–100 mg)
SNRI Duloxetine ( 5 ) 30 mg 60 mg 90 mg (max 120 mg) or add quetiapine ( 4 ) (25–100 mg)
Functional Dyspepsia Postprandial Distress Syndrome (PDS)
Week 1 initial dose Week 2 optimal dose Weeks 6–8 ( 1 ) enhanced dose
Buspirone( 6 ) 7.5 mg bid 15 mg bid 30–45 mg bid or add mirtazapine ( 7 )
Mirtazapine( 8 ) 15 mg 30 mg 45 mg or add buspirone ( 7 )
Chronic Nausea and Vomiting Syndrome
Ondansetron 4–8 mg q6h or promethazine 12.5–25 mg q6h are short-term treatments used prn for symptomatic relief. Mirtazapine or
olanzapine are indicated for chronic use. Ondansetron or promethazine may be added for acute episodes of nausea and vomiting
Week 1 initial dose Week 2 optimal dose Weeks 6–8 ( 1 ) enhanced dose
Mirtazapine ( 8 ) 15 mg 30 mg 45 mg or add olanzapine ( 7,9 )
Olanzapine ( 7,9 ) 2.5 mg 5 mg 10 mg or add mirtazapine ( 8 )
1. The enhanced dose can be used if at 6–8 weeks there is a suboptimal response. Switch medications if poorly tolerated side effects.
2. Choose the SNRI If constipation is a predominant symptom.
3. These secondary amine TCAs are preferred over tertiary amines (amitriptyline, imipramine) due to lower anticholinergic side effects (tachycardia, hypotension, consti-
pation, xerostomia) and to optimize effective dose. They are given at night.
4. Dose is optimized upon achieving nighttime sedation and reduced with side effects (daytime sedation, weight gain, glucose intolerance, rarely hepatic dysfunction).
Alternative choices, if side effects occur, include olanzapine (2.5–5 mg), aripiprazole (2.5–5 mg), or brexpiprazole (1–1.5 mg).
5. Alternative to duloxetine is milnacipran 50 to 100 mg bid or venlafaxine 150–225 mg qd. Side effects include nausea, headache diaphoresis.
6. Side effects (dizziness, fatigue, sedation, and headache) often determine dose.
7. When combining mirtazapine with buspirone or olanzapine for augmenting effect use lower doses (e.g., 7.5–15 mg qhs for mirtazapine, 7.5–15 mg bid for buspirone,
and 2.5 mg for olanzapine).
8. Side effects of mirtazapine (sedation, weight gain) often determine dose.
9. Olanzapine is usually a second line treatment for patients not responding to or having excess sedation or weight gain with mirtazapine. Side effects of olanzapine
include dizziness, headache, weight gain, and tiredness.
... Due to the contraindication of restrictive dietary therapies for individuals with EDs and the limited research on complementary/alternative therapies, we focus on pharmacologic and brain-gut behavior therapies in this review. In addition to standard management of GI symptoms with peripherally acting agents such as proton-pump inhibitors and laxatives, pharmacologic treatment of DBGI involves neuromodulators, which act on the gut-brain axis [8]. Neuromodulators, such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have effects on GI sensorimotor function and may treat comorbid psychiatric symptoms [9] (see Table 3). ...
... Amitriptyline and paroxetine have both been studied in the treatment of functional esophageal symptoms, most recently in a randomized controlled trial of a general adult population with refractory globus which found that paroxetine was more effective than amitriptyline or lansoprazole [40]. Trazodone is another neuromodulator which may be used for functional esophageal symptoms [8]. Braingut behavior therapies (e.g. ...
... For patients with abdominal painpredominant symptoms, TCAs are first line therapy, with secondary amines (e.g. desipramine and imipramine) favored due fewer anticholinergic and antihistaminic side effects [8]. SNRIs are also used for pain-predominant symptoms [8]. ...
Full-text available
Disorders of gut–brain interaction (DBGI), also known as functional gastrointestinal disorders, are common in individuals with eating disorders, and may precede or perpetuate disordered eating. Understanding the pathophysiology of common gastrointestinal symptoms in DGBI can be important for the care of many patients with eating disorders. In this review, we summarize the literature to date on the complex relationship between DBGI and eating disorders and provide guidance on the assessment and management of the most common symptoms of DBGI by anatomic region: esophageal symptoms (globus and functional dysphagia), gastroduodenal symptoms (functional dyspepsia and nausea), and bowel symptoms (abdominal pain, bloating and constipation).
