A Systematic Review on the Efficacy and Safety of Selective Serotonin Reuptake Inhibitors in Gastrointestinal Motility Disorders: More Control, Less Risk

Gastrointestinal motility disorders have been thought to occur due to an imbalance in the interaction of the gut-brain axis, which is regulated by serotonin. This recent discovery can be exploited to find newer therapeutic agents such as selective serotonin reuptake inhibitors for functional gastrointestinal disorders. PubMed, PubMed Central (PMC), and Medline databases were used to obtain the data. Meta-analyses, systematic reviews, randomized control trials, and reviews were included and analyzed in the data. Of the 19240 studies, 23 were extracted, and after appropriate quality assessment, they were utilized in this systematic review. They included two meta-analyses, four systematic reviews, two randomized control trials, and 15 review articles. The systematic review focuses on the efficacy of selective serotonin reuptake inhibitors (SSRIs) as compared to other treatment modalities for disorders of gut-brain interaction. It explores various studies analyzing SSRIs for their mechanism of action, their desirable effects for treating irritable bowel syndrome, and their tolerability in patients. SSRIs are effective and safe in treating overall symptoms of gastrointestinal motility disorders, particularly constipation-predominant disorders. They seem to have a better side effect profile than other drugs. This should encourage physicians to prescribe SSRIs early on in the disease.


Introduction And Background
Gastrointestinal motility disorders (previously called functional GI disorders) comprise majorly irritable bowel syndrome (IBS), seen in 9%-23% of the world population, and functional dyspepsia [1]. Globally, cases of gastrointestinal motility disorders have been rising for a long time. Even today, this ever-increasing burden of GI motility disorders has been taking a toll on the quality of life and available medical resources. The life of these patients is affected in many ways. They are constantly worried about eating habits, bloating, emotional stress due to altered bowel habits, consuming medications, absenteeism at work, and lower quality of life as compared to their peers [2].
IBS is a centerpiece of functional GI disorders [3]. Rome IV criteria are widely used for diagnosing the subtypes of IBS. The most common clinical features seen are altered bowel habits, changes in stool frequency and consistency, abdominal pain, and bloating [4]. Symptoms are usually chronic and relapsing in nature. The pathophysiology of these disorders is thought to be multifactorial. Disturbed gut motility, visceral hypersensitivity, gut mucosal immunity, altered gut microbiome, and disrupted central nervous system (CNS) processing that plays a role in the pathogenesis of these disorders [5]. Brain-gut axis has been a newer topic of interest in the pathophysiology of these disorders. Various neurotransmitters, including norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin (5-HT), affect the functioning of the GI tract [6]. The presence of serotonin reuptake transporters (SERT) in the gut wall proves that serotonin is a significant factor in gut peristalsis and maintaining the enteral neural system (ENS). There is also evidence of different types of serotonin receptors present on the gut wall. Serotonin increases gut motility, and its altered levels are partially responsible for gut inflammation [7]. Hence serotonergic drugs have become popular in managing delayed GI motility. Known and practiced treatment approaches for GI motility disorders are lifestyle modification, dietary changes, complementary and alternative medications, psychological and behavioral therapies, and pharmacotherapies [8]. Drugs used in the management of GI motility disorders are antispasmodics, intestinal secretagogues, antidiarrheals, laxatives, opioid agonists, probiotics, and for refractory or severe cases, antidepressants [9]. Tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) have shown clinical evidence of improvement of symptoms in constipation-predominant IBS (IBS-C) [10]. The role of serotonin in gut physiology is the basis of these treatments. SSRIs have long been used for the treatment of depression, but their implication in treating IBS-C is a crucial discovery.
Even after years of known and redefined pathophysiologies as well as advancements in pharmacotherapies for GI motility disorders, there is no specific cure. Only symptomatic management options are available. To increase the evidence for the use of current treatment choices, we need clearer and more detailed information on newer pharmacologic agents.
This study is a systematic review of the efficacy and safety of SSRIs in the management of GI motility disorders. This will help get more accurate and extensive clinical evidence on the role of SSRIs in treating IBS-C and delayed gut motility disorders.

