doi: 10.2169/internalmedicine.

9099-17
Intern Med Advance Publication
http://internmed.jp

【 ORIGINAL ARTICLE 】

A Systematic Review of the Effectiveness of Antianxiety and

Antidepressive Agents for Functional Dyspepsia

Mariko Hojo 1, Akihito Nagahara 2, Daisuke Asaoka 1, Yuji Shimada 2, Sasaki Hitoshi 3,
Kohei Matsumoto 1, Tsutomu Takeda 1, Hiroya Ueyama 1,
Kenshi Matsumoto 1 and Sumio Watanabe 1

Abstract:
Background and Aim Functional dyspepsia (FD) is defined as persistent or recurrent pain or discomfort
centered in the upper abdomen without organic disease. Psychosocial factors have been proposed as an im-
portant element in the pathophysiology of FD. Therefore, psychotropic agents having antianxiety or antide-
pressive action are expected to alleviate FD. We previously reported on the treatment of FD using such
agents in a systematic review, wherein the effectiveness of the agents on FD was suggested, although there
were several limitations. We searched for articles on this subject after our systematic review and re-reviewed
them systematically.
Methods Articles were searched for in MEDLINE from 2003 to 2014 using terms related to antianxiety or
antidepressive agents. Clinical studies in which the effectiveness of such agents was clearly stated were se-
lected from the retrieved articles. The newly selected and previously selected studies were combined, and sta-
tistical analyses were carried out.
Results Nine studies were selected. Five of the studies indicated a significant symptomatic improvement us-
ing psychotropic drugs. A statistical analysis suggested a significant treatment effect of psychotropic agents
having antianxiety or antidepressive action (pooled relative risk [PRR], 0.72; 95% confidence interval [95%
CI], 0.52-0.99; p=0.0406) but did not show a significant benefit of treatment with agents having an antide-
pressive action alone (PRR, 0.63; 95% CI, 0.38-1.03; p=0.0665).
Conclusion Our systematic review suggested that psychotropic drugs having antianxiety and antidepressive
actions as a whole might be effective in alleviating FD symptoms, whereas those having only antidepressive
action were not effective.

Key words: functional dyspepsia, psychotropic agents

(Intern Med Advance Publication)

(DOI: 10.2169/internalmedicine.9099-17)

sometimes exacerbates dyspeptic symptoms in healthy vol-

Introduction unteers (4) and FD patients (3), and patients with physical
complaints in a depressive or anxious state tend to describe
Functional dyspepsia (FD) is defined as persistent or re- their symptoms as being more severe than patients with
current pain or discomfort centered in the upper abdomen, physical complaints who are not in a depressive or anxious
without organic disease. FD is common in the general popu- state (5). Psychosocial factors have been proposed as an im-
lation, and the prevalence of FD has been reported to range portant element in the pathophysiology of FD (3). There-
from 11% to 17% in Japan (1, 2). Multiple factors are asso- fore, psychotropic agents having antianxiety or antidepres-
ciated with the development of FD (3). Psychological stress sive action are expected to alleviate FD symptoms.

１
Department of Gastroenterology, Juntendo University School of Medicine, Japan, ２ Department of Gastroenterology, Juntendo University Shi-
zuoka Hospital, Japan and ３ Department of Gastroenterology, Juntendo Tokyo Koto Geriatric Medical Center, Japan
Received: February 26, 2017; Accepted: March 31, 2017; Advance Publication by J-STAGE: October 11, 2017
Correspondence to Dr. Mariko Hojo, [email protected]

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 Intern Med Advance Publication DOI: 10.2169/internalmedicine.9099-17

We previously published a systematic review of the treat- of the agents by showing the pooled relative risk (PRR)
ment of FD with antianxiety or antidepressive agents in with its 95% confidence interval (95% CI) and p value. P
2005 (6). That review showed the effectiveness of psy- values less than 0.05 were considered statistically signifi-
chotropic agents for the treatment of FD, and the authors cant.
recommended the use of these agents for the treatment of The PRR was calculated after adding the newly searched
FD. However, as the available number of studies in that re- controlled studies to the four double-blind randomized stud-
view was small and/or the studies were of poor quality, fur- ies (7-10) from our previous review (6). The PRR was cal-
ther clinical studies were needed to verify the effectiveness culated using the DerSimonian and Laird method. To quan-
of FD treatment with psychotropic agents. We searched for tify heterogeneity, I2 was calculated. A value of 0% indicates
clinical studies of psychotropic agents with antianxiety or no observed heterogeneity, and larger values show increas-
antidepressive action for FD after our systematic review and ing heterogeneity (11). The PRR was less than 1 when dys-
reviewed the studies systematically. We added the newly pepsia symptoms were improved by treatment with true
searched studies to the studies from our previous review and drugs. A bias assessment plot was used to assess the publi-
re-analyzed all of the studies. cation bias and selection bias.