... The physician can establish a therapeutic relationship with a patient through good communication skills that are implemented by employing specifi c guidelines: (1) allowing the patient to complete his or her opening statement; (2) eliciting concerns and establishing a rapport; (3) using a combination of open-ended and closed-ended questions to gather and clarify information; (4) identifying and responding to the patient ' s personal situation, beliefs, and values; (5) using language the patient can understand to explain diagnosis and treatment plans; (6) checking for the patient ' s understanding; (7) encouraging the patient to participate in decisions and exploring the patient ' s willingness and ability to follow care plans; (8) asking for other concerns the patient might have; and (9) discussing follow-up activities expected of the patient before closing the visit. 142 This strategy must be individualized also treat major and secondary depressive symptoms when used in full antidepressant doses ( > 100 mg/day). They have antihistaminic and anticholinergic side effects that could lead to nonadherence because of constipation, orthostasis, or dry mouth and eyes. ...
... Evidence indicates that activation of glia (microglia, astrocytes) may also enhance pain amplification following psychological stress, peripheral inflammation, and other factors. 142,143,144 Glial activation is associated with the production of proinflammatory cytokines, which can up-regulate the N-methyld-aspartate receptor signaling system, thereby contributing to the development of central sensitization and chronic pain. This mechanism has yet to be fully studied for chronic GI pain, but it is recognized to be the mechanism for central hyperalgesia related to narcotic use, as in narcotic bowel syndrome (see Chapter 12). ...
... (3) depending on the agent, modifying diarrhea or constipation; (4) reducing anxiety, depression, nausea, and loss of appetite; and (5) in higher doses, treating major depression or other psychiatric disorders. 112,142 With the publication of Rome IV, 159 the Rome Foundation has established new definitional guidelines that relabel agents working both in the brain and gut as "gut-brain neuromodulators." 112 This term includes the primarily central neuromodulators (e.g., antidepressants, antipsychotics, azapirones, other centrally acting agents) and the primarily peripheral neuromodulators, including serotonergic, chloride channel, delta ligand agents, and others (not discussed in this section). ...
... SNRIs work by blocking both 5-HT and NA reuptake (27). This makes SNRIs an indicated agent for treating painful somatic disorders and they are also commonly used for treating visceral pain (28). This mode of action is similar to TCAs with comparable pain reduction but with less side effects (28). ...
... This makes SNRIs an indicated agent for treating painful somatic disorders and they are also commonly used for treating visceral pain (28). This mode of action is similar to TCAs with comparable pain reduction but with less side effects (28). A possible explanation for the lack of effectiveness for venlafaxine is that Van Kerkhoven et al. used venlafaxine in a dose of 150 mg while NA reuptake inhibition only applies for doses of 225 mg or more, reducing its central action to 5-HT blockage only (27). ...
Background and study aims: Functional dyspepsia is a common chronic condition with upper abdominal symptoms in the absence of an organic cause. The first line treatment consists of protonpomp inhibition or Helicobacter pylori eradication. However, this approach often does not provide enough symptom relief. Neuromodulating agents are commonly used in clinical practice but only tricyclic antidepressant (TCAs) are mentioned in European and American and Canadian guidelines. Methods: We performed a comprehensive review of the literature in Pubmed for full-text randomized controlled trials in English with adult participants (>18 years) who met the Rome II, III or IV criteria or were diagnosed by a physician with a negative upper endoscopy and that compared a neuromodulating agent with placebo. Results: The search strategy identified 386 articles of which 14 articles met the eligibility criteria. TCAs like amitriptyline and imipramine have been shown to be effective in the treatment of functional dyspepsia whereas other neuromodulating agents like tetracyclic antidepressants, levosulpiride and anxiolytics might be beneficial but conclusive evidence is lacking. serotonin and noradrenaline reuptake inhibitors (SNRI) and selective serotonin reuptake inhibitors (SSRI) have not shown benefit in patients with functional dyspepsia. Conclusion: Selected neuromodulators have an established efficacy in functional dyspepsia. The best supporting evidence is available for TCAs with a potential role for tetracyclic antidepressants, levosulpiride and anxiolytics.
