Fluoxetine plus psychological intervention for chemotherapy-managed colon cancer patients: Impact on mood and influencing factors

Abstract

BACKGROUND

Emotional disorders of varying severity are common among chemotherapy-treated colon cancer (CC) patients and may hinder recovery.

AIM

To investigate the effects of fluoxetine combined with psychological intervention on mood and to identify associated risk factors in chemotherapy-treated CC patients.

METHODS

A total of 145 patients with CC treated at The Affiliated Hospital of Southwest Medical University between April 2023 and April 2025 were enrolled. The control group (n = 66) received psychological intervention plus chemotherapy, whereas the observation group (n = 79) additionally received fluoxetine. Outcomes included short-term efficacy, adverse mood assessed using the Self-Rating Anxiety Scale and Self-Rating Depression Scale, serum neurotransmitters (5-hydroxytryptamine and norepinephrine), clinical safety (mucositis, diarrhea, alopecia, anorexia, nausea, insomnia, sexual dysfunction, and agitation), and quality-of-life assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30. Univariate and multivariate regression analyses were performed to identify factors influencing emotional improvement in chemotherapy-treated CC patients.

RESULTS

Short-term efficacy and clinical safety were comparable between groups. The observation group showed greater improvement in adverse mood, serum neurotransmitters, and quality-of-life than the control group. Regression analysis identified treatment modality as an independent factor influencing mood improvement in chemotherapy-treated CC patients.

CONCLUSION

Fluoxetine combined with psychological intervention is significantly effective in improving mood, normalizing neurotransmitter levels, and enhancing quality-of-life in chemotherapy-treated CC patients. Psychological intervention alone may increase the risk of inadequate emotional improvement in such patients.

Key Words: Fluoxetine; Psychological intervention; Colon cancer; Chemotherapy; Mood; Influencing factor analysis

Core Tip: This study aimed to investigate the effects of fluoxetine combined with psychological intervention on mood in chemotherapy-treated colon cancer patients and explore associated determinants. Multidimensional assessment indicates that the combined therapy provides significant clinical benefits, including improvement of adverse mood, modulation of serum neurotransmitters, and enhancement of quality-of-life, without increasing the incidence of adverse events. Further analysis suggests that this combined approach may reduce the risk of inadequate mood improvement in this population.

INTRODUCTION

Colon cancer (CC) is the third most common and the second most fatal malignancy worldwide, accounting for approximately 1.1 million deaths yearly[1]. Patients typically present with nonspecific symptoms such as fatigue, bloody stool, weight loss, and altered bowel habits. CC incidence is easily affected by obesity and unhealthy lifestyles, including smoking, alcohol consumption, and poor diet)[2]. Pathogenically, CC is associated with dysregulated signaling pathways that drive tumor occurrence, progression, and metastasis. These complex signaling networks also affect tumor phenotype, immune response, tumor microenvironment, and treatment efficacy[3-5]. Postoperative adjuvant chemotherapy remains the main treatment for stage II-III CC; however, its effectiveness can still be improved. Chemotherapy-induced adverse effects may seriously impair daily functioning and contribute to adverse mood states such as anxiety and depression[6,7]. This psychological burden may hinder recovery and reduce treatment compliance[8]. Although psychological intervention can improve emotional status, its effects may be gradual and often require long-term application to achieve desired outcomes[9]. Conversely, fluoxetine, a widely used antidepressant, is a selective serotonin reuptake inhibitor with favorable efficacy, safety and tolerance, as well as immunomodulatory and anti-inflammatory properties[10]. It also exhibits certain anti-tumor activity. In osteosarcoma, fluoxetine exerts anti-tumor effects by inducing tumor cell apoptosis, inhibiting metastasis, and targeting oncogenic signaling pathways[11]. Additionally, fluoxetine may exert anti-inflammatory effects in the intestinal mucosa by modulating intestinal cells and macrophages, thereby alleviating colitis[12].

This study hypothesizes that fluoxetine combined with psychological intervention may enhance mood improvement in chemotherapy-treated CC patients. Given the limited number of related studies, this hypothesis was systematically evaluated. In addition to mood outcomes, this study assessed short-term efficacy, serum neurotransmitters, clinical safety, and quality-of-life to comprehensively evaluate the clinical value of the combined intervention.

