Case Study
Antidepressant-Mediated
Gastroesophageal Reflux Disease
Nancy C. Brahm, Merry C. Kelly-Rehm
Anticholinergic effects of medications are factors in
autonomic control of the lower esophageal sphincter function.
Changes in sphincter control often lead to gastroesophageal
reflux disease (GERD), a chronic disease with a prevalence
of up to 25% for adults. This effect is a consideration in the
treatment of depression, the fourth-leading disease burden.
Lower esophageal-sphincter changes are well documented
in association with tricyclic antidepressants. The newer
medications, selective serotonin-reuptake inhibitors and
serotonin-norepinephrine reuptake inhibitors, are often used
as first-line agents. This case report reviews the emergence of
GERD in association with the use of newer agents.
The patient, a 55-year-old woman, presented to her
primary care physician with complaints of low energy,
dysphoric mood, and anhedonia of several months’ duration.
Trials of citalopram and escitalopram were associated with
reports of persistent nausea and gastric reflux unresolved by
changes in dosing schedule or positioning. Over-the-counter
omeprazole on an as-needed basis was added. Ultimately,
the patient was successfully managed with desvenlafaxine
for dysphoric mood and low energy and scheduled
administration of omeprazole for GERD. The adverse drug
reaction was evaluated using the Naranjo Adverse Drug
Reaction Probability Scale. This methodology indicated
a probable relationship (score of 7 out of 12) between
initiation of antidepressant therapy and the presentation of
GERD symptoms.
When evaluating patient response to medication,
inquiring about new-onset symptoms may help assess
pharmacotherapy, identify potential medication-related
effects such as the anticholinergic profile, evaluate the need
to add an antisecretory/antispasmodic agent, or consider an
alternative treatment strategy.
Key words: Antidepressant, Depression, Gastroesophageal
reflux disease, GERD, Selective serotonin-reuptake inhibitor,
Serotonin-norepinephrine reuptake inhibitor, SNRI, SSRI.
Abbreviations: ADR = Adverse drug reaction, GERD =
Gastroesophageal reflux disease, HH = Hiatal hernia, LES =
274 The Consultant Pharmacist  April 2011   Vol. 26, No. 4
Lower esophageal sphincter, SNRI = Serotonin-norepinephrine
reuptake inhibitor, SSRI = Selective serotonin-reuptake
inhibitor, TCA = Tricyclic antidepressant.
Consult Pharm 2011;26:274-77.
Introduction
Gastroesophageal reflux disease (GERD) is a chronic dis-
ease with a prevalence of up to 25% reported for adults
in Europe and the United States.1,2 Several medication
classes contribute to this effect by relaxing the lower
esophageal sphincter (LES). Control of the LES is a
function, in part, of the intrinsic and extrinsic sphincters
and is mediated by afferent and efferent enervation.
The vagal afferents communicate with the dorsal-motor
nucleus of the vagus nerve. This location is responsible
for motor innervations to the LES and either increasing
or decreasing LES tone via the efferent tracts. The excit-
atory myenteric neurons in the LES are cholinergic and
govern smooth muscle action whereas the cholinergic
effects of inhibitory motor neurons are mediated by
vagal efferents. Stimulation of the vagus nerve produces
both excitatory and inhibitory effects and may result in
LES relaxation.3
Anticholinergic drugs are muscarinic antagonists
and work by competitive antagonism of acetylcholine.4
The anticholinergic effects of some antidepressants
may contribute to the development of this disease. The
relationship between tricyclic antidepressants (TCA)
and hiatal hernias (HH) was previously reported in a
series of case reports. Five patient cases were reviewed in
which all patients reported either the onset of symptoms
consistent with those of a HH or an exacerbation of HH
symptoms following initiation of a TCA.5
Depression is the fourth-leading disease burden.
