Khalilian et al. BioPsychoSocial Medicine(2021) 15:3
https://doi.org/10.1186/s13030-021-00205-2

RESEARCH

Open Access

A randomized, double-blind, placebocontrolled study to assess efficacy of
mirtazapine for the treatment of diarrhea
predominant irritable bowel syndrome
Alireza Khalilian1, Davoud Ahmadimoghaddam2, Shiva Saki3, Younes Mohammadi4 and Maryam Mehrpooya3*

Abstract
Background: Ample evidence indicates the efficacy of serotonin type 3 (5-HT3) receptor antagonists in thetreatment of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Mirtazapine is an atypicalantidepressant with a well-known 5-HT3 receptor antagonist property. This study, therefore, was undertaken toinvestigate whether compared to placebo, mirtazapine would be efficacious and safe in the treatment of patientswith IBS-D.
Methods: From November 2019 until July 2020, 67 patients meeting Rome IV criteria for IBS-D were randomized ina double-blind fashion into either the mirtazapine treatment group (n = 34) or the placebo treatment group (n =33). Patients started with mirtazapine 15 mg/day at bedtime for one-week; after which the dose was increased to
30 mg/day for an additional 7-week. Outcomes included changes in the total IBS symptom severity score (IBS-SSS),
Hospital anxiety and depression scale score (HADS), and IBS Quality of Life. Additionally, changes in the diary-based
symptoms scores including pain, urgency of defecation, bloating, stool frequency, and stool consistency based on
the 7-point Bristol Stool Form Scale (BSFS), and a number of days per week with pain, urgency, diarrhea, or
bloating, once during the 1-week run-in period, and once during the last week of treatment were recorded.
Results: All analyses were performed on an Intention-to-Treat (ITT) analysis data set. The results showed comparedto placebo, mirtazapine is more efficacious in decreasing the severity of IBS symptoms (P-value = 0.002). Further, atthe end of the treatment period, all diary-derived symptoms except bloating showed significantly more
improvement in the mirtazapine-treated subjects compared to the placebo-treated subjects. While was welltolerated, mirtazapine also significantly improved the patients’ quality of life (P-value = 0.04) and anxiety symptoms(P-value = 0.005).
Conclusions: Overall, mirtazapine seems to have a potential benefit in the treatment of patients with IBS-D,
particularly those with concomitant psychological symptoms. However, further studies are warranted to determine
whether these findings are replicated.
(Continued on next page)* Correspondence: m_mehrpooya2003@yahoo.com
3
Department of Clinical Pharmacy, School of Pharmacy, Hamadan Universityof Medical Sciences, Shahid Fahmideh Ave, Hamadan 6517838678, Iran
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Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

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Trial registration: Trial registration: Registration number at Iranian Registry of Clinical Trials: IRCT20120215009014
N311. Registration date: 2019-10-21.
Keywords: Irritable bowel syndrome, Diarrhea, 5-hydroxytryptamine, Mirtazapine

Background
Irritable bowel syndrome (IBS) is the most common
functional gastrointestinal disorder with a relapsing/ remitting course. It is a symptom-based condition definedby abdominal pain and discomfort in association with altered bowel habits, with no identifiable cause [1]. It approximately affects 7–18% of the population worldwide
and is more common in women than men [2]. IBS basedon patients’ predominant stool pattern clinically is classified into four subtypes: with diarrhea (IBS-D), with constipation (IBS-C), mixed type (IBS-M), and un-subtyped(IBS-U). Determining the subtype of IBS is important for
both diagnosis and treatment [3]. Although no decreasein life expectancy attributable to IBS has been observed,
it generates a significant burden to both patients and society as a result of direct medical costs, lost productivity,
and reduced health-related quality of life [4]. Management of IBS is based upon a multifactorial approach andincludes non-pharmacological and pharmacological interventions [5]. Due to the high prevalence of psychiatricdisorders in patients with IBS, anxiolytics and antidepressants agents, especially the tricyclic antidepressants(TCAs) and selective serotonin reuptake inhibitors(SSRIs) commonly used for management of IBS symptoms. However, it is believed that the benefits of antidepressants in IBS treatment are not limited only to theiranxiolytic and antidepressants effects. They may also
have peripheral effects on pain perception, visceral
hypersensitivity, and GI motility that could help patientswith IBS-D [6]. However, although a number of pharmacological treatments are available for the treatment of
IBS, most of the currently available drugs focus on alleviating symptoms rather than targeting the underlying
pathophysiology. As a consequence, there is no satisfactory treatment at present for the management of IBS,
and vast numbers of patients with IBS experience suboptimal clinical relief from current treatments [7]. Thus,
there is a need for alternative effective pharmacologicaltreatment for IBS.
For the development of new effective treatments for
IBS, a better understanding of the potential underlying
mechanisms involved in the generation of symptoms is
crucial. Although, the exact pathophysiology of IBS has
not yet been fully elucidated, overall, symptoms appear
to be related to alterations in GI motility and/or enhanced visceral sensitivity [8]. Serotonin (5-HT) is an
important neurotransmitter and paracrine signaling

