Effect of phototherapy on event-related potentials in patients with post-stroke depression through serum tetrahydrobiopterin level intervention: a clinical study

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Effect of phototherapy on event-related potentials in patients with post-stroke depression through serum tetrahydrobiopterin level intervention: a clinical study

• Bingchuan Xie,
• Zhenguo Wu,
• Zixuan Zhou,
• Wenting Lu,
• Lin Liu &
• Lizhuang Zhang 

BMC Psychiatry volume 25, Article number: 6 (2025) Cite this article

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Abstract

Background

This study investigated the effects of phototherapy on serum BH4 levels, evoked potentials, and cognitive impairment in post-stroke depression patients.

Methods

We conducted a prospective study with 160 post-stroke depression patients, randomly assigned to an experimental group receiving daily 40 min of phototherapy alongside routine treatment, and a control group receiving only routine treatment. Serum tetrahydrobiopterin (BH4) levels were measured via ELISA. Evoked potentials were assessed using an ERP recorder, depressive symptoms were evaluated with the Hamilton Depression Scale (HAM-D), and cognitive function was analyzed using the Montreal Cognitive Assessment (MoCA). Inflammatory factor expression was detected via RT-PCR.

Results

Both groups exhibited increased BH4 levels, but the phototherapy group had significantly higher levels (P < 0.05). The phototherapy group also demonstrated improved ERP parameters, with higher MMN latency, P300 latency, and amplitudes compared to controls (P < 0.05). HAM-D scores decreased more in the phototherapy group (P < 0.05), while MoCA scores increased significantly (P < 0.05). Additionally, inflammatory markers IL-6, TNF-α, and IL-1β were lower in the phototherapy group (P < 0.05).

Conclusions

Phototherapy positively influenced BH4 levels, improved evoked potentials, alleviated depressive symptoms, enhanced cognitive function, and reduced inflammation in post-stroke depression patients.

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Introduction

Post-stroke depression is widely recognized as a common complication among stroke patients, significantly hindering their rehabilitation process [1, 2]. Phototherapy, a therapeutic approach designed to alleviate depressive symptoms, operates by adjusting the biological clock. This method simulates the characteristics of natural light to regulate the secretion of neurotransmitters and hormones in the brain, thereby influencing the mood and physiological state of patients. In the realm of post-stroke depression research, event-related potentials (ERPs) are frequently employed as a neurophysiological index to study the impact of stimulating events on EEG activity [3, 4]. By recording patients’ EEG activities during specific stimulation tasks, ERPs facilitate the exploration of changes in brain function. Previous studies have identified significant abnormalities in ERP parameters among patients with post-stroke depression, including alterations in P300 and N400 components, which are linked to cognitive function and emotional regulation [5, 6]. However, current research on the influence of phototherapy on ERPs in patients with post-stroke depression is still relatively limited.

Moreover, serum tetrahydrobiopterin (BH4), a critical cofactor involved in neurotransmitter synthesis, plays a crucial role and may be associated with the neurological dysfunction observed in patients with post-stroke depression [7]. Among numerous inflammatory factors, 16 may be linked to post-stroke depression, including pro-inflammatory factors (interleukin-1 β, interleukin-6, interleukin-8, interleukin-18, tumor necrosis factor alpha, and interferon gamma), anti-inflammatory factors (interleukin-4, interleukin-10, and transforming growth factor beta 1), and other non-specific factors (C-reactive protein, neopterin, adiponectin, NLRP3 inflammasome, matrix metalloproteinase 9, growth differentiation factor 15, and serum amyloid A) [8]. Counteracting the expression of pro-inflammatory factors or supplementing exogenous anti-inflammatory factors can help alleviate post-stroke depression symptoms, and treatments for post-stroke depression can alter serum inflammatory factors. These inflammatory factors contribute to post-stroke depression by interacting with their receptors, intracellular signaling pathways, neurotransmitters, or the hypothalamic-pituitary-adrenal axis. Detecting serum inflammatory markers or gene polymorphisms holds significant predictive value for diagnosing post-stroke depression.

ERP measures the electrical potential changes produced by the brain in response to specific events [9]. The principle involves recording brain electrical activity under specific stimuli through electrodes. The measurement process includes preparing the testing environment, administering stimuli, and recording and analyzing potential changes. BH4, as a significant regulator of nerve conduction, impacts ERP waveform. Changes in BH4 levels can affect T cell activity, influencing ERP components such as N1 and P2, though its specific mechanism remains to be further explored [7]. As a coenzyme factor, BH4 plays a vital role in neurotransmitter synthesis and regulation, indirectly affecting ERP production [10]. By regulating neurotransmitters like dopamine and serotonin, BH4 may influence the waveform and latency of ERPs. The relationship between BH4 levels and ERP performance is close, as BH4 directly impacts the amplitude of ERP components. A decrease in BH4 levels corresponds with an increase in ERP wave amplitude, reflecting the brain’s need to mobilize more cognitive resources in response to cognitive challenges.