... 10 The stigmatized feelings of patients would get worse when the terms such as 'brain,' 'emotional,' and 'psychological' are used in the clinician-patient communication or appear in the package inserts of medications prescribed for FD. 10,11 Stigma has non-negligible adverse consequences in patients with DGBI, including treatment non-adherence, negative emotion, increased symptoms, and barriers to accessing care. 10,12 It has been reported that poor medication compliance due to stigma mitigates the efficacy of neuromodulators in rFD therapy. ...
Background/aims: Stigma related with antidepressants is prevalent in patients with functional dyspepsia. It affects medication compliance and efficacy. Herbal medicine acquired a deep-rooted cultural identity in relieving dyspeptic symptoms in Asians. The research was designed to compare the effectiveness of Zhizhu Kuanzhong capsules (ZZKZ) versus doxepin hydrochloride (doxepin) on alleviating stigma and medication nonadherence among patients with refractory FD (rFD). Methods: Patients with rFD from February 2021 to February 2022 were randomly allocated to receive either doxepin (n = 56) or ZZKZ (n = 57) combined with omeprazole for 4 weeks. Medication possession ratio (MPR), the disease- and medication-associated stigma were analyzed. The scales were utilized to assess dyspeptic symptoms (Leeds Dyspepsia Questionnaire) and psychological conditions (Generalized Anxiety Disorder Questionnaire and Patient Health Questionnaire). Results: The MPR values for ZZKZ were significantly higher than those for doxepin (P < 0.001). The stigma scores decreased in ZZKZ group while increased in doxepin group compared to baseline after treatment. The proportion of patients showing ZZKZ-associated stigma was significantly lower than doxepin-associated stigma (P < 0.001). The MPR values were negatively correlated with post-treatment stigma scores in both groups (P < 0.001). Dyspeptic symptoms and psychological condition were improved in both groups after treatment, with no significant difference on post-treatment Leeds Dyspepsia Questionnaire, Generalized Anxiety Disorder Questionnaire, or Patient Health Questionnaire scores between 2 groups. Conclusion: ZZKZ is superior to doxepin in alleviating stigma and medication non-adherence, with comparable efficacy in improving dyspeptic symptoms and psychological condition of patients with rFD.
... Thus, it is possible to explain the symptoms that appear and develop with functional disorders of the gastrointestinal tract in the aggregate. These include: headaches, trembling, nervousness, irritability, sweating, dizziness, symptoms of dyspepsia and discomfort in the epigastric region [34][35][36][37]. ...
Being widespread prevalence of anxiety disorders, one of the main causes of functional disorders of the gastrointestinal tract is the dysfunction of the nervous system. This review article discusses various cases of correction of functional disorders of the gastrointestinal tract. Based on many medical studies, 40% of patients with functional disorders of the gastrointestinal tract suffer from anxiety disorders. This study considers psychosomatic aspects in gastroenterology, as well as to study functional disorders of the gastrointestinal tract and their possible correction in patients with anxiety disorders. Due to the presence in many patients of gastroenterological profile, concomitant anxiety, psychopathic, psychovegetative, somatic disorders and manifestations, the use of psychopharmacotherapy is advisable and is often the only effective treatment option. The use of antidepressants, neuroleptics, tranquilizers, nootropics is carried out with strict consideration of the patient's condition and his individual characteristics. Disciplinary: Medicine.
... Stress can significantly affect the neuroendocrine system's function, including impairing the secretion of hormones involved in indigestion and peristalsis, inhibiting the parasympathetic nerve's innervation on the colon, and inducing gut microbiome dysbiosis, which are collectively represented as clinical constipation symptoms [9,10]. In addition, constipation is a primary side effect of psychotropic drugs because of the reduction in serotonin-selective reuptake transporter (SERT) activity [11]. Due to the high incidence of constipation, many depressed patients have to use adjunctive laxatives [12]. ...
