Effect of paroxetine on neurological function and psychological state in patients with depression after acute ischemic stroke

Abstract

BACKGROUND

Failure to receive timely and effective treatment for post-acute ischemic stroke (post-AIS) depression will make treatment more difficult. Additionally, the effectiveness of current drug therapy needs to be optimized.

AIM

To examine the influences of paroxetine (PARX) on the neurological function and psychological well-being in post-AIS patients with depression.

METHODS

This study involved 106 patients with post-AIS depression admitted between May 2020 and May 2023. The participants included 52 in the control group (Con), who received sertraline, and 54 in the research group (Res), treated with PARX. The two groups were compared across several aspects: Neurological function (measured by the National Institutes of Health Stroke Scale), activities of daily living (assessed with the modified Barthel index), psychological status (evaluated using the Hamilton Anxiety Scale/Hamilton Depression Scales), serum biochemical markers (C-reactive protein; procalcitonin), clinical effectiveness, and the occurrence of adverse events.

RESULTS

The data showed significantly reduced scores on National Institutes of Health Stroke Scale, Hamilton Anxiety Scale, and Hamilton Depression Scale, as well as decreased levels of serum biochemical indices such as C-reactive protein and procalcitonin in the Res group after treatment, which were statistically lower than the baseline and compared to the Con group; the Res group also had a clearly higher total effective rate and modified Barthel index scores than the Con group, with a lower overall incidence of adverse events such as dry mouth, loss of appetite, headache, and insomnia.

CONCLUSION

In summary, PARX positively influences neurological function, activities of daily living, and psychological well-being in patients with post-AIS depression, warranting clinical attention.

Key Words: Acute ischemic stroke; Depression; Paroxetine; Neurological function; Psychological state

Core Tip: We analyzed the clinical effects of paroxetine vs sertraline in treating such patients with post-acute ischemic stroke depression to improve the neurological function and psychological state of patients. Our research results indicated that paroxetine can validly enhance patients’ neurological function and activities of daily living while relieving their negative psychological states, with high curative effects and clinical safety.

INTRODUCTION

Acute ischemic stroke (AIS) is deadly, disabling, and linked to a high risk of recurrence, jeopardizing patients’ quality of life and raising their economic burden[1,2]. Depression frequently affects AIS survivors, with a risk as high as 33.3% and a poor prognosis[3,4]. Additionally, factors like injury to the frontal lobe/prefrontal region or basal ganglia, multiple or extensive strokes, a recent stroke within the past year, and a history of psychiatric illness can elevate the risk of depression after AIS[5]. Post-AIS depression can cause neurological deficits, psychological issues, insomnia, and other symptoms. If not addressed promptly and effectively, these problems may worsen the condition and make treatment more challenging[6,7]. This study attempts to explore the treatment of post-AIS depression from the direction of drug therapy, the mainstay of treatment for the disease at present[8], aiming at improving the neurological function and psychological state of such patients.

Paroxetine (PARX) is a selective serotonin reuptake inhibitor (SSRI) that elevates 5-hydroxytryptamine (5-HT) levels in the postsynaptic membrane by affecting the reuptake of 5-HT, contributing to its use in treating psychiatric disorders[9]. Additionally, it proves effective in treating various mental illnesses such as generalized anxiety disorder, panic disorder, and severe depression, and can also be used for children and adolescents[10-12]. Deng et al[13] found that PARX significantly alleviated the depression level of AIS patients, with an effect superior to that of fluoxetine, imipramine, reboxetine, nortriptyline, and citalopram. Sertraline (SERT) is also an SSRI, sharing a different structure but similar mechanisms of action to PARX[9]. A study suggests that SERT may also modulate the metabolism of monoamine neurotransmitters in the brain by acting simultaneously on the central 5-HT system and the activity of indoleamine 2,3-dioxygenase, thereby preventing the pathological progression of depression[14]. This study comprised an in-depth exploration of the clinical efficacy of PARX and SERT in patients with post-AIS depression to address the lack of studies in this area.

MATERIALS AND METHODS

General information

The study involved 106 patients with post-AIS depression treated at the 900 Hospital of the Joint Logistics Support Force of the People’s Liberation Army of China, between May 2020 and May 2023. Of these, 52 patients in the control group (Con) received SERT treatment, while 54 patients in the research group (Res) received PARX treatment. The efficacy analysis post-treatment showed efficacy rates of 67.31% for one group and 85.19% for the other, with a statistical power of 0.88. This indicates that the current sample size is sufficient to support the conclusion of an approximately 18% difference in treatment effectiveness between groups.

