Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic is still spreading worldwide over 2 years since its outbreak. The psychopathological implications in COVID-19 survivors such as depression, anxiety, and cognitive impairments are now recognized as primary symptoms of the “post-acute COVID-19 syndrome.” Depressive psychopathology was reported in around 35% of patients at short, medium, and long-term follow-up after the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Post-COVID-19 depressive symptoms are known to increase fatigue and affect neurocognitive functioning, sleep, quality of life, and global functioning in COVID-19 survivors. The psychopathological mechanisms underlying post-COVID-19 depressive symptoms are mainly related to the inflammation triggered by the peripheral immune-inflammatory response to the viral infection and to the persistent psychological burden during and after infection. The large number of SARS-CoV-2-infected patients and the high prevalence of post-COVID-19 depressive symptoms may significantly increase the pool of people suffering from depressive disorders. Therefore, it is essential to screen, diagnose, treat, and monitor COVID-19 survivors’ psychopathology to counteract the depression disease burden and related years of life lived with disability. This paper reviews the current literature in order to synthesize the available evidence regarding epidemiology, clinical features, neurobiological underpinning, and pharmacological treatment of post-COVID-19 depressive symptoms.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Post-COVID-19 depressive symptoms have been reported in around 35% of patients at short, medium, and long-term follow-up after infection. |
The psychopathological mechanisms of post-COVID-19 depressive symptoms are mainly related to the peripheral immune-inflammatory response triggered by the viral infection. |
Conventional antidepressants have proved to be effective in treating post-COVID-19 depression. |
1 Introduction
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic started in China in December 2019 and, at over 2 years from its outbreak, it is still spreading around the world. According to the World Health Organization (WHO), the coronavirus disease 2019 (COVID-19) pandemic has affected almost 500 million people around the world, with more than 6 million deaths [1].
Most SARS-CoV-2-infected patients are asymptomatic or experience mild symptoms [2]. However, one in five SARS-CoV-2-infected patients presents with severe acute clinical manifestations characterized by acute respiratory distress syndrome (ARDS), severe immune response leading to an inflammatory and procoagulant state, and death [2]. Furthermore, after the acute phase of COVID-19, persistent and prolonged symptoms have been observed in several patients irrespective of the severity of the disease [3]. Persisting symptoms such as lung dysfunction, psychopathological complaints, and cognitive impairments have been reported to continue over months after acute COVID-19 [4, 5]. The National Institute for Health and Care Excellence (NICE) has termed these long-lasting symptoms after infection "post-COVID-19 syndrome," defining it as new and/or persistent signs and symptoms more than 12 weeks following SARS-CoV-2 infection [6].
Since the pandemic spread, psychopathological implications have been reported during acute infection and in the post-COVID-19 phase in COVID-19 survivors. Confusion, delirium, depression, anxiety, and sleep disturbances have been observed during acute viral infection [7]. Apart from acute infection, as previously observed in the SARS and the Middle East Respiratory Syndrome (MERS) outbreak, long-term neuropsychiatric sequelae of COVID-19 are now listed as the main symptoms of the post-acute COVID-19 syndrome [3]. The most prevalent long-term neuropsychiatric sequelae have been depressive symptoms, anxiety, and cognitive impairments [8]. Clinically significant depressive psychopathology was reported in approximately 30–40% of patients at 1-, 3-, 6-, and 12-month follow-up after SARS-CoV-2 infection [9,10,11,12,13]. Depression, characterized by depressed mood, diminished interest, and cognitive impairment, negatively influences everyday life. Both pre-existing depression and COVID-19-related depressive symptoms were found to affect SARS-CoV-2 infection outcome, being associated with higher infection rate, hospitalization, intensive care unit admission, and mortality [14, 122]. Moreover, males tend to express a stronger age-dependent activation of the innate pro-inflammatory pathways [123], leading to higher chronic subclinical systemic inflammation than that observed in females [124]. Thus, accounting for this variable is of primary importance when searching for an inflammatory biomarker.
In conclusion, evidence from the literature suggests that easily available biomarkers of innate inflammatory response such as CRP, NLR, and SII are associated with post-COVID-19 depressive symptoms. CRP, NLR, and SII are cheap, available in a real-life clinical setting, and reproducible markers of the systemic inflammation, which can be derived from a routine blood cell essay. To date, several studies have proven their utility as inflammatory biomarkers of MDD episodes [125, 126].
5 Potential Treatment for Post-COVID-19 Depressive Symptoms
The large number of people infected with SARS-CoV-2 and the high prevalence of post-COVID-19 depressive symptoms may contribute to the emergence of a serious global problem and significantly increase the pool of people suffering from depressive disorders. Untreated depression is independently associated with severe outcomes in pneumonia and respiratory diseases [127,128,129]. Even in COVID-19, meta-analytic evidence suggested that comorbid depression was associated with increased risk of hospitalization, intensive care unit admission, and mortality [14, 141]. In so doing, SSRIs may prevent the risk of inflammatory thrombosis and hyperserotonergic state leading to acute respiratory distress [142]. Finally, some SSRIs may increase plasma levels of melatonin by inhibition of cytochrome P450 enzyme CYP1A2, thus enhancing the anti-inflammatory, immunomodulatory, and antioxidant mechanisms of melatonin [143,144,145].
While growing evidence supports the promising role of SSRIs as effective repurposed drugs against a COVID-19 severe outcome, to date, to the best of our knowledge, only one study has investigated the efficacy of conventional SSRIs in treating post-COVID-19 depressive episode [146]. In 60 patients who presented with a depressive episode in the 6 months after COVID-19, we observed a rapid antidepressant response (50% HDRS reduction) in 55 patients after SSRIs treatment. Specifically, 89% and 95% of patients, respectively, with or without a previous psychiatric history completely responded to SSRI treatment, thus suggesting that first and recurrent depressive episodes triggered by COVID-19 share the same good antidepressant response. From pre-treatment to the 4-week follow-up, a significant decrease over time of depressive symptoms as rated on the Hamilton Depression Rating Scale (HDRS) was reported (baseline HDRS = 23.37 ± 3.94, post-treatment HDRS = 6.71 ± 4.41, F = 618.90, p < 0.001) irrespectively of sex, previous psychiatric history, and SSRI type. We hypothesize that SSRIs’ serotoninergic and anti-inflammatory properties can be particularly effective in counteracting post-COVID-19 depressive episode triggered by SARS-CoV-2 infection-related systemic inflammation. Antidepressants may decrease peripheral markers of inflammation including IL-6, IL-10, TNF-α, and CCL-2, notably associated both with COVID-19 and with depression severity [137, 147]. Furthermore, in the CNS, SSRIs inhibit microglial activation and decrease cytokine production by these cells [148]. Moreover, SSRIs could directly neutralize the IDO-mediated detrimental effects of inflammation by potentiating serotonin neurotransmission, modulating tryptophan metabolism, and reducing the excitotoxic quinolinic acid [149]. In line with these hypotheses, an observational study found that COVID-19 inpatients under pre-existing antidepressant treatments (n = 34) had a lower ARDS incidence than patients not taking an antidepressant (n = 402) (20.6% vs. 43.2%, p < 0.02) coupled with lower blood levels of IL-6 (12.1 vs. 25.4, p < 0.001) [150]. Accordingly, we have previously found a protective effect of the IL-1β and IL-6 receptor antagonist (anakinra and tocilizumab) against post-COVID-19 depressive symptoms possibly associated with their effect in dampening SII [151]. This suggests that modulation of IL-6 may restore the prolonged systemic inflammation that could lead to the development of persistent depressive psychopathology.