Phototherapy, a non-pharmacological treatment, is significant in treating post-stroke depression [11]. It not only improves depressive symptoms but also regulates the biological clock and neurotransmitters, aiding recovery. Phototherapy enhances the emotional and cognitive function of post-stroke depression patients by regulating neurotransmitters such as serotonin and norepinephrine and promoting the synthesis and release of melatonin, which influences the brain’s biological clock and endocrine system [11]. By affecting the release and reuptake of neurotransmitters, phototherapy regulates the concentration of neurotransmitters like dopamine and serotonin in the brain, playing a crucial role in emotional regulation. Simulating natural light, particularly blue and white light, phototherapy stimulates photosensitive cells in the retina, transmitting signals to the brain and regulating the biological clock’s rhythm. This regulation helps restore normal circadian function, improving sleep quality and emotional state in post-stroke depression patients. By simulating natural light and regulating the patient’s biological clock and hormone secretion—especially melatonin and serotonin—phototherapy alleviates emotional depression and anxiety, enhancing psychological adaptability and quality of life [12].

Furthermore, inflammatory factors such as TNF-α and IL-6 induce neuronal apoptosis, affect neuronal communication and metabolism, and activate glial cells, leading to functional abnormalities and cerebrovascular dysfunction [13]. These pathways collectively impact cognitive function, contributing to cognitive disorders. Inflammatory factors like CRP, IL-6, and TNF-α are significantly correlated with cognitive dysfunction, influencing cognitive function by inducing neuronal apoptosis, affecting neuronal communication and metabolism, activating glial cells, and damaging cerebral blood vessels.

Despite these insights, studies exploring the effects of phototherapy on BH4 levels and its relationship with ERPs are scarce. Therefore, this study aimed at investigating the effects of phototherapy on serum BH4 levels, evoked potentials, and cognitive impairment in post-stroke depression patients, offering a novel treatment strategy.

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Time for New Guidance on Poststroke Depression, Anxiety?

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Time for New Guidance on Poststroke Depression, Anxiety?

Depression and anxiety are among the most common complications of stroke, affecting 1 in 3 and about 1 in 4 survivors, respectively. These disorders are associated with higher mortality rates, often obscuring the path to recovery. 

The American Heart Association (AHA)/American Stroke Association (ASA) last published its scientific statement on poststroke depression (PSD) in 2016. Although this statement doesn’t cover poststroke anxiety (PSA), the 2019 Canadian Stroke Best Practices update recommends screening for PSA and apathy, which often coexist in the absence of PSD. It advises management with pharmacotherapy, psychotherapy, or nonpharmacologic interventions such as exercise or music therapy, while noting there is limited evidence for the use of psychostimulants.

New research on the most effective treatments for depression and the lack of information on anxiety after stroke have prompted some neurologists to ask: Is it time for new guidance?

What’s the Prevalence, Who’s at Risk?

Recent data from the South London Stroke Register Study, which followed 2295 patients with PSD for 18 years, revealed that 33% of those with stroke experienced PSD in the first 3 months following the event, 55% within a year, and 88% within 5 years. 

The study’s investigators noted that individuals with PSD were at substantial risk for persistent depression within a year and recommended PSD screening in all patients within the first 3-6 months following stroke. 

“The course of PSD is dynamic,” Nada El Husseini, MD, director of the Stroke Research Fellowship Program at Duke University Medical Center, Durham, North Carolina, and a co-author of the AHA/ASA 2016 statement on PSD, told Medscape Medical News. Some people experience depression soon after a stroke and recover within a year, whereas others develop PSD a year after stroke, she noted. 

Risk factors for PSD in the first 3 months following stroke include previous mental illness, a family history of mental illness, female gender, being younger than 70, and stroke severity.

A recent analysis in the Journal of Affective Disorders examined three cohorts from STROKOG (The Stroke and Cognition Consortium), revealing a PSA prevalence of 35%. Investigators found risk factors for PSA included female gender, co-occurrence of PSD, and poststroke cognitive impairment. 

Most cases of PSA surface within the first year after stroke. Phobia and generalized anxiety disorder were the most common anxiety subtypes. 

In addition to screening, early and aggressive intervention for PSD is necessary, Bruce Ovbiagele, MD, vice chair of the committee that developed the statement, told Medscape Medical News. 

