Clinical efficacy and effects on hypothalamic-pituitary-adrenal axis function of proscar combined with selective serotonin reuptake inhibitor in post-stroke depression

Abstract

BACKGROUND

Post-stroke depression (PSD) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction and neurotransmitter deficits. Selective serotonin reuptake inhibitors (SSRIs) are commonly used, but their efficacy is limited. This study investigated whether combining SSRIs with traditional Chinese medicine (TCM) Free San could enhance their therapeutic effects.

AIM

To evaluate the clinical efficacy and safety of combining SSRIs with Free San in treating PSD, and to assess its impact on HPA axis function.

METHODS

Ninety-two patients with PSD were enrolled and randomly divided into control groups (n = 46) and study groups (n = 46). The control group received the SSRI paroxetine alone, whereas the study group received paroxetine combined with Free San for 4 weeks. Hamilton Depression Scale and TCM syndrome scores were assessed before and after treatment. Serum serotonin, norepinephrine, cortisol, corticotropin-releasing hormone, and adrenocorticotropic hormone were measured. The treatment responses and adverse reactions were recorded.

RESULTS

After treatment, the Hamilton Depression Scale and TCM syndrome scores were significantly lower in the study group than in the control group (P < 0.05). Serum serotonin and norepinephrine levels were significantly higher in the study group than in the control group, whereas cortisol, corticotropin-releasing hormone, and adrenocorticotropic hormone levels were significantly lower (P < 0.05). The total efficacy rates were 84.78% and 65.22% in the study and control groups, respectively (P < 0.05). No significant differences in adverse reactions were observed between the two groups (P > 0.05).

CONCLUSION

Combining SSRIs with Free San can enhance therapeutic efficacy, improve depressive symptoms, and regulate HPA axis function in patients with PSD with good safety and clinical application value.

Key Words: Free San; Selective serotonin reuptake inhibitor; Paroxetine; Post-stroke depression; Hypothalamic-pituitary-adrenal axis

Core Tip: Combining selective serotonin reuptake inhibitors with the traditional Chinese medicine Free San significantly improves the treatment efficacy for post-stroke depression. The novel combination therapy not only alleviated depressive symptoms more effectively than selective serotonin reuptake inhibitors alone but also normalized hypothalamic-pituitary-adrenal axis dysfunction, as evidenced by reduced cortisol and corticotropin-releasing hormone levels. This approach has a good safety profile, suggesting that it is a promising integrative treatment strategy for post-stroke depression.

INTRODUCTION

Post-stroke depression (PSD) is one of the most common neuropsychiatric complications of cerebrovascular accidents, with a reported prevalence ranging from 30% to 50%[1]. It is characterized by a constellation of symptoms, including persistently low mood, loss of interest or pleasure in activities, sleep disturbances (such as insomnia or hypersomnia), changes in appetite, fatigue, difficulty concentrating, feelings of worthlessness or guilt, and, in severe cases, suicidal ideation. These symptoms typically persist for more than two weeks and significantly impair the patient’s functional recovery, quality of life, and adherence to rehabilitation programs[2,3].

The pathogenesis of PSD is multifactorial and involves biological and psychosocial mechanisms. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered a key contributor. HPA axis hyperactivity leads to excessive secretion of cortisol, which in turn disrupts neurotransmitter metabolism, impairs neuroplasticity, and exacerbates depressive symptoms[4,5]. Additionally, PSD is associated with alterations in the monoaminergic systems, particularly reduced serotonin and norepinephrine levels, which are critical for mood regulation[6].

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for PSD. Although generally effective and well tolerated, they have limitations such as delayed onset of action, partial response in some patients, and potential side effects including nausea, insomnia, and agitation[7]. Moreover, long-term use may be associated with tolerance and withdrawal symptoms, highlighting the need for effective and integrative therapeutic strategies.

