COVID-19, caused by SARS-CoV-2, emerged as a global pandemic in late 2019 (Lai et al., 2020). This highly transmissible respiratory pathogen has significantly impacted global health systems. As of 22 November 2023, over 772 million confirmed cases, resulting in 6,981,263 deaths, have been reported to the World Health Organization. While most SARS-CoV-2 infections present as mild-to-moderate diseases, older individuals and those with underlying conditions such as immunocompromised states, cancer, sickle cell disease, chronic kidney disease, chronic liver disease, cardiovascular diseases, organ transplant recipients, autoimmune or inflammatory conditions, HIV infection, and other conditions affecting the immune system or blood may face a higher risk of COVID-19 progression.

Notably, psychiatric disorders emerge as another significant risk factor for severe COVID-19 (Cheng et al., 2023). A retrospective cohort study involving 15,783 adult patients found that, compared to non-psychiatric patients, those with psychiatric disorders had higher rates of severe COVID-19, hospitalization, and a shorter duration to in-hospital mortality (Cheng et al., 2023). Additionally, the study by Taquet et al. highlighted that individuals with psychiatric disorders were more likely to experience severe COVID-19 symptoms and prolonged recovery periods (Taquet et al., 2021b). This elevated risk is further supported by Goldberger et al., who reported that psychiatric patients had nearly twice the mortality rate of non-psychiatric patients when infected with COVID-19 (Goldberger et al., 2022). Another study by Koyama et al. demonstrated that psychiatric disorders, particularly depression and anxiety, were associated with a higher likelihood of ICU admission and mechanical ventilation among COVID-19 patients (Koyama et al., 2022). These findings showed the importance of antiviral agents in preventing severe COVID-19 outcomes for patients with existing psychiatric diseases.

Currently, two oral antiviral agents, molnupiravir and nirmatrelvir plus ritonavir, have been developed for high-risk individuals with mild-to-moderate COVID-19. Their efficacy in preventing severe SARS-CoV-2 infections has been demonstrated in randomized controlled trials (Hammond et al., 2022; Jayk Bernal et al., 2022)and numerous real-world studies (Wong et al., 2022; Evans et al., 2023; Najjar-Debbiny et al., 2023a; b; Wai et al., 2023; Yip et al., 2023). However, studies specifically assessing the effectiveness of these two antiviral agents in treating COVID-19 in patients with psychiatric disorders are scarce. While a previous network meta-analysis suggested that oral nirmatrelvir plus ritonavir might be more effective than molnupiravir in preventing severe COVID-19 (Lai et al., 2022), concerns arise in clinical practice due to the intricate interaction between nirmatrelvir plus ritonavir and psychotropic medications (Chatterjee et al., 2023). In contrast, molnupiravir poses a lower risk of drug-drug interactions with psychotropic medications, making it a relatively safe anti-SARS-CoV-2 agent for patients with psychiatric diseases. Therefore, this study was conducted to evaluate the therapeutic efficacy of molnupiravir in individuals with pre-existing psychiatric diseases and COVID-19.

This first study assessed the effectiveness of molnupiravir for treating non-hospitalized COVID-19 patients with pre-existing psychiatric disorder. Our findings indicated that molnupiravir could be linked to a decreased risk of short-term hospitalization and mortality, as well as a reduced risk of subsequent post-COVID-19 conditions. Specifically, among patients with pre-existing psychiatric disorders, molnupiravir lowered the risk of all-cause hospitalization or mortality by 24% during the 30-day follow-up. Furthermore, it contributed to a decline in the development of post-COVID-19 symptoms, including chest/throat pain, abnormal breathing, abdominal symptoms, fatigue, headache, cognitive symptoms, myalgia, cough, and palpitation during the 1-year follow-up.

