Effects of phototherapy plus agomelatine on efficacy, negative emotions, and neurotransmitter levels in elderly patients with depressive disorders

Abstract

BACKGROUND

Treatment outcomes in patients with depressive disorders remain suboptimal, necessitating exploration of improved therapeutic strategies.

AIM

To evaluate the effects of phototherapy plus agomelatine on treatment efficacy, negative emotions, and neurotransmitter levels in elderly patients with depressive disorders.

METHODS

From August 2024 to May 2025, 127 elderly patients with depressive disorder admitted to Chongqing Mental Health Center were enrolled and assigned to control (n = 60, agomelatine monotherapy) and research (n = 67, phototherapy plus agomelatine) groups. The two groups were compared regarding overall efficacy; Hamilton Anxiety Scale scores, Hamilton Depression Scale (HAMD) scores, and Pittsburgh Sleep Quality Index scores; levels of dopamine (DA), norepinephrine, serotonin, superoxide dismutase, and malondialdehyde; and safety outcomes (nausea and vomiting, dry mouth, sweating, headache, and eye fatigue). The number needed to treat was calculated to assess the correlation between neurotransmitter changes and clinical improvement.

RESULTS

Compared with the control group (needed to treat: 8), the research group demonstrated a significantly higher total effective rate, lower post-treatment Hamilton Anxiety Scale, HAMD, and Pittsburgh Sleep Quality Index scores, and malondialdehyde levels, and higher post-treatment DA, norepinephrine, serotonin, and superoxide dismutase levels. ΔDA showed a significant positive correlation with the reduction rate of HAMD scores. The overall incidence of adverse events was comparable between groups.

CONCLUSION

Phototherapy plus agomelatine demonstrates definite therapeutic efficacy in elderly patients with depressive disorders, effectively alleviating negative emotions and improving neurotransmitter parameters.

Key Words: Phototherapy; Agomelatine; Senile depressive disorder; Treatment efficacy; Negative emotions; Neurotransmitter

Core Tip: Drug therapy, psychotherapy, and combined drug-psychological therapy are available treatment options for elderly patients with depressive disorders; however, therapeutic efficacy remains suboptimal. This study evaluated phototherapy combined with agomelatine in elderly patients with depressive disorders. The findings indicate that the combined therapy demonstrated significant treatment efficacy, effectively alleviated anxiety and depression, improved sleep quality, regulated neurotransmitter levels, and suppressed oxidative stress, without increasing adverse side effects.

INTRODUCTION

Depressive disorder contributes substantially to the global disease burden and accounts for the highest proportion of disability-adjusted life years among mental disorders. Major depressive disorder (MDD) and dysthymic disorder are two major subtypes[1]. The condition is characterized by fatigue, weight loss, appetite loss, anhedonia, and sleep disturbances, with an increasing trend in incidence yearly[2,3]. The risk of depressive disorders increases with age, with an estimated prevalence of approximately 6% among individuals older than 60 years[4]. Deficiencies in monoamine neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), as well as dysregulation of the hypothalamic-pituitary-adrenal axis under stress, may be involved in the pathophysiology[5]. Depressive disorders may lead to adverse outcomes, including suicide, poor physical health, disrupted family relationships, sedentary behavior, reduced work performance, increased self-harm risk, and shortened life expectancy, and may increase the risk of chronic diseases, such as cardiovascular disorders[6]. Current treatment options include pharmacotherapy, psychotherapy, and combined therapy aimed at maintaining remission and preventing relapse; nevertheless, further improvement in efficacy remains necessary[7].

Agomelatine, a selective agonist of melatonin receptors 1A/1B (MT1/MT2) and antagonist of 5-HT 2C receptors, exerts antidepressant effects by regulating sleep-wake rhythms and enhancing DA and NE release in the prefrontal cortex[8]. A double-blind, randomized, controlled phase 3 trial conducted across nine countries/regions demonstrated short-term efficacy and suggested a certain level of safety in children and adolescents with MDD, without significant weight gain or suicidal behavior[9]. Agomelatine has also been applied to epilepsy patients with sleep and mood disorders, showing greater improvement in depression and insomnia compared with escitalopram[10]. Phototherapy is an antidepressant therapy that can be combined with pharmacotherapy. It has been evaluated in both children and adults and can also be used to treat sleep disorders and bipolar depression[11]. This low-cost therapy is considered highly safe. By regulating cerebral 5-HT activity and restoring circadian rhythms, it alleviates negative emotions and promotes overall health[12]. Previous studies suggest that phototherapy may serve as a comprehensive treatment in patients with Alzheimer’s disease, effectively improving objective sleep and alleviating behavioral and psychological symptoms[13]. There are limited relevant studies on the effects of phototherapy plus agomelatine on treatment efficacy, negative emotions, and neurotransmitter levels in elderly patients with depressive disorders. This study may provide a convincing reference for the clinical application of this combined therapy in this population.