MATERIALS AND METHODS

Case selection

Eligible patients met the following criteria: CC diagnosed via computed tomography, color Doppler ultrasound, and pathological examination[13]; TNM stage II-III; eligibility for first-time chemotherapy; life expectancy covering the chemotherapy course; clear consciousness with intact cognitive, understanding, and communication abilities; and complete medical records. Exclusion criteria included: Other malignancies; emergency surgery due to severe complications (e.g., intestinal perforation or obstruction); history of alcohol or drug dependence; contraindications to study drugs or chemotherapy; digestive tract obstruction or dysphagia; severe dysfunction of the heart, lung, liver, kidney, or other organs; coagulation disorders; or other infectious diseases.

A total of 145 patients with CC treated at The Affiliated Hospital of Southwest Medical University between April 2023 and April 2025 were screened according to these criteria. The control group (n = 66) received psychological intervention in addition to chemotherapy, whereas the observation group (n = 79) additionally received fluoxetine.

Intervention method

All patients received oxaliplatin + calcium folinate + 5-fluorouracil (mFOLFOX6) or irinotecan + calcium folinate + 5-fluorouracil (FOLFIRI) chemotherapy intervention. In the mFOLFOX6 regimen, on day 1, oxaliplatin (85 mg/m²) was administered via intravenous (IV) infusion for 2 hours, calcium folinate (400 mg/m²) via IV infusion for 2 hours, and 5-fluorouracil via an IV bolus (400 mg/m²) followed by continuous IV infusion (2400 mg/m²) for 46 hours. The FOLFIRI regimen included irinotecan (180 mg/m², IV, 100 minutes), calcium folinate (200 mg/m², IV, 2 hours), and 5-fluorouracil (IV bolus at 400 mg/m² followed by continuous infusion at 2400 mg/m² for 46 hours) on day 1. Both regimens were repeated every 14 days as one treatment cycle.

The control group received psychological intervention delivered one-on-one by qualified medical staff: (1) Health education and cognitive support: Nursing staff provided detailed explanations of disease pathology, treatment processes, nursing care, and precautions to improve patient understanding, compliance, and cooperation with treatment and follow-up; (2) Core psychological intervention: Patients’ mood status and psychological stress related to chemotherapy-induced discomfort were assessed, and personalized psychological counseling plans were developed. One-on-one interventions were conducted in a quiet environment, 30 minutes/session, twice weekly, for six weeks. Supportive psychotherapy was combined with cognitive restructuring and behavioral activation based on cognitive behavioral therapy. Patients were encouraged to express emotions through empathic listening, identify and adjust negative automatic thoughts, and set achievable daily activity goals to restore a sense of control. Each session followed a structured sequence of “emotional evaluation-thematic focus-skill practice-summary and therapeutic homework”. Interventions were delivered by clinical psychotherapists or specialized psychological nurses, with weekly supervision to ensure quality; and (3) Confidence-building and group support: When the patient’s physiological condition permits, educational sessions on colon disease were organized and simple and understandable disease brochures were distributed to patients and families. Family members were encouraged to provide companionship and support to the patients during hospitalization, including participation in activities such as watching television, listening to music, or taking walks together, to enhance psychological and social support.

In the observation group, oral fluoxetine (20 mg per dose, once daily) was added to the above interventions. Both groups were treated for three chemotherapy cycles.

Data collection and outcome measurement

Short-term response: Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors[14], as complete remission (tumor disappearance), partial remission (> 50% reduction), stable disease (< 50% reduction or < 25% increase), or progressive disease (> 25% increase). Overall response comprised complete and partial remission rates.

Adverse mood: Anxiety and depression were assessed pre- and postintervention using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS)[15]. Total scores (maximum 100) correlated positively with symptom severity.

Serum neurotransmitters: Fasting venous blood samples (5 mL) were collected pre- and postintervention. Serum was obtained via centrifugation, and 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels were quantified using enzyme-linked immunosorbent assay (ELISA).

Clinical safety: Incidence of mucositis, diarrhea, alopecia, anorexia, nausea, insomnia, sexual dysfunction, and agitation was recorded and summarized.

Quality-of-life: Quality-of-life was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30)[16], covering physical, role, emotional, cognitive, and social functioning. Scores (maximum 100) were positively associated with quality-of-life.

Statistical analyses

Data were analyzed using SPSS 22.0. Categorical data are presented as n (%), whereas continuous data are expressed as mean ± SD. The χ² test and independent samples t-test were used for comparisons of categorical and continuous data, respectively. Univariate and multivariate logistic regression analyses were performed to identify the factors influencing emotional improvement in chemotherapy-treated CC patients. A P value < 0.05 was considered statistically significant.

RESULTS

General data analysis

Baseline data revealed no significant inter-group differences in sex, age, disease duration, tumor diameter or location, TNM stage, chemotherapy regimen, or education level (P > 0.05; Table 1).