Total disability adjusted life years, a measure of quality
and quantity of life lived, was 4.4% as of 2000.6 Primary
care physicians may be the first point of care for
patients meeting criteria for depression and for whom
pharmacotherapy would be appropriate. For this patient
population, selective serotonin-reuptake inhibitors
(SSRIs) and serotonin-norepinephrine reuptake inhibi-
tors (SNRI) may be used as first-line therapy.7,8 A survey
of drug safety monitoring participants receiving SSRIs

did not report GERD. The most frequent adverse effects
reported were sexual dysfunction, sleepiness, and weight
gain.9 While anticholinergic properties for the SSRI
category vary by agent, the more commonly reported
effects of xerostomia, gastrointestinal upset, and agita-
tion are well documented.10 Less frequently reported for
SSRIs and SNRIs are changes in autonomic control of
the LES function and peristaltic action. Physicians may
not be aware of the extent to which treatment-emergent
antidepressant adverse effects influence patient medica-
tion compliance or adherence (taking as directed) or
persistence (treatment continuation).11
A literature search was conducted for previous
reports of GERD and SSRIs or SNRIs. Databases
searched included Ovid and MEDLINE. Search terms
were gastroesophageal reflux disease, GERD, antidepres-
sant, and the generic name for each SSRI and SNRI
(escitalopram, citalopram, desvenlafaxine, duloxetine,
fluoxetine, fluvoxamine, paroxetine, sertraline, and
venlafaxine). The authors reviewed the references for
additional reports. Additional information related to
antidepressants was not found. We report the case of a
patient treated with multiple trials of antidepressants
who developed GERD. This was identified upon counsel-
ing with the pharmacist and follow-up consultation with
the nurse.
Case Report
The patient is a 55-year-old woman who presented
to her primary care physician with complaints of low
energy, dysphoric mood, and anhedonia of several
months’ duration. Her physical and medication history
were unremarkable. Current medication was limited to
a daily vitamin/mineral supplement. Citalopram 10 mg
each morning was prescribed. Side effects of persistent
nausea, occasional evening gastric reflux, and head-
aches resulted in discontinuation after three months.
Mood-specific information was not included at this
evaluation point.
The patient represented to her primary care physician
several weeks following her decision to stop citalopram,
and she reported that changing the time of ingestion
did not decrease GERD symptoms. The medication
The Consultant Pharmacist  April 2011   Vol. 26, No. 4  275
Case Study
was changed to escitalopram 10 mg each morning. The
administration schedule was changed to evening dosing
at the two-week point following continued reports of
persistent nausea and symptoms of gastric reflux. The
change to evening dosing resulted in sleep disturbances,
primarily reported as increasing reflux that disrupted
sleep. When interviewed regarding reflux symptoms, the
patient reported it presented as coughing followed by an
increase in saliva. This was addressed with the addition
of over-the-counter omeprazole 20 mg on an as-needed
basis per physician instructions.
Complaints of low energy, depressed mood, and
anhedonia remained at baseline levels. The patient
was reluctant to try a dosage increase in escitalopram
because of the continuation of GERD-like symptoms.
The physician elected a trial of desvenlafaxine as a strat-
egy to ameliorate any serotonin-related gastrointestinal
effects. Desvenlafaxine 50 mg once daily at bedtime
was prescribed with omeprazole 20 mg each morning.
The patient reported this combination resulted in
occasional reflux at bedtime that was primarily dietary
intake-related, particularly if carbohydrate intake was
close to bedtime or eaten within three hours of bedtime.
Positional changes continued to be problematic, and she
reported reflux was worse when lying down. Mood and
energy improved with the change to desvenlafaxine. No
additional medication changes were made.
The Naranjo ADR Probability Scale was used to
evaluate the probability the effects noted could establish
a causal relationship between use of a drug and develop-
ment of an adverse-medication effect. Applying the
assessment criteria and scoring the probability scale
worksheet can lead to a more objective clinical determi-
nation. Criteria for this instrument encompass previous
conclusive reports of the effect, improvement following
discontinuation, inclusion of other causes, and a similar
effect to the same or similar agent in a prior exposure.
