Ulcerative colitis (UC) is an inflammatory bowel disease characterized by continuous mucosal inflammation extending from the rectum to the proximal colon (1). UC is influenced by various factors, including genetics, environmental influences, changes in the intestinal microbiota, and the reactivity of the intestinal immune system (2). This disease follows a relapsing-remitting course (3). During inactive periods or remission, patients experience complete resolution of symptoms. Stool frequency returns to normal without bleeding or urgency, the colonic mucosa appears normal upon endoscopy, and the sigmoidoscopy score falls within the range of 0 or 1 according to the Mayo score (4).

One of the challenges in managing UC is the presence of functional gastrointestinal symptoms among patients during UC remission (5). Some UC patients in remission report frequent abdominal symptoms such as pain and discomfort along with changes in bowel habits, referred to as “irritable bowel syndrome (IBS)-like symptoms” (6). The prevalence of these symptoms has been reported to range from 9 to 46% (7). Investigations into their etiology suggest common factors shared between UC and IBS, including mucosal inflammation, alterations in the microbiome, increased intestinal permeability, genetic factors, and, importantly, interactions within the brain-gut axis (5). Several pathogenic mechanisms explain why some UC patients in remission experience symptoms of functional origin. These mechanisms include persistent inflammation, dysmotility, heightened visceral sensitivity, increased mucosal permeability following UC, microbiota disturbances, and psychological distress (8). Various interventions have been introduced to manage IBS-like symptoms in UC patients during remission. These interventions encompass psychological therapies, probiotics, fecal microbial transplantation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diets, and antidepressants. However, controlled clinical trials evaluating the effectiveness of these interventions in UC patients experiencing IBS-type symptoms are limited (5, 8, 9).

Psychological problems, such as anxiety and depression, plays a significant role in the development of functional gastrointestinal symptoms in both IBS and UC, influencing both their production and perception (5, 10, 11). Additionally, the presence of gut-brain axis dysfunction has been established in both IBS and IBD (12). As a result, antidepressants are considered a suitable treatment option due to their capacity for neuromodulation (13) and anti-inflammatory effects (14) and their positive impact on gut-brain axis disorders (15).

Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) represent two classes of antidepressants known for their effectiveness in alleviating both functional and anti-inflammatory symptoms in the digestive system. SSRIs and SNRIs act on the brain’s neurotransmitter systems to alleviate depressive symptoms. SSRIs primarily target the serotonin transporter, elevating serotonin levels, while SNRIs target both serotonin and noradrenaline transporters, increasing levels of both neurotransmitters. This distinction influences their efficacy and side effect profiles, with SSRIs being associated with lower seizure risk but higher rates of sexual dysfunction and weight gain, whereas SNRIs may be more effective for depression with anxiety symptoms and have a lower risk of sexual dysfunction but higher rates of nausea, dizziness, and dry mouth. Notably, their impact on nocturnal urinary frequency varies, with sertraline users experiencing increased frequency compared to duloxetine users (16–18). Paroxetine and gabapentin are both medications utilized in treating certain aspects of ulcerative colitis. Although differing in their primary neuroscientific aspects and clinical applications, they share some similarities in their potential therapeutic roles in managing specific aspects of ulcerative colitis. Paroxetine primarily targets the psychological and emotional dimensions of the condition by modulating serotonin levels in the brain, while gabapentin focuses on alleviating chronic pain and discomfort by modulating neurotransmitter activity in the central nervous system (19–22).

A comprehensive review of previous literature reveals a gap in understanding the comparative effectiveness of SSRIs and other medications like gabapentin in managing IBS-like symptoms in UC patients. While several studies have highlighted the potential benefits of SSRIs in improving gastrointestinal symptoms, less is known about the specific roles of paroxetine and gabapentin in this context, emphasizing the novelty of the present study. This study assessed the efficacy of paroxetine and gabapentin among UC patients in remission on the IBS-like symptoms, psychological factors, and overall quality of life. Paroxetine was selected for its effectiveness in modulating serotonin levels and its documented anti-inflammatory properties, which may contribute to alleviating symptoms in UC patients. Gabapentin, on the other hand, is known for its efficacy in managing neuropathic pain and discomfort associated with functional gastrointestinal symptoms, making it a suitable choice for this study (23–25).

