Persistent Neuropsychiatric Symptoms: A Pervasive Challenge in Post-COVID-19 Syndrome


The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has left a profound impact on global health, with manifestations extending beyond the acute phase of infection. While initially recognized for its respiratory implications, COVID-19 has revealed its ability to affect various organ systems, giving rise to a spectrum of disorders ranging from pulmonary to neurological complications (Bowe et al., 2022; Davis et al., 2023). Among the multifaceted sequelae, neuropsychiatric symptoms have emerged as significant concerns, persisting long after the resolution of the acute infection (Rogers et al., 2020, 2021; Taquet et al., 2021a; Han et al., 2021).

These neuropsychiatric symptoms encompass a wide array of manifestations, including anxiety, depression, sleep disturbances, cognitive deficits, and mental fatigue (Rogers et al., 2020, 2021; Taquet et al., 2021a). While many individuals experience resolution of these symptoms within weeks or months, a notable proportion continue to endure them as part of the post-COVID syndrome (PCS) (Quan et al., 2023). Defined as symptoms persisting beyond 12 weeks following SARS-CoV-2 infection, PCS affects up to 10% of COVID-19 survivors, predominantly among adults (Quan et al., 2023).

Contrary to expectations, the severity of the initial COVID-19 illness does not reliably predict the likelihood of developing PCS, with even asymptomatic individuals at risk (Quan et al., 2023). The clinical presentation of PCS mirrors the heterogeneity observed during acute infection, encompassing somatic, neurological, and psychiatric symptoms (Taquet et al., 2021b; Sudre et al., 2021; Subramanian et al., 2022; Davis et al., 2023). Notably, psychiatric symptoms often mark the onset of new psychiatric disorders, posing significant challenges for affected individuals, particularly younger patients (Badenoch et al., 2021; Tang et al., 2022; Kubota et al., 2022; Koczulla et al., 2022).

The persistence of neuropsychiatric symptoms in PCS profoundly impacts patients’ well-being and quality of life (Badenoch et al., 2021; Tang et al., 2022; Kubota et al., 2022; Koczulla et al., 2022). Fatigue, a hallmark feature of PCS, presents as debilitating exhaustion disproportionate to exertion levels, hindering both physical and cognitive functions (Taquet et al., 2021b; Sudre et al., 2021; Subramanian et al., 2022; Davis et al., 2023). Notably, post-COVID fatigue disrupts daily activities, leading to a decline in overall functioning and quality of life, despite adequate rest (Taquet et al., 2021b; Sudre et al., 2021; Subramanian et al., 2022; Davis et al., 2023).

However, the diagnostic specificity and duration of post-COVID fatigue remain subjects of debate (Corfield et al., 2016; Joli et al., 2022). Although many individuals with PCS experience profound suffering and impairment, they often fail to meet the diagnostic criteria for chronic fatigue syndrome (CFS) or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) outlined by the Centers for Disease Control and Prevention (CDC) (CDC, 2021).

The Complex Pathophysiology of Fatigue and Cognitive Impairment in Post-COVID Syndrome

In the wake of the COVID-19 pandemic, attention has increasingly turned to the lingering effects of the virus, particularly in individuals experiencing post-COVID syndrome (PCS). While initial focus centered on respiratory symptoms, emerging evidence highlights the prevalence of neuropsychiatric manifestations, including fatigue and cognitive impairment, which persist long after the acute phase of the illness (Quan et al., 2023; Chen et al., 2022; Joli et al., 2022; Calabria et al., 2022; Ceban et al., 2022a; Crivelli et al., 2022).

Studies indicate a notable overlap between fatigue and cognitive deficits in PCS, reminiscent of findings in other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (Azcue et al., 2022; Wong and Weitzer, 2021). This convergence suggests a potential common pathophysiology underlying these symptoms.

Although the precise mechanisms driving fatigue remain elusive, accumulating evidence implicates oxidative stress, mitochondrial dysfunction, and chronic inflammation (Booth et al., 2012; Filler et al., 2014; Morris et al., 2019; Han et al., 2021). Proteomic analyses of peripheral blood mononuclear cells from ME/CFS patients and post-COVID individuals with ME/CFS have underscored the role of chronic inflammation in these conditions (Sweetman et al., 2020; Paul et al., 2021).

Moreover, the brain appears particularly vulnerable to the effects of chronic inflammation, potentially contributing to cognitive impairment observed in PCS (Baumeister et al., 2022; Kappelmann et al., 2021). This inflammatory milieu may also contribute to the overlapping depressive symptoms seen in conjunction with fatigue (Dabrowska et al., 2021; Al-Hakeim et al., 2021; Butler et al., 2022; Almulla et al., 2022; Lyra E Silva et al., 2022).