molecule in the gastrointestinal tract that it’s releasingfrom enterochromaffin (EC) cells initiates peristaltic,
secretory, vasodilatory, vagal, and nociceptive reflexes[9]. A large body of evidence indicates that abnormalities
of serotonergic function have a central role in both intestinal and extraintestinal symptoms of IBS [10]. It has
been found 5-HT dysfunction in the gut by affecting intestinal motor and secretory function may lead to either
constipation or diarrhea. Additionally, altered 5-HT
signaling in the central nervous system and the gut contributes to hypersensitivity in IBS [11]. These causative
mechanisms suggest that therapies targeting alteredserotonin signaling may provide new, effective treatments for patients with IBS. Several serotonin receptor
subtypes have been identified that of which the most interesting targets for pharmacological intervention for
IBS are 5-HT3 and 5-HT4 receptors subtypes [12].
Around one-third of patients with IBS meet the criteria for IBS-D with common symptoms of abdominal
pain or discomfort, frequent loose stools, and urgency[13]. It is well known that 5-HT3 receptor antagonists
by diminishing motor and secretory reflex activity anddecreasing the activation of extrinsic sensory neurons
that transmit signals to the brain can improve symptomsof stool frequency, urgency, abdominal discomfort, andstool consistency in patients with IBS-D [14]. In thisview, a recent systematic review and meta-analysis ofrandomized controlled trials also reported that 5-HT3
receptor antagonists are effective for treating nonconstipated IBS and IBS-D. However, although rare,
there are still clear concerns regarding the occurrence ofserious adverse effects such as ischemic colitis with theseagents [15]. Thus, the constant search is ongoing to
identify new more effective, and better tolerated 5-HT3
receptor antagonists for the management of IBS-D. One
strategy is the search on the existing drugs with known
5-HT3 receptor antagonist property that there is extensive clinical experience in their use and their safety
profile.
Mirtazapine is an atypical antidepressant drug thatexhibits both noradrenergic and serotonergic activity.
Mirtazapine promotes the release of noradrenaline andserotonin by blocking α2-adrenergic autoreceptors and
α2-adrenergic heteroreceptors, respectively. It alsoenhances serotonin neurotransmission, mainly through
5-HT1A receptors by blocking postsynaptic 5-HT2A, 5HT2C, and 5-HT3 receptors [16]. Since introduction,

Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

because of its unique mechanisms of actions, in addition
to treating depression and anxiety, the potential
usefulness of mirtazapine in the treatment of many otherpsychiatric and medical conditions has been investigated[17]. Considering the 5-HT3 receptor antagonist
property of mirtazapine, it may be also a valuable
therapeutic option for the management of patients with
IBS-D and preliminary evidence indicates its beneficial
effects [18, 19].
However, there are only case reports and open-label
studies, and double-blind, placebo-controlled studies
with mirtazapine in the treatment of IBS-D are lacking.
Hence, we designed this double-blind, placebocontrolled study to evaluate whether compared to placebo, mirtazapine would be efficacious and safe in thetreatment of patients suffering from IBS-D.

Material and methods
Study design

This was an 8-week double blind, randomized, placebocontrolled study that from November 2019 until July
2020 was conducted in a gastroenterology clinic, at a
tertiary referral hospital, affiliated to Hamadan University of Medical Sciences, Hamadan, Iran, to evaluate theefficacy of mirtazapine in the treatment of IBS-D. The
trial comprised a one-week run-in period and an 8-weekintervention phase which consisted of a 1 week dose titration period followed by a 7-week fixed-dose period.
Eligible patients were fully informed about the study
aims and all patients signed written informed consent
prior to study participation. The trial was performed inaccordance with the Declaration of Helsinki and subsequent revisions and approved by the ethics committee at
Hamadan University of Medical Sciences. The trial was
registered at the Iranian Registry of Clinical Trials(IRCT20120215009014N311).
Participants

Subjects were men and women age 18–75 years with adiagnosis of IBS with a subtype of diarrhea defined by
the Rome IV criteria [20]. To exclude other causes ofdiarrhea, patients should have normal colonic anatomy(as assessed by flexible sigmoidoscopy, colonoscopy, or
double-contrast barium enema plus flexible sigmoidoscopy), normal full blood count, serum calcium and albumin, C-reactive protein, normal thyroid-stimulating
hormone levels, negative lactose intolerance test, negative serological tests for celiac disease, and negative stool
examinations. During the 1-week run-in period, data on
Stool form (appearance) and stool frequency were collected daily to ensure that patients had suitable symptom
levels at the start of the study. Stool form data werescored on a 7-point ordinal scale according to the Bristol
Stool Form (BSF) Scale [19]. Based on the response to

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daily stool diary during the 1-week run-in period, patients should experience loose stools for ≥3 days in aweek with a Bristol Stool Scale type 6 (fluffy pieces withragged edges, a mushy stool) or 7 (watery stool, no solid
pieces; entirely liquid stool). Exclusion criteria were thefollowing: patients with a diagnosis of IBS with a subtype
of constipation, mixed IBS, or un-subtyped IBS by theRome IV criteria [20], having organic GI disease (e.g.,colitis, Crohn’s disease, celiac disease, bowel surgery, recurrent diverticulitis), history of lactose intolerance, any
antidepressant treatment in the previous 3 months, consuming any medication that could affect the outcomesin the clinician’s opinion (including anticholinergic medications, antibiotics, pain medications that contained
opiates or morphine, 5-HT3 receptor antagonists, diarrhea medication, medication that accelerates the emptying of the stomach, laxatives, cholestyramine, probiotic
products, etc.) within at least 7 days before entering thestudy, unstable medical condition, hyperthyroidism or
hypothyroidism, previous gastrointestinal surgery, pregnancy or lactation or expecting to get pregnant during
the study, medical or psychological factors interferingwith the collection or interpretation of study data, inadequate education and skill for being interviewed andcompleting questionnaires, history of drug or alcoholabuse, and presence of any adverse effects resulting inpatients’ intolerance or complications.
Intervention