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Introduction Major depressive disorder (MDD) is a leading global psychiatric disease. MDD is highly comorbid with gastrointestinal abnormalities, such as gut motility dysfunction. An effective strategy to manage depression and its accompanying gastrointestinal symptoms is warranted. Objectives Three probiotic strains (Bifidobacterium breve CCFM1025, Bifidobacterium longum CCFM687, and Pediococcus acidilactici CCFM6432) had previously been validated in mice to possess antidepressant-like potential. This study investigated the potential psychotropic effects of a combined three-strain probiotic intervention for human MDD patients. The mechanism of action was further investigated in the stress-induced depression mice model. Methods MDD patients were given a freeze-dried, mixed probiotic formula for four weeks. The patients’ psychometric and gastrointestinal conditions were evaluated using clinical rating scales before and after treatment. Their gut microbiome was also analysed using 16S rRNA gene amplicon sequencing. The mechanisms underlying the beneficial probiotic effects were determined using a chronic stress-induced depressive mouse model. Results Multi-probiotics significantly reduced depression scores, and to a greater extent than the placebo (based on the Hamilton Depression Rating, Montgomery-Asberg Depression Rating, and Brief Psychiatric Rating Scales). Multi-probiotics also significantly improved the patients’ gastrointestinal functions (based on self-evaluation using the Gastrointestinal Symptom Rating Scale). Serotonergic system modification was demonstrated as the key mechanism behind the probiotics’ benefits for the brain and the gut. Conclusion Our findings suggest a novel and promising treatment to manage MDD and accompanying gut motility problems, and provide options for treating other gut-brain axis-related disorders.
Severe chronic small bowel dysmotility occurs when there is a failure to propel the gut luminal contents without there being an organic obstructing lesion. Patients with dysmotility are challenging to manage both as the diagnosis can be difficult to make since other contributing factors (e.g. opioid/cyclizine, abdominal surgery, psychosocial problems and malnutrition) can all cause/exacerbate dysmotility. There are overlapping diagnostic sub-categories which include chronic intestinal pseudo-obstruction (CIPO) defined by a dilated small bowel and non-CIPO which does not. Enteric dysmotility is a sub-category of non-CIPO with abnormal small bowel manometry or transit. Histopathologically, CIPO patients are more likely to have a myopathy whilst non-CIPO/enteric dysmotility are more likely to have a neuropathy, and these may be either primary or secondary as part of a systemic disease. Most patients however will not receive a histopathological diagnosis and are termed idiopathic. The management starts with determining and ordering the primary symptoms/problems and assessing the contributing factors. Mechanical obstruction is excluded (CT abdomen with oral contrast) and a nutritional assessment made. If malnourished or at risk of becoming so nutritional treatment should be started taking into account the risks of refeeding problems. Tests for the underlying aetiology are performed and include excluding hypothyroidism, coeliac disease, diabetes, hypokalaemia or hypercalcaemia, thymoma or other neoplastic condition [chest X-ray (or CT/PET CT)]. Antibodies for connective disorders and those associated with paraneoplastic conditions are performed along with tests for mitochondrial disorders. If none of these are positive a full thickness jejunal biopsy may be considered on a careful risk/benefit analysis, bearing in mind that the results rarely lead to any change in management or outcome at present. The patient may be taking medication that slows gut transit or is very malnourished both of which affect tests of motility (e.g. mamometry and isotope studies). These patients should not be given a definite diagnosis, but rather one of probable/possible or working diagnosis of dysmotility. The primary symptoms/problems are addressed (e.g. pain, distention, vomiting, constipation, malnutrition/bacterial overgrowth, psycho-social issues and quality of life). Bacterial overgrowth may be treated by giving rotating courses of antibiotics and supplements of fat soluble vitamins may be needed. Surgical options (full thickness jejunal biopsy/enteral tube/venting stoma/resection/transplantation) may be considered. Regular MDTs, which include psychological and pain team input should review and reconsider the diagnosis as the clinical situation changes. Opioid medication and cyclizine (especially intravenously) should be avoided due to associated harms.
Eating disorders include a spectrum of disordered thinking patterns and behaviours around eating. There is increasing recognition of the bi-directional relationship between eating disorders and gastrointestinal disease. Gastrointestinal symptoms and structural issues might arise from eating disorders, and gastrointestinal disease might be a risk factor for eating disorder development. Cross-sectional research suggests that individuals with eating disorders are disproportionately represented among people seeking care for gastrointestinal symptoms, with avoidant-restrictive food intake disorder in particular garnering attention for high rates among individuals with functional gastrointestinal disorders. This Review aims to describe the research to date on the relationship between gastrointestinal disorders and eating disorders, highlight research gaps, and provide brief, practical guidance for the gastroenterology provider in detecting, potentially preventing, and treating gastrointestinal symptoms in eating disorders.