The interplay of inflammation, fatigue, and cognitive impairment in PCS mirrors similar associations observed in other conditions like multiple sclerosis, further highlighting the complexity of the underlying pathophysiology (Brys et al., 2020; Heitmann et al., 2022).

However, the multifactorial nature of PCS poses challenges for treatment. Existing drugs, often repurposed from other conditions, may not adequately address the diverse mechanisms contributing to fatigue, cognitive impairment, and depression in PCS (Ceban et al., 2022b; Chee et al., 2023). Clinical trials evaluating potential treatments for PCS typically target individual aspects of the pathophysiology, potentially overlooking the intricate interplay of factors contributing to the syndrome.

Recent investigations into nutritional supplements, such as oxaloacetate, have offered glimpses into potential avenues for intervention (Cash and Kaufman, 2022). Despite questions regarding methodology, studies suggest that oxaloacetate supplementation may mitigate inflammation, enhance mitochondrial function, and bolster antioxidant defenses (Wilkins et al., 2014; Li et al., 2022; Cash and Kaufman, 2022).

In essence, the persistence of fatigue and cognitive impairment in PCS underscores the need for a comprehensive understanding of its underlying pathophysiology. Addressing the multifaceted nature of the syndrome requires innovative approaches that consider the intricate interplay of oxidative stress, mitochondrial dysfunction, and inflammation. Only through such nuanced strategies can effective treatments be developed to alleviate the burden of PCS on affected individuals.

Exploring the Therapeutic Potential of Herbal Multitarget Drugs: A Focus on Post-COVID Treatment

In the realm of pharmacotherapy, the conventional approach often involves the development of synthetic drugs tailored to address specific symptoms or target particular pathways. However, an emerging paradigm shift is observed in the utilization of herbal medicines, particularly in the context of multitarget drugs. Unlike their synthetic counterparts, medical herbs often contain a myriad of compounds with diverse pharmacological profiles, enabling them to potentially address multiple targets and offer multifaceted benefits in complex diseases.

This notion is underscored by numerous studies highlighting the versatility of herbal medicines in targeting various facets of illnesses. For instance, Luo et al. (2019) and Zaa et al. (2023) have elucidated how medical herbs, owing to their complex composition, can modulate different physiological targets, thereby exerting beneficial effects across a spectrum of conditions. However, a critical impediment to the widespread adoption of herbal medicines lies in the lack of standardized formulations, leading to variations in compositions and concentrations of active ingredients.

The ambiguity surrounding the efficacy of herbal medicines is exemplified in the case of ginseng, wherein disparate preparations and dosages have precluded definitive conclusions regarding its effectiveness in enhancing cognition or alleviating fatigue (Geng et al., 2010; Zhou et al., 2022). This variability underscores the need for standardized extracts and rigorous clinical evaluations to discern the true therapeutic potential of herbal remedies.

Focusing on post-COVID treatment, efforts have been directed towards identifying herbal drugs with standardized formulations and robust evidence supporting their therapeutic efficacy. Notable among these are the standardized extract of Ginkgo biloba leaves (EGb761®) and two standardized extracts of the roots and rhizome of Rhodiola rosea (SHR5, WS® 1375), which have demonstrated promise in addressing post-COVID-associated fatigue, cognitive impairment, and symptoms of depression.

Singh et al. (2019) and Müller et al. (2019) have provided compelling evidence supporting the efficacy of EGb761® in ameliorating cognitive deficits post-COVID. Similarly, studies by Panossian et al. (2021), Ivanova Stoijcheva and Quintela (2022), and Anghelescu et al. (2018) have underscored the therapeutic potential of Rhodiola rosea extracts, particularly SHR5 and WS® 1375, in mitigating post-COVID symptoms.

These herbal drugs, classified as adaptogens, exhibit multitarget properties, thereby offering a holistic approach to managing post-COVID complications. Adaptogens are characterized by their ability to enhance the body’s resilience to stressors and restore homeostasis, making them particularly relevant in the context of post-viral syndromes such as those seen in COVID-19 survivors.

Herbal multitarget drugs represent a promising therapeutic avenue, especially in the management of post-COVID complications. However, standardized formulations and rigorous clinical validation are imperative to unlock their full therapeutic potential and facilitate their integration into mainstream medical practice. Efforts in this direction hold the promise of harnessing the diverse pharmacological arsenal of herbal medicines for the betterment of global healthcare.

