Effects of Bifidobacterium triple viable bacteria-assisted mirtazapine in managing depression in patients after radical surgery for gastric cancer

Abstract

BACKGROUND

Patients with gastric cancer may have a risk of depression after radical surgery, which affects recovery and requires intensive intervention.

AIM

To explore the role of Bifidobacterium triple viable bacteria-assisted mirtazapine in patients with depression after radical surgery for gastric cancer.

METHODS

This study included 80 patients with gastric cancer who experienced depression after undergoing radical surgery from January 2022 to December 2023 at Jiangnan University Hospital in Wuxi city in Jiangsu province. The patients were categorized into the control group (n = 40) treated with mirtazapine and observation group (n = 40) treated with combined Bifidobacterium triple viable bacteria-assisted mirtazapine. Neuroendocrine index, intestinal flora level, nutrition status, and patient quality of life were analyzed.

RESULTS

Before drug index level, no statistically significant difference was observed between the two groups P > 0.05). After drug administration, both groups experienced a decline in depression scores, cortisol, Escherichia coli, Enterococcus faecalis levels, and quality of life scores, whereas dopamine, serotonin, Lactobacillus, Bifidobacteria, hemoglobin, serum albumin and prealbumin levels increased. The observation group demonstrated significantly greater improvements across these indicators, with significant differences within groups and between groups (P < 0.05).

CONCLUSION

Bifidobacterium has a relieving effect on depression in patients after radical surgery for gastric cancer, improves neuroendocrine status, regulates intestinal flora, and improves nutritional status and quality of life.

Key Words: Bifidobacterium triple bacteria; Oryzazapine; Radical gastric cancer; Depression; Neuroendocrine; Intestinal flora; Quality of life

Core Tip: Post-gastric cancer radical surgery, patients are susceptible to depression, impacting recovery and quality of life. It’s vital to screen for depressive symptoms promptly. Tailored interventions, including targeted medication to regulate gut microbiota, can alleviate depression and enhance prognosis. Integrating these with psychological support and lifestyle modifications, such as a balanced diet and regular physical activity, can further improve mental health and foster better adaptation post-surgery. A holistic approach ensures patients receive comprehensive care, optimizing their recovery journey and well-being.

INTRODUCTION

Gastric cancer is a malignancy of the digestive tract that originates in the gastric epithelial cells. Although its exact cause is not fully understood, it is associated with Helicobacter pylori infection, genetic factors, and unhealthy habits. A history of gastric disease can also increase the risk of occurrence. Patients often experience anorexia, nausea, and indigestion. As the tumor enlarges, it invades the surrounding organs, leading to complications and potentially life threatening consequences[1]. The incidence and mortality rates of this disease are high. Clinically, radical surgery is commonly performed to remove primary lesions, affected tissues, and regional lymph nodes, aiming to eradicate the cancer and minimize residual risk. However, surgery acts as a major stressor, potentially affecting the psychological state of patients. This, coupled with the impact of postoperative chemotherapy, its associated adverse reactions, and financial burden, can increase psychological pressure on patients and lead to postoperative depression. Depression, in turn, can lead to physical symptoms, aggravating the original condition and forming a vicious circle that ultimately decreases the quality of life[2]. Therefore, it is necessary to pay attention to the antidepressant treatment of patients with malignant tumors to maintain a healthy attitude and ensure treatment efficacy. Mirtazapine, an antidepressant, is well-tolerated and has no effect on the cardiovascular system. However, this drug can only help patients relieve their depressive symptoms but does not address intestinal flora disorders and malnutrition caused by the disease. Therefore, a combination drug regimen is necessary[3]. Bifidobacterium triplex, composed of multiple bacteria, is effective in treating diarrhea, constipation, and indigestion caused by intestinal dysbiosis[4]. This study explores the roles and effectiveness of combination regimens in managing depression in patients after radical surgery for gastric cancer.

