Content uploaded by Douglas A. Drossman
Author content
All content in this area was uploaded by Douglas A. Drossman on Feb 25, 2019
Content may be subject to copyright.
Content uploaded by Douglas A. Drossman
Author content
All content in this area was uploaded by Douglas A. Drossman on Oct 10, 2017
Content may be subject to copyright.
REVIEW
1
© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
CLINICAL AND SYSTEMATIC REVIEWS
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.
RATIONALE FOR THE USE OF CENTRAL
NEUROMODULATORS IN GASTROENTEROLOGY
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 ).
QUALIFICATIONS RELATING TO THE USE
OF CENTRAL NEUROMODULATORS IN
GASTROENTEROLOGY
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: harleysobin@gmail.com
CME
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017 www.nature.com/ajg
REVIEW
2
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.
EVIDENCE FOR THE BENEFIT OF CENTRAL
NEUROMODULATORS
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-MECHANISM OF
ACTION
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
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
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
reuptake
Increase serotonin AD Antianxiety Nausea diarrhea SSRI SNRI TCA
NET (t) Inhibit norepinephrine
reuptake
Increase norepinephrine AD and analgesic Dry mouth sweats
Constipation
SNRI TCA
DAT (t) Inhibit dopamine
reuptake
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
compliance
Buspirone
5HT2A Receptor antagonist Increase dopamine in
striatum +pituitary
Antipsychotic without EPS
or galactorhea
Atypical antipsychotics
5HT3 Receptor antagonist Inhibit 5HT3 Less nausea, diarrhea,
pain
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
REVIEW
3
DAT
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
fundus.
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-
psychotics.
CENTRAL NEUROMODULATORS USED IN
GASTROENTEROLOGY
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.
TRICYCLIC ANTIDEPRESSANTS
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 www.nature.com/ajg
REVIEW
4
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.
CLINICAL RECOMMENDATIONS
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.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
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
TCAs
Amitriptyline Elavil 25–150 mg qd
Desipramine Norpramin 25–150 mg qd
Imipramine Tofranil 25–150 mg qd
Nortriptyline Pamelor 25–150 mg qd
SSRIs
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
SNRIs
Duloxetine Cymbalta 30–90 mg qd
Minacipran Savella 50–100 mg bid
Venlafaxine Effexor 75–225 mg qd
MISC AGENTS
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
ATYPICAL ANTIPSYCHOTICS
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
REVIEW
5
CLINICAL RECOMMENDATIONS
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.
SEROTONIN AND NOREPINEPHRINE REUPTAKE
INHIBITORS
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
benzodiazepine.
Table 3 . Choosing and avoiding central neuromodulators for FGIDs based on associated symptoms
Symptom/syndrome Choose Avoid
CAPS
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 www.nature.com/ajg
REVIEW
6
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.
CLINICAL RECOMMENDATIONS
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.
MISCELLANEOUS AGENTS: BUSPIRONE,
TRAZODONE, MIRTAZAPINE
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.
CLINICAL RECOMMENDATIONS
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.
CENTRAL NEUROMODULATORS TO TREAT CHRONIC
NAUSEA
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
range.
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”.
CLINICAL RECOMMENDATIONS
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.
ATYPICAL ANTIPSYCHOTICS
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
REVIEW
7
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.
CLINICAL RECOMMENDATIONS
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
properties.
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 www.nature.com/ajg
REVIEW
8
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
dilation.
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.
DISCONTINUING CENTRAL NEUROMODULATORS
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.
FINAL THOUGHTS
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.
CONFLICT OF INTEREST
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
REVIEW
9
23. Drossman DA , Toner BB , Whitehead WE et al. Cognitive-behavioral
therapy versus education and desipramine versus placebo for moderate to
severe functional bowel disorders . Gastroenterology 2003 ; 125 : 19 – 31 .
24. i w a n S , D r o s s m a n D A , M o r r i s C B et al. Not all side e ects associated
with tricyclic antidepressant therapy are true side e ects . Clin Gastro-
enterol Hepatol 2009 ; 7 : 446 – 51 .
25. Varia I , Logue E , O’connor C et al. Randomized trial of sertraline in patients
with unexplained chest pain of noncardiac origin . Am Heart J 2000 ; 140 : 367 – 72 .
26. Doraiswamy PM , Varia I , Hellegers C et al. A randomized controlled trial of
paroxetine for noncardiac chest pain . Psychopharmacol Bull 2006 ; 39 : 15 – 24 .