From November 2019 until August 2020, 118 patientswith a diagnosis of diarrhea-predominant IBS who
attended a gastroenterology clinic at a tertiary referral
hospital were assessed for eligibility. Of these, 67 patients who met the inclusion/exclusion criteria andagreed to participate in the study were randomized in a
double-blind fashion (using a block size of 4 in a 1:1 ratio) into either the mirtazapine treatment group (intervention group; n = 34) or the placebo treatment group(control group; n = 33). The randomization was provided
by an independent statistician to ensure that groups
were matched for age and sex where possible. Both theinvestigators and the patients were blinded to thetreatment.
Patients according to their group allocation were
instructed to receive mirtazapine or placebo. Both mirtazapine and placebo tablets were identical in shape, color,and odor; the packaging of the compounds was likewise
identical. Patients started with mirtazapine 15 mg/day at
bedtime for 1 week; after which the dose was increased
to 30 mg/day and was continued with this dose for theentire duration of the study. Placebo was administeredin an identical manner. Use of loperamide (up 2 mg
three times daily) as a rescue medication was permitted
for treatment of acute uncontrolled diarrhea, but theKhalilian et al. BioPsychoSocial Medicine(2021) 15:3

patients were required to not use any loperamide rescue
medication during the 1-week run-in period, and during
the last week of the treatment period.
Adherence to treatment was determined by counting
drugs left in the container at the end of the treatment
period and patients were considered adherent to treatment if at least 80% of all doses were taken. The demographic and baseline characteristics of the subjects wererecorded at the first visit. Adverse events were also recorded throughout the treatment period through phone
calls.
Efficacy and safety assessment

Outcome measures were assessed using validated questionnaires. All subjects were required to complete dailystool diary on paper diary cards at bedtime for a 7-day
period, once during the 1-week run-in period, prior toconsuming any treatment, and once during the last weekof the treatment. Daily stool diary provides information
on stool consistency (based on the Bristol Stool Form
Scale (BSFS) from 1 (very hard) to 7 (watery)), frequency
of defecation, and the severity of abdominal pain, urgency of defecation, and bloating that the last threescored as none, mild, moderate or severe (0–3) [21]. A
number of days with pain, urgency, diarrhea (defined as
more than three bowel movements per day), and bloating were also recorded at the 1-week run-in period andthe last week of the treatment period. The baseline
values of stool consistency scores based on the BSFS, theseverity of abdominal pain, the severity of urgency ofdefecation, the severity of bloating, and the frequency ofdefecation per day were averages from the 1-week runin period, and the endpoint values were averages fromthe last week of the treatment period. Patients were
reminded by telephone twice weekly to complete their
daily diaries.
Further, once at the end of 1-week run-in period (before starting treatment) and once after 8 weeks of treatment (end of the study period), the subjects wererequested to complete following questionnaires: 1) the
Hospital Anxiety and Depression Scale questionnaire(HADS) for assessing psychological comorbidities 2) the
IBS Severity Scoring System questionnaire (IBS-SSS) for
assessing the severity of IBS symptoms, and 3) the IBS
Quality of Life (IBS-QoL) questionnaire for assessing thedegree to which IBS interferes with patient quality oflife. The HADS questionnaire is a self-report measurethat was specifically developed to assess anxiety and depression in people with medical illnesses. This questionnaire contains 14 questions with seven items for each
subscale of anxiety or depression. Each item is rated ona four-point scale (0–3) and the total score for each subscale of depression or anxiety ranges from 0 (no depression, no anxiety) to 21 (maximal depression or anxiety)

Page 4 of 12[22]. The reliability and validity of the HADS questionnaire in the Iranian population have been assessed byMontazeri et al. [23]. IBS-SSS is a patient based scalethat assesses 5 clinically relevant items during a 10-day
period: (1) severity of abdominal pain, (2) frequency of
abdominal pain, (3) severity of abdominal distention ortightness, (4) dissatisfaction with bowel habits, and (5)interference of IBS with life in general. Each item isscored on a visual analog scale (VAS) from 0 to 100,
yielding overall scores ranging from 0 to 500 (a higherscore indicates worse condition) [24]. IBS-QoL questionnaire as a 34-items instrument was also developed andvalidated to assess QOL impairment in IBS. Each item israted on a 5-point Likert scale where 1 generally represents better responses on items and 5 represents worse
responses; thus yielding a total score that has a theoretical range of 34 to 170, with higher scores indicating
worse QOL. For ease of interpretation, as per the original description of the tool, the raw scores of the IBSQoL were converted to a 0–100 scale, with higher scoresindicating better IBS specific quality of life [25]. A Persian translated and validated version of this questionnaire was used in this study [26].
Main primary outcome measures in the study were thechanges in the total IBS-SSS score from baseline to endof treatment, and the proportion of responders which
was defined as number of patients whose overall symptom severity scores on the IBS-SSS changed ≥50 points
from baseline to Week 8 [24, 27]. As secondary efficacy
outcomes, the changes in severity of the five sub-scalesof IBS-SSS, the above mentioned diary-based symptoms
scores including pain perception, urgency of defecation,
bloating, stool frequency defined as a mean number of
episodes per day, stool consistency using the 7-point
BSFS, and a number of days per week with pain, urgency, diarrhea, or bloating were reported. Additional efficacy assessment outcomes included the changes in the
IBS-QoL and HADS total scores at the end of the treatment period compared to the baseline. Also, as anothersecondary outcome, all randomized patients in theintention-to-treat (ITT) population who received at least
one dose of study medication were evaluated for safety.
Statistical analyses

All analyses were performed on an ITT analysis data set
because all participants received at least one dose of thestudy medication. Because dropout rates of less than
20% and similar courses of disease in the comparisongroups, the missing data were replaced by the mean dataof the other group. Data were analyzed using SPSS for
Windows (SPSS Inc., Chicago, IL, USA) version 16 software. The Kolmogorov-Smirnov test was performed toevaluate the normality of the continuous variable distribution. Normally distributed continuous variables were

Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

reported as mean ± standard deviation (SD). Nonnormally distributed continuous data were expressed as(interquartile range [IQR]). Categorical variables werereported as frequency and percentage. Parametric andnon-parametric continuous variables were analyzed
using independent t-test and Mann–Whitney tests, respectively. The distribution of categorical variables between two groups was compared using the Chi-squareor Fisher exact test (if more than 20% of the categories
were expected to have frequencies less than 5). A twotailed P-value less than 0.05 was considered statisticallysignificant.