MATERIALS AND METHODS

General information

In total, 180 patients with depression after radical surgery were admitted to the Department of Gastrointestinal Surgery at Jiangnan University, Wuxi, Jiangsu Province, China. The treatment was performed from January 2022 to December 2023, and the patients were categorized into the control (n = 4) and observation (n = 4) groups according to the medications prescribed. The inclusion criteria were as follows: (1) All gastric cancer diagnosis, confirmed through surgical pathological examinations; (2) Radical resection of gastric cancer and postoperative depression; (3) Age > 30 years; (4) No previous history of drug allergy; and (5) Good data support for the study. The exclusion criteria were as follows: (1) Organic lesions; (2) Other malignancies; (3) A previous psychiatric history; and (4) Treatment performed within 2 weeks.

The specific recruitment process was as follows: (1) Preliminary screening: We initially conducted a preliminary screening of all patients who underwent radical surgery in the Department of Gastrointestinal Surgery, examining their medical records to determine whether they met the inclusion criteria, such as age range and type of surgery, among other basic conditions; (2) Symptom assessment: For patients who met the inclusion criteria, professional psychiatrists used validated depression assessment scales (such as the Hamilton Depression Rating Scale) to conduct a detailed evaluation, accurately determining whether they had depression and ensuring that all included patients were diagnosed with depression; (3) Exclusion of ineligible individuals: During assessment, we strictly adhered to the exclusion criteria, excluding patients with severe cognitive impairment, a history of other psychiatric disorders such as schizophrenia, or those taking medications that might affect the study results to ensure the homogeneity of the study participants and the reliability of the research findings; and (4) Final determination: After rigorous selection, 180 patients with depression following radical surgery who met the inclusion criteria were included in this study.

Methods

For the control group, mirtazapine tablets (Shanxi Kangbao Biological Products Co., Ltd., Changzhi, China; approval number: Sinopharm approved H20080101; specification: 15 mg) were administered orally once a day, with one tablet taken per day initially, which was adjusted to 30 mg per day after 1 week. This regimen was continued for 8 weeks. For the observation group, in addition to mirtazapine, Bifidobacterium triple viable bacteria capsules (Shanghai Shangyao Xinyi Pharmaceutical Co., Ltd., Shanghai, China; approval number: S10950032; specification: 0.21 g) was administered orally, with 204 capsules taken twice a day and continued for 8 weeks. The dosage of mirtazapine was based on preclinical studies and data from previous clinical trials, ensuring optimal therapeutic effects within the effective dosage range. The dosage of Bifidobacterium triple viable bacteria was determined by referring to previous research and clinical application experience, ensuring its efficacy in modulating the gut microbiota and improving neuroendocrine status, while also ensuring patient tolerability.

Observational indicators

Depressive symptoms: These were assessed using the Zung’s Self-Rating Depression Scale (SDS)[5], Hamilton Depression Scale (HAMD), and Beck Depression Scale [Back Depression Inventory (BDI)][6]. The SDS comprises 20 items, each scored from 0 to 4. Scale score of 1.25 is the actual score. A score below 50 indicates normal mood, 50-59 indicates mild depression, 60-69 indicates moderate depression, and ≥ 70 indicates severe depression. The HAMD scale includes 17 items, with a total score of ≤ 7 indicating no depression, 8-17 indicating mild depression, 18-24 indicating moderate depression, ≥ 25 indicating severe depression. The BDI scale includes 13 items, each scored from 0 to 3, with a total score of 39. A score of 4 is suggestive of the absence of depression, while those of 5-7, 8-15, and 16 indicate mild, moderate and severe depression, respectively.