Table 1 General data analysis, n (%).

Data	n	Control group (n = 66)	Observation group (n = 79)	t/Z/χ2 value	P value
Sex				0.570	0.450
Male	84	36 (54.55)	48 (60.76)
Female	61	30 (45.45)	31 (39.24)
Age (years)	145	59.62 ± 13.00	59.19 ± 9.10	0.233	0.816
Disease duration (months)	145	7.00 (5.75, 8.00)	7.00 (6.00, 9.00)	0.316	0.752
Tumor diameter (cm)	145	4.06 ± 1.42	4.26 ± 1.73	0.751	0.454
Lesion location				0.469	0.494
Left hemicolon	68	33 (50.00)	35 (44.30)
Right hemicolon	77	33 (50.00)	44 (55.70)
TNM staging				1.293	0.255
II	50	26 (39.39)	24 (30.38)
III	95	40 (60.61)	55 (69.62)
Chemotherapy regimen				0.425	0.514
mFOLFOX6	77	37 (56.06)	40 (50.63)
FOLFIRI	68	29 (43.94)	39 (49.37)
Educational level				0.055	0.815
Below senior high school	60	28 (42.42)	32 (40.51)
Senior high school or above	85	38 (57.58)	47 (59.49)

Short-term therapeutic effectiveness

The overall response rates were 72.15% in the observation group and 60.61% in the control group, with no significant differences between groups (P > 0.05; Table 2).

Table 2 Short-term efficacy, n (%).

Therapeutic effectiveness	Control group (n = 66)	Observation group (n = 79)	χ2 value	P value
Complete remission	10 (15.15)	18 (22.78)
Partial remission	30 (45.45)	39 (49.37)
Stable disease	20 (30.30)	17 (21.52)
Progressive disease	6 (9.09)	5 (6.33)
Overall response	40 (60.61)	57 (72.15)	2.165	0.141

Adverse mood analysis

Based on the SAS and SDS assessments, baseline SAS scores were 75.45 ± 6.63 in the control group and (73.04 ± 7.97) in the observation group, decreasing to 55.05 ± 6.58 and 44.39 ± 5.25 postintervention, respectively. The pre- and postinterventional SDS scores were 71.47 ± 8.35 and 49.41 ± 7.84 in the control group and 70.38 ± 5.75 and 41.35 ± 6.68 in the observation group, respectively. Baseline adverse mood was comparable between groups (P > 0.05). Both groups showed significant reductions in SAS and SDS scores postintervention (P < 0.05), with greater reductions observed in the observation group (P < 0.05; Figure 1).

Figure 1 Adverse mood analysis. A: Pre- and post-interventional Self-Rating Anxiety Scale scores; B: Pre- and post-interventional Self-Rating Depression Scale scores. ^aP < 0.05 and ^bP < 0.01 vs the pre-interventional level; ^cP < 0.05 vs control at the same time point. SAS: Self-Rating Anxiety Scale; SDS: Self-Rating Depression Scale.

Serum neurotransmitter profiling

Serum 5-HT and NE levels were measured in both groups. Baseline 5-HT levels were 11.79 ± 2.81 ng/mL in the control group and 12.14 ± 2.65 ng/mL in the observation group, increasing to 14.42 ± 4.25 ng/mL and 17.56 ± 4.05 ng/mL postintervention, respectively. Baseline NE levels were 325.85 ± 64.80 pg/mL and 326.09 ± 67.84 pg/mL, decreasing to 302.58 ± 42.61 pg/mL and 262.73 ± 36.91 pg/mL postintervention in the control and observation groups, respectively. Baseline levels were comparable (P > 0.05). Postintervention, 5-HT levels increased while NE levels decreased in both groups (P < 0.05), with higher 5-HT and lower NE levels in the observation group than in the control group (P < 0.05; Figure 2).

Figure 2 Serum neurotransmitter measurements. A: Pre- and post-interventional 5-hydroxytryptamine; B: Pre- and post-interventional norepinephrine. ^aP < 0.05 and ^bP < 0.01 vs the pre-interventional level; ^cP < 0.05 vs control at the same time point. 5-HT: 5-hydroxytryptamine; NE: Norepinephrine.

Clinical safety evaluation

The incidence adverse events, including mucositis, diarrhea, alopecia, anorexia, nausea, and insomnia (P > 0.05). Additionally, neither group developed sexual dysfunction or agitation (Table 3).

Table 3 Clinical safety evaluation, n (%).