All these factors were reviewed and evaluated in this
patient. Applying this methodology indicated a probable
relationship (score of 7, range 0-12) between initiation
of antidepressant therapy and the presentation of GERD
symptoms in this patient.12
Case Study
Discussion
Primary care physician providers may be more familiar
with identification of GERD than depressive symptoms
in the primary care setting.13 The clinical presentation of
GERD may be identified with either typical or atypical
features. Typical features include heartburn, hypersaliva-
tion, belching, or regurgitation. Heartburn symptoms
may be experienced by as many as one in four persons
on a monthly basis.14 Atypical symptoms presentation
may make diagnosis more difficult. Atypical presentation
includes asthma of nonallergic origin, chronic cough/
hoarseness, pharyngitis, and/or chest pain.15 The reduced
integrity of the LES is recognized as a significant factor
in the etiology of GERD. A number of factors impact
LES functionality. These include anatomical changes,
such as HH, dietary intake, and medication.16 Individual
patient sensitivity to anticholinergic effects was consid-
ered. No reports of changes in mental status, such as
confusion, blurred vision, constipation, dry mouth or
eyes, problems wearing contact lenses, light-headedness,
difficulty starting and continuing voiding, and/or prob-
lems with urination, were reported. The patient reported
no increase in fluid consumption, did not use chewing
gum, and did not like hard candy. It should be noted that
at this time omeprazole was ordered on an as-needed
basis. The mechanism of action for omeprazole involves
irreversible binding with the enzyme responsible for
adenosine triphosphate degradation, which inhibits acid
secretion. While the elimination half-life ranges between
0.25 and 1.5 hours, a single 40-mg dose can inhibit acid
output by 34% after day 3 and 18% after day 4.17 It is not
known if consistent rather than intermittent use may
have alleviated GERD for the patient at this point.
The time course in the relationship between use
of a newer class of antidepressant and the onset of
GERD was considered. The patient did not experience
GERD-related symptoms during the antidepressant-free
periods, and the onset of symptoms consistent with
GERD was consistent with initiating or reinitiating an
antidepressant. The extent to which anticholinergic
effects are reported for each agent was considered,
and the literature was searched for comparative trials
between agents. In the absence of this information,
276 The Consultant Pharmacist  April 2011   Vol. 26, No. 4
clinical trial findings for treatment-emergent adverse
effects were reviewed. Results for the antidepressant ver-
sus placebo found higher percentage rates for dry mouth
and nausea with citalopram (20/14 and 21/14), desven-
lafaxine 50 mg dose (20/14 and 22/10), escitalopram 10
mg dose (4/1; nausea not reported), fluoxetine for major
depression (10/7 and 21/9), and venlafaxine (22/11 and
37/11) in the manufacturer-provided data.18–22
The relationship between use of the newer categories
of antidepressants and the development of GERD has
not been extensively reported. The bulk of the literature
related to antidepressant treatment-emergent effects
reflects the use of TCAs. A series of five case reports
presented information on patients who either developed
symptoms of HH/GERD or reported an increase in
severity following initiation of a TCA.5 This relationship
was investigated by a Dutch population-based, case-
control study. Using database information for the period
1996-2005, researchers found an increased risk of GERD
for current TCA users of clomipramine, the agent most
associated with the increase.23
Using the United Kingdom primary care database,
Martin-Marino and colleagues assessed the relationship
between a diagnosis of depression, antidepressant phar-
macotherapy, and the development of GERD or reflux
symptoms.24 An increased risk was identified for persons
who received a TCA, whereas use of an SSRI was not
associated with GERD (odds ratio of 1.71 vs. 0.93).
The potential for psychological stressors as a
contributing factor to GERD cannot be overlooked. In
a community-based study, researchers demonstrated
the presence of increased heartburn symptoms during
a four-month period following patient reports of stress.