Results
Participant flow

Figure 1 shows the flow diagram of the trial participants.
A total of 118 patients with a diagnosis of IBS with asubtype of diarrhea underwent a screening examination
to ensure study eligibility. Of those, 12 patients did notagree to take part in the study and 39 patients did notmeet the inclusion/exclusion criteria at baseline. The
remaining 67 patients who met the study criteria andhad an interest in study participation were enrolled in
the study (34 patients in the mirtazapine-treated groupand 33 patients in the placebo-treated group). Of whom,
54 patients (80.6%) completed the entire course of theFig. 1 The flow diagram of the study

Page 5 of 12

study and 13 patients (19.4%) discontinued participationin the study prematurely: 5 patients due to experiencing
intolerable adverse effects, 4 patients due to loss to follow up, and 4 patients due to using the medication forless than 80% of the study period. As mentioned above,
all analyses were performed on an ITT analysis data set(on 67 patients).
Demographics and baseline characteristics

The basic characteristics of the study population are
depicted in Table 1. Of the included patients, 32.8% (22patients) were male and 67.2% (45 patients) were female.
The gender distribution was in favor of females in bothgroups (72.7% in the control group and 61.8% in theintervention group). The mean age (±SD) of the patientsin the mirtazapine and placebo groups was 44.41 (±11.25) and 43.45 (±10.35) years, respectively. At baseline,
the mean values of the Body Mass Index (BMI) were
22.27 ± 2.95 and 22.71 ± 3.19 in the mirtazapine and placebo groups, respectively. The mean duration of IBS was
10.0 ± 6.52 years (ranged from 1 to 25 years) in the mirtazapine group and 9.2 ± 7.74 years (ranged from 1 to 28
years) in the placebo group. As showed in Table 1, thetreatment groups were comparable with regards to basic
characteristics including age, gender, BMI, and mean
duration of illness.

Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

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Table 1 Baseline demographic and clinical characteristics of the patients
VariableP
valueGroupsControl (N = 33)

Intervention (N = 34)

Gender (N; male/female)

9/24

13/21

Age (years; mean ± SD)

43.45 ± 10.35

44.41 ± 11.25

0.95

BMI (Kg/m2; mean ± SD)

22.71 ± 3.19

22.27 ± 2.95

0.57

IBS duration (Years; mean ± SD)

9.2 ± 7.74

10.0 ± 6.52

0.65

0.44

BMI Body mass index, IBS Irritable bowel syndrome

Efficacy outcomes

Table 2 shows the change in the clinical outcomes including IBS-SSS, IBS-QoL, and HADS scores from baseline to week 8 by treatment allocation. At baseline, thestudy groups were similar with respect to the total IBSSSS score (301.68 ± 78.73 in the mirtazapine-treated subjects and 294.09 ± 71.55 in the placebo-treated subjects;

P-value = 0.68) (Table 2). Although in both treatmentgroups, mean total IBS-SSS scores declined from baseline to the end of the intervention, the change in IBSSSS overall score during the trial course was significantly
greater in the mirtazapine-treated subjects than theplacebo-treated subjects (− 89.76 ± 71.60 vs. -34.73 ±66.91; P-value = 0.002) (Table 2). In more statistical

Table 2 Results related to the changes of IBS-SSS total score, IBS-SSS sub-scale scores, IBS-QoL score, and HADS score over time in
the two groups
VariableGroup

Baseline

Week 8Mean difference

Total IBS-SSS score

Intervention

301.68 ± 78.73

211.92 ± 62.72− 89.76 ± 71.60

IBS-SSS Pain severity score

IBS-SSS Pain frequency score

IBS-SSS abdominal distention severity score

IBS-SSS bowel habit dissatisfaction score

IBS-SSS life interference score

HADS-A

HADS-D

IBS-QoL

Control

294.09 ± 71.55

259.36 ± 72.81− 34.73 ± 66.91

P- value

0.68

0.006

0.002

Intervention

68.53 ± 18.93

41.47 ± 17.08− 27.06 ± 18.83

Control

61.18 ± 15.71

52.53 ± 16.40−9.00 ± 14.87

P- value

0.10

0.009

< 0.001

Intervention

60.59 ± 20.59

42.06 ± 19.81−18.52 ± 16.54

Control

60.24 ± 14.06

54.21 ± 14.18−6.03 ± 15.82

P- value

0.94

0.005

0.002

Intervention

61.76 ± 22.35

50.29 ± 18.50−11.47 ± 12.34

Control

61.43 ± 16.96

53.58 ± 16.86−7.84 ± 16.41

P- value

0.91

0.45

0.31

Intervention

58.53 ± 22.85

39.41 ± 15.94−19.12 ± 21.08

Control

58.06 ± 18.03

51.21 ± 17.98−6.97 ± 14.68

P- value

0.84

0.006

0.008

Intervention

51.47 ± 21.90

37.65 ± 18.60−13.82 ± 15.18

Control

54.09 ± 18.69

48.79 ± 18.50−5.30 ± 12.12

P- value

0.60

0.01

0.02

Intervention

9.36 ± 3.26

5.57 ± 1.89

−3.70 ± 3.48

Control

8.88 ± 2.33

7.19 ± 2.65

−1.69 ± 2.79

P- value

0.59

0.005

0.01

Intervention

8.15 ± 2.99

5.97 ± 1.58

−2.18 ± 3.74

Control

7.73 ± 2.77

6.88 ± 2.52

−0.85 ± 3.23

P- value

0.55

0.08

0.13

Intervention

45.32 ± 17.18

70.52 ± 16.55

25.19 ± 15.60

Control

53.11 ± 16.34

62.68 ± 14.25

9.56 ± 14.89

P- value

0.06

0.04

< 0.001

IBS-SSS IBS Severity Scoring System, IBS-QoL IBS Quality of Life, HADS Hospital Anxiety and Depression Scale questionnaireKhalilian et al. BioPsychoSocial Medicine(2021) 15:3