The Therapeutic Potential of Ginkgo biloba Extract (EGb761®) in Post-COVID Syndrome and Beyond

Ginkgo biloba, with its standardized extract EGb761®, emerges as a prominent herbal drug with a rich pharmacological profile under intensive investigation. The formulation primarily consists of 6% terpenoids (ginkgolides and bilobalide) and 24% flavonoid glycosides, including quercetin, kaempferol, and isorhamnetin, serving as major active constituents (Singh et al., 2022). Extensive experimental and clinical studies have shed light on its multifaceted therapeutic effects, ranging from antioxidative and anti-inflammatory properties to enhancements in mitochondrial function and neuroplasticity (Akanchise et al., 2023; Baliutyte et al., 2014; Singh et al., 2019; Müller et al., 2019; Müller et al., 2012).

Notably, EGb761® has exhibited promising results in ameliorating cognitive deficits across various age-associated memory disorders, from mild cognitive impairment to neurodegenerative and vascular dementia (Müller et al., 2019). Its efficacy extends to mitigating neuro-inflammation and associated behavioral manifestations induced by lipopolysaccharide (LPS) in animal models, suggesting a potential role in addressing chronic fatigue and depressive symptoms stemming from prolonged immune system activation (Zhao et al., 2015; Yeh et al., 2015; Foster et al., 2021; Roth et al., 2021). Furthermore, EGb761® has demonstrated the ability to reduce serum cytokine levels, including IL-6, implicated in COVID-19 pathogenesis (Mousavi et al., 2022; Müller et al., 2022; Wang et al., 2022).

While the evidence supporting the cognitive benefits of EGb761® is robust, its efficacy in alleviating fatigue warrants further exploration. Previous studies investigating Ginkgo biloba extract’s effect on fatigue associated with multiple sclerosis (MS) have yielded promising outcomes. In a study by Johnson et al. (2006), MS patients treated with EGb761® exhibited significant improvements in fatigue scores compared to placebo, as measured by the modified fatigue impact scale (MFIS) and disease-specific assessment tools (Johnson et al., 2006). Despite the study’s limited sample size, the findings align with the multitarget pharmacology of EGb761®.

Building upon these observations, Zifko et al. (2022) conducted a case series involving five post-COVID patients experiencing persistent fatigue and cognitive impairments following SARS-CoV-2 infection. Treatment with EGb761® at 160 mg/day for up to four months resulted in notable improvements in fatigue and cognitive function, as evidenced by clinical evaluations and standardized assessment tools (Zifko et al., 2022). The favorable outcomes, coupled with the drug’s tolerability, suggest EGb761® as a viable option for managing post-COVID symptoms over an extended duration.

The multifaceted pharmacological properties of EGb761® align well with the complex pathophysiology underlying fatigue and post-COVID syndrome. Its antioxidative, anti-inflammatory, and neuroprotective actions make it a promising candidate for addressing the diverse symptomatology associated with these conditions. However, further well-designed clinical trials are warranted to delineate its precise mechanisms of action and optimize therapeutic protocols.

Ginkgo biloba extract EGb761® emerges as a versatile herbal remedy with significant potential in the management of post-COVID syndrome and fatigue-related disorders. Its multitarget pharmacology and favorable safety profile position it as a promising therapeutic option deserving further investigation and clinical validation. Efforts in this direction hold promise for improving the quality of life for individuals grappling with the lingering effects of COVID-19 and other debilitating conditions.

The Therapeutic Potential of Rhodiola rosea: A Comprehensive Review

Rhodiola rosea, a member of the adaptogen family, has garnered significant attention in recent years due to its purported ability to enhance resistance to various stressors and improve physiological and psychological well-being. Adaptogens, including Rhodiola rosea, have been utilized in numerous countries for their potential in combating stress, exhaustion, and various ailments such as cancer, viral infections, and bacterial diseases (Panossian et al., 2020; Anghelescu et al., 2018). Within the realm of Rhodiola rosea research, extensive investigations have been conducted to elucidate its pharmacological properties and clinical efficacy, particularly in enhancing cognitive function, combating fatigue, and alleviating symptoms of depression and burnout.