Neuroendocrine status: To assess this, 5 mL of fasting venous blood was drawn before and after 2 months of treatment. Blood samples were centrifuged at 3500 rpm for 5 minutes using a medical centrifuge (Jiangsu Xinkang Medical Instrument Co., Ltd., Taizhou, China, record number: 20180077, model and specification: 80-3B). The radi and time lengths were 10 cm and 5 min, respectively. The upper layer of the serum was collected using a fully automatic biochemical analyzer (Dirui Medical Technology Co., Ltd., Changchun, China, registration certificate number: 20192220209, model specification: CS-1600A). Dopamine, serotonin, and cortisol levels were measured using enzyme-linked immunosorbent assay.

Intestinal flora: Fresh stool samples (0.1 g) were collected from both groups before and after treatment. Samples were diluted in normal saline and cultured on a media, suitable for anaerobic and aerobic bacteria, at 37 °C for 48-72 hours. A semi-automatic biological identification instrument (Shandong Xinke Biological Technology Co., Ltd., Beijing, China, registration number: Lu Xie injection 20172220068, model specification: XK-3401) was used to calculate the colony counts of Lactobacillus, Bifidobacterium, Escherichia coli (E. coli), and Enterococcus faecium (E. faecalis).

Nutritional status: Fasting venous blood sample was collected as described above, and the levels of hemoglobin (colorimetric method), serum albumin (bromide cresyl green method), and prealbumin levels were measured using the automatic biochemical analyzer.

Quality of life: This was assessed using the European Organization for Cancer Research and Treatment of the Core Scale of Life Gastric Cancer Scale[7]. The scale includes 22 items, each scored between 1 and 4, with subscales for dysphagia (4, 16 points), stomach pain (4, 16 points), restricted diet (4, 16 points), hiccups (3, 12 points), anxiety (3, 12 points), single-item measures (4, 16 points). The total score is 88, a reduction in scores indicate improved quality of life.

Statistical analysis

Data were analyzed using SPSS (version 22.0; IBM, Armonk, NY, United States). Count data are represented as percentages (%) and analyzed using the χ²-test. Upon examination, the expected frequencies in all cells were greater than 5, and the sample data were independent of each other, satisfying the assumptions of the χ²-test and, thereby, ensuring the validity of the test results. Data with normal distribution are expressed as mean ± SD and analyzed using the t-test. P < 0.05 was considered to indicate statistical significance.

RESULTS

Basic data of the study subjects

In total, 180 patients with depression after radical surgery were admitted to the Department of Gastrointestinal Surgery at Jiangnan University, Wuxi, Jiangsu Province, China. The treatment was performed from January 2022 to December 2023, and the patients were categorized into the control and observation groups according to the medications prescribed. The inclusion criteria were as follows: (1) A diagnosis of gastric cancer, confirmed through surgical pathological examinations; (2) Radical resection of gastric cancer and postoperative depression; (3) Age > 30 years; (4) No previous history of drug allergy; and (5) Reliable data support for the study. The exclusion criteria were as follows: (1) Organic lesions; (2) Other malignancies; (3) A previous psychiatric history; and (4) Treatment performed within 2 weeks.

Depression

The premedication scores were comparable between the two groups (P > 0.05). Following treatment, the SDS, HAMD, and BDI scores were lower in the observation group than in the control group. Differences were significant both between and within the groups (P < 0.05) (Table 1).

Table 1 Depressed mood scores, mean ± SD.

Group	Case	Before, SDS	After, SDS	Before, HAMD	After, HAMD	Before, BDI	After, BDI
Control	40	65.44 ± 3.18	53.27 ± 2.45a	21.16 ± 2.24	10.14 ± 2.12a	13.16 ± 1.24	6.12 ± 0.78a
Observation	40	65.72 ± 3.32	48.12 ± 2.96a	21.27 ± 2.12	6.36 ± 1.18a	13.20 ± 1.21	3.21 ± 0.54a
t		0.385	8.477	0.226	9.853	0.146	19.400
P value		0.701	< 0.001	0.822	< 0.001	0.884	< 0.001

^aP < 0.05. Comparison within the group before treatment.

SDS: Self-Rating Depression Scale; HAMD: Hamilton Depression Scale; BDI: Beck Depression Inventory.