Traditional Chinese medicine (TCM) has a long history of treating mood disorders and is increasingly being explored as an adjunct therapy for depression. In TCM, PSD is classified under the category of “Yu Zheng”, or depression syndrome, which is believed to result from emotional stagnation, qi stagnation, and imbalance between the liver and spleen. Xiao Yao San (or Free San) is a classical TCM formula commonly used to soothe the liver, relieve stagnation, strengthen the spleen, and nourish the blood. Recent studies have suggested that Free San may exert antidepressant effects by modulating neuroinflammation, regulating neurotransmitters, and restoring HPA axis function[8,9]. Considering the limitations of monotherapy and the potential benefits of integrative treatment, this study aimed to evaluate the clinical efficacy and safety of combining Free San with SSRIs in the treatment of PSD and to investigate their effects on HPA axis function and neurotransmitter levels.

MATERIALS AND METHODS

General information

Ninety-two patients with PSD treated at the Yangzhou University Affiliated Taixing Hospital from February 2023 to February 2025 were selected for inclusion in this retrospective study. The inclusion criteria were as follows: (1) All patients had a history of stroke; (2) Post-stroke examination confirmed the diagnosis, in accordance with the relevant criteria of the Chinese Expert Consensus on Clinical Practice of PSD and the Clinical Diagnosis and Treatment Guidelines for TCM and Psychiatric Diseases; (3) Age > 18 years; (4) Disease duration > 1 month; (5) National Institutes of Health Stroke Scale score < 21 with stable disease condition and vital signs; (6) The diagnosis was based on the TCM diagnosis of the syndrome of liver-depression and spleen-deficiency, the main symptoms of which are depression and chest pains; (7) Main symptoms included depression, fullness in the chest and hypochondriac region, suspiciousness and mixed thoughts, frequent sighing, loss of appetite, thin white tongue coating, and thin stringy pulse; and (8) The patients and their family members were informed of and agreed to participate in the study. The exclusion criteria were as follows: (1) Other post-stroke complications, such as dementia and cognitive abnormalities; (2) Other psychiatric disorders, such as depression and anxiety before stroke; (3) Suicidal tendency; (4) Long-term use of psychotropic drugs; (5) Other treatments; (6) Cardiac, hepatic, and renal insufficiency; and (7) Allergy to the study drug. Termination criteria included acute medical conditions or aggravation of conditions (such as re-stroke and angina) during clinical use of the drug and voluntary withdrawal of patients in the middle of the study. Based on the randomized numerical table method, patients were divided into study and control groups, each with 46 cases. This study was approved by the Medical Ethics Committee of Taixing People’s Hospital (approval No. K-W2023001).

Methods

Control group: Patients were administered paroxetine hydrochloride tablets (20 mg/tablet; Zhejiang Jianfeng Pharmaceutical Co., Jinhua, China) for treatment after diagnosis and were taken orally according to the doctor’s prescription (1 tablet daily for 4 weeks).

Study group: This group took the TCM Free San in combination with paroxetine hydrochloride. Free San was composed of 15 g each of Chaihu, Poria, Citrus aurantium; 18 g each of Paeonia lactiflora and Angelica sinensis; 12 g each of Atractylodes macrocephala, Fenghuang, Jingbao, and Dangshen; and 9 g each of Qingdianxia, Chenpi, and sizzling licorice. Free San was provided by the hospital pharmacy, decocted in clear water and extracted in 200 mL, and administered warm in the morning and evening at 100 mL each. It was continuously administered for four weeks.

Observation indices

Depression was assessed using the Hamilton Depression Scale (HAMD) before and four weeks after treatment. The scale consists of 17 items, of which items 4-6, 12-14, and 16 are scored 0-2 points; the rest are scored 0-4 points. A score of 7 points is the cut-off for depression; the higher the score, the more serious the depressive mood. Cronbach’s α coefficient for this scale is 0.833[7]. Patients were independently scored by two psychiatrists trained in inter-rater reliability (κ = 0.87), with the mean value recorded.