Disorders of gut-brain interaction, previously called functional gastrointestinal disorders, are prevalent, disabling, expensive, and difficult to treat. In this review, I trace the available scientific knowledge on the pathophysiology of these disorders and describe how the proposed pathways are integrated into treatment approaches. A novel treatment approach, heart rate variability biofeedback (HRVB), is described, and outcome literature is reviewed. It is concluded that an approach such as HRVB offers benefits beyond more traditional treatment approaches.
Objective: The increased prevalence and incidence of affective disorders among patients with gastrointestinal disease has been well established. However, few studies have investigated the inverse relationship. We aimed to identify all evidence of the prevalence and incidence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) in people with depression and bipolar disorder. Methods: We conducted a systematic review of studies reporting the association between affective disorders (exposure) and IBS or IBD (outcome) in adults. Evidence was evaluated for quality using Joanna Briggs Institute Critical Appraisal tools. Where suitable data were available, meta-analyses were performed. Results: We identified eighteen studies that met selection criteria, of which eleven provided data on IBS, five on IBD, and two on both. Overall, people with depression were significantly more likely to have comorbid IBS (RR = 2.42, 95% CI 1.98-2.96) as well as to develop new-onset IBS (RR = 1.90, 95%CI 1.41-2.56) compared to people without depression. They were also more likely to have and develop IBD and, among patients with IBD, significantly increased rates of depression were observed as early as 5 years pre-diagnosis. Bipolar disorder was not consistently associated with risk of either condition. Conclusions: People with depression are at an increased risk of both having and developing lower gastrointestinal disorders. These findings have important implications for how we understand, manage and prevent this comorbidity in clinical practice. Further studies are needed to improve our understanding of the relationship between bipolar disorder and bowel disease as well as the role of psychotropic medication, particularly SSRIs.
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We provide a general framework for understanding functional gastrointestinal disorders (FGIDs) from a biopsychosocial perspective. More specifically, we provide an overview of the recent research on how the complex interactions of environmental, psychological, and biological factors contribute to the development and maintenance of FGIDs. We emphasize that considering and addressing all these factors is a conditio sine qua non for appropriate treatment of these conditions. First, we provide an overview of what is currently known about how each of these factors - the environment, including the influence of those in an individual's family, the individual's own psychological states and traits, and the individual's (neuro)physiological make-up - interact to ultimately result in the generation of FGID symptoms. Second, we provide an overview of commonly used assessment tools that can assist clinicians in obtaining a more comprehensive assessment of these factors in their patients. Finally, the broader perspective outlined earlier is applied to provide an overview of centrally acting treatment strategies, both psychological and pharmacological, which have been shown to be efficacious to treat FGIDs.
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Chronic abdominal pain in the context of the functional gastrointestinal disorders departs from a more traditional approach to treating gastrointestinal symptoms. Chronic abdominal pain involves a dysregulation of brain-gut modulation of afferent signaling, so treatments directed toward the gut are not usually sufficient to achieve a clinical response. Rather the methods of treatment depend on re-establishing central pain regulation. A conceptual model of predisposing, precipitating, and perpetuating factors is used to explain how a situation of chronic pain develops and it provides the evidence for central neuron degeneration as relevant to this chain of events. The rationale for centrally targeted medications, in particular antidepressants, is discussed with regard to effects independent of their role in treating psychiatric disorders: with regard to downregulation of afferent pain signals and their potential role in neuron proliferation. Finally, guiding examples of which drug to use and treatment combinations involving multiple drugs, augmentation treatment, are outlined and some brief clinical cases of centrally targeted pharmacotherapy. © 2015 John Wiley & Sons Ltd.
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Objectives: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate. Methods: We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or "usual management," were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Results: The search strategy identified 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or "usual management," sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95% CI=0.58-0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not improving with psychological therapies was 0.68 (95% CI=0.61-0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all beneficial. Conclusions: Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable.