MATERIALS AND METHODS

General data

A total of 127 elderly patients with depressive disorders admitted to Chongqing Mental Health Center from August 2024 to May 2025 were enrolled for retrospective analysis. According to the treatment regimen received, patients were assigned to the control group (n = 60, agomelatine intervention) or the research group (n = 67, phototherapy plus agomelatine intervention). Baseline general data were comparable between groups, with no statistically significant differences (P > 0.05). The patient screening process is shown in Figure 1.

Figure 1 The patient screening process.

Inclusion and exclusion criteria

Inclusion criteria: Patients meeting the diagnostic criteria for depressive disorders[14]; aged 60-80 years; with normal cognitive function and the ability to communicate verbally or in writing; Montreal Cognitive Assessment score ≥ 26; no significant functional impairment of major organs; and complete medical records.

Exclusion criteria: Allergy to the study drug; recent use of other sleep medications; insomnia caused by physical illness or other factors; serious impulsive tendencies toward harming others or self-harm/suicide; organic brain disorders, secondary depression, or use of other psychiatric medications (e.g., benzodiazepines or atypical antipsychotics) within the past month; ocular disease, systemic retinal disorders, or current use of photosensitizing agents; pregnancy or breastfeeding; severe hepatic or renal failure; systemic diseases; serious suicidal ideation or history of suicidal behavior.

Treatment method

Patients in the control group received agomelatine once daily at bedtime (1 tablet per dose). After two weeks, the dose could be increased to two tablets per dose according to symptom improvement, as assessed using the Hamilton Depression Scale (HAMD) score reduction rate. Treatment continued for four weeks. Dose adjustment principles were consistent in both groups.

In addition to the control regimen, the research group received phototherapy. A full-spectrum LED lamp (240 mm × 146 mm × 17 mm; 23 W) was used. Phototherapy parameters were standardized as follows: Light intensity fixed at 8000 Lux (measured at 15 cm from the device to the eye) and color temperature fixed at 5000 K (mid-range setting simulating natural morning light). Phototherapy was administered daily, from 7:00 AM to 7:30 AM. The lamp stand was placed on a table with the light surface parallel to the ground. Patients maintained an eye-to-light distance < 15 cm while avoiding direct gaze to minimize discomfort. By adjusting the stand height and clamp angle, patients lightly rested or touched their foreheads against the lamp’s long edge. Treatment was conducted for four consecutive weeks, with each session lasting 30 minutes. Standardized phototherapy logs were distributed to patients or their family members to record daily treatment start and end times, as well as equipment usage. The study nurse conducted telephone follow-up twice weekly to reinforce adherence and confirm compliance. Logs were collected after treatment, and 20% of patients were randomly selected for telephone verification to ensure record authenticity.

Outcome measures

Treatment efficacy: Treatment efficacy was recorded according to the HAMD reduction rate: < 25% was defined as ineffective; 25%-50% (inclusive) as effective; 50% ≤ 75% (inclusive) as effective; and > 75% as recovered. The HAMD reduction rate was calculated as the percentage difference between pre-treatment and post-treatment scores relative to the pre-treatment score[15].

Negative emotions: Anxiety and depression were assessed using the Hamilton Anxiety Scale (HAMA) and HAMD. The HAMA comprises 14 items (score range 0-56), with higher scores indicating greater anxiety severity. The HAMD comprises 17 items (score range 0-68), with higher scores indicating greater depression intensity[16].

Sleep quality: Sleep quality was evaluated using the Pittsburgh Sleep Quality Index, which comprises seven dimensions: Subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. Each dimension is scored 0-3 points, totaling 21 points. Scores are negatively correlated with sleep quality[17].