Safety	Control group (n = 66)	Observation group (n = 79)	χ2 value	P value
Mucositis	2 (3.03)	2 (2.53)	0.033	0.855
Diarrhea	6 (9.09)	4 (5.06)	0.908	0.341
Alopecia	8 (12.12)	7 (8.86)	0.412	0.521
Anorexia	13 (19.70)	10 (12.66)	1.335	0.248
Nausea	2 (3.03)	4 (5.06)	0.375	0.541
Insomnia	1 (1.52)	3 (3.80)	0.698	0.403
Sexual dysfunction	0 (0.00)	0 (0.00)	-	-
Agitation	0 (0.00)	0 (0.00)	-	-

Quality-of-life analysis

Quality-of-life assessment using the EORTC QLQ-C30 showed comparable baseline scores across all domains between groups (P > 0.05). Scores in all domains increased significantly postintervention in both groups, with higher scores observed in the observation group (P < 0.05; Table 4).

Table 4 Quality of life assessment.

EORTC QLQ-C30 (points)		Control group (n = 66)	Observation group (n = 79)	Z/t value	P value
Physical function	Before	52.00 (50.00, 55.25)	53.00 (49.00, 58.00)	-1.082	0.279
	After	58.50 (52.75, 61.00)	64.00 (59.00, 70.00)	-5.788	< 0.001
Role function	Before	50.92 ± 5.08	50.14 ± 5.70	0.862	0.390
	After	60.12 ± 5.06	67.33 ± 7.64	6.557	< 0.001
Emotional function	Before	55.64 ± 5.77	54.96 ± 6.15	0.682	0.496
	After	60.95 ± 5.27	63.97 ± 6.46	3.044	0.003
Cognitive function	Before	53.95 ± 4.92	52.71 ± 6.56	1.266	0.207
	After	60.02 ± 5.94	64.32 ± 7.05	3.925	< 0.001
Social function	Before	58.05 ± 4.97	59.70 ± 5.84	1.812	0.072
	After	64.53 ± 6.41	69.46 ± 6.64	4.523	< 0.001

EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30.

Factors influencing mood improvement in chemotherapy-treated CC patients

Patients were grouped based on SAS/SDS improvement rates (≥ 35% defined as effective), yielding 111 cases in the effective group and 34 cases in the ineffective group. Univariate analysis showed that 5-HT levels and treatment modality were significantly correlated with mood improvement (P < 0.05), whereas sex, age, disease duration, tumor diameter, lesion location, TNM stage, chemotherapy regimen, education level, and NE level were not (P > 0.05). Multivariate analysis further identified treatment modality as an independent risk factor (P < 0.05), suggesting that psychological intervention combined with fluoxetine is beneficial for mood improvement in chemotherapy-treated CC patients (Tables 5 and 6).

Table 5 Mood improvement-associated determinants in chemotherapy-managed colon cancer patients (univariate screening), n (%).

Data	n	Ineffective group (n = 34)	Effective group (n = 111)	χ2 value	P value
Sex				2.154	0.142
Male	84	16 (47.06)	68 (61.26)
Female	61	18 (52.94)	43 (38.74)
Age (years)				2.605	0.107
< 60	73	13 (38.24)	60 (54.05)
≥ 60	72	21 (61.76)	51 (45.95)
Disease duration (months)				0.273	0.601
< 7	48	10 (29.41)	38 (34.23)
≥ 7	97	24 (70.59)	73 (65.77)
Tumor diameter (cm)				3.664	0.056
< 4	72	12 (35.29)	60 (54.05)
≥ 4	73	22 (64.71)	51 (45.95)
Lesion location				0.584	0.445
Left hemicolon	68	14 (41.18)	54 (48.65)
Right hemicolon	77	20 (58.82)	57 (51.35)
TNM staging				0.089	0.765
II	50	11 (32.35)	39 (35.14)
III	95	23 (67.65)	72 (64.86)
Chemotherapy regimen				0.584	0.445
mFOLFOX6	77	20 (58.82)	57 (51.35)
FOLFIRI	68	14 (41.18)	54 (48.65)
Educational level				0.591	0.442
Below senior high school	60	16 (47.06)	44 (39.64)
Senior high school or above	85	18 (52.94)	67 (60.36)
5-HT (ng/mL)				6.555	0.011
< 12	62	21 (61.76)	41 (36.94)
≥ 12	83	13 (38.24)	70 (63.06)
NE (pg/mL)				1.078	0.299
< 330	71	14 (41.18)	57 (51.35)
≥ 330	74	20 (58.82)	54 (48.65)
Treatment modality				28.337	< 0.001
Psychological intervention + fluoxetine	79	5 (14.71)	74 (66.67)
Psychological intervention	66	29 (85.29)	37 (33.33)

5-HT: 5-hydroxytryptamine; NE: Norepinephrine.