Given this background, we suggest routinely monitoring psychopathology status after COVID-19 to treat as soon as possible emergent depressive symptoms in order to reduce the risk of a vicious cycle of infection, persistent sub-chronic inflammation, and structural and functional brain abnormalities [26] leading to subsequent treatment-resistant depressive symptomatology.
5.2 Other Interventions
When considering post-COVID-19 depressive symptoms, to date, only scarce research has investigated the use of different molecules known to target shared immunological pathways in depressive psychopathology and COVID-19.
Melatonin as well as SSRIs was found to be effective in reducing susceptibility, need for hospitalization, length of hospital stay, and symptoms of acute COVID-19 [152,153,154]. Melatonin supplementation is known to restore the night–day circadian rhythm typically disturbed in depressive episodes [155, 156]. Moreover melatonin increases heme oxygenase-1 (HO-1), thus enhancing its anti-inflammatory activity [157]. In animal models, melatonin has been shown to relieve a depressed behavioral state in mice as well as stimulating neurogenesis in the hippocampus [158, 159]. The melatonin receptor agonist agomelatine, which is already approved for treating MDD episodes [155, 160], is known to reduce plasma and brain IL-1β, IL-6, and CRP levels, and prevents microgliosis and astrogliosis in rat models [161,162,163]. Therefore, even if no studies are yet available, melatonin as well as agomelatine could prove beneficial in the treatment of post-COVID-19 depressive symptoms, due to its antioxidant, anti-inflammatory, and antiapoptotic properties [157, 161,162,163].
Pharmacological blockade of cytokines involved in the COVID-19-induced cytokine storm suggested a protective effect of IL-1 and IL-6 antagonism on hyper-inflammation and progression to respiratory failure [164, 165]. Given the central role of IL-1 and IL-6 in depressive psychopathology, we explored the effect of IL-1 and IL-6 blocking on depressive symptoms [151]. Eighty-four male COVID-19 survivors who during hospitalization had treatment as usual (n = 55) or combined with a cytokine blocking agent (n = 29) were prospectively evaluated 1 and 3 months after discharge. We observed a protective effect of treatment with cytokine-blocking agents (anakinra and tocilizumab) in early phases of COVID-19 against the later onset of depressive symptoms (Time × treatment interaction: F = 3.96, p = 0.0228). Specifically, clinical depressive symptoms at 3 months’ follow-up was found in 9/55 (16.4%) patients treated without and 1/28 (3.6%) treated with cytokine blockers. This preliminary finding, suggesting a potential antidepressant effect of cytokine-blocking agents, needs to be replicated in a larger population in order to possibly identify new therapeutic strategies for treatment-resistant depressive symptomatology [166].
Lithium salts classically belong to the pharmacological class of mood stabilizers; moreover, antidepressant and anti-suicidal effects have been proven for lithium itself [167,168,169]. Among the immune-inflammatory mechanisms of action, lithium has shown an anti-apoptotic effect on T-lymphocytes [170] and anti-inflammatory effects by reducing the cyclooxygenase-2 expression, IL-1β and TNF-α [171]. Moreover, lithium salt seems to have direct antiviral properties by competing with magnesium that represent an essential cofactor for enzymes that are needed for the replication of viral proteins and nucleosides [172]. In this context, lithium was found to reduce COVID-19-related inflammation and immune response in six patients when compared to patients not treated with lithium [173]. Specifically, lithium significantly reduced CRP and NLR while promoting T-cell proliferation. Interestingly, lithium influences T-cell proliferation and differentiation via a GSK3 pathway, and promotes white matter integrity in mood disorders by enhancing axial diffusivity, which is reduced by COVID-19 [174, 175]. These preliminary findings encourage a possible evaluation of lithium as a potential treatment for severe cases of COVID-19 infection, and given its parallel anti-inflammatory and anti-depressive efficacy, in post-COVID-19 depressive symptoms.
Finally, in order to bolster both the inflammatory response related to SARS-CoV-2 infection, as well as treat post-COVID-19 depressive symptoms, the use of transcranial direct current stimulation (tDCS), ayurveda, curcumin, and oxytocin have been considered, but not yet adequately tested. A single case report documented successful treatment of post-COVID-19 depressive and anxiety symptoms using tDCS [176]. tDCS is a promising nonpharmacological intervention for treating depressive psychopatology [177], potentially able to modulate the levels of IL-1β, IL-6, and TNF-α [178]. Ayurveda, proposed by the Indian government during the COVID-19 crisis, could positively influence immunity with possible direct effects on symptoms of depression or anxiety [179]. A potential modulation of monoamine function, stress axis response, and autonomic activity, paired with a reduction of anxiety and depressive symptomatology, has been postulated to be associated with ayurveda traditional practices [180]. Therefore, such a traditional practice could be beneficial both in terms of psychological effect and in terms of moderating the risk or severity of SARS-CoV-2 infection, and its safety and efficacy should be tested in future studies [181]. Curcumin is known for an antiviral activity against many types of enveloped viruses, including SARS-CoV-2 [182], by modulating NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways [183]. Moreover, curcumin 1 g/day exhibits antidepressant activity, and improves cognitive/mood function [182], thus offering a promising option for treating post-COVID-19 depressive symptoms. Oxytocin is a peptide characterized by a well-known anti-inflammatory, anti-oxidant, and immune-modulator activity [184] with possible efficacy in attenuating COVID-19 pathogenesis [185]. Considering that oxytocin has proven to be effective for stress, anxiety, and depression [184], its activity could be useful in treating post-COVID-19 depressive symptoms, maybe as add-on therapy.
All these mechanisms could potentially target the neuroinflammation triggered by SARS-CoV-2 associated with post-COVID-19 depressive symptoms, and its detrimental effects. However, despite the impressive rates of affected patients, no report is available about the efficacy of pharmacological treatment of post-COVID-19 depressive symptoms. Given the alarming prevalence of post-COVID-19 depressive symptomatology, further investigations are needed to explore the efficacy and tolerability of all these potential pharmacological interventions.