The pharmacological arsenal of Rhodiola rosea encompasses a wide array of beneficial effects, ranging from cognitive enhancement to neuroprotective and anti-inflammatory properties (Liu et al., 2015; Guan et al., 2012; Agapounda et al., 2022; Kumar et al., 2019). Notably, its active constituent, salidroside, has been implicated in conferring many of these therapeutic benefits. Studies have demonstrated Rhodiola rosea’s capacity to ameliorate cognitive deficits, enhance neuroplasticity, and mitigate ischemic damage, thereby positioning it as a promising candidate for neurological disorders and cognitive decline (Ma et al., 2018; Kumar et al., 2019; Zhong et al., 2019).

Throughout the past two decades, Rhodiola rosea has been extensively studied in both experimental and clinical settings, primarily utilizing two standardized extracts: SHR-5 and WS® 1375 (Melzig et al., 2019). These extracts, derived from the roots and rhizomes of Rhodiola rosea, exhibit varying compositions and pharmacological profiles. Noteworthy is the overlap in pharmacological activities between Rhodiola rosea and Ginkgo biloba, further underscoring its potential therapeutic utility (Ivanova Stojcheva & Quintela, 2022; Zhong et al., 2019).

Clinical investigations have highlighted the efficacy of Rhodiola rosea in improving resilience, physical and mental performance, and alleviating stress-related symptoms (Hung et al., 2011; Edwards et al., 2012). Studies employing WS® 1375 have demonstrated positive effects on cognitive function, particularly in adult populations, further substantiating its cognitive-enhancing properties (Koop et al., 2020).

Moreover, Rhodiola rosea has shown promise in addressing symptoms of fatigue, depression, and burnout. Clinical trials have reported significant improvements in fatigue-related parameters and mood disorders following Rhodiola rosea supplementation (Darbinyan et al., 2000, 2007; Goyvaerts et al., 2012; Kasper & Dienel, 2017). Despite mixed findings in some studies, the overall trend suggests a favorable impact on both physical and mental fatigue (Ishaque et al., 2012; Olsson et al., 2009).

Recent investigations have also explored the potential of Rhodiola rosea in mitigating post-COVID-associated fatigue and neuropsychiatric symptoms. While preliminary suggestions have been made regarding its utility in post-COVID fatigue management, empirical evidence remains scarce (Wegener et al., 2023). A notable study by Karosanisze et al. (2022) evaluated the efficacy of ADAPT-232, a herbal tonic containing Rhodiola rosea extract, in post-COVID patients. However, the findings were rather underwhelming, raising questions about the formulation’s efficacy and study design (Karosanisze et al., 2022).

Despite the promising therapeutic potential of Rhodiola rosea, several challenges and limitations persist in research and clinical application. Issues such as study design variability, extract standardization, and dosage optimization warrant further investigation to harness its full therapeutic benefits effectively.

Rhodiola rosea stands as a promising natural remedy with multifaceted therapeutic properties, ranging from cognitive enhancement to fatigue alleviation. While existing evidence supports its efficacy in various clinical conditions, further research is needed to elucidate optimal dosing regimens, formulation standardization, and its role in emerging health challenges such as post-viral fatigue syndrome. With continued scientific inquiry and rigorous clinical trials, Rhodiola rosea holds significant promise as a valuable addition to the armamentarium of natural therapeutics.

The Therapeutic Potential of Lavandula angustifolia: A Comprehensive Analysis

Lavandula angustifolia, commonly known as lavender, has garnered significant interest in the field of natural medicine, particularly for its potential in alleviating anxiety-related disorders. This aromatic herb, renowned for its soothing fragrance, has been harnessed for therapeutic purposes in various forms, with a specific preparation of lavender oil, Silexan®, emerging as a notable intervention in the realm of anxiety management (Kasper et al., 2018).

The advent of Silexan® in liquid gelatine capsules has marked a significant advancement in lavender-based therapeutics, offering a standardized and convenient form for administration. Preclinical and clinical investigations have underscored the efficacy of Silexan® in the treatment of anxiety disorders, as well as mixed anxiety and depression (Müller et al., 2021; Bartova et al., 2023).

Clinical evidence supporting the anxiolytic properties of Silexan® has prompted discussions regarding its potential utility in addressing anxiety and mood disturbances in post-COVID patients. Mixed anxiety and depression are prevalent sequelae in individuals recovering from COVID-19, prompting exploration into novel therapeutic modalities (Dold et al., 2023; Kasper et al., 2023). Case reports have emerged, suggesting favorable outcomes with Silexan® supplementation in post-COVID patients, thereby warranting further investigation into its therapeutic usefulness in this population.