Neurotransmitter levels: For each patient, 5 mL of venous blood was collected before and after treatment. Serum was obtained via centrifugation, and DA, NE, and 5-HT levels were measured using an enzyme-linked immunosorbent assay.

Oxidative stress: Serum superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured before and after treatment using a fully automated analyzer.

Safety: Adverse events, including nausea, vomiting, dry mouth, sweating, headache, and eye fatigue, were monitored. The number and incidence of adverse events were recorded.

To minimize information bias during data collection, all outcome data were independently extracted by two investigators blinded to group allocation, and consistency checks were performed.

Statistical analysis

For measurement data, mean ± SD was applied for descriptive statistics; comparisons between groups were performed using the independent-samples t-test, and within-group comparisons before and after treatment were conducted using the paired t-test. Enumeration data were expressed as n (%) and compared with the χ² test. The number needed to treat (NNT) was calculated to assess clinical benefit using the formula: NNT = 1/(effective rate in the study group - effective rate in the control group), with the 95% confidence interval (CI) derived from the confidence interval of the rate difference. Spearman’s correlation coefficient was used to assess the relationship between changes in neurotransmitter markers and clinical improvement. SPSS 21.0 was used for statistical analysis. P < 0.05 was considered statistically significant. Post-hoc power analysis was performed using PASS 15.0 software, assuming sample sizes of 67 and 60 in the two groups, with an efficacy rate of 78.33% in the control group and 91.04% in the study group. With α = 0.05 (two-tailed), the calculated statistical power was 81.2%, exceeding the recommended 80% threshold. These results indicate that the sample size was sufficient to detect differences in primary efficacy outcomes between groups, confirming adequate statistical power.

RESULTS

Comparative analysis of baseline data

As shown in Table 1, no significant differences were observed in baseline characteristics between the control and research groups, including gender, age, disease duration, body mass index, marital status, and family history (P > 0.05).

Table 1 Comparative analysis of baseline data, n (%).

Indicator	Control group (n = 60)	Research group (n = 67)	χ2/t/Z	P value
Gender			0.348	0.555
Male	38 (63.33)	39 (58.21)
Female	22 (36.67)	28 (41.79)
Age (years)	70.25 ± 4.62	70.01 ± 5.00	0.280	0.780
Disease duration (years)	3.00 (2.25, 4.00)	4.00 (2.00, 4.00)	-0.917	0.359
BMI (kg/m2)	23.15 ± 2.20	23.04 ± 2.01	0.294	0.769
Marital status			1.736	0.188
Not married	20 (33.33)	30 (44.78)
Married	40 (66.67)	37 (55.22)
Family history			0.241	0.624
Absent	47 (78.33)	50 (74.63)
Present	13 (21.67)	17 (25.37)

Comparative analysis of treatment efficacy

Table 2 shows that the total effective rate in the research group (91.04%) was significantly higher than in the control group (78.33%; P = 0.045). The calculated NNT was 8 (95%CI: 4-417), indicating the clinical benefit of the combined regimen relative to monotherapy.

Table 2 Comparative analysis of treatment efficacy, n (%).

Indicator	Control group (n = 60)	Research group (n = 67)	χ2	P value
Markedly effective	18 (30.00)	30 (44.78)
Effective	29 (48.33)	31 (46.27)
Ineffective	13 (21.67)	6 (8.96)
Total effective rate	47 (78.33)	61 (91.04)	4.020	0.045

Comparative analysis of negative emotions

Figure 2 presents HAMA and HAMD scores in both groups. At baseline, no significant intergroup differences were observed (P > 0.05). After treatment, both groups showed significant reductions in HAMA and HAMD scores in the research group.

Figure 2 Comparative analysis of negative emotions. A: Hamilton Anxiety Scale scores before and after treatment in the two groups; B: Hamilton Depression Scale scores before and after treatment in the two groups. ^aP < 0.05, ^bP < 0.01 vs before treatment; ^cP < 0.05 vs the control group. HAMA: Hamilton Anxiety Scale scores; HAMD: Hamilton Depression Scale scores.