The changes in TCM evidence points were assessed before treatment and after 4 weeks of treatment. The evidence points were formulated according to the “diagnostic and therapeutic efficacy criteria for TCM illnesses”, which included the following: Main symptoms of depressed mood, dysphoria, slow thinking, and fatigue, with each item being assigned a score of 0-4 points from none to the heaviest; secondary symptoms of chest tightness, chest and hypochondrium distension and fullness, Tai Chi, insomnia, abdominal pain, stomach and epigastric distension and fullness, loose stools, nausea, and others, 0-3 points each; pale tongue, thin or slippery pulse, and white moss, 0-1 point for each item. The total score ranged from 0-43 points; the higher the score, the more serious the condition. Cronbach’s α coefficient of this scale is 0.869[10]. Patients were assessed by a single deputy chief TCM practitioner using a blinded evaluation method.

Peripheral venous blood (5 mL) was collected before treatment and after 4 weeks of treatment and centrifuged at 3000 rpm for 15 minutes. The upper layer of the clear liquid was collected to determine serotonin and norepinephrine levels by enzyme-linked immunosorbent assay and cortisol, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) by chemiluminescence. A fully automatic biochemical analyzer was applied. All procedures were performed in strict accordance with manufacturer’s instructions. Quality control materials are also included. Adverse reactions during medication in both groups were assessed after treatment, including nausea, diarrhea, and insomnia.

Fasting cortisol was assessed using 5 mL of fasting venous blood collected between 7:30 and 8:00 am at baseline and week 4 to avoid circadian fluctuation. After centrifugation (3000 rpm, 15 minutes), serum was stored at -80 °C until measurement. Cortisol was quantified using an electrochemiluminescence immunoassay using a fully automated analyzer (Cobas e601; Roche Diagnostics, Mannheim, Germany) and a commercially available kit (Roche, catalog no. 11774975, Basel, Switzerland). The intra- and inter-assay coefficients of variation were < 4.2% and < 6.1%, respectively, and analytical sensitivity was 0.5 μg/dL. All samples were run in duplicate, and the investigators performing the assay were blinded to the group allocation.

Efficacy assessment

Efficacy was assessed according to the changes in HAMD scores before and after treatment. Curative effect was defined as when depressive symptoms basically disappeared, emotion and mood were basically normal, and HAMD scores were reduced by > 80%. A significant effect was defined as significant improvement in depressive symptoms and HAMD score reduction by 50%-80%. Effective treatment was defined as some relief in depressive symptoms and HAMD score reduction by 25%-50%. Ineffective treatment was defined as no significant improvement in depressive symptoms and HAMD score reduction of < 25% or even aggravated. The total effectiveness was the sum of the cure, obvious effects, and effective effects.

Statistical analysis

The study was statistically analyzed by SPSS 25.0 software. Count data are expressed as n (%) and were compared between groups using χ². Normally distributed data were expressed as mean ± SD and compared between groups by the t-test. Statistical significance was set at P < 0.05.

RESULTS

In the study group, there were 25 males and 21 females, aged 48-72 years, with a mean age of 60.44 ± 4.15 years. The disease duration ranged from 2-6 months (mean: 4.11 ± 1.24 months). There were 31 cases of cerebral infarction and 15 cases of cerebral hemorrhage. There were 29 patients with middle school education, nine with high school education, and eight with university education. In the control group, there were 23 males and 23 females, aged 50-71 years old, with a mean age of 60.53 ± 4.08 years. The disease duration ranged from 2-7 months (mean: 4.14 ± 1.22 months). There were 28 cases of cerebral infarction and 18 cases of cerebral hemorrhage. There were 26 patients with middle school education, 10 with high school education, and 10 with university education. There was no significant difference in the general clinical data between the two groups (P > 0.05).

Comparison of HAMD scores between groups

There was no significant difference in the HAMD scores between the groups before treatment (P > 0.05), and the study group had significantly lower HAMD scores than the control group after treatment (P < 0.05) (Table 1).

Table 1 Comparison of Hamilton Depression Scale scores between groups, mean ± SD.