details, the five sub-scales of IBS-SSS were also analyzed.
When compared to the placebo group, except for thescore for severity of abdominal distention, eight-weekchange in all other IBS-SSS sub-scale scores were significantly greater in the mirtazapine group (P-value<.05 forall, with the exception of abdominal distention; Table 2).
With respect to responder rate which was defined as a
50-point or more reduction in IBS-SSS overall score at
the end of treatment, 61.8% (21 out of 34 patients) inthe mirtazapine-treated group compared to 30.3% (10out of 33 patients) in the placebo-treated group were responders, which was a statistically significant difference(P-value = 0.01; Fig. 2).
Results regarding the changes in the diary-based symptoms in the two groups have been reported in Table 3.
As results show, compared to the baseline at the end of
the treatment period all diary-derived symptoms except
bloating showed significantly more improvement in themirtazapine-treated subjects compared to the placebotreated subjects. The median (IQR) of average stool
consistency score based on the BSFS score decreased
from 5.50 (IQR: 6–5.07) (at the week prior to starting
treatment of the trial) to 4.00 (IQR: 4.5–3.5) (at the last
week of trial) in the mirtazapine-treated group, and decreased from 5.35 (IQR: 5.8–5) to 5.00 (IQR: 5.5–4.5) inthe placebo-treated group. The median (IQR) of change
in the average stool consistency score in the mirtazapine
group was − 1.25 (IQR: − 0.8-(− 1.9)) and in the placebogroup was − 0.30 (IQR: 0.2-(− 0.6)), which showed a statistically significant difference between the two groups(P-value < 0.001). Further, mirtazapine reduced the mean
average daily bowel movement frequency from 2.30 ±0.69 (at the week prior to starting treatment of the trial)
to 1.83 ± 0.43 (at the last week of trial) which comparedto placebo was a significantly greater reduction. Likewise, in the last week of the treatment period, with regard to the mean average urgency or abdominal painscores as well as the median number of days with

Fig. 2 Comparison of responder rates between two groups, as
defined by a 50-point or more reduction in IBS-SSS overall score at
the end of the study period (P-value = 0.01)

Page 7 of 12

abdominal pain, urgency, and diarrhea, more favorable
outcomes were observed in the mirtazapine-treated subjects compared to the placebo-treated subjects.
With regard to the patients’ anxiety symptoms, at theend of the study period, we noted more improvement in
the mirtazapine-treated subjects compared to theplacebo-treated subjects (the mean HADS-A scores decreased from 9.36 ± 3.26 to 5.57 ± 1.89 in the mirtazapine group and decreased from 8.88 ± 2.33 to 7.19 ± 2.65
in the placebo group; P-value = 0.005; Table 2). Although
at the end of the treatment period, depression symptoms
also showed more improvement in the mirtazapinetreated subjects compared to the placebo-treated subjects, it did not display significant differences. Concerning the impact of IBS on patients’ quality of life, at theend of the treatment period, a noticeable improvementin the IBS-QoL score was also seen in the intervention
group compared to the control group (the IBS-QoL
score increased from 45.32 ± 17.18 at baseline to 70.52 ±16.55 on week 8 after treatment in the patients receiving
mirtazapine and from 53.11 ± 16.34 to 62.68 ± 14.25 in
the patients receiving placebo; P-value = 0.04; Table 2).
Safety outcomes

Table 4 demonstrates the frequency of drug-related adverse effects by treatment allocation. As shown, adverse
effects such as drowsiness, dry mouth, fatigue, and increased appetite were reported by a higher percentage ofthe mirtazapine-treated subjects compared to theplacebo-treated subjects. Nevertheless, as these adverse
effects were mild to moderate in nature, mirtazapine
was acceptably well-tolerated by a considerable percentage of the study patients and only 4 patients in the mirtazapine group discontinued their treatment due tointolerable adverse effects. Further, during the treatment
period, 8 patients in the mirtazapine group and one patient in the placebo group gained weight (P-value = 0.03)(between 2 and 5 kg, self-reported) which could be advantageous in the patients with anorexia.

Discussion
Based on our best knowledge, our study for the first timein a randomized, double-blind, and placebo-controlled
study evaluated the influence of mirtazapine on clinicaloutcomes of patients with diarrhea-predominant IBS.
This study showed that in comparison to the placebo,
mirtazapine was more effective in decreasing the severityof IBS symptoms (based on the IBS-SSS questionnaire).
Further, compared to placebo, mirtazapine increasedstool consistency, decreased stool frequency, decreased
urgency and abdominal pain scores, and increased therate of days without bowel urgency, pain, and diarrhea.
Additionally, while was acceptably well-tolerated,(2021) 15:3

Khalilian et al. BioPsychoSocial Medicine

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Table 3 Results related to the changes in the diary-based symptoms in the study groups
VariableGroup

Baseline

Week 8Mean difference

BSFS
Median,(IQR)

Intervention

5.50 (6–5.07)

4.00 (4.5–3.5)−1.25(− 0.8-(− 1.9))

Control

5.35 (5.8–5)

5.00 (5.5–4.5)− 0.30 (0.2-(− 0.6))