Our findings align with prior studies demonstrating the short- and long-term benefits of molnupiravir in treating patients with mild-to-moderate COVID-19 (Bajema et al., 2023; Hsu et al., 2023b). Bajema et al. highlighted the efficacy of molnupiravir in reducing viral load and improving recovery times in general populations, while Hsu et al. showed its role in decreasing hospitalization rates and mortality among COVID-19 patients. Additionally, a study by Xie et al. (2023) emphasized molnupiravir’s effectiveness in lowering the incidence of long COVID symptoms , which aligns with our findings of reduced post-COVID-19 conditions such as chest/throat pain, abnormal breathing, and fatigue. Notably, this study focuses on patients with psychiatric disorders, a demographic often underrepresented in clinical research, thereby expanding the treatment spectrum of molnupiravir. Previous research by Korzeniowska et al. (2023) indicated that individuals with psychiatric disorders face higher risks of severe COVID-19 outcomes, making our findings particularly relevant. By demonstrating the safety and efficacy of molnupiravir in this specific high-risk group, our study endorses its use and advocates for more inclusive treatment protocols. This is supported by De Rose et al. (2023), who also emphasized the need for tailored therapeutic strategies for patients with psychiatric conditions, recognizing their unique vulnerabilities during the pandemic. Consequently, our study not only corroborates existing evidence but also provides new insights into the management of COVID-19 among patients with psychiatric disorders, advocating for broader adoption of molnupiravir in clinical practice.

Our findings carry significant clinical implications. Given the elevated risk of COVID-19 progression in patients with psychiatric disorders (Cheng et al., 2023), the prompt and appropriate use of antiviral agents becomes crucial in preventing the development of severe COVID-19. While a previous study identified nirmatrelvir plus ritonavir as the primary drug choice for the patients with mild-to-moderate COVID-19 (Lai et al., 2022), and more effective than molnupiravir, concerns remain regarding its potential drug-drug interactions with antipsychotic medications in patients with psychiatric disorders (Chatterjee et al., 2023). Consequently, our findings offer robust evidence regarding the clinical effectiveness of molnupiravir in patients with psychiatric disorders, underscoring its significance within this specific high-risk group.

Although the present and previous studies (Wong et al., 2022; Evans et al., 2023; Najjar-Debbiny et al., 2023a; Najjar-Debbiny et al., 2023b; Wai et al., 2023; Yip et al., 2023) have demonstrated the clinical benefits of oral antiviral agents for treating COVID-19 in high-risk patients, our findings reveal that only a small proportion of patients with both COVID-19 and psychiatric disorders received molnupiravir. After excluding patients receiving nirmatrelvir plus ritonavir or remdesivir, only less than 1% (n = 9426) among the 1,031,524 patients with psychiatric disorders in this study received. This finding underscores the importance for healthcare authorities to invest additional efforts in improving compliance and appropriately prescribing oral antiviral agents for high-risk patients, especially those with psychiatric disorders.

This study had several strengths. Its real-world design, encompassing a large and diverse population, enhances the applicability of its findings to real-life scenarios. The use of PSM to align demographic features between the treated and untreated groups helps mitigate potential confounding effects. Finally, the study was conducted between January 2022 and May 2023, during the predominance of the Omicron variant. Consequently, our findings hold relevance to the current stage of the pandemic.

This study had certain limitations. The utilization of electronic health records introduces the possibility of coding errors, potentially leading to inaccuracies during data collection and analysis. This could impact the robustness of the study’s conclusions. Additionally, despite efforts to control various variables, residual confounding remains a challenge in real-world studies, acknowledging potential influences that were not entirely accounted for in the analysis. Lastly, we did not assess the effect of molnupiravir for each specific psychiatric disorder; however, further study is warranted to explore this aspect in detail.

In summary, our study indicates that molnupiravir can effectively reduce all-cause hospitalizations and deaths in COVID-19 patients with psychiatric conditions. Furthermore, it demonstrates significant benefits in long-term outcomes, including a decreased risk of post-COVID-19 conditions within 1 year after a COVID-19 diagnosis. These findings support the use of molnupiravir in managing COVID-19 in patients with psychiatric conditions.