Group	Cases	Pre-treatment	Post-treatment	T value	P value
Control	46	23.08 ± 1.17	8.68 ± 1.26	56.805	0.001
Study	46	23.12 ± 1.09	6.73 ± 1.12	71.128	0.000
T value		0.169	7.845
P value		0.866	0.000

Comparison of TCM evidence points between groups

There was no significant difference in the TCM evidence points between the groups before treatment (P > 0.05), and the TCM evidence points in the study group were significantly lower than those in the control group after treatment (P < 0.05) (Table 2).

Table 2 Comparison of traditional Chinese medicine evidence points after treatment between groups, mean ± SD.

Group	Cases	Pre-treatment	Post-treatment	T value	P value
Control	46	26.78 ± 2.24	10.26 ± 1.35	42.841	0.000
Study	46	27.01 ± 2.18	7.32 ± 1.27	52.932	0.000
T value		0.499	10.758
P value		0.619	0.000

Comparison of serum hormone levels between the groups

There was no significant difference in serum serotonin and norepinephrine between the two groups before treatment (P > 0.05); both increased after treatment, with the study group having significantly higher serotonin and norepinephrine levels than the control group (P < 0.05) (Table 3).

Table 3 Comparison of serum serotonin and norepinephrine levels before and after treatment between groups, mean ± SD.

Group	Cases	Serotonin (ng/L)		T value	P value	Norepinephrine (ng/L)		T value	P value
		Pre-treatment	Post-treatment			Pre-treatment	Post-treatment
Control	46	324.31 ± 30.84	582.18 ± 41.93	33.601	0.000	92.28 ± 10.34	195.23 ± 21.09	29.727	0.000
Study	46	324.08 ± 31.72	649.71 ± 52.33	36.091	0.000	92.41 ± 10.22	218.07 ± 23.19	33.630	0.000
T value		0.035	6.830			0.061	4.941
P value		0.972	0.001			0.952	0.001

Comparison of HPA axis function-related indices between groups

There was no significant difference in the serum cortisol, CRH, or ACTH levels between the groups before treatment (P > 0.05). The study group had significantly lower cortisol, CRH, and ACTH levels than the control group after treatment (P < 0.05) (Tables 4 and 5).

Table 4 Comparison of serum cortisol and corticotropin-releasing hormone levels before and after treatment between groups, mean ± SD.

Group	Cases	Cortisol (μg/dL)		T value	P value	Corticotropin-releasing hormone (pg/mL)		T value	P value
		Pre-treatment	Post-treatment			Pre-treatment	Post-treatment
Control	46	11.42 ± 1.44	8.23 ± 1.05	12.140	0.000	305.38 ± 21.42	257.66 ± 18.29	11.491	0.000
Study	46	11.51 ± 1.37	6.84 ± 1.12	17.899	0.001	306.03 ± 22.26	198.28 ± 14.49	27.514	0.000
T value		0.307	6.141			0.143	17.259
P value		0.759	0.001			0.887	0.001

Table 5 Comparison of serum adrenocorticotropic hormone levels before and after treatment between groups, mean ± SD.

Group	Cases	Adrenocorticotropic hormone (pg/mL)		T value	P value
		Pre-treatment	Post-treatment
Control	46	33.89 ± 2.29	26.39 ± 2.16	16.159	0.000
Study	46	34.02 ± 2.55	23.75 ± 2.09	21.126	0.000
T value		0.257	5.957
P value		0.797	0.001

Comparison of total clinical treatment efficiency between groups

After treatment evaluation, the total efficacy rate in the study group was 84.78%, which was significantly higher than that in the control group (65.22%; P < 0.05) (Table 6).

Table 6 Comparison of the total effective rate of clinical treatment between groups, n (%).

Group	Cases	Cured	Markedly effective	Effective	Ineffective	Total effective
Control	46	10 (21.74)	16 (34.78)	13 (28.26)	7 (15.22)	39 (84.78)
Study	46	7 (15.22)	11 (23.91)	12 (26.09)	16 (34.78)	30 (65.22)

Comparison of the incidence rate of adverse reactions to treatment between groups

The incidence rates of adverse reactions in the study and control groups were 10.86% and 8.69%, respectively, with no significant difference between groups (P > 0.05) (Table 7).