In this study, we conducted a randomized single-blind clinical trial involving a total of 97 patients, evenly divided into two treatment arms: 49 patients received treatment with paroxetine, while 48 patients received treatment with gabapentin. We assessed several key outcomes, including the levels of anxiety and depression, the quality of life.

In this study, all evaluated patients experienced improvements in the severity of IBS symptoms, a reduction in anxiety and depression, and an enhanced quality of life in both treatment groups after 3 months of intervention compared to their pre-intervention status. Significantly, the group treated with paroxetine exhibited marked improvements in all areas, while the gabapentin group showed significant improvement only in the severity of IBS symptoms. Both groups remained in remission. A comparative analysis between the two treatment groups revealed that paroxetine outperformed gabapentin in terms of alleviating symptom severity, reducing anxiety and depression, and enhancing quality of life. Notably, some patients using gabapentin reported side effects, including drowsiness, nausea, and vomiting. As a result, three patients (out of the initial 100 patients) were excluded from the study due to these side effects, a phenomenon consistent with findings in prior studies (34–36) that have also reported dizziness and drowsiness associated with gabapentin use.

Based on our findings, paroxetine offers some advantages, notably in enhancing the quality of life and alleviating both digestive and psychological functional symptoms in UC patients in remission with IBS-liked symptoms. These results align with the study conducted by Stasi et al. (37), who observed significant improvements in psychiatric and gastrointestinal symptoms when IBS patients with moderate to severe symptoms and psychiatric disorders were treated with low-dose paroxetine (5 mg/day) in a longitudinal evaluation. Lu et al. (38) also reported similar positive effects in IBS patients after 7 weeks of daily paroxetine administration (20–40 mg), with notable improvements in gastrointestinal symptoms, particularly diarrhea, followed by a reduction in psychological symptoms such as anxiety and somatization While our research found no recent clinical trials investigating paroxetine’s effects on IBS patients, older studies, revealed varying outcomes regarding pain symptoms. In a study by Masnad et al. (39) a 12-week treatment with paroxetine (12.5–50 mg) resulted in enhanced global effect and severity-improvement ratings, although it did not lead to a reduction in pain scores. The authors emphasized that despite paroxetine’s limited impact on abdominal pain symptoms, it offers broad and potential benefits to individuals with IBS. A study conducted by Tabas et al. (40) found that a 12-week treatment with paroxetine (10 mg daily) did not significantly alleviate symptoms related to abdominal pain, bloating, or social functioning compared to a placebo. However, they noted a notable increase in the overall sense of well-being. Additionally, Creed et al. (41) further supported the effectiveness of paroxetine in IBS management. A common feature in all these studies was the patients’ good tolerance of paroxetine, which aligns with our findings.

Serotonin, a neurotransmitter present in both the central nervous system and the intestinal nervous system, plays a vital role in regulating intestinal motility. In IBS, disruptions in serotonin synthesis and secretion are linked to the onset of symptoms (42). Reduced intestinal serotonin production has been associated with a weakened intestinal lining, leading to cramping or constipation, while elevated serotonin levels in the gut can also contribute to symptoms (43). Selective serotonin reuptake inhibitors (SSRIs), the most commonly used medications for anxiety and depression, work by increasing synaptic serotonin levels. By inhibiting the reuptake of serotonin from the synaptic space, SSRIs elevate serotonin levels in the brain (44, 45). Studies in rats have shown that paroxetine, an SSRI, can reduce stool production and delay gastrointestinal motility (46). It is suggested that paroxetine’s impact on mucosal serotonin signaling mechanisms contributes to symptom improvement in IBS (47). Moreover, there is evidence supporting the anti-inflammatory properties of SSRIs (23). Previous research has indicated that paroxetine can inhibit the expression of various inflammatory factors at the mRNA level and reduce inflammation-related pathways (48). Since inflammation is known to be involved in the pathogenesis of IBS (49), it is plausible that paroxetine’s ability to reduce inflammation has led to symptom improvement.