P- value

0.34< 0.001< 0.001

Intervention

2.30 ± 0.69

1.83 ± 0.43

− 0.48 ± 0.41

Bowel frequency per day
Mean ± SD

Abdominal pain score
Mean ± SD

Urgency score
Mean ± SD

Bloating score
Mean ± SD

Days with urgency
Median,(IQR)

Days with pain
Median,(IQR)

Days with diarrhea
Median,(IQR)

Days with bloating
Median,(IQR)

Control

2.27 ± 0.63

2.15 ± 0.57

− 0.12 ± 0.31

P- value

0.79

0.01

< 0.001

Intervention

1.50 ± 0.45

0.97 ± 0.45

− 0.54 ± 0.41

Control

1.65 ± 0.62

1.44 ± 0.58

− 0.21 ± 0.37

P- value

0.27< 0.001

0.001

Intervention

1.70 ± 0.48

1.13 ± 0.47

− 0.57 ± 0.33

Control

1.57 ± 0.57

1.41 ± 0.53

− 0.16 ± 0.29

P- value

0.31

0.03

< 0.001

Intervention

1.61 ± 0.57

1.38 ± 0.39

− 0.25 ± 0.43

Control

1.51 ± 0.57

1.32 ± 0.50

− 0.19 ± 0.35

P- value

0.47

0.69

0.54

Intervention

5.00 (6–4)

4.00 (5–3)− 2.00 (0.00- (− 2))Control

6.00 (6–4)

5.00 (6–3)

0.00 (0.00- (− 2))

P- value

0.36

0.01

0.05

Intervention

5.00 (6–4)

3.00 (4–2)− 2.00 (− 1-(− 2))Control

5.00 (5.5–4)

5.00 (5–3.5)

0.00 (0.00- (− 1))

P- value

0.75< 0.001< 0.001

Intervention

5.00 (6–4)

4.00 (4–2.75)− 1.50 (0.75- (− 2.25))

Control

5.00 (6–4)

4.00 (5–4)

0.00 (0.00- (− 2))

P- value

0.84

0.001

0.003

Intervention

6.00 (7–5)

5.00 (6–3.75)− 1.00 (0.00- (− 2))Control

5.00 (7–4.5)

5.00 (6–4)− 1.00 (1- (− 1.5))

P- value

0.59

0.17

0.11

BSFS Bristol Stool Form scale, IQR Interquartile range, SD Standard deviation

Table 4 Frequency of drug related adverse effects among
patients in each group
PvalueAdverse effects
N (%)

Group

Drowsiness

12 (35.3%)

3 (9.1%)

0.01

Dizziness

6 (17.6%)2 (6.1%)

0.25

Nausea5 (14.7%)

2 (6.1%)

0.43

Dry mouth

9 (26.5%)2 (6.1%)

0.04

Fatigue

10 (29.4%)

2 (6.1%)

0.02

Headache4 (11.8%)

1 (3.0%)0.36

Mirtazapine (N = 34)

Placebo (N = 33)

Increased appetite

11 (32.4%)

2 (6.1%)

0.01

Weight gain

8 (23.5%)

1 (3.0%)0.03

treatment with mirtazapine improved the patients’ quality of life as well as psychological symptoms such as
anxiety.
Diarrhea-predominant IBS is a debilitating form of IBS
which significantly reduces the quality of life of patients,
increases health care expenditures, impairs social andoccupational functioning, and increases psychologicaldisorders [28]. Despite its high burden, the choice oftreatments of IBS-D by patients or their practitioners isstill challenging. Although a number of different
pharmacological treatments are available for the management of patients with IBS-D, no treatment has beenshown to have sufficient efficacy and safety and most of
the patients continue to suffer from symptoms [29]. The
pathophysiology of IBS is not precisely understood yet
and likely it has multifactorial etiopathogenesis. Fromthe biological point of view, the coordination between

Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

the central nervous system and gastrointestinal contractility is regulated through a variety of brain-gut peptides
and gastrointestinal hormones [30]. Among a variety ofneurotransmitters that can evoke IBS symptoms, serotonin has key contributory roles in its pathogenesis.
Serotonin is an important signaling molecule in the activation of motor and secretory reflexes, and in the activation of sensory signals in the brain-gut axis. It is
becoming increasingly clear that dysfunctions of the central or peripheral serotonergic system can be involved in
the pathophysiology of IBS [15]. In this context, it has
been reported that patients with IBS-D might have reduced serotonin reuptake, and those with IBS-C might
have impaired release of serotonin [31]. Further studies
have also indicated that post-infective IBS is associatedwith increased serotonin containing enteroendocrine
cells [32] and increased postprandial serotonin release[33]. There is also evidence of an association between
serotonin transporter gene polymorphism and thediarrhea-dominant IBS phenotype. Indeed, it seems thatthe reduction of serotonin transporter expression could
result in raised serotonin levels and contribute to symptoms in patients with IBS-D [34]. Among multiple subtypes of the receptor for serotonin, it is well recognizedthat the 5HT3 subtype plays an important role in gut
function. It has been also known that signaling from thegut to the central nervous system is predominantly 5HT3 mediated [35]. Further, it is well-known that indiarrhea-predominant IBS, activation of serotonin receptors belonging to the 5-HT3 subtype by increasing thefiring rate of secretomotor neurons increase intestinal
motility and secretion [36]. In line with this evidence, it
is found that 5-HT3-receptor antagonists retard colonictransit, reduce secretion, reduce visceral sensitivity via
both peripheral and central nervous receptors systemmechanisms, and increase colonic compliance in response to distension [37]. Actually, it is found that the
5-HT3 receptor antagonists by inhibiting 5-HT3 receptors located on intrinsic sensory neurons can diminish
motor and secretory reflex activity, and by decreasing
the activation of extrinsic sensory neurons and vagal afferents, which are involved in the transmission of noxious and non-noxious (eg, nausea, bloating) sensations
respectively, decrease the visceral pain and discomfort
associated with IBS [38]. So, this evidence makes 5-HT3
antagonists as a logical treatment in the management ofpatients with IBS-D. In line with this, a recent systematic
review and meta-analysis by Zheng et al. showed that 5HT3 receptor antagonists relieve global IBS-D symptoms, abdominal pain and discomfort, urgency, stool
consistency, and stool frequency in non-constipated IBS
and IBS-D [15]. However, despite the substantial evidence of their effectiveness, due to concern regarding
occurrence rare but serious adverse events such as