Criteria for patient enrollment and exclusion

Inclusion criteria: Patients had to meet the criteria for post-AIS depression, and have a Hamilton Depression Scale (HAMD) score above 7, a Hamilton Anxiety Scale (HAMA) score above 7, complete clinical data, and high levels of other specified measures. Exclusion criteria include inability to complete the examination due to poor eyesight, hearing, language expression abilities, or general condition; a history of drug dependence; other stroke-related complications; new cerebrovascular disease or critical illness; cognitive impairment; and allergies to research medications.

Treatment methods: All patients received standard drug therapy and routine nursing care for cerebrovascular diseases. Additionally, the Con group was given SERT tablets orally at 50 mg once daily for 4 weeks. The Res group was treated with PARX hydrochloride tablets orally at a dose of 20 mg once daily for 4 weeks. Treatment choices (SERT or PARX) were non-random and made by attending doctors based on patient conditions, with no random assignment or allocation concealment.

Endpoints: Data on pre-treatment and post-treatment neurological function [measured by the National Institutes of Health Stroke Scale (NIHSS)], activities of daily living (ADL) [assessed with the modified Barthel index (MBI)], psychological state (evaluated using the HAMA/HAMD), serum biochemical markers, such as C-reactive protein (CRP), procalcitonin (PCT), clinical efficacy, and the occurrence of adverse events (AEs) were gathered for analysis. The study employed blinding for outcome evaluators and data analysts to reduce measurement biases: (1) Neurological function was evaluated before and after treatment by assessing patients’ neurological impairment and ADL with the NIHSS and MBI, respectively. The NIHSS, scored out of 42, indicates more severe neurological impairment, with higher scores indicating greater severity. The MBI ranges from 0 to 100, where a higher score reflects greater independence in ADLs; (2) Psychological state: We used the HAMA and HAMD to evaluate patients’ anxiety and depression, respectively. The HAMA consists of 14 items, each scored from 0 to 4, with higher scores indicating more severe anxiety. The HAMD includes 17 items, with scores ranging from 0 to 68; higher scores reflect more intense depression. Patients were assessed twice: Once before treatment and again after 8 weeks of treatment; (3) Serum biochemical indexes were measured by collecting 5 mL of venous blood on an empty stomach both before and after treatment. The levels of CRP and PCT in the serum were determined using an enzyme-linked immunosorbent assay (ELISA) for CRP and a radioimmunoassay for PCT, respectively; (4) Clinical efficacy was assessed using the HAMD scale. A decrease of ≥ 75% in the HAMD score indicated a cure. Marked effectiveness was defined by a reduction of 50% to less than 75%, while effectiveness corresponded to a reduction of 25% to less than 50%. A decrease of less than 25% was considered ineffective. The total effective rate is calculated as the percentage of cases classified as cured, marked effectiveness, or effectiveness out of the total cases; and (5) Incidence rate of AEs. We documented the occurrence of AEs, including dry mouth, loss of appetite, headache, and insomnia, in both groups.

Statistical analysis

For continuous variables expressed as mean ± SD, t tests were used for inter-group comparisons, while paired t tests were applied for before-and-after comparisons within the same group. Categorical variables, presented as n (%), were compared between groups using χ² tests. All analyses in this study were conducted using SPSS 24, with a significance level of P < 0.05.

RESULTS

Baseline data of the two groups

No notable differences were found between groups in terms of age, sex, disease duration, body mass index, or other baseline characteristics (P > 0.05) (Table 1).

Table 1 Baseline data of two groups, mean ± SD.

Indicators	Control group (n = 52)	Research group (n = 54)	χ2	P value
Age (years)	51.48 ± 7.95	51.70 ± 7.96	0.142	0.887
Sex (male/female)	28/24	33/21	0.572	0.757
Disease course (months)	9.19 ± 1.70	8.74 ± 2.44	1.098	0.275
Body mass index (kg/m2)	23.08 ± 2.37	22.28 ± 2.20	1.802	0.074
Diabetes mellitus (with/without)	10/42	8/46	0.366	0.545
Hypertension (with/without)	18/34	17/37	0.118	0.732
Coronary heart disease (with/without)	6/46	10/44	1.007	0.316

Neurological function and ADL in two groups

The neurological function and ADL in patients with post-AIS depression were assessed using NIHSS and MBI, respectively. The results indicated no significant difference in pre-intervention NIHSS and MBI scores between the Res and Con groups (P > 0.05). After the intervention, both groups showed increased MBI scores and decreased NIHSS scores (P < 0.05), with the Res group exhibiting even lower NIHSS and higher MBI scores compared to the Con group (P < 0.05) (Figure 1).