Materials and Methods Results

We retrieved 80 articles by performing a computer search

Literature search
of the MEDLINE database from 2003 to 2014. Nine studies
We retrieved articles by searching the MEDLINE database were ultimately selected according to the inclusion criteria
limited to English-language, peer-reviewed articles on hu- (Table 1) (12-20). Seventy-one articles were excluded.
mans from 2003 to 2014 using the following keywords: Among them, 43 articles were review articles, including 1
functional dyspepsia AND (“antidepressant[s] OR antide- systematic review, 5 articles did not pertain to the adult
pressant drug[s] OR antidepressive drug[s] OR antidepres- population, and 23 articles were not reports concerning the
sive agent[s]” OR “antianxiety drug[s] OR antianxiety agent efficacy of psychotropic drugs with antianxiety or antide-
[s] OR anxiolytic drug[s] OR [minor] tranquilizer”). We also pressive action for FD (Fig. 1). No articles were newly se-
examined the reference lists of published papers, such as re- lected from the reference lists of published papers.
views, to search for more articles. In five of the nine studies, treatment with psychotropic
drugs significantly improved dyspeptic symptoms. Signifi-
Study selection
cant improvement was reported in two of the four studies on
The inclusion criteria for selection were studies that re- drugs having antianxiety action (12-15) and in three of the
ported whether or not symptoms of FD were improved by five studies on drugs having antidepressive action (16-20).
antianxiety or antidepressive agents, studies that pertained to The recruited patients in two studies (16, 17) that showed
the adult population, and studies that were the most infor- that antidepressants were effective were patients who had
mative when plural studies were published with the same not responded to acid-suppressive agents or prokinetic
content. agents.
For the statistical quantitative analyses, three of the nine
Data extraction
studies were selected (13, 19, 20), and six were excluded.
The following data were extracted from the selected stud- The reasons why the six studies were excluded were as fol-
ies: the number of recruited patients, background character- lows : four studies were not placebo-controlled
istics of the recruited patient population (age, sex, disease, (14, 15, 17, 18), and two studies did not include sufficient
mental state), study design, treatment dose and duration, the information about the number of patients who received the
number of patients who received the allocated intervention, allocated intervention and the number who showed improve-
the effects of treatment based on the intention-to-treat prin- ment (12, 16) (Fig. 1). A statistical analysis was done on a
ciple or full analysis set, the symptoms that improved after total of seven studies by adding these three studies to the
treatment, and the number of subjects who dropped out be- four studies from our previous systematic review (7-10) (Ta-
cause of side effects. ble 2).
The numerical values necessary to calculate the PRR and
Statistical analyses
95% CI are shown in Table 2. The PRR was 0.72 (95% CI,
All statistical analyses were performed using the StatsDi- 0.52-0.99; p=0.0406; Fig. 2). This result showed a signifi-
rect Version 3.0.150 software program (StatsDirect Ltd., cant benefit of the actual drugs over the placebo. The I2 was
Cheshire, UK). Regarding controlled studies in which the 77.9% (95% CI, 44.4%-87.7%), which showed that there
treatment efficacy was evaluated by comparing the percent- was heterogeneity among the studies. The bias assessment
age of patients with dyspeptic symptoms that improved or plot (Fig. 3) exhibited asymmetry, which indicated both
disappeared among a group receiving an actual agent with publication bias and selection bias.
that in a group receiving a placebo, we assessed the effect Drugs with antidepressive action were used in five of the