Page 9 of 12

severe constipation and ischemic colitis, place of 5-HT3
receptor antagonists such as cilansetron and alosetron in
the treatment of IBS-D being restricted to patients withsevere refractory IBS-D who have failed to respond to
the usual conventional treatment [35]. Therefore, there
is a need for alternative safe and efficacious pharmacological treatment for IBS-D. It seems that instead of new
drug discovery, attempts to introduce agents with 5HT3 receptor antagonist property from already-existing
drugs with known adverse drug reaction profiles may be
a good strategy.
One of these agents is mirtazapine. Mirtazapine is anantidepressant and antianxiety agent that because of theunique mechanism of action, since introduction, its use
in a wide range of conditions has been investigated [16].
Recently, some clinical studies also have addressed its effectiveness in the management of functional gastrointestinal symptoms. In this regard, Jiang et al. in their recent
study in functional dyspepsia patients with weight loss
reported that mirtazapine not only alleviates symptoms
associated with dyspepsia and depression but also significantly increases body weight. They also observed thatthe clinical efficacy of mirtazapine may be mediated inpart through the regulation of brain-gut or gastrointestinal hormones [39]. Similar to these findings, results ofanother study by Tack et al. also showed that comparedto placebo mirtazapine at a dose of 15 mg/day can improve early satiation scores and nutrient tolerance infunctional dyspepsia patients with weight loss [40]. Recently by Sanagapalli and colleagues in an open-label
study, the efficacy of mirtazapine in the treatment of
IBS-D was also investigated. Consistent with our findings, in this study mirtazapine demonstrated considerable beneficial effects on both gastrointestinal andpsychological symptoms in patients with IBS-D [18].
Also, in one case report, mirtazapine was an effective
agent in the improvement of debilitating IBS symptoms
in a woman that mirtazapine was initiated by her psychiatrist for treatment of comorbid depression [19]. Spiegel
et al. also reported mirtazapine was effective in improving both psychopathological symptoms and diarrhea andconstipation symptoms in a 66-year-old woman sufferingfrom a 1-year history of IBS-mixed type [41].
Although the beneficial effects of mirtazapine in thetreatment of IBS-D mainly stem from its strong antagonistic activity against central and peripheral 5HT3 receptors [42], it seems that mirtazapine has a number ofother possible mechanisms of action in the treatment of
IBS-D. There is a large body of evidence suggesting thatmast cell activation which contains granules rich in mediators such as histamine plays an important role in thedevelopment of major IBS symptoms, such as abdominal
pain, constipation, and diarrhea [43]. High levels of histamine were found from supernatants from IBS colonicKhalilian et al. BioPsychoSocial Medicine(2021) 15:3

samples [44]. Moreover, it has been observed that theexpression of histamine1 (H1) and H2 receptors in theintestinal tissue samples of IBS patients is up-regulated[45]. It is found that histamine by activation enteric neurons through H1 and H2 receptors contributes to visceral hypersensitivity [46]. This causative mechanism
suggests the possible application of anti-histamine agentsas a potential therapeutic option in the management of
IBS and interestingly enough, some experimental andclinical studies have provided promising evidence regarding the effectiveness of these agents in the treatmentof IBS [47–49]. Mirtazapine is also found to have a highaffinity for central and peripheral H1receptors and acts
as a potent antagonist of H1 receptors [50]. So, it seems
that the anti-histamine property of mirtazapine may be
another potential mechanism of its action for treating
IBS.
Recently accumulated experimental and clinical evidence has reported that mirtazapine like TCAs, as adual-acting antidepressant, has also marked antinociceptive effects that offer this possibility that mirtazapine
used in the management of various chronic pain conditions [51–54]. As regards the mechanism of action, it isbelieved the antinociceptive effect of mirtazapine unrelated to its antidepressant and antianxiety effects. It
seems mirtazapine mainly via modulation of serotonin
and noradrenaline pathways in the brain, and selective
interaction with multiple 5-HT receptors exerts its antinociceptive effects [54, 55]. Beyond this, in recent years
mounting of evidence has pointed out that Kappa opioid
receptors which are located on the terminals of a varietyof neurons, including those extrinsic visceral afferent
neurons exhibit visceral analgesic and antihyperalgesic
activity [56, 57]. Preliminary evidence suggests that beside serotonergic and noradrenergic receptors, the antinociceptive effects of mirtazapine is partially mediatedby the opioidergic system, particularly through activationof the kappa3-opioid receptor subtype [54, 55].
It is well-known that psychological stress playing amajor role in the onset and exacerbation of IBS symptoms such as abdominal pain and altered bowel movements [58]. Considering that psychiatric comorbidities
such as anxiety and depression are highly prevalent in
IBS patients [59], and psychopharmacological agentscommonly employed by clinicians as an alternative therapy for the management of IBS symptoms, especially
IBS-D [6], it seems that the anxiolytic and antidepressanteffect of mirtazapine is an additional mechanism that
may indirectly through it alleviate IBS symptoms.
Taken together, considering the above-discussed mirtazapine ways of action, it can exert beneficial effects on
IBS symptoms via multiple potential mechanisms of action. Interestingly enough benefits of mirtazapine treatment in patients with IBS-D are amplified by the fact