Figure 1 Neurological function and activities of daily living in the two groups. A: The research group showed lower postinterventional National Institutes of Health Stroke Scale scores than the control group; B: The research group showed lower postinterventional modified Barthel index scores than the control group. ^aP < 0.05 vs before treatment; ^bP < 0.01 vs before treatment; ^cP < 0.05 vs control group. NIHSS: National Institutes of Health Stroke Scale.

Psychological state of the two groups

HAMA and HAMD scales were used to evaluate the anxiety and depression of the two groups of patients with post-AIS depression before and after treatment. The analysis showed no significant inter-group difference in pre-interventional HAMA and HAMD scores (P > 0.05); however, the scores of both scales decreased significantly to varying degrees after intervention (P < 0.05), with lower scores in the Res group compared to the Con group (P < 0.05) (Figure 2).

Figure 2 Psychological state of the two groups. A: The research group showed lower Hamilton Anxiety Scale scores than the control group after treatment; B: The research group showed lower Hamilton Depression Scale scores than the control group after treatment. ^aP < 0.05 vs before treatment; ^bP < 0.01 vs before treatment; ^cP < 0.05 vs control group. HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale.

Serum biochemical indexes of the two groups

Before and after intervention, we performed ELISA and radioimmunoassay to assess CRP and PCT levels of both groups of patients with post-AIS depression, respectively. The two groups did not differ significantly in pre-interventional CRP and PCT levels (P > 0.05); however, CRP and PCT concentrations were significantly inhibited in both groups after intervention, with even lower levels in the Res group (P < 0.05) (Figure 3).

Figure 3 Serum biochemical indexes of the two groups. A: The research group showed lower C-reactive protein levels than the control group after treatment; B: The research group showed lower procalcitonin levels than the control group after treatment. ^aP < 0.05 vs before treatment; ^bP < 0.01 vs before treatment; ^cP < 0.05 vs control group. CRP: C-reactive protein; PCT: Procalcitonin.

Clinical efficacy of the two groups

The overall treatment success rate in the Res group was 85.19%, compared to 67.31% in the Con group, with this difference being statistically significant (P < 0.05) (Table 2).

Table 2 Clinical efficacy of the two groups, n (%).

Indicators	Control group (n = 52)	Research group (n = 54)	χ2	P value
Cure	10 (19.23)	14 (25.93)
Marked effectiveness	13 (25.00)	20 (37.04)
Effectiveness	12 (23.08)	12 (22.22)
Ineffectiveness	17 (32.69)	8 (14.81)
Effective rate	35 (67.31)	46 (85.19)	4.698	0.030

Incidence rate of AEs in two groups

The incidence rates of AEs were 21.15% in the Con group and 7.41% in the Res group, indicating a significantly lower AE rate in the Res group (P < 0.05) (Table 3).

Table 3 Incidence rate of adverse events in two groups, n (%).

Indicators	Control group (n = 52)	Research group (n = 54)	χ2	P value
Dry mouth	2 (3.85)	0 (0.00)
Loss of appetite	3 (5.77)	1 (1.85)
Headache	2 (3.85)	1 (1.85)
Insomnia	4 (7.69)	2 (3.70)
Total	11 (21.15)	4 (7.41)	4.121	0.042

DISCUSSION

Patients experiencing depression after an AIS may show symptoms such as depressed mood, loss of joy in life, feelings of worthlessness, and even suicidal thoughts, which can persist for at least two weeks[15]. The precise pathophysiology of the disease remains unclear, but it is believed to be strongly linked to the gut-brain axis, neuroinflammation, monoamine imbalance, and the glutamatergic system. Additionally, neural circuit abnormalities resulting from frontal lobe or basal ganglia injury, as well as reduced levels of brain-derived neurotrophic factor (BDNF), which affect nerve repair, may also play a role[16-18]. This study aims to explore treatment options that better enhance the recovery and psychological well-being of patients with post-AIS depression, focusing on SSRI perspectives to facilitate quicker relief.