27. Broekaert D , Fischler B , Sifrim D et al. I n uence of citalopram, a selective
serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-
blind, placebo-controlled study . Aliment Pharmacol er 2006 ; 23 : 365 – 70 .
28. Sandson NB , Armstrong SC , Cozza KL . An overview of psychotropic
drug-drug interactions . Psychosomatics 2005 ; 46 : 464 – 94 .
29. Bellingham GA , Peng PWH . Duloxetine . Reg Anesth Pain Med 2010 ; 35 : 294 – 303 .
30. Gaynor PJ , Gopal M , Zheng W et al. Duloxetine versus placebo in the
treatment of major depressive disorder and associated painful physical
symptoms: a replication study . Curr Med Res Opin 2011 ; 27 : 1859 – 67 .
31. Smith EML , Pang H , Cirrincione C et al. E ect of duloxetine on pain,
function, and quality of life among patients with chemotherapy-induced
painful peripheral neuropathy . JAMA 2013 ; 309 : 1359 .
32. Saarto T , Wi en PJ . Antidepressants for neuropathic pain . Cochrane
database Syst Rev 2007 , CD005454 .
33. Sperber AD , Drossman DA . Review article: the functional abdominal pain
syndrome . Aliment Pharmacol er 2011 ; 33 : 514 – 24 .
34. Törnblom H , Drossman DA . Centrally targeted pharmacotherapy for
chronic abdominal pain . Neurogastroenterol Motil 2015 ; 27 : 455 – 67 .
35. van Kerkhoven LAS , Laheij RJF , Aparicio N et al. E ect of the antidepressant
venlafaxine in functional dyspepsia: a randomized, double-blind, placebo-
controlled trial . Clin Gastroenterol Hepatol 2008 ; 6 : 746 – 52 .
36. Maglione M , Maher AR , Hu J et al. O -Label Use of Atypical Antipsychotics:
An Update. Report no. 11-EHC087-EF. Agency for Healthcare Research and
Quality: Rockville MD, USA, 2011.
37. Grover M , Dorn SD , Weinland SR et al. Atypical antipsychotic quetiapine
in the management of severe refractory functional gastrointestinal
disorders . Dig Dis Sci 2009 ; 54 : 1284 – 91 .
38. Baune BT , Caliskan S , Todder D . E ects of adjunctive antidepressant
therapy with quetiapine on clinical outcome, quality of sleep and
daytime motor activity in patients with treatment-resistant depression .
Hum Psycho pharmacol 2007 ; 22 : 1 – 9 .
39. Clouse RE , Lustman PJ , Eckert TC et al. Low-dose trazodone for sympto-
matic patients with esophageal contraction abnormalities. A double-blind,
placebo-controlled trial . Gastroenterology 1987 ; 92 : 1027 – 36 .
40. Schatzberg AF , DeBattista MDC . Manual of Clinical Psychopharmacology.
American Psychiatric Association Publishing: Arlington, VA, USA, 2015.
41. Aronson JK . Meyler’s Side E ects of Psychiatric Drugs, Elsevier: UK, 2009 .
42. Loke YK , Trivedi AN , Singh S . Meta-analysis: gastrointestinal bleeding due to
interaction between selective serotonin uptake inhibitors and non-steroidal
anti-in ammatory drugs . Aliment Pharmacol er 2007 ; 27 : 31 – 40 .
43. Anglin R , Yuan Y , Moayyedi P et al. Risk of upper gastrointestinal bleeding
with selective serotonin reuptake inhibitors with or without concurrent
nonsteroidal anti-in ammatory use: a systematic review and meta-analysis .
Am J Gastroenterol 2014 ; 109 : 811 – 9 .
44. Richter JA , Patrie JT , Richter RP et al. Bleeding a er percutaneous endo-
scopic gastrostomy is linked to serotonin reuptake inhibitors, not aspirin
or clopidogrel . Gastrointest Endosc 2011 ; 74 : 22 – 34 .
45. Boyer EW , Shannon M . e Serotonin Syndrome . N Engl J Med 2005 ;
352 : 1112 – 20 .
46. Chalasani NP , Hayashi PH , Bonkovsky HL et al. ACG Clinical Guideline:
the diagnosis and management of idiosyncratic drug-induced liver injury .
Am J Gastroenterol 2014 ; 109 : 950 – 66 .
REFERENCES
1. Clouse RE , Lustman PJ . Use of psycho-pharmacological agents for
functional gastrointestinal disorders . Gut 2005 ; 54 : 1332 – 41 .