Comparative analysis of sleep quality

As shown in Figure 3, no significant differences were observed in Pittsburgh Sleep Quality Index scores across all dimensions before treatment (P > 0.05). Post-treatment scores decreased significantly across all dimensions (P < 0.05), with significantly lower scores in the research group (P < 0.05).

Figure 3 Comparative analysis of sleep quality. A: Subjective sleep quality before and after treatment in the two groups; B: Sleep latency before and after treatment in the two groups; C: Sleep duration before and after treatment in the two groups; D: Habitual sleep efficiency before and after treatment in the two groups; E: Sleep disturbances before and after treatment in the two groups; F: Use of sleeping medications before and after treatment in the two groups; G: Daytime dysfunction before and after treatment in the two groups; H: Total Pittsburgh Sleep Quality Index scores before and after treatment in the two groups. ^aP < 0.05, ^bP < 0.01 vs before treatment; ^cP < 0.05 vs the control group. PSQI: Pittsburgh Sleep Quality Index.

Comparative analysis of neurotransmitter levels

Figure 4 illustrates neurotransmitter levels in the two groups. No significant intergroup differences in DA, NE, or 5-HT were detected before treatment (P > 0.05). After treatment, all three parameters increased significantly, with higher DA, NE, and 5-HT levels in the research group (P < 0.05). Table 3 presents the correlations between changes in neurotransmitter levels and clinical improvement (HAMD score reduction rate). Only ΔDA showed a significant positive correlation with the HAMD score reduction rate (r = 0.225, P = 0.011), whereas ΔNE and Δ5-HT were not significantly correlated (P > 0.05).

Figure 4  Comparative analysis of neurotransmitter levels. A: Dopamine before and after treatment in the two groups; B: Norepinephrine before and after treatment in the two groups; C: Serotonin before and after treatment in the two groups. ^aP < 0.05, ^bP < 0.01 vs before treatment; ^cP < 0.05 vs the control group. DA: Dopamine; NE: Norepinephrine; 5-HT: Serotonin.

Table 3 Correlation analysis between changes in neurotransmitter levels and Hamilton Depression Scale score reduction rate.

Marker	r	P value
ΔDA (pmol/L) vs HAMD score reduction rate (%)	0.225	0.011
ΔNE (mg/L) vs HAMD score reduction rate (%)	0.122	0.173
Δ5-HT (μg/L) vs HAMD score reduction rate (%)	0.097	0.280

DA: Dopamine; NE: Norepinephrine; 5-HT: Serotonin; HAMD: Hamilton Depression Scale score.

Comparative analysis of oxidative stress between the two groups

As shown in Figure 5, no significant intergroup differences were observed in SOD and MDA levels before treatment (P > 0.05). After treatment, SOD levels increased significantly in both groups and were higher in the research group (P < 0.05), whereas MDA levels decreased significantly and were lower in the research group (P < 0.05).

Figure 5 Comparative analysis of oxidative stress. A: Serum superoxide dismutase before and after treatment in the two groups; B: Malondialdehyde before and after treatment in the two groups. ^aP < 0.05, ^bP < 0.01 vs before treatment; ^cP < 0.05 vs the control group. SOD: Serum superoxide dismutase; MDA: Malondialdehyde.

Comparative analysis of safety

As shown in Table 4, the overall incidence of adverse events (e.g., nausea and vomiting, dry mouth, sweating, headache, and eye fatigue) did not differ significantly between groups (P > 0.05).

Table 4 Comparative analysis of safety, n (%).

Indicator	Control group (n = 60)	Research group (n = 67)	χ2	P value
Nausea and vomiting	2 (3.33)	1 (1.49)
Dry mouth	2 (3.33)	2 (2.99)
Sweaty	4 (6.67)	3 (4.48)
Headache	1 (1.67)	4 (5.97)
Eye fatigue	2 (3.33)	3 (4.48)
Total	11 (18.33)	13 (19.40)	0.024	0.878