As a first-line treatment option for patients with post-AIS depression, SSRIs are reported to have a therapeutic role by reducing inflammation and promoting neurogenesis through increased neurotrophin production and stimulation of mitochondrial energy conversion, thereby improving metabolism. They also prevent neuronal reuptake of 5-HT[6,19,20]. In this study, SERT was used in the control group, while PARX was employed in the Res group for comparison. Following intervention, the Res group exhibited a significant reduction in the NIHSS score compared to the control, along with a notable increase in the MBI score, suggesting that PARX intake leads to greater improvements in neurological function. A prospective observational study indicated that SERT was helpful for early neurological recovery in patients with post-AIS depression, leading to greater reductions in NIHSS scores compared to controls who did not receive the same prescription[21]. Additionally, SERT’s neuroprotective effect might be linked to increasing non-BDNF neurotrophins levels in depression patients[22]. PARX, in contrast, produces an antidepressant-like impact through binding to the serotonin transporter and also reduces neuroinflammation by protecting dopaminergic neurons and increasing the number of branched microglia[23]. In a mouse model experiment of Alzheimer’s disease with depression, Ai et al[24] reported that early intervention with PARX significantly reduced abnormal negative emotions in mice and repaired memory deficits. The neuroprotective mechanism of PARX might involve regulating glutamate receptor. Additionally, assessments using HAMA and HAMD in patients showed that both scale scores decreased significantly in the Res group after treatment, falling below baseline and the Con group, indicating that PARX intervention is more effective than SERT in alleviating anxiety and depression following ischemic stroke depression. As reported by Peng et al[25], the HAMA and HAMD scores in patients with type 2 diabetes combined with gastrointestinal dysfunction and liver cancer significantly decreased after treatment with PARX, aligning with our results. Additionally, PARX proved to be most effective when combined with repetitive transcranial magnetic stimulation in patients with post-ischemic stroke depression at week eight[26]. After measuring CRP and PCT using ELISA and radioimmunoassay, respectively, the Res group showed significant reductions in both markers following the intervention, with levels notably lower than baseline compared to the Con group. This suggests that PARX effectively decreases CRP and PCT in patients with post-AIS depression. Post-intervention, mean CRP and PCT levels in both groups fell within normal ranges (CRP < 10 mg/L; PCT < 0.5 μg/L). The CRP compliance rate after treatment was 51.92% in the control group and 92.59% in the research group, with both groups achieving a 100.00% compliance rate for PCT. These findings suggest that PARX may inhibit systemic inflammation by substantially downregulating CRP and PCT, thereby exerting an antidepressant effect. Elevated CRP levels have been associated with increased depression risk after AIS, and lowering CRP to reduce systemic inflammation could help in alleviating early depression symptoms post-stroke[27,28]. As a serological index used to diagnose bacterial infections and assess the severity of systemic inflammation, high levels of PCT are strongly associated with carotid artery wall thickening and significant stenosis in patients with AIS. They can somewhat predict adverse clinical outcomes[29-31]. After evaluating efficacy and safety, the overall effective rate was significantly higher in the Res group compared to the Con group (85.19% vs 67.31%). In comparison, the incidence of AEs was notably lower (7.41% vs 21.15%). This suggests that PARX intervention provides considerable benefits for improving outcomes in post-AIS depression with high safety. The greater efficacy of PARX may be due to its higher affinity for SERT compared to SERT, which has a slightly lower affinity[32]. Furthermore, PARX exhibits relatively low selectivity and can significantly inhibit the CYP2D6 enzyme, leading to more drug interactions and side effects. In contrast, SERT has higher selectivity and fewer drug interactions[32]. This study suggests that individual differences and the small sample size might influence the high clinical safety of PARX in patients with post-AIS depression.

This study has several limitations: First, the four-week treatment cycle is too short to assess the efficacy of antidepressants. Extending the treatment duration to 8-12 weeks is necessary to better align with standard practice and to clarify the ongoing treatment effects of the two drugs. Second, nerve remodeling-related markers like BDNF have not been analyzed, making it impossible to determine whether PARX alleviates depression by promoting nerve repair. Future studies should include such analyses to understand the therapeutic mechanisms of PARX better. Finally, a 3-5-year follow-up should be supplemented in the future to determine the long-term prognosis of the two therapies.

CONCLUSION

PARX can notably enhance neurological function and ADL performance in patients with post-AIS depression, alleviate negative psychological states, and improve treatment outcomes with a certain degree of safety, making it valuable for clinical use promotion.