Methods
A systematic review was conducted with the aid of Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [11]. An initial, comprehensive search was done on April 24, 2022. Three databases were searched: PubMed, PubMed Central (PMC), and Medline. The basic search was carried out using the following concepts: ("selective serotonin reuptake inhibitors (SSRI)" or "antidepressants" or "serotonin") AND ("gastrointestinal motility disorders" or " irritable bowel syndrome" or " functional gastrointestinal (GI) motility"). This yielded 811 studies. For a more targeted Medical Subject Heading (MeSH) search, SSRI medications were also added: fluoxetine OR paroxetine OR escitalopram OR citalopram OR sertraline. The final studies obtained were 19240.

Inclusion criteria
Before screening the studies, inclusion criteria were applied. Those with full free text in English and between the years 2013 and 2022 were considered. Only meta-analysis, systematic reviews, randomized controlled trials (RCT), and reviews were retained. Studies were limited to humans only.

Exclusion criteria
Articles in other languages, before 2013, gray literature, and animal or clinical trials were excluded. Figure 1 explains the complete and sequential data extraction process [12].  Table 1 and Figure 1 explain the search strategy and data extraction process respectively. Upon applying the search strategy, 19240 studies were obtained. The inclusion criteria were used, and duplicates were removed both by automation and manual methods. Those were then subjected to quality assessment using appropriate tools. After screening, a total of 23 studies were retained. The risk of bias in individual studies was reduced by using quality assessment tools: PRISMA for meta-analysis and systematic review; Cochrane Risk-of-bias tool for RCT; Scale for Assessment of Narrative Review Articles (SANRA) for review studies.

Results
They included two RCTs including 306 patients with an odds ratio of 0.94 in those administered escitalopram and p<0.05 [13,14]; four systematic reviews each studying six to 15 RCTs with greater significance and low risk of bias [9,[15][16][17] and two meta-analyses [5,10]. One of which included seven RCTs with 346 patients comparing SSRI treatment with placebo treatment and showed that 54.5% (96/176) patients with SSRI trial demonstrated improvement in their symptoms (I²=49%, p=0.07) [5]. The other one included six RCTs with a low risk of bias and modest heterogeneity [10].

Review
This systematic review aims to review trials of SSRIs in patients with Gastrointestinal motility disorders and find strong evidence of safety for their use.

GI motility disorders
GI motility disorders, or a more updated term disorders of gut-brain interaction (DGBI), include irritable bowel syndrome (majorly), functional dyspepsia, and functional constipation. IBS is classified into four different types according to Rome IV criteria: IBS-D (diarrhea-predominant), IBS-C (constipationpredominant), IBS-M (mixed-both diarrhea and constipation), and IBS-U (unclassified) [4]. Adriani et al. have described the universal Rome IV criteria for diagnosing IBS ( Table 2) [4].

Rome IV criteria
Recurrent abdominal pain, on average at least 1 day/week in the past 3 months and the onset of symptoms 6 months before diagnosing along with ≥2 of the following: -Related to defecation -Associated with a change in stool frequency -Associated with a change in stool consistency (form). Saha, in her review, highlights that the pathophysiology of IBS has been linked to changes in gastrointestinal motility, visceral hypersensitivity, post-infectious reactivity, brain-gut connections, fecal microflora, bacterial growth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation [1]. We can say that targeting these aspects for management will lead to optimum remission of the disease. Radovanovic-Dinic et al. explain the minor role of genetic polymorphism in inflammatory factors such as catecholamine receptors, SERT, and cholecystokinin (CCK) receptors in determining the severity of symptoms [2]. This will help in the early diagnosis of DGBI in those with polymorphism and who receive targeted pharmacotherapy.

Serotonin
Serotonin (5-hydroxytryptamine or 5-HT) is a key regulator of the gut-brain axis, and >90% of it is found in the GI tract. It is derived from tryptophan, an essential amino acid. In the GI tract, serotonin is produced by enterochromaffin cells (EC) and serotonergic neurons of the enteric nervous system (ENS), while in the CNS, it is produced only by serotonergic neurons. The biosynthesis of serotonin is shown in Figure 2.  Table 4 [7].  The knowledge of varied functions carried out by serotonin in the gut will aid in prescribing a particular drug that acts at a specific choice of receptor. This will prevent unnecessary serotonin signaling and thus reduce adverse effects. Table 5 highlights the studies providing data on serotonin.