2
 Table 1. Clinical Studies Using Antianxiety Or Antidepressive Agents for the Treatment of Functional Dyspepsia.

Studies The number Mean The number of patients

Male: The condition of Exclusion criteria for mental Treatment agent dose ITT or Side
(reference of recruited age in Study design that received allocated Improved symptomsa
Female recruited patients state (duration) FAS effectsb
number) patients years intervention
Antianxiety agents
Double-blind Buspiroe 30mg (4 weeks) 7 post prandial fullness, 1
Excluding patients with
(12) 20 4:13 38.5 FDc randomized p<0.005* early satiation, upper
current anxiety or depression Placebo (4 weeks) 10 1
cross-over study abdominal bloating
Double-blind Tandospirone 30mg (4 weeks) 74 1
Excluding patients with upper abdominal pain
(13) 150 40:110 46.4 FDc randomized p=0.036*
anxiety or depression Placebo 71 and discomfort 0
controlled study
Famotidine 40mg 25 0
No exclusion criteria for Randomized
(14) 79 29:50 52.9 FDc Mosapride 15mg 27 N/A*** 0
mental state controlled study
Tandospirone 30mg 27 0
Famotidine 40mg (8 weeks) 23 0
No exclusion criteria for Randomized
(15) 64 N/A N/A FDc Mosapride 15mg (8 weeks) 21 NS**** 0
mental state controlled study
Tandospirone 30mg (8 weeks) 20 0
Tricyclic antidepressive agents
FDd who did not Double-blind Amitriptyline 12.5-50mg
Excluding patients with 20 4
(16) 38 15:23 40.0 respond to PPI or randomized (8 weeks) p=0.02* nausea
depression
Intern Med Advance Publication

prokinetic therapy controlled study Placebo 18 0

FDc who did not Amitriptyline 30mg
Excluding patients with Randomized 14 0

3
(17) 27 N/A N/A respond to famotidine (4 weeks) p<0.01* N/A
depression controlled study
or mosapride therapy no medication (4 weeks) 13 0
Levosulpiride
Pain/discomfort, fullness,
69 bloating, early satiety, 3
FDe with
No exclusion criteria for Randomized Levosulpiride 75mg nausea, and vomiting
(18) 140 34:106 N/A dysmotility-like p=0.01**
mental state controlled study (8 weeks) Pain/discomfort, fullness,
dyspepsia
71 bloating, early satiety, 6
nausea, and vomiting
Serotonin reuptake inhibitors
Double-blind 98 14
Excluding patients with a Sertraline 50mg
(19) 193 54:139 42.4 FDc randomized NS*
history of antidepressant use (8 weeks) 95 8
controlled study
Serotonin and norepinephrine reuptake inhibitor
DOI: 10.2169/internalmedicine.9099-17

Excluding patients with a Double-blind Venlafaxine 75-150mg

80 19
(20) 160 65:95 52.0 FDf history of bipolar disorder or randomized (8 weeks) NS*
recent use of antidepressant controlled study Placebo 80 6
FD: functional dyspepsia, PPI: proton pump inhibitor, ITT: intention to treat,, FAS: full analysis set, N/A: not available, NS: not significant,
a, Symptoms which improved significantly after treatment; b, The number of study subjects who dropped out because of side effects; c, FD based on ROME II criteria; d, FD based on ROME III criteria; e, FD based on ROME I criteria; f, Patients had
persistent dyspeptic symptoms without any organic abnormality.
* Comparison of treatment effect by true drug and placebo. Significant improvement by a true drug was established when p<0.05.
** Comparison of pre-and posttreatment. Significant improvement after treatment was established when p<0.05.
*** Statistical analysis was not done for comparison of pre-and posttreatment by tandospirone. Famotidine was significantly superior to tandospirone (p<0.05).
****Comparison of pre-and post-treatment by tandospirone. Famotidine was significantly superior to other drugs (p<0.05).
 Intern Med Advance Publication DOI: 10.2169/internalmedicine.9099-17