6 Future Research Needs
Scientific evidence on post-COVID-19 depressive psychopathology is still limited. Further research might increase our knowledge on how the immune-inflammatory response translates from organic to psychiatric illness, potentially providing some valuable insight into the etiopathogenetic underpinnings of depressive psychopathology and its therapeutic management.
Findings from different independent meta-analyses consistently showed a high prevalence of post-COVID-19 depressive symptoms (see Table 1); however, to date there is still high heterogeneity that needs to be addressed in order to identify risk and protective factors. Several factors, such as social isolation, psychological stress, medical comorbidity, and COVID-19 severity, are known to possibly increase the risk of presenting post-COVID-19 depressive symptomatology by interacting with the neuro-immune pathway. Although it is reasonable that all these factors contribute to a higher risk of post-COVID-19 depressive symptoms, no clear answers have been provided from research apart from female sex and positive previous psychiatric history. Clarifying the underlying biological and psychological variables associated with post-COVID-19 depressive symptomatology will provide new clinical insights to tailor effective and personalized treatments.
A growing literature is exploring the efficacy of antidepressants for treating acute SARS-CoV-2 infection [130, 131]. In this context, we recommend all clinical trials of serotonergic compounds repurposed against COVID-19 to assess depressive symptomatology at baseline and follow-up in order to explore whether the direct antidepressant effect could reduce the risk for a vicious cycle of infection, inflammation, depression, hospitalizations, and poor prognosis.
To date there are very few available studies that tested the efficacy and tolerability of conventional antidepressant and other pharmacological treatment on post-COVID-19 depressive symptoms; furthermore these preliminary findings were based on single-case, case series, or small sample size studies. High-quality clinical trials investigating different drugs are needed to assess their efficacy for treating post-COVID-19 depressive symptoms. In this context, future pharmacological research is needed to investigate whether the antidepressant efficacy would be paired with a reduction of inflammation, thus reversing the inflammation triggered by the infection. Anti-inflammatory drugs and immunomodulators that are currently being tested for treatment-resistant MDD and that have proved efficacious in reducing depressive symptoms in patients with inflammation could prove useful for inflammation-induced depressive episodes both as prevention and as a treatment strategy [186]. Moreover, the potential effect of non-pharmacological interventions such as light therapy, non-invasive somatic stimulation, horticultural therapy, and nutraceuticals should be explored [187,188,189].
The available literature suggests that routine biomarkers of innate inflammatory response are associated with post-COVID-19 depressive symptoms (see Table 2); however, larger studies are needed to replicate these preliminary findings. Therefore, we suggest all future investigations of post-COVID-19 depressive symptomatology should explore the potential association of depressive symptomatology with routine biomarkers of inflammation. Moreover, future research needs to improve the in-depth immunophenoty** of post-COVID-19 depressive psychopathology by implementing cytokine assessment and T-cell subpopulation study. This approach could identify at-risk populations and possible new specific targets for the treatment of inflammation-related depressive conditions.
6.1 Limitations
The main limitation of the present review deals with the small number of available studies exploring the biomarkers of post-COVID-19 depressive psychopathology and investigating the pharmacological treatment of post-COVID-19 depressive symptoms that meant we had to conduct a narrative review without a quantitative approach. Moreover, in the majority of reviewed studies, psychopathological evaluation was based on self-assessment questionnaires in the absence of psychiatric interviews, thus allowing us to consider only depressive symptoms and preventing us from dealing with a diagnosis of a MDD episode. This limitation clearly affects the prevalence rate, the pathophysiology, and potentially the treatments.
7 Conclusion
In conclusion, considering the alarming prevalence of post-COVID-19 depressive symptoms and its impact on global functioning, according to current literature [3], follow-up services for COVID-19 survivors should be implemented in order to monitor mental health and provide early treatment. From a clinical perspective, we suggest that routine assessment of psychopathology of COVID-19 survivors will be critical for the rapid diagnosis and treatment of emergent depressive symptomatology, thus reducing the high disease burden typically associated with psychiatric conditions.
References
Organization WH. WHO Coronavirus (COVID-19) Dashboard. 2022. p. https://covid19.who.int/.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. https://doi.org/10.1016/S0140-6736(20)30183-5.
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–15. https://doi.org/10.1038/s41591-021-01283-z.
Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open. 2021;4(5): e2111417. https://doi.org/10.1001/jamanetworkopen.2021.11417.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220–32. https://doi.org/10.1016/S0140-6736(20)32656-8.
Venkatesan P. NICE guideline on long COVID. Lancet Respir Med. 2021;9(2):129. https://doi.org/10.1016/S2213-2600(21)00031-X.
Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7(7):611–27. https://doi.org/10.1016/S2215-0366(20)30203-0.
Khraisat B, Toubasi A, AlZoubi L, Al-Sayegh T, Mansour A. Meta-analysis of prevalence: the psychological sequelae among COVID-19 survivors. Int J Psychiatry Clin Pract. 2021. https://doi.org/10.1080/13651501.2021.1993924.
Mazza MG, Palladini M, De Lorenzo R, Bravi B, Poletti S, Furlan R, et al. One-year mental health outcomes in a cohort of COVID-19 survivors. J Psychiatr Res. 2021;22(145):118–24. https://doi.org/10.1016/j.jpsychires.2021.11.031.
Mazza MG, Palladini M, De Lorenzo R, Magnaghi C, Poletti S, Furlan R, et al. Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up. Brain Behav Immun. 2021;94:138–47; https://doi.org/10.1016/j.bbi.2021.02.021.
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416–27. https://doi.org/10.1016/S2215-0366(21)00084-5.
Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry. 2021;8(2):130–40. https://doi.org/10.1016/S2215-0366(20)30462-4.
Mazza MG, De Lorenzo R, Conte C, Poletti S, Vai B, Bollettini I, et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594–600; https://doi.org/10.1016/j.bbi.2020.07.037.
Vai B, Mazza MG, Delli Colli C, Foiselle M, Allen B, Benedetti F, et al. Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis. Lancet Psychiatry. 2021;8(9):797–812. https://doi.org/10.1016/S2215-0366(21)00232-7.
Ceban F, Nogo D, Carvalho IP, Lee Y, Nasri F, **ong J, et al. Association between mood disorders and risk of COVID-19 infection, hospitalization, and death: a systematic review and meta-analysis. JAMA Psychiat. 2021;78(10):1079–91. https://doi.org/10.1001/jamapsychiatry.2021.1818.
Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun. 2020;87:34–9. https://doi.org/10.1016/j.bbi.2020.04.027.
Passavanti M, Argentieri A, Barbieri DM, Lou B, Wijayaratna K, Foroutan Mirhosseini AS, et al. The psychological impact of COVID-19 and restrictive measures in the world. J Affect Disord. 2021;15(283):36–51. https://doi.org/10.1016/j.jad.2021.01.020.
Deng J, Zhou F, Hou W, Silver Z, Wong CY, Chang O, et al. The prevalence of depression, anxiety, and sleep disturbances in COVID-19 patients: a meta-analysis. Ann N Y Acad Sci. 2021;1486(1):90–111. https://doi.org/10.1111/nyas.14506.