Study
Author/ reference no.

Gut-brain axis
The gut-brain-microbiota axis links the psychological and neurological system to the intestine, its occupants, and metabolic, neurohormonal, and immunologic activities. Moser et al. also explained that bacteria in the GI tract do affect the metabolism of the key regulator serotonin. Due to this reason, infections in the gut are responsible for the psychological symptoms in disorders of gut-brain interaction [18]. Mishima et al. published data saying altered gut flora causes fluctuations in the local serotonin levels, leading to changes in GI motility [19]. These altered serotonin levels in the gut are regulated by the serotonin reuptake transporter (SERT). This observation can be extrapolated for the use of pharmacologic agents acting on SERT, such as SSRIs in GI motility disorders.
The above two studies prove that changes in gut physiology result in nervous system symptoms, while conversely also holds. To support this, Aziz et al. stated in their review article that psychosomatic disorders, including depression, have two times greater chances of exhibiting GI symptoms of IBS [20]. This explains the bi-directional pathway of the gut-brain axis. Therefore the drug therapies used for psychosomatic disorders must be effective in DGBI, including antidepressants. To further support this, they also mention a high-quality RCT of vortioxetine (SSRI) by Seddighnia et al. involving 72 patients (36=vortioxetine, 36=placebo, p<0.01). Those who received vortioxetine demonstrated an increased quality of life with improvement in IBS symptoms like abdominal pain, stool consistency, and GI motility. Figure 3 shows the factors contributing to gut-brain axis.

Illustration by author
Ghaffari et al., along with data depicting a link between the gut microbiome and the pathophysiology of GI motility disorders, also published data that demonstrates the use of SSRIs in IBS-C relieves pain as they help reduce the intestinal transit time [21]. The use of SSRIs for IBS-C cases should be promoted. Table 6 highlights the studies providing data on the gut-brain axis.

Abdominal Pain
As the name suggests, SSRIs selectively inhibit the serotonin reuptake into the cells (pre-synaptic in case of CNS action and EC cells in case of GI tract) by blocking SERT. This results in a sudden rise of serotonin levels either in the brain or gut and causes desired therapeutic effect. Camilleri, in his review, agrees that antidepressants have multifactorial effects in the treatment of DGBI [8]. The central (CNS) action is by decreasing the activation of pain centers in the brain in the anterior cingulate cortex and also reducing the central processing of pain stimuli, whereas the peripheral (GI tract) action is on alleviating pain by downregulating gut nociceptors, increasing intestinal compliance, and decreasing visceral afferents. This helps us understand the mechanism of action of SSRIs in conditions of chronic pain.

GI Motility
Along with improving abdominal pain in IBS, antidepressants also have effects on GI motility. TCAs are effective in IBS-D as they slow gut transit, and SSRIs are used for IBS-C as they hasten the transit [16].
Mawe et al., while explaining the function of SERT, say that serotonin transporters are present on epithelial cells in the intestine [22]. They reuptake the 5-HT molecule as soon as they are secreted by EC and thus modulate the levels of 5-HT in the mucosa. They also provide evidence for elevated serotonin levels in IBS-D and post-infectious-IBS, whereas reduced levels in IBS-C. It can be interpreted that the pharmacological blockade of SERT by SSRI can increase the local levels of serotonin and relieve the symptoms of IBS-C. Table  7 highlights the studies providing data on the mechanism of action of SSRIs.

Study
Author/ Reference no.