80 studies were identified from databases sults of the current review showed that there is a subgroup
of FD patients for whom psychotropic agents are effective.
71 studies were excluded.
However, heterogeneity and publication or selection bias
Reasons for exclusion: persisted in the present review as in the previous one (6).
reviews of clinical studies (n=43), We examined two kinds of psychotropic agents: drugs
not adult subject research (n=5), having antianxiety action and drugs having antidepressive
not reports concerning the effect of agents action. Regarding drugs having antianxiety action, only two
(n=23) placebo-controlled studies using chlordiazepoxide-clidinium
bromide or tandospirone (7, 13)were included in the statisti-
9 studies were selected cal analysis. Both studies showed that the actual drugs were
superior to the placebo. Aside from these two studies, one
6 studies were excluded from the statistical placebo-controlled study using propantheline bromide in ad-
analyses. Reasons for exclusion:
dition to diazepam (22) was included in the descriptive
not placebo-controlled studies (n=4),
not studies with sufficient information
analysis of the former systematic review, and one placebo-
(n=2) controlled study using buspirone (12) was included in the
current review. Propantheline bromide in addition to diaze-
3 studies were selected for the statistical analyses pam had a comparable effect to the placebo, while buspi-
rone had a stronger effect than the placebo. Both tandospi-
Figure 1. Flow chart illustrating the process of study selec- rone and buspirone are 5-hydroxytryptamine 1A (5HT1A) re-
tion. ceptor agonists. 5HT1A receptor agonists may be effective for
FD, although further clinical studies are necessary.
Chlordiazepoxide-clidinium bromide, tandospirone, and bus-
seven studies (Table 2). The PRR of the studies on these pirone are not simple anxiolytic drugs. Chlordiazepoxide-
drugs was 0.63 (95% CI, 0.38-1.03; p=0.0665; Fig. 4). This clidinium bromide allays anxiety and blocks cholinergic ac-
showed that there was no significant benefit of the actual tivity (7). Tandospirone and buspirone have an anxiolytic ac-
drugs over the placebo. The I2 was 82.9% (95% CI, 51.5%- tion that is not associated with benzodiazepines and are as-
90.9%), which showed that there was heterogeneity among sumed to relax the proximal stomach (23, 24). Although
the studies. benzodiazepine agents are often used as antianxiety agents,
More than 10% of patients treated with buspirone, ami- no studies investigated the effectiveness of a single use of
triptyline, sertraline, or venlafaxine dropped out from the re- benzodiazepine for FD in the previous or current reviews.
spective study protocols because of side effects. The symp- Benzodiazepines are associated with increased risks of falls
toms of side effects were as follows: nausea and abdominal and hip fractures as well as vehicle crashes and induce toler-
discomfort for buspirone; drowsiness and skin rash for ami- ance and dependence (25). Therefore, when benzodiazepines
triptyline; insomnia, constipation, and agitation for sertra- are prescribed to FD patients, their potential benefits and
line; and nausea, palpitations, sweating, sleeping disorders, risks should be carefully weighed.
dizziness, and visual impairment for venlafaxine. The study Regarding drugs having antidepressive action, the current
that showed the highest rate of protocol failure was the review did not show their effectiveness, although the effec-
study on venlafaxine (20), and 19 of 80 patients who were tiveness of these drugs was shown in the previous system-
treated with venlafaxine dropped out of the study. atic review. The serotonin reuptake inhibitor (SSRI) sertra-
line and the serotonin and norepinephrine reuptake inhibitor
Discussion (SNRI) venlafaxine were not superior to the placebo
(19, 20). In the study with the SSRI fluoxetine, which was
In the descriptive analysis of the current systematic re- included in the previous review (6), the symptoms im-
view, the effectiveness of drugs having antianxiety action proved significantly after treatment (26). However, this
and antidepressive action in patients with FD was found in study was an open study, and the symptoms improved in
more than half of the studies examined. Futhermore, the re- only the depressed FD patients. Although a recent meta-
sults of the statistical quantitative analyses of the current re- analysis of placebo-controlled studies of irritable bowel syn-
view showed that the effectiveness of these drugs was the drome showed the effectiveness of SSRIs (27), there have
same as that in the previous systematic review (6). FD is a been no studies on FD showing the effectiveness of SSRIs
multifactorial disease with complex pathophysiology. The in- or SNRIs to date. Recently Tally et al. (28) conducted a
teraction of psychosocial factors and altered gut physiology randomized controlled trial to evaluate the effects of a tri-
via the brain-gut axis is known to be one of the pathophysi- cyclic antidepressant and an SSRI on FD. Unfortunately, in
ologies of FD (21). It has also been described that psycho- this study, the effectiveness of the SSRI was not shown.
social factors contribute to symptoms of FD in the evidence- Furthermore, in the current review, 14% of the patients
based clinical practice guidelines for FD published by the treated by sertraline and 24% of the patients treated by ven-
Japanese Society of Gastroenterology (JSGE) (3). The re- lafaxine dropped out of their respective study because of

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 Intern Med Advance Publication DOI: 10.2169/internalmedicine.9099-17

Table 2. Studies for which Statistical Analyses were Done.

The number of patients that The number of patients that

received an actual drug received a placebo
improved† not-improved‡ improved† not-improved‡
Antianxiety agents
Chlordiazepoxide-clidinium bromide (7) 16 1 13 4
Tandospirone (13) 23 50 9 62
Antidepressive agents
Levosulpiride (9) 16 1 9 6
Levosulpiride (10) 14 1 6 9
Mianserin (8) 19 6 4 18
Sertraline (19) 21 77 21 74
Venlafaxine (20) 30 50 31 49
† the number of patients with improved dyspeptic symptoms
‡ the number of patients with not improved dyspeptic symptoms

Relative risk (95%CI)

Chlordiazepoxide-clidinium bromide[7] 0.25 (0.04-1.47)