Dong F, Liu HL, Dai N, Yang M, Liu JP. A living systematic review of the psychological problems in people suffering from COVID-19. J Affect Disord. 2021;1(292):172–88. https://doi.org/10.1016/j.jad.2021.05.060.
Liu C, Pan W, Li L, Li B, Ren Y, Ma X. Prevalence of depression, anxiety, and insomnia symptoms among patients with COVID-19: A meta-analysis of quality effects model. J Psychosom Res. 2021;147:110516; https://doi.org/10.1016/j.jpsychores.2021.110516.
Soltani S, Tabibzadeh A, Zakeri A, Zakeri AM, Latifi T, Shabani M, et al. COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis. Rev Neurosci. 2021;32(3):351–61. https://doi.org/10.1515/revneuro-2020-0108.
Wu T, Jia X, Shi H, Niu J, Yin X, **e J, et al. Prevalence of mental health problems during the COVID-19 pandemic: a systematic review and meta-analysis. J Affect Disord. 2021;15(281):91–8. https://doi.org/10.1016/j.jad.2020.11.117.
Walker J, Burke K, Wanat M, Fisher R, Fielding J, Mulick A, et al. The prevalence of depression in general hospital inpatients: a systematic review and meta-analysis of interview-based studies. Psychol Med. 2018;48(14):2285–98. https://doi.org/10.1017/S0033291718000624.
Wang J, Wu X, Lai W, Long E, Zhang X, Li W, et al. Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. BMJ Open. 2017;7(8): e017173. https://doi.org/10.1136/bmjopen-2017-017173.
Collaborators C-MD. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–12. https://doi.org/10.1016/S0140-6736(21)02143-7.
Benedetti F, Palladini M, Paolini M, Melloni E, Vai B, De Lorenzo R, et al. Brain correlates of depression, post-traumatic distress, and inflammatory biomarkers in COVID-19 survivors: A multimodal magnetic resonance imaging study. Brain Behav Immun Health. 2021;18:100387. https://doi.org/10.1016/j.bbih.2021.100387.
Benedetti F, Palladini M, D’Orsi G, Furlan R, Ciceri F, Rovere-Querini P, et al. Mood-congruent negative thinking styles and cognitive vulnerability in depressed COVID-19 survivors: a comparison with Major Depressive Disorder. J Affect Disord. 2022 (in press).
Mattioli F, Stampatori C, Righetti F, Sala E, Tomasi C, De Palma G. Neurological and cognitive sequelae of Covid-19: a four month follow-up. J Neurol. 2021;268(12):4422–8. https://doi.org/10.1007/s00415-021-10579-6.
Poletti S, Palladini M, Mazza MG, De Lorenzo R, group C-BOCS, Furlan R, et al. Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life. Eur Arch Psychiatry Clin Neurosci. 2021. https://doi.org/10.1007/s00406-021-01346-9.
Gouraud C, Bottemanne H, Lahlou-Laforet K, Blanchard A, Gunther S, Batti SE, et al. Association between psychological distress, cognitive complaints, and neuropsychological status after a severe COVID-19 episode: a cross-sectional study. Front Psychiatry. 2021;12:725861. https://doi.org/10.3389/fpsyt.2021.725861.
Alnefeesi Y, Siegel A, Lui LMW, Teopiz KM, Ho RCM, Lee Y, et al. Impact of SARS-CoV-2 infection on cognitive function: a systematic review. Front Psychiatry. 2020;11:621773. https://doi.org/10.3389/fpsyt.2020.621773.
Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139(3):230–9. https://doi.org/10.1016/j.jad.2011.08.003.
Poletti S, Mazza MG, Calesella F, Vai B, Lorenzi C, Manfredi E, et al. Circulating inflammatory markers impact cognitive functions in bipolar depression. J Psychiatr Res. 2021;140:110–6. https://doi.org/10.1016/j.jpsychires.2021.05.071.
Al-Jassas HK, Al-Hakeim HK, Maes M. Intersections between pneumonia, lowered oxygen saturation percentage and immune activation mediate depression, anxiety, and chronic fatigue syndrome-like symptoms due to COVID-19: a nomothetic network approach. J Affect Disord. 2022;15(297):233–45. https://doi.org/10.1016/j.jad.2021.10.039.
Mazza M, Palladini M, Poletti S, Benedetti FP. 0086 Clinical and psychopathological predictors of fatigue in COVID-19 survivors: a machine learning study. Eur Neuropsychopharmacol. 2021;53:S60–1.
Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE. 2020;15(11): e0240784. https://doi.org/10.1371/journal.pone.0240784.
Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, et al. Fatigue and cognitive impairment in Post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2021;29(101):93–135. https://doi.org/10.1016/j.bbi.2021.12.020.
Bottemanne H, Gouraud C, Hulot JS, Blanchard A, Ranque B, Lahlou-Laforet K, et al. Do anxiety and depression predict persistent physical symptoms after a severe COVID-19 episode? A prospective study. Front Psychiatry. 2021;12:757685. https://doi.org/10.3389/fpsyt.2021.757685.
Babicki M, Bogudzinska B, Kowalski K, Mastalerz-Migas A. Anxiety and depressive disorders and quality of life assessment of poles—a study covering two waves of the COVID-19 pandemic. Front Psychiatry. 2021;12:704248; https://doi.org/10.3389/fpsyt.2021.704248.
Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22. https://doi.org/10.1016/j.bbi.2020.03.031.
** Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020;12(4). https://doi.org/10.3390/v12040372.
Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes ESAC. The anti-inflammatory potential of ACE2/angiotensin-(1–7)/mas receptor axis: evidence from basic and clinical research. Curr Drug Targ. 2017;18(11):1301–13. https://doi.org/10.2174/1389450117666160727142401.
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607–13. https://doi.org/10.1016/j.**f.2020.03.037.
Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020;53:25–32. https://doi.org/10.1016/j.cytogfr.2020.05.003.
Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM. Glucocorticoids, cytokines and brain abnormalities in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):722–9. https://doi.org/10.1016/j.pnpbp.2010.04.011.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12. https://doi.org/10.1016/j.bbi.2016.03.010.
Stefano GB, Buttiker P, Weissenberger S, Martin A, Ptacek R, Kream RM. Editorial: the pathogenesis of long-term neuropsychiatric COVID-19 and the role of microglia, mitochondria, and persistent neuroinflammation: a hypothesis. Med Sci Monit. 2021;27:e933015; https://doi.org/10.12659/MSM.933015.
Hegazy HG, Ali EH, Elgoly AH. Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model. Cytokine. 2015;71(2):173–80. https://doi.org/10.1016/j.cyto.2014.10.027.
Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87(1):10–20. https://doi.org/10.1016/j.brainresbull.2011.10.004.