In our study, we also investigated the effectiveness of gabapentin, a drug with known antidepressant (50), anti-inflammatory (51) and anti-neural pain properties, often used in IBS patients (36). This led us to hypothesize that gabapentin might positively impact gastrointestinal functional symptoms in UC patients in remission. Our results revealed that gabapentin did lead to a significant improvement in the severity of IBS symptoms, suggesting its potential utility in this context. However, it’s worth noting that the improvement in symptom severity was more pronounced with paroxetine compared to gabapentin. The superior effect of paroxetine in managing both gastrointestinal and psychological symptoms can be attributed to its multi-faceted impact on the gut-brain axis (52). By selectively inhibiting the reuptake of serotonin, paroxetine enhances serotonergic signaling in both the brain and the gut, which may explain its broad therapeutic effects on both psychiatric and gastrointestinal symptoms in IBS patients (53). Moreover, SSRIs like paroxetine are known to modulate the activity of serotonin receptors in the enteric nervous system, which helps reduce visceral hypersensitivity—a core feature of IBS (46).

Also, gabapentin increases the level of serotonin in the whole blood Lee et al. demonstrated that gabapentin (300–600 mg daily) reduced rectal sensory thresholds, resulting in decreased rectal sensitivity to distension and increased rectal compliance in IBS patients (35). Additionally, Zhang et al. reported that gabapentin had a pain and anxiety-inhibiting effect in rats with IBS (54). While our study showed that gabapentin had some positive impact on anxiety, depression, and quality of life, these improvements were not statistically significant. This finding aligns with a review study by Berlin et al., who suggested that while gabapentin might be useful for some anxiety disorders, clear evidence for its efficacy in addressing anxiety and depression remains inconclusive (55). The lesser efficacy of gabapentin than paroxetine could be because gabapentin, although it possesses some serotonergic and anti-neural properties, primarily acts through the inhibition of calcium channels, thereby reducing neuronal excitability. While this mechanism can alleviate neuropathic pain and modulate sensory processing, its impact on the serotonergic system is less direct than that of SSRIs (56, 57).

Another noteworthy finding from our study is that both the gabapentin and paroxetine groups of patients remained in remission, with no UC relapse observed. This outcome may partly be due to the known anti-inflammatory properties of these drugs (48, 51). Paroxetine, for example, has been shown to reduce intestinal inflammation by effectively managing the microbial balance within the digestive system (48). Similarly, gabapentin’s role in preventing inflammation is attributed to its regulation of mast cell signaling and its capacity to reduce the activation of inflammatory genes associated with inflammatory bowel diseases (58). This anti-inflammatory action may explain the sustained remission observed in both treatment groups in our study.

The present study boasts several strengths, including a 3-month follow-up period for patients, the focus on individuals with no prior history of psychiatric drug use, and the examination of the effects of two distinct drugs, paroxetine and gabapentin, on UC patients in remission with IBS-liked symptoms. However, we acknowledge certain limitations our study was single-centered, and we did not conduct long-term follow-ups to investigate the recurrence of symptoms following the discontinuation of these drugs. To address this gap, future research should encompass multicenter studies and implement extended follow-up periods to assess symptom recurrence rates after treatment cessation. Furthermore, we use low Gabapentin dosage which is lower than therapeutic dosage. Considering that this low dose was well tolerated in the patients of this study, we suggest that future studies investigate standard therapeutic doses in this group of patients. Lack of control on several confounding factors like type of IBS-like syndromes is another limitation of our study that should be investigated clearly in the future studies. Also, Limitations of our study include the lack of specific examination and documentation of side effects associated with the medications used in the trial. While adverse events were monitored and managed throughout the study, including the exclusion of three patients due to gabapentin-related side effects, we did not systematically collect data on all potential side effects. This omission limits our ability to comprehensively assess the safety profiles of gabapentin and paroxetine in this context. Future studies should incorporate more robust methods for monitoring and reporting side effects, including standardized assessments and documentation procedures, to provide a more thorough understanding of the risks associated with these medications in patients with UC and irritable bowel syndrome-like symptoms.

In conclusion, paroxetine exhibited significant improvement effects in gastrointestinal functional symptoms, anxiety, depression, and quality of life in UC patients in remission. On the other hand, while gabapentin led to a significant improvement in IBS symptoms, it did not yield significant improvements in anxiety, depression, and quality of life. It’s worth noting that the rate of improvement in gastrointestinal functional symptoms, anxiety, depression, and quality of life was significantly superior with paroxetine compared to gabapentin.