Tandospirone[13] 0.78 (0.64-0.93)

Levosulpiride[9] 0.15 (0.02-0.79)

Levosulpiride[10] 0.11 (0.02-0.54)

Mianserin[8] 0.29 (0.14-0.56)

Sertraline[19] 1.01 (0.87-1.18)

Venlafaxine[20] 1.02 (0.80-1.31)

Pooled relative risk=0.72 (95%CI, 0.52-0.99; p=0.0406)
0.72 (0.52-0.99)
Heterogeneity: I2=77.9% (95%CI, 44.4%-87.7%)
0.01 0.02 0.03 0.05 0.1 0.2 0.3 0.5 1 2
In favor of the actual drugs In favor of placebo

Figure 2. A meta-analysis of seven trials using the DerSimonian and Laird method: Actual drugs
(antianxiety or antidepressive agents) vs. placebo for functional dyspepsia. The diamond-shaped box
with the horizontal line presents the pooled relative risk and the 95% confidence interval (95% CI).

0.0
side effects (19, 20). When an SSRI or SNRI is prescribed
to FD patients, the merits and demerits should be carefully
0.3 weighed. The beneficial effects of the tricyclic and tetracy-
clic antidepressant agents amitriptyline and mianserin were
Standard error

shown in two placebo-controlled studies (8, 16). In the

0.6
study with amitriptyline as the actual drug and no medica-
tion as the control (17), the effectiveness of amitriptyline
0.9 was also shown. The mechanisms of the beneficial effects of
tricyclic and tetracyclic antidepressant agents for FD are not
fully understood. However, the beneficial effects could be
1.2
-2.8 -1.8 -0.8 0.2 1.2 2.2 attributed not just to their antidepressant properties but also
Log (Relative risk)
to several actions, such as reducing pain perception (29),
Figure 3. Bias assessment plot: Active drugs vs. placebo. The and their anticholinergic properties (30). A total of 20% of
bias assessment plot exhibited asymmetry, which indicated the patients treated by amitriptyline dropped out of the study
both publication and selection bias. because of side effects (16). Although the incidence of side
effects among patients taking amitriptyline was high, tri-

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 Intern Med Advance Publication DOI: 10.2169/internalmedicine.9099-17

Relative risk (95%CI)

Levosulpiride[9] 0.15 (0.02-0.79)

Levosulpiride[10] 0.11 (0.02-0.54)

Mianserin[8] 0.29 (0.14-0.56)

Sertraline[19] 1.01 (0.87-1.18)

Venlafaxine[20] 1.02 (0.80-1.31)

Pooled relative risk=0.63 (95%CI, 0.38-1.03; P=0.0665)

Heterogeneity: I2=82.9% (95%CI, 51.5%-90.9%) 0.63 (0.38-1.03)

0.01 0.02 0.03 0.05 0.1 0.2 0.3 0.5 1 2

In favor of the actual drugs In favor of placebo

Figure 4. A meta-analysis of five trials using the DerSimonian and Laird method: Actual drugs
(antidepressive agents) vs. placebo for functional dyspepsia. The diamond-shaped box with the hori-
zontal line presents the pooled relative risk and the 95% confidence interval (95% CI).

cyclic and tetracyclic antidepressant agents may have a treatment options for FD were shown: 5HT1A receptor ago-
beneficial effect in FD patients who do not respond to a nists such as tandospirone may be effective, tricyclic and
first-line treatment like a proton pump inhibitor or prokinetic tetracyclic antidepressant agents may have a beneficial effect
therapy (16). Further clinical studies are necessary to prove in FD patients who do not respond to first-line treatment,
the effectiveness of these antidepressant agents. Regarding and levosulpiride may have a promising effect on
levosulpiride, we were unable to find any placebo-controlled dysmotility-like FD. In clinical practice, these kinds of
studies in our current literature search, but a controlled drugs are recommended for FD patients whose symptoms do
study with cisapride in which the subjects were patients not improve with first-line treatment like proton pump in-
with dysmotility-like FD (18) was newly added in the pre- hibitors or prokinetics. Further clinical studies and experi-
sent review. Dyspeptic symptoms improved significantly in ence in clinical practice will prove the effectiveness of these
both the group treated with levosulpiride and the group drugs.
treated with cisapride. There were four randomized con-
trolled studies with levosulpiride in our previous systematic The authors state that they have no Conflict of Interest (COI).
review (9, 10, 31, 32). In these studies, levosulpiride was
superior to the placebo. Notably, only 4% of the patients
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