Balcioglu YH, Yesilkaya UH, Gokcay H, Kirlioglu SS. May the central nervous system be fogged by the cytokine storm in COVID-19?: an appraisal. J Neuroimmune Pharmacol. 2020;15(3):343–4. https://doi.org/10.1007/s11481-020-09932-9.
De Lorenzo R, Loré NI, Finardi A, Mandelli A, Cirillo DM, Tresoldi C, et al. Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients. J Neurol. 2021;268(12):4436–42.
Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552–5. https://doi.org/10.1002/jmv.25728.
Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699–702. https://doi.org/10.1002/jmv.25915.
Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol. 2020;77(8):1018–27. https://doi.org/10.1001/jamaneurol.2020.2065.
Daly JL, Simonetti B, Klein K, Chen KE, Williamson MK, Anton-Plagaro C, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science. 2020;370(6518):861–5. https://doi.org/10.1126/science.abd3072.
Esposito G, Pesce M, Seguella L, Sanseverino W, Lu J, Sarnelli G. Can the enteric nervous system be an alternative entrance door in SARS-CoV2 neuroinvasion? Brain Behav Immun. 2020;87:93–4; https://doi.org/10.1016/j.bbi.2020.04.060.
Arbour N, Day R, Newcombe J, Talbot PJ. Neuroinvasion by human respiratory coronaviruses. J Virol. 2000;74(19):8913–21. https://doi.org/10.1128/jvi.74.19.8913-8921.2000.
Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19(11):919–29. https://doi.org/10.1016/S1474-4422(20)30308-2.
Spudich S, Nath A. Nervous system consequences of COVID-19. Science. 2022;375(6578):267–9. https://doi.org/10.1126/science.abm2052.
Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev. 2018;98(1):477–504. https://doi.org/10.1152/physrev.00039.2016.
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuroinflammation and psychiatric illness. J Neuroinflamm. 2013;10:43. https://doi.org/10.1186/1742-2094-10-43.
Benedetti F, Aggio V, Pratesi ML, Greco G, Furlan R. Neuroinflammation in bipolar depression. Front Psychiatry. 2020;11:71. https://doi.org/10.3389/fpsyt.2020.00071.
Maes M, Vandoolaeghe E, Ranjan R, Bosmans E, Bergmans R, Desnyder R. Increased serum interleukin-1-receptor-antagonist concentrations in major depression. J Affect Disord. 1995;36(1–2):29–36. https://doi.org/10.1016/0165-0327(95)00049-6.
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24(1):27–53. https://doi.org/10.1007/s11011-008-9118-1.
Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in depression. Brain Behav Immun. 2011;25(2):221–9. https://doi.org/10.1016/j.bbi.2010.10.008.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17(8):497–511. https://doi.org/10.1038/nrn.2016.69.
Simon MS, Schiweck C, Arteaga-Henríquez G, Poletti S, Haarman BC, Dik WA, et al. Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021;111: 110391.
Cheng Y, Desse S, Martinez A, Worthen RJ, Jope RS, Beurel E. TNFalpha disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav Immun. 2018;69:556–67; https://doi.org/10.1016/j.bbi.2018.02.003.
Halaris A. Inflammation and depression but where does the inflammation come from? Curr Opin Psychiatry. 2019;32(5):422–8. https://doi.org/10.1097/YCO.0000000000000531.
Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17(8):524–32. https://doi.org/10.1038/nrn.2016.57.
Borroto-Escuela DO, Ambrogini P, Chruscicka B, Lindskog M, Crespo-Ramirez M, Hernandez-Mondragon JC, et al. The role of central serotonin neurons and 5-HT heteroreceptor complexes in the pathophysiology of depression: a historical perspective and future prospects. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22041927.
Onaolapo AY, Onaolapo OJ. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule. World J Psychiatry. 2021;11(7):297–315. https://doi.org/10.5498/wjp.v11.i7.297.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56. https://doi.org/10.1038/nrn2297.
Paul ER, Schwieler L, Erhardt S, Boda S, Trepci A, Kampe R, et al. Peripheral and central kynurenine pathway abnormalities in major depression. Brain Behav Immun. 2022;6(101):136–45. https://doi.org/10.1016/j.bbi.2022.01.002.
Ogyu K, Kubo K, Noda Y, Iwata Y, Tsugawa S, Omura Y, et al. Kynurenine pathway in depression: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2018;90:16–25. https://doi.org/10.1016/j.neubiorev.2018.03.023.
Lorkiewicz P, Waszkiewicz N. Biomarkers of post-COVID depression. J Clin Med. 2021;10(18):4142.
Ida T, Hara M, Nakamura Y, Kozaki S, Tsunoda S, Ihara H. Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide. Neurosci Lett. 2008;432(3):232–6. https://doi.org/10.1016/j.neulet.2007.12.047.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732–41. https://doi.org/10.1016/j.biopsych.2008.11.029.
Wake H, Moorhouse AJ, **no S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29(13):3974–80. https://doi.org/10.1523/JNEUROSCI.4363-08.2009.
Eyo UB, Wu LJ. Bidirectional microglia-neuron communication in the healthy brain. Neural Plast. 2013;2013:456857. https://doi.org/10.1155/2013/456857.
Lindenau J, Noack H, Asayama K, Wolf G. Enhanced cellular glutathione peroxidase immunoreactivity in activated astrocytes and in microglia during excitotoxin induced neurodegeneration. Glia. 1998;24(2):252–6.
Enache D, Pariante CM, Mondelli V. Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun. 2019;81:24–40. https://doi.org/10.1016/j.bbi.2019.06.015.
Tremblay ME, Madore C, Bordeleau M, Tian L, Verkhratsky A. Neuropathobiology of COVID-19: the role for glia. Front Cell Neurosci. 2020;14:592214. https://doi.org/10.3389/fncel.2020.592214.
Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet Microbe. 2020;1(6):e245–53. https://doi.org/10.1016/S2666-5247(20)30115-4.
Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018;15:490–503. https://doi.org/10.1016/j.redox.2018.01.008.
Maes M, Galecki P, Chang YS, Berk M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):676–92. https://doi.org/10.1016/j.pnpbp.2010.05.004.
Morris G, Berk M, Klein H, Walder K, Galecki P, Maes M. Nitrosative stress, hypernitrosylation, and autoimmune responses to nitrosylated proteins: new pathways in neuroprogressive disorders including depression and chronic fatigue syndrome. Mol Neurobiol. 2017;54(6):4271–91. https://doi.org/10.1007/s12035-016-9975-2.
Raony I, de Figueiredo CS, Pandolfo P, Giestal-de-Araujo E, Oliveira-Silva Bomfim P, Savino W. Psycho-neuroendocrine-immune interactions in COVID-19: potential impacts on mental health. Front Immunol. 2020;11:1170. https://doi.org/10.3389/fimmu.2020.01170.