Table 7 Comparison of the incidence of adverse effects of treatment between groups, n (%).

Group	Cases	Nausea	Diarrhea	Insomnia	Total incidence
Control	46	3 (6.52)	1 (2.17)	1 (2.17)	5 (10.86)
Study	46	3 (6.52)	0 (0)	1 (2.17)	4 (8.69)
χ2					0.137
P value					0.711

DISCUSSION

PSD is a type of psychiatric complication after stroke, and patients usually show sadness, sleep disorder, poor energy, anxiety and suspicion, emotional indifference, and other emotions, and even symptoms such as despair. The large gap caused by the physical and mental function damage after stroke can exacerbate depression in post-stroke patients; this forms a vicious cycle, seriously affecting neurological rehabilitation and reducing the quality of life of patients, and clinical treatment of PSD must be emphasized[11,12]. Currently, SSRIs such as fluoxetine, paroxetine, and sertraline are commonly used to treat PSD. These drugs inhibit the reabsorption of serotonin in the presynaptic membrane to increase its content in the synaptic gap, which produces an antidepressant effect. The side effects of these drugs on the central nervous system are relatively small, but the efficacy in some patients is poor with prolonged adverse reactions, such as nausea and insomnia. The therapeutic effect is also often delayed, usually taking a few weeks of treatment[13]. In recent years, the combination of Chinese and Western therapies for the treatment of depression has shown significant advantages. This provides a new direction for exploring the combination of Chinese and Western medicine therapies for the treatment of PSD and helps promote innovation and progress in the field of PSD treatment.

TCM categorizes PSD as a “depression disease”, which is a common disease in TCM that is not directly fatal but often causes long-term suffering. Stroke is a disease of the brain, which is the house of the spirit. Damage to the brain can lead to disorders of thinking, consciousness, and mental activity. Stroke patients often have difficulty adapting to functional deficits such as limb loss and speech impairment, which lead to excessive worry and ultimately liver qi stagnation[14]. According to TCM theory, the liver corresponds to wood and dominates qi excretion, and its physiological characteristics are smooth and organized; the spleen corresponds to earth and is easily restrained by excessive liver wood. Under normal physiological conditions, the detoxification function of the liver helps maintain the coordination of the spleen and stomach qi, thereby ensuring its normal ability to transport and digest. If someone is emotionally disturbed, they are prone to liver qi stagnation and a lack of detachment. At that point, the overactive liver wood excessively attacks the spleen, resulting in the loss of healthy transportation in the spleen. Therefore, the syndrome of liver depression and splenic deficiency is a typical diagnosis of depression. Based on the visceral diagnosis system, the core treatment for PSD is to dredge the liver and strengthen the spleen[15,16]. In clinical practice, the PSP formula is often used, or a combination of PSP and other formulas/therapies. The formula is derived from “Taiping Huimin Hejiaobu Fang” (Tai Ping Hui Min He Duo Gui Fang), which was derived from Zhang Zhongjing’s Dang Gui Shao Yao San (Angelica sinensis and Paeonia lactiflora) and Si Reverse San (Si Reverse San), and is a representative formula for harmonizing the functions of liver and spleen. Its efficacy focuses on dispersing the stagnated liver qi and relieving depression, nourishing blood, and strengthening the spleen qi, supplementing the lack of blood due to the failure of the spleen’s transportation. Several clinical evidence-based studies have confirmed that the treatment of liver depression/spleen deficiency-type depression has definite efficacy[17,18].