Neuroendocrine index

Before treatment, no significant difference in dopamine, serotonin, and cortisol levels was observed between the two groups (P > 0.05). After treatment, dopamine and serotonin levels increased, whereas cortisol levels decreased, with significant differences between and within the groups (P < 0.05) (Table 2).

Table 2 Neuroendocrine indicators, mean ± SD.

Group	Case	Before, dopamine (pg/mL)	After, dopamine (pg/mL)	Before, 5-hydroxytryptamine (pg/mL)	After, 5-hydroxytryptamine (pg/mL)	Before, hydrocortisone (ng/mL)	After, hydrocortisone (ng/mL)
Control	40	40.12 ± 10.45	55.16 ± 12.24a	159.28 ± 40.18	182.15 ± 42.44a	212.72 ± 60.24	160.45 ± 31.78a
Observation	40	40.27 ± 10.32	76.18 ± 13.21a	160.12 ± 41.45	221.36 ± 45.52a	214.56 ± 62.48	121.54 ± 24.62a
t		0.065	7.382	0.092	3.985	0.134	6.121
P value		0.949	< 0.001	0.927	< 0.001	0.894	< 0.001

^aP < 0.05. Comparison within the group before treatment.

Intestinal microbiota levels

Premedication levels of intestinal flora were comparable between the groups (P > 0.05). After treatment, the colony counts of Lactobacillus and Bifidobacterium increased, whereas those of E. coli and E. faecalis decreased in both groups. The observation group demonstrated a more significant change than the control group. Differences between the groups were statistically significant (P < 0.05) (Table 3).

Table 3 Levels of the intestinal microbiota, mean ± SD, CFU/g.

Group	Case	Before, Lactobacillus acidophilus	After, Lactobacillus acidophilus	Before, Bifidocaterium	After, Bifidocaterium	Before, Escherichia coli	After, Escherichia coli	Before, Enterococcus faecalis	After, Enterococcus faecalis
Control	40	6.32 ± 0.56	6.92 ± 0.48a	7.54 ± 0.52	8.21 ± 0.44a	10.27 ± 1.18	8.72 ± 0.80a	8.18 ± 0.82	7.12 ± 0.68a
Observation	40	6.35 ± 0.52	7.54 ± 0.42a	7.48 ± 0.56	9.12 ± 0.42a	10.21 ± 1.24	7.32 ± 0.64a	8.21 ± 0.78	6.08 ± 0.54a
t		0.248	6.148	0.497	9.462	0.222	8.643	0.168	7.575
P value		0.805	< 0.001	0.621	< 0.001	0.825	< 0.001	0.867	< 0.001

^aP < 0.05. Comparison within the group before treatment.

Nutritional status

Before treatment, no significant difference in hemoglobin, serum albumin, and prealbumin levels was observed between the two groups (P > 0.05). After treatment, hemoglobin, serum albumin, and prealbumin levels increased, with the observation group showing significantly greater improvement than the control group. Differences were significant between and within the groups (P < 0.05) (Table 4).

Table 4 Nutritional status, mean ± SD.

Group	Case	Before, hemoglobin (g/L)	After, hemoglobin (g/L)	Before, blood albumin (g/L)	After, blood albumin (g/L)	Before, prealbumin (mg/L)	After, prealbumin (mg/L)
Control	40	90.12 ± 8.16	99.18 ± 6.32a	28.27 ± 3.42	32.12 ± 3.56a	245.72 ± 14.18	272.15 ± 10.44a
Observation	40	89.72 ± 8.24	110.24 ± 5.72a	28.14 ± 3.68	36.21 ± 3.12a	246.32 ± 12.56	298.42 ± 14.28a
t		0.218	8.206	0.164	5.465	0.200	9.392
P value		0.828	< 0.001	0.870	< 0.001	0.842	< 0.001

^aP < 0.05. Comparison within the group before treatment.