Turrin NP, Rivest S. Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems. Exp Biol Med (Maywood). 2004;229(10):996–1006. https://doi.org/10.1177/153537020422901003.
Pariante CM. Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation. Eur Neuropsychopharmacol. 2017;27(6):554–9. https://doi.org/10.1016/j.euroneuro.2017.04.001.
Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science. 1984;226(4680):1342–4. https://doi.org/10.1126/science.6334362.
Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25(2):181–213. https://doi.org/10.1016/j.bbi.2010.10.015.
Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054–9. https://doi.org/10.1038/nature04671.
Bourgognon JM, Cavanagh J. The role of cytokines in modulating learning and memory and brain plasticity. Brain Neurosci Adv. 2020;4:2398212820979802. https://doi.org/10.1177/2398212820979802.
Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;29(246):199–229. https://doi.org/10.1016/j.neuroscience.2013.04.060.
Benedetti F, Poletti S, Hoogenboezem TA, Mazza E, Ambrée O, de Wit H, et al. Inflammatory cytokines influence measures of white matter integrity in bipolar disorder. J Affect Disord. 2016;202:1–9.
Singh S, Roy D, Sinha K, Parveen S, Sharma G, Joshi G. Impact of COVID-19 and lockdown on mental health of children and adolescents: a narrative review with recommendations. Psychiatry Res. 2020;293:113429. https://doi.org/10.1016/j.psychres.2020.113429.
Guo Q, Zheng Y, Shi J, Wang J, Li G, Li C, et al. Immediate psychological distress in quarantined patients with COVID-19 and its association with peripheral inflammation: a mixed-method study. Brain Behav Immun. 2020;88:17–27. https://doi.org/10.1016/j.bbi.2020.05.038.
Cava MA, Fay KE, Beanlands HJ, McCay EA, Wignall R. The experience of quarantine for individuals affected by SARS in Toronto. Public Health Nurs. 2005;22(5):398–406. https://doi.org/10.1111/j.0737-1209.2005.220504.x.
**n M, Luo S, She R, Yu Y, Li L, Wang S, et al. Negative cognitive and psychological correlates of mandatory quarantine during the initial COVID-19 outbreak in China. Am Psychol. 2020;75(5):607–17. https://doi.org/10.1037/amp0000692.
Mumtaz F, Khan MI, Zubair M, Dehpour AR. Neurobiology and consequences of social isolation stress in animal model—a comprehensive review. Biomed Pharmacother. 2018;105:1205–22; https://doi.org/10.1016/j.biopha.2018.05.086.
Juruena MF, Eror F, Cleare AJ, Young AH. The role of early life stress in HPA axis and anxiety. Adv Exp Med Biol. 2020;1191:141–53. https://doi.org/10.1007/978-981-32-9705-0_9.
Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology. 1994;60(4):436–44. https://doi.org/10.1159/000126778.
Cruz-Pereira JS, Rea K, Nolan YM, O’Leary OF, Dinan TG, Cryan JF. Depression’s unholy trinity: dysregulated stress, immunity, and the microbiome. Annu Rev Psychol. 2020;4(71):49–78. https://doi.org/10.1146/annurev-psych-122216-011613.
Walker FR, Nilsson M, Jones K. Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr Drug Targ. 2013;14(11):1262–76. https://doi.org/10.2174/13894501113149990208.
Mullins N, Power RA, Fisher HL, Hanscombe KB, Euesden J, Iniesta R, et al. Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. Psychol Med. 2016;46(4):759–70. https://doi.org/10.1017/S0033291715002172.
Poletti S, Aggio V, Brioschi S, Bollettini I, Falini A, Colombo C, et al. Impact of early and recent stress on white matter microstructure in major depressive disorder. J Affect Disord. 2018;1(225):289–97. https://doi.org/10.1016/j.jad.2017.08.017.
Vai B, Serretti A, Poletti S, Mascia M, Lorenzi C, Colombo C, et al. Cortico-limbic functional connectivity mediates the effect of early life stress on suicidality in bipolar depressed 5-HTTLPR*s carriers. J Affect Disord. 2020;15(263):420–7. https://doi.org/10.1016/j.jad.2019.11.142.
Poletti S, Aggio V, Brioschi S, Dallaspezia S, Colombo C, Benedetti F. Multidimensional cognitive impairment in unipolar and bipolar depression and the moderator effect of adverse childhood experiences. Psychiatry Clin Neurosci. 2017;71(5):309–17. https://doi.org/10.1111/pcn.12497.
Ahmed GK, Khedr EM, Hamad DA, Meshref TS, Hashem MM, Aly MM. Long term impact of Covid-19 infection on sleep and mental health: a cross-sectional study. Psychiatry Res. 2021;305:114243. https://doi.org/10.1016/j.psychres.2021.114243.
He X, Zhang D, Zhang L, Zheng X, Zhang G, Pan K, et al. Neurological and psychiatric presentations associated with COVID-19. Eur Arch Psychiatry Clin Neurosci. 2022;272(1):41–52. https://doi.org/10.1007/s00406-021-01244-0.
Hu Y, Chen Y, Zheng Y, You C, Tan J, Hu L, et al. Factors related to mental health of inpatients with COVID-19 in Wuhan, China. Brain Behav Immun. 2020;89:587–93. https://doi.org/10.1016/j.bbi.2020.07.016.
Iglesias-Gonzalez M, Boigues M, Sanagustin D, Giralt-Lopez M, Cuevas-Esteban J, Martinez-Caceres E, et al. Association of serum interleukin-6 and C-reactive protein with depressive and adjustment disorders in COVID-19 inpatients. Brain Behav Immun Health. 2022;19:100405. https://doi.org/10.1016/j.bbih.2021.100405.
Kahve AC, Kaya H, Okuyucu M, Goka E, Barun S, Hacimusalar Y. Do anxiety and depression levels affect the inflammation response in patients hospitalized for COVID-19. Psychiatry Investig. 2021;18(6):505–12. https://doi.org/10.30773/pi.2021.0029.
Yuan B, Li W, Liu H, Cai X, Song S, Zhao J, et al. Correlation between immune response and self-reported depression during convalescence from COVID-19. Brain Behav Immun. 2020;88:39–43. https://doi.org/10.1016/j.bbi.2020.05.062.
Huarcaya-Victoria J, Barreto J, Aire L, Podesta A, Caqui M, Guija-Igreda R, et al. Mental health in COVID-2019 survivors from a general hospital in peru: sociodemographic, clinical, and inflammatory variable associations. Int J Ment Health Addict. 2021. https://doi.org/10.1007/s11469-021-00659-z.
Li X, Cai Q, Jia Z, Zhou Y, Liu L, Zhou Y, et al. The correlation between mental health status, sleep quality, and inflammatory markers, virus negative conversion time among patients confirmed with 2019-nCoV during the COVID-19 outbreak in China: an observational study. Medicine (Baltimore). 2021;100(27): e26520. https://doi.org/10.1097/MD.0000000000026520.