“With stroke, we speak about the three dreaded Ds: death, dementia, and disability. But there is a fourth, and that is depression, and it is not addressed to the degree it should be,” said Ovbiagele, professor of neurology, health policy, and global health at the University of California, San Francisco.

PSD is underdiagnosed and undertreated, he added. The same appears to be true for PSA, the authors of a commentary published in October in Stroke wrote. 

“While awareness of PSA has increased in recent years, research into the identification and treatment of PSA continues to receive less attention than poststroke depressive disorders,” they added. “With similar prevalence rates between PSA and poststroke depression, an increased understanding of the diagnosis and treatment of PSA disorders is needed.”

What Causes PSD and PSA? 

Although psychosocial factors can contribute to the development of depression or anxiety after a stroke, research suggests that neurologic damage caused by the stroke itself plays a significant role. 

A 2023 literature review examining the potential mechanisms underlying PSD showed stroke in regions such as the prefrontal cortex, limbic area, and basal ganglia can disrupt key pathways of mood-related neurotransmitters, potentially leading to depressive disorders. 

The review also cited numerous studies linking PSD to neuroinflammation. Some experts theorize that inflammation from stroke causes the release of pro-inflammatory cytokines, which can lead to decreased serotonin. Serotonin deficiency is believed to play a significant role in the development of depressive symptoms.

Another 2023 study revealed that more than 80% of immune proteins associated with mood were elevated among individuals with PSD, suggesting a link between an overactive immune system and the disorder. 

These investigators also found that several pro-inflammatory cytokines, such as interleukin-6, were associated with PSD. Experts believe that such biomarkers can be used to guide treatment. 

Depression and anxiety after stroke often co-occur alongside cognitive impairment, physical disability, and neurologic damage, making the conditions more challenging to treat than depression or anxiety in the general population, Ovbiagele noted. Effective treatment may require a multidisciplinary approach, he added. 

For instance, if depressive symptoms appear at any point as a stroke patient transitions from the acute setting to rehabilitation to primary care, there must be clear communication between the patient’s treatment team about treatment strategies. Ongoing treatment may involve a psychiatric consult and psychotherapy, he said, and all clinicians should remain informed about the treatment plan. 

As reported previously by Medscape Medical News, there are a few theories about what distinguishes PSD from nonstroke depression. A 2023 meta-analysis showed greater severity and prevalence of emotional dysregulation and less anhedonia in people with PSD compared with their counterparts with depression and no stroke history. People with PSD were more likely to have cognitive impairment and difficulty controlling muscle contractions, which is not uncommon after stroke.

Unlike major depression, PSD is linked to the ischemic event, a 2018 review suggests. In particular, the size and number of ischemic lesions, and whether the lesions disrupt the midbrain, limbic, and medial prefrontal cortical circuitry, are implicated in depression. “In particular, white matter lesions are associated with metabolic alterations in this circuitry and are correlated with major depression,” the article states.

What Works for PSD? 

As the authors of the 2016 AHA/ASA statement noted, there are few large studies to help guide clinical management of PSD. However, some evidence suggests that escitalopram and sertraline may be effective treatment options. 

A 2022 meta-analysis of seven randomized controlled trials showed a standardized mean difference of -1.25 on Hamilton Depression Scale (HAM-D) scores (P < .001) among participants allocated to escitalopram vs placebo. 

A 2024 study added to those findings. The randomized controlled trial of 60 stroke patients showed that treatment with sertraline (100 mg) or escitalopram (20 mg) was associated with a statistically significant decrease in HAM-D scores (P < .05) after 8 weeks of treatment. 

Data on fluoxetine are mixed. As previously reported by Medscape Medical News, the 2021 AFFINITY trial showed that 20 mg of fluoxetine for 26 weeks did not prevent or alleviate PSD. However, a post hoc analysis of the EFFECTS trial published in 2022 showed that stroke patients reported lower depression scores after receiving 20 mg daily for 6 months. 

There has also been some debate over whether the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) might be linked to an increased risk for bleeding in stroke patients. 

A study published about a decade ago showed that SSRI users experienced a higher risk for overall major bleeding that contributed to mortality rates. A subsequent study, also covered by Medscape Medical News, revealed that SSRI use in patients with intracerebral hemorrhage increased the risk for recurrence. However, other research showed no such increased risk.

But new data appear to put this controversy to rest. In an analysis presented at the 2024 AHA annual meeting, researchers examined the health records of more than 650,000 stroke patients, comparing the bleeding risk among those taking SSRIs/SNRIs vs that in patients who took other antidepressants or none at all. 