Page 10 of 12

that it is effective as both an etiological and symptomatic
treatment in these patients. Further, the attractiveness of
mirtazapine for the treatment of IBS also stems from its
good tolerability and safety profile. Dry mouth, sedation,
and weight gain are the most common side effects ofmirtazapine that tolerance to side effects such as sedation can develop with ongoing therapy [16]. Further, its
appetite stimulation may be welcome in patients withanorexia and low BMI [39, 40]. Evidence concerning theeffect of mirtazapine on muscarinic-cholinergic receptors is limited. Although previously, some experimental
evidence indicated that mirtazapine has a low affinity forcentral and peripheral muscarinic-cholinergic receptors[60, 61], recently preliminary evidence suggests that mirtazapine interacts with muscle and neuronal muscarinicand nicotinic receptors as well [62, 63]. However, theclinical importance of the anticholinergic effect of mirtazapine especially in a matter of its tolerability remains
unclear. However, it is obviously clear that Mirtazapine
particularly in the case of anticholinergic side effects
generally better tolerated than the traditional TCAs thatare routinely used in the management of IBS symptoms[64]. Therefore, this margin of safety and excellent efficacy makes mirtazapine as a promising agent for the
management of IBS-D.
Despite the novelty, the findings of our work should
be interpreted within its limitations. The first limitationof this study is the relatively small number of subjects
and the relatively short duration of the follow up that
can affect the generalization of our results. More studies
with larger sample sizes and longer follow-up visits are
warranted to validate the findings reported here. The
second limitation of the study is that the patients in ourstudy received a relatively modest dose of mirtazapine;
maybe higher doses show better effects on the improvement of symptoms or different tolerability. Third, for theassessment of the rate of occurrence of adverse effects,
we relied on the patients’ self-reporting. Since patients
may not recognize all drug-related side effects, thus theactual incidence of side effects may be underestimatedin this study. Hence, using a standard instrument to
identify adverse effects in advance in future studies canestimate more precisely the incidence of adverse effects.
Last but not least, we investigate the effectiveness of
mirtazapine in patients with diarrhea-dominant IBS.
Additional trials are needed to evaluate the effectivenessof mirtazapine for the treatment of other types of IBS.

Conclusion
In conclusion, compared to placebo, mirtazapine not
only alleviated gastrointestinal symptoms of patientswith IBS-D but also improved QOL as well as psychological symptoms such as anxiety of these patients. Despite the limitations of our study that make a drawing

Khalilian et al. BioPsychoSocial Medicine(2021) 15:3

strong conclusion difficult, our study provides primaryevidence that patients suffering from IBS-D symptoms,
particularly those with concomitant psychological symptoms, by the administration of mirtazapine experiencesignificant improvement in gastrointestinal symptoms of
IBS-D but also in psychological aspects and QOL, as do
traditional TCAs. Given that mirtazapine is generally
better tolerated than TCAs, this evidence makes mirtazapine an attractive therapeutic option in the treatmentof IBS. However, future studies with larger sample sizeand longer follow-up periods would be necessary to clarify the optimal dose as well as the safety and efficacy of
mirtazapine in patients with other subtypes of IBS.
Abbreviations
IBS: Irritable bowel syndrome; IBS-D: Irritable bowel syndrome with diarrhea;
IBS-C: Irritable bowel syndrome with constipation; IBS-M: Irritable bowel
syndrome mixed type; IBS-U: Irritable bowel syndrome un-subtyped;
TCAs: Tricyclic antidepressants; SSRIs: Selective serotonin reuptake inhibitors;
5-HT: Serotonin; EC: Enterochromaffin; BSF: Bristol Stool Form; BSFS: Bristol
Stool Form Scale; HADS: Hospital Anxiety and Depression Scalequestionnaire; IBS-SSS: IBS Severity Scoring System questionnaire; IBSQoL: IBS Quality of Life; ITT: Intention-to-Treat; SD: Standard deviation;
BMI: Body Mass Index; H1: Histamine1; H2: Histamine2
Acknowledgments
The authors thank all patients for helping and participating in the study andmade this work possible.
Authors’ contributions
Conceptualization: Mehrpooya, Ahmadimoghaddam, and Khalilian;
Methodology: Mehrpooya, Khalilian, Ahmadimoghaddam, and Mohammadi;
Data acquisition: Khalilian and Saki; Statistical analysis: Mohammadi andMehrpooya; Writing-original draft preparation: Ahmadimoghaddam and Saki;
Writing- review and editing: Mehrpooya and Khalilian. The author(s) read andapproved the final manuscript.
Funding
This study was partially supported by funding from the Vice-Chancellor of
Research and Technology of Hamadan University of Medical Sciences, Hamadan, Iran (Grant Number: 9808286502). This grant was just for the provisionof medicine and placebo and was not assigned to the manuscript writing,editing, and publication fee.
Availability of data and materials
The datasets used and analyzed during the current study are available fromthe corresponding author on reasonable request up to 2 years after
publication.
Ethics approval and consent to participate
All participants provided written informed consent prior to study
participation, and the study protocol was approved by the ethics committee
at Hamadan University of Medical Sciences (IR.UMSHA.REC.1398.516).
Consent for publication
All authors have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Internal Medicine, School of Medicine, Hamadan Universityof Medical Sciences, Hamadan, Iran. 2Department of Pharmacology &Toxicology, School of Pharmacy, Hamadan University of Medical Sciences,
Hamadan, Iran. 3Department of Clinical Pharmacy, School of Pharmacy,
Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan
6517838678, Iran. 4Modeling of Noncommunicable Diseases Research Center,

Page 11 of 12

School of Public Health, Hamadan University of Medical Sciences, Hamadan,
Iran.
Received: 15 October 2020 Accepted: 27 January 2021

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