Mirtazapine as a Potential Therapy for Post-COVID-19 Syndrome (Long COVID): A Comprehensive Review

Post-COVID-19 syndrome (PCS), also known as Long COVID, is a multifaceted condition characterized by persistent fatigue, cognitive dysfunction, sleep disturbances, and mood disorders. Emerging evidence suggests that serotonergic system disruption plays a central role in PCS pathophysiology, with reduced serotonin levels linked to chronic inflammation, platelet hyperactivity, and altered tryptophan metabolism. This review explores the potential therapeutic role of mirtazapine, a tetracyclic antidepressant that antagonizes 5-HT₂ and 5-HT₃ receptors while blocking α₂-adrenergic autoreceptors, leading to enhanced serotonin and norepinephrine release. Mirtazapine’s pharmacological properties extend beyond mood stabilization, encompassing sleep regulation, neuroplasticity promotion, and anti-inflammatory effects. By modulating serotonergic and noradrenergic transmission, it may alleviate key PCS symptoms such as cognitive impairment, chronic fatigue, and sleep disturbances. Furthermore, its neuroprotective role in preventing neuronal apoptosis and mitigating neuroinflammation makes it a promising candidate for addressing the long-term neurological consequences of PCS. Despite its potential, clinical trials evaluating mirtazapine in PCS are lacking, necessitating well-designed studies to assess its efficacy and safety. This review synthesizes current knowledge on mirtazapine’s mechanisms of action, its impact on neuroimmune interactions, and its potential advantages over conventional selective serotonin reuptake inhibitors (SSRIs) in the context of PCS. Future research should focus on randomized controlled trials and longitudinal studies to establish mirtazapine as a viable therapeutic option for PCS management.