DISCUSSION

In this study, phototherapy combined with agomelatine demonstrated superior efficacy in elderly patients with depressive disorders compared with agomelatine monotherapy. The NNT was 8 (95%CI: 4-417), indicating that one additional responder would be achieved for every eight elderly patients treated with the combined regimen rather than pharmacotherapy alone. This NNT value represents a moderate clinical benefit in psychiatric practice, suggesting that the phototherapy combination regimen is both statistically significant and clinically meaningful. According to a mouse study, by acting on melatonin and 5-HT, agomelatine exerts antidepressant effects to reduce oxidative stress, preserve mitochondrial function, and enhance synaptic plasticity[18]. Additionally, mouse models demonstrated that phototherapy inhibits neuroinflammation and apoptosis by upregulating brain-derived neurotrophic factor signaling pathways, thereby restoring hippocampal synaptic function and alleviating depressive-like behaviors and neural damage[19]. As these therapies act via different pathways, their combination synergistically enhances antidepressant effects. In the present study, phototherapy plus agomelatine significantly reduced negative emotions, including anxiety and depression, in elderly patients. Xie et al[20] reported that phototherapy increased serum tetrahydrobiopterin levels, improved evoked potentials, and alleviated depressive symptoms in post-stroke depression patients, partially supporting its antidepressant effect in this population. A systematic review and meta-analysis further indicated that phototherapy combined with antidepressants yields superior clinical efficacy for major depressive episodes compared with monotherapy[21], consistent with our findings. Additionally, sleep quality improved further in elderly patients receiving combination therapy. Zhang et al[22] demonstrated that phototherapy was closely associated with improved sleep disturbances in elderly patients in long-term care, consistent with our findings. The improvement in sleep disturbances may be related to enhanced cerebral blood flow and improved immune regulation induced by phototherapy[23].

Neurotransmitter analysis revealed significantly increased serum DA, NE, and 5-HT levels following combined intervention. DA signaling is closely related to synaptic plasticity and is suppressed by chronic stress[24]. NE, released from the locus coeruleus, regulates multiple neural functions, including olfactory, motor, and sensory functions, and exerts antidepressant effects through neuroprotective and anti-inflammatory mechanisms when its bioavailability is enhanced[25]. 5-HT, a neuromodulatory neurotransmitter with specific neuroplasticity properties, mediates the pathophysiology of MDD[26]. Notably, ΔDA was significantly positively correlated with the HAMD score reduction rate, suggesting that DA improvement is closely related to symptom relief in elderly patients with depressive disorders. The combined regimen also alleviated oxidative stress in elderly patients with depressive disorders, as evidenced by increased SOD and decreased MDA. Liu et al[27] similarly reported that phototherapy in post-stroke depression enhanced antioxidant capacity and alleviated depressive symptoms, consistent with this study’s results. Safety assessments indicated no significant increase in the overall incidence of adverse events with combined therapy. Notably, although the incidence of headache was (5.97% vs 1.67%) and eye fatigue (4.48% vs 3.33%) was slightly higher in the combination group, these effects may be related to temporary light-induced discomfort caused by or subclinical ocular surface dysfunction in some elderly patients. Continuous exposure to high brightness (8000 Lux) may temporarily disturb tear film stability, leading to mild eye discomfort. Donmez et al[28] reported that phototherapy demonstrated higher clinical efficacy without increasing treatment-related adverse effects in perinatal depression. However, the efficacy of phototherapy in elderly patients requiring long-term care remains controversial and may be influenced by exposure timing, duration, light intensity, and equipment applied[22]. These factors highlight the importance of standardized phototherapy regimens during results interpretation in this study. Future research should determine the optimal phototherapy parameters for elderly patients with depressive disorders.

This study has some limitations. First, as a single-center study, the sample size was relatively small; larger, multi-center studies are needed to enhance the generalizability of findings. Second, serum SOD and MDA levels were insufficient to reflect the state of the patients’ central nervous system. Future studies incorporating cerebrospinal fluid or imaging markers may further clarify the impacts of the combined treatment regimen on the central nervous system of elderly patients with depressive disorders. Lastly, the follow-up duration was short. Longer-term follow-up extending to at least 5 years is warranted to assess long-term efficacy and prognosis.

CONCLUSION

In summary, without significantly increasing the overall incidence of adverse events, phototherapy plus agomelatine enhanced treatment efficacy, alleviated anxiety and depression, improved sleep quality, positively modulated neurotransmitter levels, and reduced oxidative stress in elderly patients with depressive disorders. Additionally, the DA pathway may be a key neurobiological target underlying the antidepressant effects of the combined regimen.