Serrano Garcia A, Montanchez Mateo J, Franch Pato CM, Gomez Martinez R, Garcia Vazquez P, Gonzalez RI. Interleukin 6 and depression in patients affected by Covid-19. Med Clin (Engl Ed). 2021;156(7):332–5. https://doi.org/10.1016/j.medcle.2020.11.013.
Zhou F, Wang RR, Huang HP, Du CL, Wu CM, Qian XM, et al. A randomized trial in the investigation of anxiety and depression in patients with coronavirus disease 2019 (COVID-19). Ann Palliat Med. 2021;10(2):2167–74; https://doi.org/10.21037/apm-21-212.
Wu C, Zhou Z, Ni L, Cao J, Tan M, Wu X, et al. Correlation between anxiety-depression symptoms and immune characteristics in inpatients with 2019 novel coronavirus in Wuhan, China. J Psychiatr Res. 2021;141:378–84; https://doi.org/10.1016/j.jpsychires.2021.07.027.
Peckham H, de Gruijter NM, Raine C, Radziszewska A, Ciurtin C, Wedderburn LR, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11(1):6317. https://doi.org/10.1038/s41467-020-19741-6.
Albert PR. Why is depression more prevalent in women? J Psychiatry Neurosci. 2015;40(4):219–21. https://doi.org/10.1503/jpn.150205.
Marquez EJ, Chung CH, Marches R, Rossi RJ, Nehar-Belaid D, Eroglu A, et al. Sexual-dimorphism in human immune system aging. Nat Commun. 2020;11(1):751. https://doi.org/10.1038/s41467-020-14396-9.
Bonafe M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, et al. A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol. 2001;31(8):2357–61. https://doi.org/10.1002/1521-4141(200108)31:8%3c2357::aid-immu2357%3e3.0.co;2-x.
Mazza MG, Lucchi S, Tringali AGM, Rossetti A, Botti ER, Clerici M. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):229–36. https://doi.org/10.1016/j.pnpbp.2018.03.012.
Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Goncalves CA, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(12):1147–56. https://doi.org/10.1016/S2215-0366(16)30370-4.
Davydow DS, Hough CL, Zivin K, Langa KM, Katon WJ. Depression and risk of hospitalization for pneumonia in a cohort study of older Americans. J Psychosom Res. 2014;77(6):528–34. https://doi.org/10.1016/j.jpsychores.2014.08.002.
Kao LT, Liu SP, Lin HC, Lee HC, Tsai MC, Chung SD. Poor clinical outcomes among pneumonia patients with depressive disorder. PLoS ONE. 2014;9(12): e116436. https://doi.org/10.1371/journal.pone.0116436.
Papaioannou AI, Bartziokas K, Tsikrika S, Karakontaki F, Kastanakis E, Banya W, et al. The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations. Eur Respir J. 2013;41(4):815–23. https://doi.org/10.1183/09031936.00013112.
Facente SN, Reiersen AM, Lenze EJ, Boulware DR, Klausner JD. Fluvoxamine for the early treatment of SARS-CoV-2 infection: a review of current evidence. Drugs. 2021;81(18):2081–9. https://doi.org/10.1007/s40265-021-01636-5.
Hashimoto Y, Suzuki T, Hashimoto K. Mechanisms of action of fluvoxamine for COVID-19: a historical review. Mol Psychiatry. 2022. https://doi.org/10.1038/s41380-021-01432-3.
Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs. placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292–300. https://doi.org/10.1001/jama.2020.22760.
Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022;10(1):e42–51. https://doi.org/10.1016/S2214-109X(21)00448-4.
Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis. 2021;8(2):ofab050. https://doi.org/10.1093/ofid/ofab050.
Hoertel N, Sanchez-Rico M, Cougoule C, Gulbins E, Kornhuber J, Carpinteiro A, et al. Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-021-01254-3.
Pashaei Y. Drug repurposing of selective serotonin reuptake inhibitors: could these drugs help fight COVID-19 and save lives? J Clin Neurosci. 2021;88:163–72. https://doi.org/10.1016/j.jocn.2021.03.010.
Lu Y, Ho CS, Liu X, Chua AN, Wang W, McIntyre RS, et al. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS ONE. 2017;12(10): e0186700. https://doi.org/10.1371/journal.pone.0186700.
Carpinteiro A, Edwards MJ, Hoffmann M, Kochs G, Gripp B, Weigang S, et al. Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells. Cell Rep Med. 2020;1(8): 100142. https://doi.org/10.1016/j.xcrm.2020.100142.
Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. Identification of novel functional inhibitors of acid sphingomyelinase. PLoS ONE. 2011;6(8): e23852. https://doi.org/10.1371/journal.pone.0023852.
Homolak J, Kodvanj I. Widely available lysosome targeting agents should be considered as potential therapy for COVID-19. Int J Antimicrob Agents. 2020;56(2): 106044. https://doi.org/10.1016/j.ijantimicag.2020.106044.
Schlienger RG, Meier CR. Effect of selective serotonin reuptake inhibitors on platelet activation: can they prevent acute myocardial infarction? Am J Cardiovasc Drugs. 2003;3(3):149–62. https://doi.org/10.2165/00129784-200303030-00001.
Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme VV. Fluvoxamine: a review of its mechanism of action and its role in COVID-19. Front Pharmacol. 2021;12:652688. https://doi.org/10.3389/fphar.2021.652688.
Anderson G, Reiter RJ. Melatonin: Roles in influenza, Covid-19, and other viral infections. Rev Med Virol. 2020;30(3): e2109. https://doi.org/10.1002/rmv.2109.
Anderson GM. Fluvoxamine, melatonin and COVID-19. Psychopharmacology. 2021;238(2):611. https://doi.org/10.1007/s00213-020-05753-z.
Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;250:117583. https://doi.org/10.1016/j.lfs.2020.117583.
Mazza MG, Zanardi R, Palladini M, Rovere-Querini P, Benedetti F. Rapid response to selective serotonin reuptake inhibitors in post-COVID depression. Eur Neuropsychopharmacol. 2022;54:1–6. https://doi.org/10.1016/j.euroneuro.2021.09.009.
Kohler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol Neurobiol. 2018;55(5):4195–206. https://doi.org/10.1007/s12035-017-0632-1.
Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A. Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology. 2011;61(4):592–9. https://doi.org/10.1016/j.neuropharm.2011.04.033.
Eskelund A, Li Y, Budac DP, Muller HK, Gulinello M, Sanchez C, et al. Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior. J Neurochem. 2017;142(1):118–31. https://doi.org/10.1111/jnc.14043.
Fei L, Santarelli G, D'Anna G, Moretti S, Mirossi G, Patti A, et al. Can SSRI/SNRI antidepressants decrease the 'cytokine storm' in the course of COVID-19 pneumonia? Panminerva Med. 2021. https://doi.org/10.23736/S0031-0808.21.04436-0.