Early use of SSRIs or SNRIs during the subacute recovery phase of acute ischemic stroke was not associated with increased bleeding risk in most patients, although a 29% higher risk for hemorrhagic stroke was observed in those who took antidepressants while also on dual antiplatelet therapy. Bleeding risk was also 15% higher with the use of other antidepressants compared with SSRIs or SNRIs. 

“Our findings should reassure clinicians that for most stroke survivors, it is safe to prescribe SSRI and/or SNRI antidepressants early after stroke to treat post-stroke depression and anxiety, which may help optimize their patients’ recovery,” lead investigator Kent Simmonds, DO, PhD, UT Southwestern Medical Center, Dallas, Texas, said in a press release. 

What Works for PSA?

If research on PSD is lacking, data on the most effective treatments for PSA are even more scarce. 

In fact, authors of a 2021 narrative review published in Stroke found only three small trials on treatments for PSA. One study compared paroxetine or paroxetine plus psychotherapy vs standard care. Another examined buspirone hydrochloride vs standard care. 

The third study included data on a relaxation compact disc vs a waitlist control. Reviewers said the studies were sufficient to guide clinical practice, citing a high risk of methodological bias in all three.

A fourth study, on the feasibility of a guided self-help cognitive-behavioral therapy (CBT) program delivered online and over the phone, was inconclusive. 

“Thus, large-scale, adequately powered, well-designed trials are needed to evaluate interventions to treat poststroke anxiety,” the authors wrote. 

In the absence of more defined recommendations, recent data suggest that more clinicians may be turning to benzodiazepines, often prescribing far more than the American Geriatrics Society advises. 

Use of these drugs in adults older than 65 years is associated with higher risk for cognitive impairment, delirium, falls, fractures, and motor vehicle accidents. In addition, some research shows that benzodiazepine use is associated with increased poststroke mortality at 90 days.

Despite these warnings, investigators at Massachusetts General Hospital in Boston recently reported that nearly 5% of Medicare patients with acute ischemic stroke received a prescription for benzodiazepines within 90 days of discharge. 

Of these patients, 55% were prescribed benzodiazepines for durations ranging from 15 to 30 days. Guidance from the World Health Organization suggests that benzodiazepines should be prescribed for no more than 7 days.

In an editorial accompanying this study, Justin J. MacKenzie, PhD, and Veronica Moreno-Gomez, MD, said the findings highlight “a concerning pattern of possible BZD [benzodiazepine] overprescription in vulnerable adults following ischemic stroke.”

Some evidence suggests that various nonpharmacologic treatments are effective for PSA and PSD. 

A 2021 meta-analysis of 10 studies showed CBT was associated with improvement in PSD and PSA symptoms and that the benefits persisted up to 3 months after treatment. 

Other studies suggest potential benefits from exercise, acupuncture, and neuromodulation, although many of these trials were small or yielded inconsistent results.

Time for New Guidance?

Updated guidance for managing PSD and PSA would enable physicians to screen stroke patients more effectively for symptoms, Moreno-Gomez, who is an associate professor of neurology at the University of Utah in Salt Lake City, told Medscape Medical News. Any new guidance should identify the most effective and safest pharmacologic and nonpharmacologic treatments, she added.

“While there is still room for improvement, the development of standardized guidelines for the short- and long-term management of anxiety will help minimize the misuse of benzodiazepines and their associated risks,” Moreno-Gomez said.

The majority of studies published since the release of the statement are meta-analyses of randomized clinical trials (RCTs) with small numbers, of short duration, or with problematic diagnostic approaches, Ovbiagele said. As a result, the AHA/ASA currently has no plans to update its 2016 statement on PSD. 

“What we really need is a large, multidisciplinary RCT headed by neurologists, psychiatrists, and perhaps primary care physicians — all of whom play a role in the diagnosis and treatment of patients with PSD,” Ovbiagele said. 

The results of such large-scale research would provide a solid foundation for developing new guidance on the screening, treatment and management of PSD and PSA, he added. 

Amytis Towfighi, MD, chair of the AHA/ASA panel that developed the 2016 statement, told Medscape Medical News that although she could not comment on the need for updated guidance, she agreed there is a need for PSD and PSA screening. She also noted that repeated screening might be necessary because the timeline of PSD is unclear.

Towfighi, chief of neurology at Los Angeles General Hospital and professor of neurology at the University of Southern California, agreed with Ovbiagele that more large-scale studies are needed to identify the most effective therapies. 

She highlighted the importance of including research on nonpharmacologic strategies such as music therapy, mindfulness, deep breathing, meditation, visualization, physical activity, motivational interviewing, acupuncture, and herbal remedies.

El Husseini, Ovbiagele, Moreno-Gomez, and Towfighi reported no relevant financial relationships.