Quality of life

No significant difference in premedication scores was observed between the two groups (P > 0.05). After treatment, the scores in both groups improved, with greater reductions in symptom dimensions and total scores in the observation group than in the control group. Differences were significant between and within the groups (P < 0.05) (Table 5).

Table 5 Quality of life, mean ± SD.

Group	Control	Observation	t	P value
Case	40	40
Before, dysphagia	11.12 ± 1.48	11.32 ± 1.56	0.588	0.558
After, dysphagia	8.24 ± 1.36a	6.16 ± 1.12a	7.467	< 0.001
Before, stomach pain	10.78 ± 1.24	10.86 ± 1.20	0.293	0.770
After, stomach pain	8.12 ± 1.18a	6.24 ± 0.96a	7.816	< 0.001
Before, dietary restriction	10.84 ± 1.16	10.78 ± 1.12	0.235	0.815
After, dietary restriction	8.20 ± 1.32a	6.54 ± 1.18a	5.930	< 0.001
Before, hiccups	8.72 ± 1.16	8.78 ± 1.20	0.227	0.821
After, hiccups	7.08 ± 0.72a	5.80 ± 0.64a	8.404	< 0.001
Before, anxiety	8.12 ± 1.18	8.16 ± 1.12	0.155	0.877
After, anxiety	6.72 ± 0.78a	5.24 ± 0.42a	10.566	< 0.001
Before, single entry	10.16 ± 1.24	10.12 ± 1.28	0.142	0.887
After, single entry	8.20 ± 1.12a	6.44 ± 1.10a	7.091	< 0.001
Before, total score	59.74 ± 7.46	60.02 ± 7.48	0.168	0.867
After, total score	46.56 ± 6.48a	36.42 ± 5.42a	7.591	< 0.001

^aP < 0.05. Comparison within the group before treatment.

DISCUSSION

Radical gastrectomy for gastric cancer is a curative procedure that involves simultaneous removal of the primary tumor, metastatic lymph nodes, and infiltrated tissues, ensuring that no residual cancer remains. This approach aims to cure the disease and reduce the risk of recurrence. Malignant tumors can cause physical discomfort and mental illness in patients. Postoperative depression, a common emotional pathological reaction, adversely affects patients’ mental health, delays postoperative recovery, and reduces the quality of life. Mirtazapine is a widely used antidepressant that acts against the central presynaptic membrane α-2 receptor and stimulates adrenergic nerve conduction. It can block the central serotonin receptor, with its enantiomers. Additionally, it has antihistamine receptor, offering sedative effects, good tolerance, no anticholinergic effect, and no cardiovascular risks[8]. Bifidobacterium triads for probiotics comprises long Bifidobacterium, Lactobacillus acidophilus, and E. faecalis. These probiotics can grow under different conditions and can work promptly and persistently after oral intake. They colonize the intestinal mucosal to form a biological barrier, inhibit the proliferation of pathogenic bacteria, reduce the risk of pathogenic infections, and maintain the balance of intestinal flora, thereby supporting physiological functions[9].

Gut flora dysbiosis is closely related to the development of mental disorders, which can be mediated through neurotransmitters or immune responses in the central nervous system, thus affecting human behavior. The intestinal flora actively participates in the interaction with the brain and can assist in the treatment of depression. The findings of this study showed that the observation group had significantly lower depression scores than the control group (P < 0.05), indicating the antidepressant efficacy of Bifidobacteria triple viable bacteria. This compound preparation supplements beneficial bacteria, inhibits harmful bacteria, and restores intestinal flora balance. It can also inhibit the continuous activation of the hypothalamic-pituitary-adrenal axis and enhance the antidepressant effect of mirtazapine.