The therapeutic mechanisms underlying the anxiolytic effects of Lavandula angustifolia remain a subject of interest and ongoing research. Lavender oil, the primary constituent of Silexan®, exerts its pharmacological actions through various pathways, including modulation of neurotransmitter systems and reduction of oxidative stress (López et al., 2020). Additionally, its aromatic properties are believed to elicit calming effects on the central nervous system, thereby contributing to its anxiolytic properties.

Despite the promising evidence supporting the efficacy of Silexan® in anxiety management, several considerations merit attention. Variability in individual response, optimal dosing regimens, and potential drug interactions necessitate careful clinical monitoring and customization of treatment protocols. Moreover, the long-term safety profile of Silexan® warrants further exploration, particularly in vulnerable populations such as the elderly and individuals with preexisting medical conditions.

The integration of Lavandula angustifolia-based interventions, such as Silexan®, into mainstream psychiatric practice represents a paradigm shift towards holistic and natural approaches to mental health management. However, the translation of research findings into clinical practice necessitates robust evidence from well-designed randomized controlled trials and meta-analyses to establish its efficacy, safety, and comparative effectiveness against conventional pharmacotherapeutic agents.

Lavandula angustifolia, epitomized by the standardized preparation Silexan®, holds promise as a viable therapeutic option for anxiety-related disorders, including mixed anxiety and depression. Its potential utility in addressing post-COVID psychological sequelae underscores the need for further research and clinical exploration. With ongoing scientific inquiry and rigorous clinical validation, Lavandula angustifolia stands poised to make significant contributions to the field of mental health therapeutics, offering a natural and holistic approach to anxiety management.

Harnessing the Potential of Herbal Medicine for Post-COVID Syndrome: A Comprehensive Analysis

Cognitive impairment, depression, and fatigue have emerged as prevalent and overlapping symptoms of the post-COVID syndrome (PCS). Understanding the underlying pathophysiology of these symptoms is imperative for developing effective therapeutic strategies. Oxidative stress, mitochondrial dysfunction, and neuroinflammation have been identified as common pathophysiological factors contributing to the manifestation of PCS (Panossian et al., 2022). Despite extensive research and the availability of various pharmacotherapeutic agents targeting similar symptoms in other disorders, many have failed to demonstrate significant efficacy in treating PCS, highlighting the multifactorial nature of its pathophysiology.

Contrary to synthetic drugs that often target specific mechanisms of action, herbal medicines comprise diverse compounds with varied pharmacological properties, offering a multifaceted approach to symptom management. Among the notable herbal drugs, Ginkgo biloba and Rhodiola rosea have garnered attention for their antioxidant, anti-inflammatory, and cognition-enhancing properties (Panossian & Wikman, 2010).

Preclinical investigations have underscored the potential of Ginkgo biloba and Rhodiola rosea extracts in addressing the multifactorial pathophysiology of PCS. These herbal remedies exhibit antioxidant, cognition-enhancing, neurorestorative, anti-inflammatory, and antidepressant properties, thereby offering a comprehensive therapeutic approach to alleviate symptoms associated with PCS (Liu et al., 2015; Guan et al., 2012; Panossian & Wikman, 2010).

Clinical studies investigating the efficacy of these herbal drugs in PCS patients have yielded promising results, particularly in alleviating symptoms of mental and physical fatigue. However, the quality of available studies is variable, necessitating cautious interpretation of the findings (Panossian et al., 2022). While limited data exist on the beneficial effects of Ginkgo biloba and Rhodiola rosea in PCS patients, preliminary evidence suggests their potential utility in symptom management over extended treatment periods (Kasper & Dienel, 2017; Ivanova Stojcheva & Quintela, 2022).

Despite the promising therapeutic potential of herbal medicines in PCS, further research is warranted to elucidate their precise mechanisms of action, optimal dosing regimens, and long-term safety profiles. Rigorous clinical trials with well-defined inclusion criteria and standardized outcome measures are essential to corroborate the preliminary findings and establish the efficacy of herbal medicines in PCS management (Panossian et al., 2022).

In conclusion, Ginkgo biloba and Rhodiola rosea represent promising herbal remedies for addressing the complex symptomatology of PCS. Their multifaceted pharmacological properties align well with the multifactorial pathophysiology of PCS, offering a holistic approach to symptom management. While existing evidence is encouraging, ongoing research efforts are imperative to validate their efficacy, safety, and long-term benefits in PCS patients. By harnessing the therapeutic potential of herbal medicines, clinicians can broaden their armamentarium in tackling the challenges posed by PCS, thereby enhancing the quality of life and functional outcomes of affected individuals.

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