Table 6 Factors impacting mood improvement in chemotherapy-managed colon cancer patients (multivariate analysis).

Variable	β	SE	Wald	P value	OR	95%CI
5-HT (ng/mL)	-0.765	0.446	2.946	0.086	0.465	0.194-1.115
Treatment modality	2.357	0.529	19.865	< 0.001	10.564	3.746-29.788

5-HT: 5-hydroxytryptamine; OR: Odds ratio; CI: Confidence interval.

DISCUSSION

This study found that fluoxetine combined with psychological intervention in chemotherapy-treated CC patients could increased the clinical response rate by 11.54%, although the difference was not statistically significant. However, the combined intervention demonstrated superior effects in alleviating anxiety and depression compared with psychological intervention alone. Animal studies have shown that fluoxetine can counteract the effects of prenatal maternal stress on depression- and anxiety-like behaviors in offspring, possibly through inhibition of hyperactivity of the hypothalamic-pituitary-adrenal axis[17]. Tumor-related depression-like behaviors, associated with the over-expression of proinflammatory cytokines in the brain, have also been alleviated by fluoxetine in a tumor-related fatigue mouse model[18]. In a study by Hunter et al[19], fluoxetine demonstrated a faster onset of action than psychological intervention in women with premenstrual dysphoria, consistent with our results. Previous studies have also reported that fluoxetine combined with psychological intervention effectively alleviates depressive symptoms in patients with moderate depression[20], supporting our results. ELISA-based serum neurotransmitter profiling indicated that the combined intervention significantly increased 5-HT levels and decreased NE levels in chemotherapy-treated CC patients, suggesting a stronger effect on improving serum neurotransmitter levels. Reduced 5-HT levels are strongly associated with depression, and increasing its levels may help normalize β-receptor downregulation, thereby improving adaptive self-regulation[21]. In contrast, NE overactivation is closely associated with sympathetic activation, heightened arousal, and anxiety, which may impair adaptive function[22]. Similarly, Wang et al[23] reported that fluoxetine effectively restores 5-HT and NE levels in patients with mild to moderate depression. However, although peripheral increases in 5-HT levels and decreases in NE were associated with mood improvement in this study, these findings likely represent downstream or accompanying changes rather than direct evidence of central mechanisms.

Clinical safety analysis showed that the addition of fluoxetine did not significantly increase the incidence of adverse events, including mucositis, diarrhea, alopecia, anorexia, nausea, insomnia, sexual dysfunction, and agitation, indicating good tolerability and safety. Additionally, fluoxetine combined with psychological intervention improved quality-of-life across physical, role, emotional, cognitive, and social function domains. These effects may be attributed to enhanced serotonergic neurotransmission via the inhibition of central 5-HT reuptake[24], along with the synergy of psychological intervention in down-regulating the excessive sympathetic activity mediated by NE, thereby alleviating anxiety and depression. Improved emotional state may further enhance treatment compliance and participation in daily activities, ultimately translating into improvements in multiple dimensions of quality-of-life, such as physical and social functioning. Finally, treatment modality (psychological intervention alone) was identified as an independent risk factor for emotional improvement in chemotherapy-treated CC patients, suggesting that the addition of fluoxetine is a key factor for optimizing emotional outcomes. Fluoxetine increases synaptic 5-HT levels by inhibiting neuronal reuptake, facilitating neurotransmission and enhancing adaptive capacity, thereby improving mood[25].

This study has several limitations. First, all patients were recruited from a single center, with uneven group sizes (observation n = 79; control n = 66), which may introduce selection bias. Future multicenter studies are needed to improve sample representativeness and generalizability. Second, although correlations between peripheral 5-HT and NE changes and emotional improvement, direct evidence of central mechanisms is lacking. Future studies should incorporate central nervous system measures, such as functional magnetic resonance imaging or electroencephalogram, to further elucidate the underlying mechanisms. Third, although EORTC QLQ-C30 scores improved significantly across multiple domains, the independent contributions of emotional and functional domains were not distinguished. Future studies should consider mediation analysis or structural equation modeling to clarify these relationships.

CONCLUSION

Conclusively, without increasing the risk of adverse events, fluoxetine combined with psychological intervention in chemotherapy-treated CC patients improves mood, enhances quality-of-life, and effectively regulates serum neurotransmitter levels. This combined approach may synergistically enhance emotional outcomes in this population.