2 . D e k e l R , D r o s s m a n D A , S p e r b e r A D . e use of psychotropic drugs in
irritable bowel syndrome . Expert Opin Investig Drugs 2013 ; 22 : 329 – 39 .
3. Drossman DA . Beyond tricyclics: new ideas for treating patients with
painful and refractory functional gastrointestinal symptoms . Am J Gastro-
enterol 2009 ; 104 : 2897 – 902 .
4. Grover M , Drossman DA . Psychotropic agents in functional gastrointestinal
disorders . Curr Opin Pharmacol 2008 ; 8 : 715 – 23 .
5. Grover M , Drossman DA . Psychopharmacologic and behavioral treatments
for functional gastrointestinal disorders . Gastrointest Endosc Clin N Am
2009 ; 19 : 151 – 70 .
6. Creed F . How do SSRIs help patients with irritable bowel syndrome?
Gut 2006 ; 55 : 1065 – 7 .
7. Kim SE , Chang L . Overlap between functional GI disorders and other
functional syndromes: what are the underlying mechanisms? Neurogastro-
enterol Motil 2012 ; 24 : 895 – 913 .
8. Van Oudenhove L , Crowell MD , Drossman DA et al. Biopsychosocial aspects
of functional gastrointestinal disorders . Gastroenterology 2016 ; 150 :
1355 – 67 .
9 . M a y e r E A , T i l l i s c h K . e brain-gut axis in abdominal pain syndromes .
Annu Rev Med 2011 ; 62 : 381 – 96 .
10. Keefer L , Drossman DA , Guthrie E et al. Centrally mediated disorders of
gastrointestinal pain . Gastroenterology 2016 ; 150 : 1408 – 19 .
11. Pae C-U . Low-dose mirtazapine may be successful treatment option for
severe nausea and vomiting . Prog Neuropsychopharmacol Biol Psychiatry
2006 ; 30 : 1143 – 5 .
12. Kim S-W , Shin I-S , Kim J-M et al. E ectiveness of mirtazapine for nausea
and insomnia in cancer patients with depression . Psychiatry Clin Neurosci
2008 ; 62 : 75 – 83 .
13. Navari RM . Olanzapine for the prevention and treatment of chronic
nausea and chemotherapy-induced nausea and vomiting . Eur J Pharmacol
2014 ; 722 : 180 – 6 .
14. Malberg JE , Duman RS . Cell proliferation in adult hippocampus is
decreased by inescapable stress: reversal by uoxetine treatment . Neuro-
psychopharmacology 2003 ; 28 : 1562 – 71 .
15. Brunoni AR , Lopes M , Fregni F . A systematic review and meta-analysis
of clinical studies on major depression and BDNF levels: implications for
the role of neuroplasticity in depression . Int J Neuropsychopharmacol
2008 ; 11 : 1169 – 80 .
16. Ford AC , Quigley EMM , Lacy BE et al. E ect of antidepressants and psy-
chological therapies, including hypnotherapy, in irritable bowel syndrome:
systematic review and meta-analysis . Am J Gastroenterol 2014 ; 109 :
1350 – 65 .
17. Stahl SM . Stahl’s Essential Psychopharmacology, 4th edn. Cambridge Press:
NY, USA, 2013.
18. Tack J , Janssen P , Masaoka T et al. E cacy of buspirone, a fundus-relaxing
drug, in patients with functional dyspepsia . Clin Gastroenterol Hepatol
2012 ; 10 : 1239 – 45 .
19. Tack J , Ly HG , Carbone F et al. E cacy of mirtazapine in patients
with functional dyspepsia and weight loss . Clin Gastroenterol Hepatol
2016 ; 14 : 385 – 92 .
20. Coskun M , Alyanak B . Psychiatric co-morbidity and e cacy of mirtazapine
treatment in young subjects with chronic or cyclic vomiting syndromes:
a case series . J Neurogastroenterol Motil 2011 ; 17 : 305 – 11 .
21. Sindrup SH , Otto M , Finnerup NB et al. Antidepressants in the treatment
of neuropathic pain . Basic and Clin Pharmacol and Toxicol 2005 ; 96 :
399 – 409
22. Talley NJ , Locke GR , Saito YA et al. E ect of amitriptyline and escitalopram
on functional dyspepsia: a multicenter, randomized controlled study .
Gastroenterology 2015 ; 149 : 340 – 9 .
Sobin et al.
The American Journal of GASTROENTEROLOGY VOLUME XXX | XXX 2017 www.nature.com/ajg
REVIEW
10
APPENDIX - TREATMENT SCENARIOS
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.