In the present study, a combination of Free San and SSRIs was used for the treatment of PSD. From the results of this study, the HAMD scores and TCM evidence points of the study group were lower than those of the control group who routinely used Western drugs alone, which was consistent with the reports of related studies[19,20]. The use of prolonged dispersal for PSD treatment can effectively enhance the efficacy and promote the improvement of depressive symptoms. In this prescription, Chaihu is a monarch drug, which has the characteristics of ascending and dispersing, and can have light and clear ascending and dispersing efficacy. At the same time, it can be used for excretion, which can evacuate depressed qi and improve depression, anxiety, and other negative psychological states, and can be used to comprehensively regulate the liver and spleen. Modern pharmacological studies have shown that the effective components of Chaihu have good antidepressant effects, such as Chaihu saponin A, Chaihu saponin D, and polysaccharides, which can regulate and repair dysfunction of the HPA axis, reduce the neuroinflammatory response, and enhance the supply of neurotrophies, thus producing antidepressant effects[21]. The subject drugs, Fangfeng and Jingwu, have the functions of ascending, dispersing, clearing, and diarrhea caused by liver fire. The two act synergistically in this formula to improve depression by elevating the depressed clear yang, evacuating the rebellious stagnant qi, dissipating the stuffiness of depression, and constraining the over-exuberance of liver wood to restrain the spleen earth. Recent research has confirmed that pro-inflammatory factors play a key role in the development of depression, and that active ingredients such as the volatile oil of Jingwu and dihydropyranochromone in Fangfeng effectively inhibit the production of pro-inflammatory factors[22]. Codonopsis, Rhizoma Atractylodis Macrocephalae, and Poria, which are also ministerial herbs, work together to strengthen the spleen and harmonize the middle. Poria is especially good at tranquilizing the mind and relieving depression, helping to stabilize the mind, harmonize emotions, and dissipate depression. Poria is mainly used to treat “chest and hypochondriacs with rebellious qi, worry and anger, fear and palpitations”. Studies have shown that acidic Poria polysaccharides can inhibit the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing receptor 3 inflammatory pathway, promote neuronal regeneration, and regulate neurotransmitter balance, thus exerting antidepressant effects[23]. The core pathomechanisms of PSD, such as depression of mood and spirit and spleen dysfunction, can be treated using the adjuvant drugs of Qing Bianxia and Citrus aurantium, which dry dampness, eliminate phlegm, disperse knots, promote qi, and can open and disperse stagnant qi. The growth characteristics of semen xia make it effective for transporting yin and yang and converting yang into yin, which can improve sleep and adjust the mental state. Modern pharmacological research has confirmed that Pinellia has sedative and inhibitory effects on nervous system excitement. In addition, white peony was used as an adjuvant to check and balance the pungent dispersion of Chaihu with its acidic and astringent properties to suppress liver fires. Studies have confirmed that paeoniflorin lactone glycoside in white peony is the main antidepressant component, and the pairing of white peony and Chaihu has shown increased antidepressant effects in pharmacological studies[24]. Roasted licorice strengthens the spleen and stomach, removes boredom, replenishes five labors and seven injuries, relieves boredom and forgetfulness, and simultaneously harmonizes all medicines. Pharmacological studies have confirmed that the main antidepressant components in licorice are glycyrrhizin flavonoids and glycyrrhizin, which alleviate depressive symptoms through anti-inflammatory effects and exert antidepressant effects by reducing free radicals in the body. The combination of all herbs can nourish the heart and tranquilize the mind, tonify qi and blood, and relieve depression in the liver. Previously, in an experiment using a rat model of depression, hormone levels and behaviors of rats returned to normal after the instillation of pseudoscience[25]. Previous studies have confirmed that depression is usually associated with reduced levels of monoamine neurotransmitters such as serotonin and norepinephrine[26]. This study showed that serum serotonin and norepinephrine levels in the study group were significantly higher after treatment than those in the control group. This suggests that Free San can effectively improve neurotransmitter levels in patients with PSD.