The researchers established the presence of stress using
a life-stress measure and found that stress positively
predicted increased heartburn during the four-month
follow-up period. Depression was also strongly positively
correlated to heartburn-medication use.25
Strategies for managing treatment-emergent adverse
effects include a change in antidepressant, dosage
form, or antidepressant with a lower anticholinergic
impact.23,26,27 The addition of an agent specific for GERD-
related symptoms, such as a proton-pump inhibitor
 Case Study

Table 1. Selected Antidepressant Anticholinergic Treatment-Emergent Adverse Effects

Treatment- Patients Trial Sample Size
Agent (Reference) Category Emergent Reporting Effect (n) Antidepressant/
Adverse Effect (%) Drug/Placebo Placebo
Citalopram (18) SSRI Dry mouth 20/14 1,063/446
Nausea 21/14
Desvenlafaxine* (19) SNRI Dry mouth 11/9 Not included
Nausea 22/10
Escitalopram† (20) for SSRI Dry mouth 4/3 310/311
major depression Nausea Not reported
Fluoxetine (21) for SSRI Dry mouth 10/7 1,728/975
major depression Nausea 21/9
Venlafaxine (22) SNRI Dry mouth 22/11 1,033/609
Nausea 37/11
Source: Information adapted from the manufacturer findings.
Abbreviations: SNRI = Serotonin-norepinephrine reuptake inhibitor, SSRI = Selective serotonin-reuptake inhibitor.
*For the 50 mg dose. †For the 10 mg dose.

like omeprazole, may be another treatment strategy. Nancy C. Brahm, PharmD, MS, BCPP, CGP, is clinical associate
Increasing recognition of the potential for medication- professor, The University of Oklahoma College of Pharmacy,
Tulsa, Oklahoma. Merry C. Kelly-Rehm, MS, RN, is assistant
related effects by practitioners in medicine, pharmacy,
clinical professor of nursing, School of Nursing, The University of
and nursing may prevent the addition of another medi- Tulsa, Tulsa.
cation without considering other strategies.
Disclosures: No funding was received for the development of the
manuscript. The authors report no potential conflicts of interest.
Conclusion
For correspondence: Nancy C. Brahm, PharmD, MS, BCPP, CGP,
Anticholinergic effects associated with SSRIs and SNRIs University of Oklahoma College of Pharmacy, 4502 E. 41st Street,
may not be recognized in the primary care setting. The 2H17, Tulsa, OK 74135-2512; Phone: 918-660-3579;
potential for medication-related side effects may be Fax: 918-660-3009; E-mail: nancy-brahm@ouhsc.edu.
mistaken for new onset disorders. Consequently, anti-
© 2011 American Society of Consultant Pharmacists, Inc.
depressants with more prominent anticholinergic effects All rights reserved.
that contribute to GERD may be under-recognized by Doi:10.4140/TCP.n.2011.274
health care providers. When evaluating patient response
to medication, inquiring about new onset symptoms will
help identify potential medication-related effects and
assessment of the need to a consider a less anticholin-
ergic antidepressant, the addition of an antisecretory/
antispasmodic agent, or an alternative treatment strategy.

The Consultant Pharmacist  April 2011   Vol. 26, No. 4  277

Case Study
References
1 Dent J, El-Serag HB, Wallander MA et al. Epidemiology of
gastro-oesophageal reflux disease: a systematic review. Gut
2005;54:710-7.
2 Moayyedi P, Soo S, Deeks J et al. Eradication of Helicobacter
pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev
2005:CD002096.
3 Sidhu AS, Triadafilopoulos G. Neuro-regulation of lower
esophageal sphincter function as treatment for gastroesophageal
reflux disease. World J Gastroenterol 2008;14:985-90.
4 Ali-Melkkila T, Kanto J, Iisalo E. Pharmacokinetics and related
pharmacodynamics of anticholinergic drugs. Acta Anaesthesiol
Scand 1993;37:633-42.
5 Tyber MA. The relationship between hiatus hernia and
tricyclic antidepressants: a report of five cases. Am J Psychiatry
1975;132:652-3.
6 Ustun TB, Ayuso-Mateos JL, Chatterji S et al. Global burden
of depressive disorders in the year 2000. Br J Psychiatry
2004;184:386-92.