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Objectives: There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. Methods: MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. Results: Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). Conclusions: SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.
Twenty-nine patients with esophageal symptoms and contraction abnormalities of the esophageal body completed a 6-wk, double-blind, placebocontrolled trial of trazodone (100–150 mg1day). Measures of esophageal and psychologic symptoms were completed at entry and at each follow-up visit. Esophageal manometry was repeated at the termination of the trial. Upon completion of the treatment, patients receiving trazodone (n = 15) reported a significantly greater global improvement than those receiving placebo (n =14; p=0.02). Although a variable clinical response was observed, the trazodone group had less residual distress over esophageal symptoms compared with the placebo group (59% ± 9% vs. 108% ± 19%, p=0.03). Manometric changes observed during the course of the trial were not influenced by treatment nor by clinical response. Remarkable reductions in ratings of chest pain were reported by both treatment groups, emphasizing the importace of controlled trials when studying this patient population. We conclude that low-dose trazodone therapy can be of benefit in the management of symptomatic patients with esophageal contraction abnormalities. In addition, our findings support recent observations that manometric abnormalities characterizing this patient group may not be solely responsible for symptoms.
Background & aims: A subset of patients with functional dyspepsia (FD) present with early satiation and weight loss, for which there are no established therapeutic options. We investigated the efficacy of mirtazapine (an antidepressant and antagonist of the histamine receptor H1, the α2 adrenergic receptor, and the serotonin receptors 5-HT2C and 5-HT-3) in patients with FD and weight loss. Methods: We conducted a randomized, placebo-controlled pilot trial that studied 34 patients with FD (29 women; mean age, 35.9 ± 2.3 years) with weight loss >10% of original body weight (mean loss, 12.4 ± 2.3 kg) without depression or anxiety. After a run-in period, patients were randomly assigned to groups given placebo (n = 17) or mirtazapine 15 mg each day for 8 weeks (n = 17) in a double-blind manner. Subjects were evaluated during a 2-week baseline and 8-week treatment for dyspepsia symptom severity, quality of life (on the basis of the Nepean Dyspepsia Index), and gastrointestinal-specific anxiety; they were given a nutrient challenge test and weighed. Data were analyzed by using linear mixed models, followed by planned contrasts with adaptive step-down Bonferroni multiple testing correction. Results: Two patients in each group dropped out. At weeks 4 and 8, mirtazapine significantly reduced mean dyspepsia symptom severity scores compared with week 0 (P = .003 and P = .017, respectively); there was no significant reduction in the placebo group (P > .37 for weeks 4 and 8). The difference in change from week 0 between mirtazapine and placebo showed a trend with a large effect size at week 4 (P = .059) that was not significant at week 8 (P = .55). However, improvements from week 0 to weeks 4 and 8 were significantly larger in the mirtazapine group than placebo group for early satiation, quality of life, gastrointestinal-specific anxiety, weight, and nutrient tolerance (mostly with large effect sizes). Conclusions: In a randomized, placebo-controlled trial, mirtazapine significantly improved early satiation, quality of life, gastrointestinal-specific anxiety, nutrient tolerance, and weight loss in patients with FD. number: NCT01240096.
Anti-depressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or post-prandial fullness. However, there is little evidence for the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of anti-depressant therapy effects on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use anti-depressants. Subjects (n=292; 44±15 y old, 75% female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary endpoint was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (out of 12). Secondary endpoints included GE time, maximum tolerated volume in a nutrient drink test, and FD-related quality of life. An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P=.05, following treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were more than 3-fold more likely to report adequate relief than those given placebo (odds ratio=3.1; 95% confidence interval, 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10 week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio=0.4; 95% confidence interval, 0.2-0.8). Both anti-depressants improved overall quality-of-life. Amitriptyline, but not escitalopram, appears to benefit some patients with FD-particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. number: NCT00248651. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction and it can lead to jaundice, liver failure, or even death. Antimicrobials and herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world. DILI is a diagnosis of exclusion and thus careful history taking and thorough work-up for competing etiologies are essential for its timely diagnosis. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis and management of DILI with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease.Am J Gastroenterol advance online publication, 17 June 2014; doi:10.1038/ajg.2014.131.