Efficacy
In a high-quality RCT (2021), performed by Kreiter. et al., a total of 14 IBS patients were grouped into placebo (n=9) and escitalopram (n=5). Results were obtained using node strength and were statistically significant. They showed a positive effect on the improvement of both physical and mood symptoms [14]. On comparing these results with another RCT (2015) by Talley et al. that included 292 subjects with functional dyspepsia assigned to three groups, placebo (n=97), amitriptyline (n=97), and escitalopram (n=98) [13], it showed that relief rates were higher in the amitriptyline group (53%) as opposed to 40% with placebo and 38% with escitalopram. Of the three groups, none was able to relieve gastric emptying or meal-related satiety significantly. However, those with delayed gastric emptying did exhibit relief in the escitalopram group as compared to the placebo. It can be said that if the subject groups were to be classified according to the symptom predominance, there would have been more conclusive data for the use of a specific drug in a certain type of disorder.
A systematic review by Qin et al. included 12 studies on antidepressants, including 948 patients of all types of IBS [9]. The risk ratio (RR) for overall symptom relief was 1.56 with a 95% confidence interval (CI) (1.19-2.04) and p<0.05. In another systematic review by Black et al., which included 10 RCTs on TCAs and five RCTs on SSRIs, TCAs (RR=0.66, 95%CI 0.53-0.83, p=0.77) showed greater benefit over SSRIs [15]. While both studies support the use of antidepressants, when choosing the type of antidepressants, TCAs seem to be most likely prescribed over SSRIs. This could be because the trials with SSRIs are lower in number, include a lesser subject population, and have higher heterogeneity.
Gewandter et al., in their systematic review of chronic pain conditions, highlight the relief of abdominal pain in IBS when pharmacologic therapy is utilized [16]. To support this, they have included the results of six  [10]. When compared to TCAs, trials with SSRIs have higher heterogeneity and, therefore, are less likely to provide strong evidence for their use. The meta-analysis also mentions that some studies of SSRIs that included only IBS-C patients and treated with fluoxetine (SSRI) were found to have reduced abdominal discomfort, increased stool frequency, and better stool consistency [10]. This concludes that SSRIs can be effectively used in patients with IBS-C but with lesser efficacy in other types of IBS.
While the above studies help understand the efficacy of SSRIs for GI symptoms of IBS, a review by Törnblom et al. highlights that SSRIs also alleviate the accompanying mood symptoms, including anxiety, depression, and psychological distress [23]. Thus they improve the quality of life in patients with co-morbid psychiatric disorders. Table 8 highlights the studies providing data on the efficacy of SSRIs.

Study
Author/ reference no.
Year of publication

Adverse effects
The common adverse effects noted by Xie et al. in their study were headache, poor sleep, anxiety, and nausea [10]. Although SSRIs show lower efficacy than TCAs, they are more tolerable. They show significantly lower drop-out rates than TCAs. Qin et al. and Wall et al. both in their studies also reinforce the common side effects of SSRIs found were headache and nausea, but still demonstrated greater tolerability than TCAs [9,24]. The fact that SSRIs lack anticholinergic, cardiovascular, and neurological side-effects seen in TCAs makes them a preferred choice over TCAs. Table 9 highlights studies providing data on the adverse effects of SSRIs.

Limitations
This systematic review has certain limitations, such as few studies included had a lesser population indicating lower power of the study. Also, those studies with no or low statistical significance would be unavailable or unpublished and therefore were unable to procure them. Studies in any other language than English were not included in this review.

Conclusions
SSRIs are quite efficient and safe in improving the global symptoms of Gastrointestinal motility disorders or DGBI, especially in cases of IBS-C. Early diagnosis and appropriately classifying into IBS subtypes are crucial in deciding the pharmacological therapy for DGBI. Serotonin-targeted therapies are key in managing IBS, mainly in those with abnormal SERT polymorphism. SSRIs have shown promising effects in cases of delayed intestinal motility symptoms of IBS. SSRIs have demonstrated central as well as peripheral therapeutic effects and a better side-effect profile than TCAs.
In our opinion, larger trials of SSRIs specific for IBS-C are lacking. This will encourage physicians to prescribe SSRIs in cases of constipation-predominant symptoms. Furthermore, even after decades of diagnosing these disorders, no cure has been discovered. With the increasing incidence of DGBI, there may be ways to prevent the occurrence, such as dietary habits, lifestyle changes, and early stress management strategies.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.