7 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th ed., Text Revision.
Washington, DC: American Psychiatric Association; 2000.
8 Alexopoulos GS, Katz IR, Reynolds CF 3rd et al.
Pharmacotherapy of depression in older patients: a summary of
the expert consensus guidelines. J Psychiatr Pract 2001;7:361-76.
9 Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI
antidepressant side effects. Psychiatry (Edgmont) 2009;6:16-8.
10 Goldstein BJ, Goodnick PJ. Selective serotonin reuptake
inhibitors in the treatment of affective disorders—III.
Tolerability, safety, and pharmacoeconomics. J Psychopharmacol
1998;12:55-87.
11 Lin EH, Von Korff M, Katon W et al. The role of the primary
care physician in patients’ adherence to antidepressant therapy.
Med Care 1995;33:67-74.
12 Naranjo CA, Busto U, Sellers EM et al. A method for estimating
the probability of adverse drug reactions. Clin Pharmacol Ther
1981;30:239-45.
13 Ani C, Bazargan M, Hindman D et al. Depression
symptomatology and diagnosis: discordance between patients and
physicians in primary care settings. BMC Fam Pract 2008;9:1.
278 The Consultant Pharmacist  April 2011   Vol. 26, No. 4
14 Moayyedi P, Axon AT. Review article: gastro-oesophageal reflux
disease—the extent of the problem. Aliment Pharmacol Ther
2005;22 Suppl 1:11-9.
15 Williams DB, Schade RR. Gastroesophageal Reflux Disease.
In DiPiro JT, Talbot RL, Yee GC, Matzke GR, Wells BG,
Posey LM, eds. Pharmacotherapy: A Pathophysiological
Approach. 7th ed. Available at http://wwwaccesspharmacycom/
contentaspx?aID=3181422. Accessed April 23, 2010.
16 Castell DO, Murray JA, Tutuian R et al. Review article: the
pathophysiology of gastro-oesophageal reflux disease—
oesophageal manifestations. Aliment Pharmacol Ther 2004;20
Suppl 9:14-25.
17 Lind T, Cederberg C, Ekenved G et al. Effect of omeprazole—a
gastric proton pump inhibitor—on pentagastrin stimulated acid
secretion in man. Gut 1983;24:270-6.
18 Celexa (citalopram hydrobromide) package insert. St. Louis,
MO: Forest Pharmaceuticals, Inc.; January 2009.
19 Pristiq (desvenlafaxine) package insert. Philadelphia, PA: Wyeth
Pharmaceuticals Inc.; Septemeber 2010.
20 Lexapro (escitalopram oxalate) package insert. St. Louis, MO:
Forest Pharmaceuticals, Inc.; January 2009.
21 Prozac (fluoxetine hyudrochloride) package insert. Indianapolis,
IN: Eli Lilly and Company; October 2009.
22 Effexor (venlafaxine hydrochloride) package insert.
Philadelphia, PA: Wyeth Pharmaceuticals Inc.; January 2010.
23 van Soest EM, Dieleman JP, Siersema PD et al. Tricyclic
antidepressants and the risk of reflux esophagitis. Am J
Gastroenterol 2007;102:1870-7.
24 Martin-Merino E, Ruigomez A, Garcia Rodriguez LA et al.
Depression and treatment with antidepressants are associated
with the development of gastroesophageal reflux disease.
Aliment Pharmacol Ther 2010;31:1132-40.
25 Naliboff BD, Mayer M, Fass R et al. The effect of life stress on
symptoms of heartburn. Psychosom Med 2004;66:426-34.
26 Dording CM, Mischoulon D, Petersen TJ et al. The
pharmacologic management of SSRI-induced side effects: a
survey of psychiatrists. Ann Clin Psychiatry 2002;14:143-7.
27 Papakostas GI. Limitations of contemporary antidepressants:
tolerability. J Clin Psychiatry 2007;68 Suppl 10:11-7.