Progress in Neuro-Psychopharmacology and

Biological Psychiatry
Volume 109, 13 July 2021, 110266

Gastrointestinal side effects associated with

antidepressant treatments in patients with major
depressive disorder: A systematic review and meta-
analysis
Vincenzo Oliva a, Matteo Lippi a, Riccardo Paci a, Lorenzo Del Fabro b, Giuseppe Delvecchio b, Paolo Brambilla b,
Diana De Ronchi a, Giuseppe Fanelli a, Alessandro Serretti a

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https://doi.org/10.1016/j.pnpbp.2021.110266
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Highlights

• Knowing the tolerability profile of each drug helps to improve patient

compliance.

• Escitalopram and sertraline have the least favorable tolerability profile on gut.

• Mirtazapine shows only increased appetite and may be useful in treating

nausea.

• Fluoxetine is associated with a significantly lower risk of inducing dyspepsia.

• Dose-related side effects are nausea for citalopram, constipation for

vortioxetine.

Abstract

Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD)
while taking antidepressants and may lead to treatment discontinuation. The aim of this meta-analysis is to
provide quantitative measures on short-term rates of gastrointestinal SEs in MDD patients treated with
second-generation antidepressants.
An electronic search of the literature was conducted by using MEDLINE, ISI Web of Science – Web of Science
Core Collection, and Cochrane Library databases. Eligible studies had to focus on the use of at least one of 15
antidepressants commonly used in MDD (i.e., agomelatine, bupropion, citalopram, desvenlafaxine,
duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, paroxetine, reboxetine,
sertraline, venlafaxine, and vortioxetine) and report data on treatment-emergent gastrointestinal SEs (i.e.
nausea/vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry
mouth) within 12 weeks of treatment.

Overall, 304 studies were included in the meta-analyses. All the considered antidepressants showed higher
rates of gastrointestinal SEs than placebo. Escitalopram and sertraline were shown to be the least tolerated
antidepressants on the gastrointestinal tract, being associated with all the considered SEs with the
exception of constipation and increased appetite, while mirtazapine was shown to be the antidepressant
with fewer side effects on the gut, being only associated with increased appetite.

In conclusion, commonly used antidepressants showed different profiles of gastrointestinal SEs, possibly
related to their mechanisms of action. The specific tolerability profile of each compound should be
considered by clinicians when prescribing antidepressants in order to improve adherence to treatment and
increase positive outcomes in patients with MDD.

Introduction

Major depressive disorder (MDD) has been one of the most important causes of non-fatal health loss for
nearly three decades, affecting ~264 million people worldwide (James et al., 2018). The economic burden of
depressive disorders in the USA has been estimated to be more than 210 billion US$ in 2010, due to direct,
suicide-related and workplace costs, with an increase of 21.5% in five years (Greenberg et al., 2015).

Antidepressant drugs, with more than 40 available molecules among the different classes, are the mainstay
of psychopharmacological treatment of moderate and severe forms of MDD. Guidelines recommend to
personalise the treatment of patients with MDD based on factors that range from medical history (e.g.,
previous depressive episodes), disease symptoms and severity, to patient's preferences and the specific side-
effect profile of each antidepressant (Jenkins and Kontos, 2016; Kennedy et al., 2016; Malhi et al., 2015).

In daily practice, clinicians have a wide range of psychotropic compounds at their disposal, and evidence-
based medicine may help to make the best choice for each patient. “The right drug at the right time for the
right patient” is the promise of personalised medicine (Binder and Holsboer, 2006). Genomic research is
working in this direction by offering additional advice for the choice of psychopharmacological treatment
compared to clinical evaluation alone and guiding the identification of promising candidate drugs (García-
González et al., 2017; Niitsu et al., 2013; Fabbri et al., 2021). Nonetheless, pharmacogenetic tests are still not
widely implemented in routine clinical practice in many countries, mainly due to the paucity of standard
procedures for prescribing tests, genotyping and indications on the interpretation of results (Fabbri and
Serretti, 2020).

While awaiting the implementation of biological and genetic biomarkers, it is already possible to optimise
the current prescription practice by relying on other information, such as patient's past response or the
pharmacodynamic and tolerability profile of each specific molecule. The tolerability profile varies greatly
from one drug to another, and it is probably the most reliable criterion for choosing the best compound for
each patient. As an example, the awareness of possible somatic comorbidities of the patient may guide the
clinician in avoiding the prescription of antidepressants that could have a greater impact on organs and
functions already impaired, thus also facilitating compliance and tolerability in the patient (Serretti, 2018).
Noteworthy, side effects (SEs) represent one of the main reasons for treatment discontinuation (Bull et al.,
2002; Ho et al., 2017), which in turn may cause suboptimal duration of antidepressant treatment while
increasing the risk of relapse and chronicity (Lin et al., 1998; Montgomery and Kasper, 1998). Despite their
SEs, meta-analyses of existing data estimated that all antidepressants are more effective than placebo in
treating adults with MDD, with a dropout rate due to SEs no higher than placebo. Some antidepressants
showed a better efficacy and tolerability profile than others but differences were small (Cipriani et al., 2018).

Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)
are among the most prescribed antidepressants, mainly due to their favourable safety and tolerability
profiles compared to older molecules, such as tricyclic antidepressants (TCAs) and monoamine oxidase
inhibitors (MAOIs) (Jenkins and Kontos, 2016; Kennedy et al., 2016; Malhi et al., 2015). Recent
psychopharmacological research has contributed to clarifying the safety and tolerability profiles of second-
generation antidepressants, including SSRIs, SNRIs, norepinephrine–dopamine reuptake inhibitor (NDRI)
and noradrenergic and specific serotonergic antidepressants (NaSSAs) (Alberti et al., 2015; Serretti and
Chiesa, 2009; Serretti and Mandelli, 2010). Some of the most frequently reported SEs associated with the
use of second-generation antidepressants include gastrointestinal SEs, such as nausea, diarrhoea,
constipation, dyspepsia and abdominal pain (Uher et al., 2009).

Connections between the central nervous system (CNS) and enteric nervous system (ENS) occur on multiple
levels. The gut contains most of the body serotonin (5-HT), which regulates both CNS and ENS development
as well as their long-term functionality. 5-HT plays a complex role in intestinal inflammation, and
serotonergic neurons have shown to be essential for the physiological gastrointestinal motility (Gershon,
2013; Israelyan et al., 2019). The relationship between CNS and ENS has been made even more evident by
the recent evidence regarding the microbiome-gut-brain axis, which constitutes a bidirectional
communication system involving neural, endocrine/metabolic, immunological and microbial signals.
Thanks to this interconnection, emotional alterations may cause intestinal disturbances and vice versa
(Cepeda et al., 2017; Collins, 2020). Early preclinical evidence showed that oral administration of fluoxetine
resulted in significant alterations in the microbiota composition, which come along with body weight
gain/loss. This evidence could be the basis for an interpretation of gastrointestinal SEs as mediated by a
microbial endocrinology-based mechanism of action (Lyte et al., 2019).

Available meta-analyses have shown differences in gastrointestinal SEs incidence between SSRIs and TCAs.
For example, gastrointestinal SEs have been more often reported in patients treated with fluoxetine than in
patients treated with TCAs. The latter have been less associated with nausea, anorexia, and weight loss, but
more associated with constipation and weight gain when compared with fluoxetine, probably due to their
anticholinergic effects (Brambilla et al., 2005); within SSRIs, nausea, vomiting, diarrhoea, weight loss and
anorexia appear to be more frequent in patients treated with fluoxetine (Brambilla et al., 2005). Differences
in tolerability were also shown between SNRIs (e.g., duloxetine and venlafaxine) and SSRIs. The use of
venlafaxine was associated with higher rates of nausea and vomiting when compared to SSRIs and
duloxetine, while sertraline appeared to be associated with a higher incidence of diarrhoea when compared
to other SSRIs and venlafaxine (Gartlehner et al., 2011). Vortioxetine, one of the latest antidepressants
released on the market, has nausea, constipation and vomiting among the most frequently observed adverse
events in short-term trials, specifically nausea was the most common SE of vortioxetine, and its frequency
was shown to be dose-related, more common in women and during the first week of treatment (Citrome,
2014).

Nonetheless, despite this evidence, a comprehensive meta-analysis, that provides a qualitative and
quantitative comparison of the gastrointestinal SEs of different second-generation antidepressants, has not
been performed yet. Hence, the present work aims to summarise the previous amount of evidence from
previously published and unpublished randomised controlled trials (RCTs) regarding the short-term rates of
gastrointestinal SEs associated with the 15 most used second-generation antidepressants (i.e., agomelatine,
bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran,
mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, and vortioxetine) in patients with MDD.

Section snippets

Literature lookup

The screening of the literature was conducted by using the MEDLINE, ISI Web of Science – Web of Science
Core Collection, and Cochrane Library databases plus the references of the retrieved articles. The initial
search included articles written in English and published from 1985 up to May 31st, 2020.

The search was conducted using both Subject Headings Terms and simple keywords, referring to the
chemical and trade names of 15 second-generation antidepressants (i.e., agomelatine, bupropion,…

Results

The initial literature search yielded 24,949 published studies. 16,467 studies were not considered for
inclusion because they were duplicates, reviews, meta-analyses, case reports, case series, and studies
conducted on animal models. After the inclusion and the exclusion criteria were applied to the remaining
8,482 studies, 8,209 studies were excluded, and 273 studies could be included in the present meta-analysis
(see Fig. 1 – Study flow diagram).

In addition, appropriate documents providing…

Discussion

The present study aimed to quantify, through a meta-analytical approach, the association between
gastrointestinal SEs and 15 different second-generation antidepressants during the short-term treatment of
patients with MDD.

Our analyses suggested that nausea and vomiting are the gastrointestinal SEs associated with the majority
of the considered antidepressants, likely occurring as a consequence of increased availability of 5-HT in the
gastrointestinal tract and CNS. These results are in line…

Conclusions

In conclusion, our meta-analysis indicates that the majority of second-generation antidepressants are
associated with a higher risk than placebo of inducing gastrointestinal SEs during the short-term treatment
of MDD. Escitalopram and sertraline were shown to be the least tolerated antidepressants on the
gastrointestinal tract, being associated with all the considered SEs except for constipation and increased
appetite, while mirtazapine was the antidepressant with fewer side effects on the gut, …

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
profit sectors.…
Declaration of Competing Interest
Serretti is or has been consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data,
Boheringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck,
Naurex, Pfizer, Polifarma, Sanofi, and Servier.

The other authors declare no conflict of interest.…

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