Studies have revealed that the acute stress response after stroke and the destruction of cranial HPA axis inhibitory regions, such as the hippocampus or frontal lobe, together with an increase in inflammatory factors in the early stages of stroke and the subsequent stress of chronic complications, contribute to the overactivity of the HPA axis in stroke patients. Continuation of this state leads to hypoglucocorticoid receptor dysfunction, causing HPA axis dysfunction, which in turn triggers and exacerbates depression and other psychiatric symptoms[27]. Under stress, CRH secreted by the hypothalamus activates the HPA axis and stimulates the blue spot-sympathetic-adrenomedullary system via pontine blue spots, thereby triggering anxiety and depression. This might be the pathological basis of PSD. Human HPA activity exhibits a rhythmic pattern of daytime activation and nocturnal inhibition, whereas the opposite is true in rodents. However, CRH promotes arousal and reduces sleep in both species, whereas ACTH has similar effects. In a previous study, CRH injections increased nocturnal arousal and worsened sleep quality[28]. In this study, serum cortisol, CRH, and ACTH levels were lower in the study group than in the control group after treatment. This suggests that, among the HPA axis hormones, elevated levels of CRH can drive the onset of major depression. High levels of cortisol contribute to the development of depression by altering the function of specific brain regions, inhibiting the expression of key enzymes, and affecting the synthesis and secretion of proinflammatory cytokines. Thus, increased CRH, ACTH, and cortisol is hypothesized to be involved in PSD pathology. Several studies have confirmed that cortisol and ACTH levels tend to increase when an organism is stressed. According to TCM theory, long-term emotional depression and fire can lead to anxiety and irritability; in this state, the HPA axis is hyperfunctional, which in turn induces depressive symptoms. The reason is that Codonopsis pilosulae, Atractylodes macrocephala, and Poria in this study have the effect of calming and tranquilizing the mind, which can help the body and mind to become calm, improve stress, and reduce the levels of blood cortisol and ACTH, which can return the HPA axis to normal function and alleviate the symptoms of depression, which is in line with a previous study[29]. This suggests that the antidepressant effect of Puanxuan may work by lowering cortisol, CRH, and ACTH levels in patients with PSD. Paroxetine, which was used in this study, also positively affected the functional recovery of the HPA axis. It has been noted that the high activity of the HPA axis in patients with depression may be related to serotonin and norepinephrine[30]. The serotonin system in the brain can inhibit ACTH secretion; thus, when serotonin function is low, the pituitary gland overproduces ACTH, which in turn elevates cortisol in the peripheral blood.

To bridge TCM concepts with neuroendocrine pathways, we propose that Free San’s saikosaponin A/D downregulates hippocampal FK506 binding protein 5, restoring glucocorticoid-receptor sensitivity and silencing paraventricular nucleus-CRH neurons. Paeoniflorin suppresses microglial nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing receptor 3-interleukin-1 beta signaling, further lowering CRH/ACTH/cortisol, whereas glycyrrhizic acid upregulates tryptophan hydroxylase-2 and aromatic L-amino acid decarboxylase while allosterically blocking serotonin transporter, rapidly elevating serotonin and norepinephrine. These convergent molecular actions reconcile the observed HPA-axis normalization and monoamine enhancement with traditional “liver qi” regulation.

Our study has certain limitations. First, the observation window was confined to 4 weeks, which is insufficient to capture the time-to-relapse, durability of response, or delayed adverse events of the SSRI-Free San combination. Second, the single-center design and modest sample size (n = 92) limited generalizability and may have predisposed the study to type I/II errors. Third, although a random number allocation table was used, the absence of a placebo or sham control precluded separation of specific treatment effects from placebo effects. Fourth, biomarkers were assessed only at baseline and at week 4; a denser sampling profile would have clarified the temporal dynamics of HPA axis normalization. Finally, concomitant rehabilitation or psychotherapy was not standardized, leaving residual variability in outcomes potentially attributable to unmeasured co-interventions. Multicenter, double-blind, placebo-controlled trials with extended follow-up (≥ 6 months) and serial biomarker sampling are therefore warranted to verify the long-term efficacy and safety of this integrative regimen.

CONCLUSION

The combination of Free San and SSRIs for the treatment of PSD can enhance the therapeutic effect, improve the patient’s depressive symptoms, and improve the function of the HPA axis with good efficacy, which is worthy of clinical application.