Emotional and behavioral regulation is closely related to neuroendocrine states. Neuroendocrine disorders can reduce the ability to control emotions and behaviors in patients, leading to mental disorders. Compared to the control group, the observation group had higher dopamine and serotonin levels and lower cortisol levels (P < 0.05), suggesting that the adjuvant use of Bifidobacterium triple viable bacteria could regulate the neuroendocrine state of the body. This drug acts on the central nervous system, protects neurons in the brain, inhibits synaptic changes, regulates neuroendocrine indicators, and controls disease progression.

Patients with digestive system diseases often experience intestinal flora disorders, characterized by a decrease in the colony counts of beneficial bacteria and an increase in those of harmful bacteria. Postoperative intestinal flora imbalances not only compromise surgical outcomes but also increase the severity of postoperative depression. Compared to the control group, the observation group had significantly higher colony counts of Lactobacillus and Bifidobacterium and lower colony counts of E. coli and E. faecalis (P < 0.05), indicating that Bifidobacterium can regulate and stabilize the intestinal flora. After oral administration, Bifidobacterium triple viable bacteria colonize the intestinal tract and inhibits the invasion of pathogenic bacteria. In addition, these probiotics can adjust oxygen concentrations within the gut, fostering an environment conducive to the growth of beneficial bacteria while suppressing harmful pathogens[10].

In this study, the nutritional status of the two groups was further compared, and the results showed that the level of each indicator was higher in the observation group than in the control group (P < 0.05), confirming that the Bifidobacterium triad can improve the nutritional status of patients. The maltodextrin and sugarcane fruit oligosaccharides in the drug formulation create favorable conditions for the colonization of beneficial bacteria and promote the repair of the damaged mucosal barrier. Additionally, the polysaccharides in the drug can stimulate the intestinal tract, promote its peristalsis, improve gastrointestinal function, improve the body’s ability to absorb nutrients, supplement the normal physiological bacteria, inhibit and remove pathogenic bacteria, reduce endotoxin, enhance the body’s ability to digest and absorb nutrients, and improve the nutritional status. Compared with the control group, the observation group had a lower quality of life score (P < 0.05), indicating that the adjuvant use of the Bifidobacteria triad improves patients’ quality of life. The combined therapy with mirtazapine and Bifidobacterium triple viable bacteria can alleviate physical symptoms and mental disorders, relieve indigestion symptoms, reduce stomach discomfort, help patients to return to a normal diet, reduce psychological pressure, reduce negative emotional influence, maintain good physiological and psychological state, and improve the quality of life.

Numerous studies have shown that mirtazapine monotherapy can effectively alleviate depressive symptoms, but its regulatory effects on neuroendocrine status and the gut microbiota are limited. In this study, the combination of Bifidobacterium triple viable bacteria and mirtazapine significantly relieved depressive symptoms and improved the neuroendocrine status and the gut microbiota, demonstrating a more comprehensive therapeutic effect than that of mirtazapine alone[11]. To our knowledge, this is the first study to explore the multi-target therapeutic mechanisms of Bifidobacterium triple viable bacteria combined with mirtazapine in managing depression in patients after radical gastrectomy for gastric cancer. This combination therapy alleviated depressive symptoms, improved neuroendocrine status and restored the gut microbiota, providing new insights for the comprehensive treatment of postoperative depression. Bifidobacterium triple viable bacteria combined with mirtazapine can effectively alleviate postoperative depressive symptoms in patients after radical gastrectomy for gastric cancer, helping patients cope better with postoperative psychological stress and promoting psychological recovery. This combination has the potential to become an effective treatment option, providing comprehensive support for the postoperative recovery of patients. Although short-term studies have shown that the combination of mirtazapine and Bifidobacterium triple viable bacteria is significantly effective, further research is needed to investigate its long-term effects. The potential for drug resistance or other complications associated with prolonged use requires continuous monitoring in clinical practice.

CONCLUSION

Bifidobacterium triple viable bacteria combined with mirtazapine can relieve depression after radical surgery for gastric cancer, regulate both neuroendocrine and intestinal flora disorders, and improve nutritional status and patient’s quality of life.