Benedetti F, Mazza M, Cavalli G, Ciceri F, Dagna L, Rovere-Querini P. Can cytokine blocking prevent depression in COVID-19 survivors? J Neuroimmune Pharmacol. 2021;16(1):1–3. https://doi.org/10.1007/s11481-020-09966-z.
Farnoosh G, Akbariqomi M, Badri T, Bagheri M, Izadi M, Saeedi-Boroujeni A, et al. Efficacy of a low dose of melatonin as an adjunctive therapy in hospitalized patients with COVID-19: a randomized, double-blind clinical trial. Arch Med Res. 2022;53(1):79–85. https://doi.org/10.1016/j.arcmed.2021.06.006.
Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, et al. A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biol. 2020;18(11): e3000970. https://doi.org/10.1371/journal.pbio.3000970.
Hooper PL. Heme oxygenase agonists-fluvoxamine, melatonin-are efficacious therapy for Covid-19. Cell Stress Chaperones. 2022;27(1):3–4. https://doi.org/10.1007/s12192-021-01246-w.
Cardinali DP, Srinivasan V, Brzezinski A, Brown GM. Melatonin and its analogs in insomnia and depression. J Pineal Res. 2012;52(4):365–75. https://doi.org/10.1111/j.1600-079X.2011.00962.x.
Stanford SC. Recent developments in research of melatonin and its potential therapeutic applications. Br J Pharmacol. 2018;175(16):3187–9. https://doi.org/10.1111/bph.14371.
Ali T, Rahman SU, Hao Q, Li W, Liu Z, Ali Shah F, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res. 2020;69(2): e12667. https://doi.org/10.1111/jpi.12667.
Estrada-Reyes R, Valdes-Tovar M, Arrieta-Baez D, Dorantes-Barron AM, Quero-Chavez D, Solis-Chagoyan H, et al. The timing of melatonin administration is crucial for its antidepressant-like effect in mice. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19082278.
Valdes-Tovar M, Estrada-Reyes R, Solis-Chagoyan H, Argueta J, Dorantes-Barron AM, Quero-Chavez D, et al. Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression. Br J Pharmacol. 2018;175(16):3200–8. https://doi.org/10.1111/bph.14197.
Guaiana G, Gupta S, Chiodo D, Davies SJ, Haederle K, Koesters M. Agomelatine versus other antidepressive agents for major depression. Cochrane Database Syst Rev. 2013;17(12):CD008851. https://doi.org/10.1002/14651858.CD008851.pub2.
De Berardis D, Fornaro M, Orsolini L, Iasevoli F, Tomasetti C, de Bartolomeis A, et al. Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: an exploratory study in “real-world,” everyday clinical practice. CNS Spectr. 2017;22(4):342–7. https://doi.org/10.1017/S1092852916000572.
Molteni R, Macchi F, Zecchillo C, Dell’agli M, Colombo E, Calabrese F, et al. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur Neuropsychopharmacol. 2013;23(11):1645–55. https://doi.org/10.1016/j.euroneuro.2013.03.008.
Tchekalarova J, Atanasova D, Kortenska L, Atanasova M, Lazarov N. Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling. Neurobiol Dis. 2018;115:127–44. https://doi.org/10.1016/j.nbd.2018.04.005.
Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med. 2020;76:43–9. https://doi.org/10.1016/j.ejim.2020.05.021.
Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325–31. https://doi.org/10.1016/S2665-9913(20)30127-2.
Arteaga-Henriquez G, Simon MS, Burger B, Weidinger E, Wijkhuijs A, Arolt V, et al. Low-grade inflammation as a predictor of antidepressant and anti-inflammatory therapy response in MDD patients: a systematic review of the literature in combination with an analysis of experimental data collected in the EU-MOODINFLAME consortium. Front Psychiatry. 2019;10:458. https://doi.org/10.3389/fpsyt.2019.00458.
Bschor T. Lithium in the treatment of major depressive disorder. Drugs. 2014;74(8):855–62. https://doi.org/10.1007/s40265-014-0220-x.
Del Matto L, Muscas M, Murru A, Verdolini N, Anmella G, Fico G, et al. Lithium and suicide prevention in mood disorders and in the general population: a systematic review. Neurosci Biobehav Rev. 2020;116:142–53; https://doi.org/10.1016/j.neubiorev.2020.06.017.
Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs. 2013;27(2):135–53. https://doi.org/10.1007/s40263-013-0039-0.
Pietruczuk K, Lisowska KA, Grabowski K, Landowski J, Witkowski JM. Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder. Sci Rep. 2018;8(1):3327. https://doi.org/10.1038/s41598-018-21769-0.
Nassar A, Azab AN. Effects of lithium on inflammation. ACS Chem Neurosci. 2014;5(6):451–8. https://doi.org/10.1021/cn500038f.
Murru A, Manchia M, Hajek T, Nielsen RE, Rybakowski JK, Sani G, et al. Lithium’s antiviral effects: a potential drug for CoViD-19 disease? Int J Bipolar Disord. 2020;8(1):21. https://doi.org/10.1186/s40345-020-00191-4.
Spuch C, Lopez-Garcia M, Rivera-Baltanas T, Rodrigues-Amorim D, Olivares JM. Does lithium deserve a place in the treatment against COVID-19? A preliminary observational study in six patients, case report. Front Pharmacol. 2020;11:557629. https://doi.org/10.3389/fphar.2020.557629.
Benedetti F, Bollettini I, Barberi I, Radaelli D, Poletti S, Locatelli C, et al. Lithium and GSK3-β promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology. 2013;38(2):313–27.
Furlan R, Melloni E, Finardi A, Vai B, Di Toro S, Aggio V, et al. Natural killer cells protect white matter integrity in bipolar disorder. Brain Behav Immun. 2019;81:410–21.
Gomez L, Vidal B, Cabrera Y, Hernandez L, Rondon Y. Successful treatment of post-COVID symptoms with transcranial direct current stimulation. Prim Care Companion CNS Disord. 2021. https://doi.org/10.4088/PCC.21cr03059.
Zhang R, Lam CLM, Peng X, Zhang D, Zhang C, Huang R, et al. Efficacy and acceptability of transcranial direct current stimulation for treating depression: a meta-analysis of randomized controlled trials. Neurosci Biobehav Rev. 2021;126:481–90. https://doi.org/10.1016/j.neubiorev.2021.03.026.
Perrin AJ, Pariante CM. Endocrine and immune effects of non-convulsive neurostimulation in depression: a systematic review. Brain Behav Immun. 2020;87:910–20; https://doi.org/10.1016/j.bbi.2020.02.016.
Rajkumar RP. Ayurveda and COVID-19: where psychoneuroimmunology and the meaning response meet. Brain Behav Immun. 2020;87:8–9. https://doi.org/10.1016/j.bbi.2020.04.056.
Sarris J. Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res. 2018;32(7):1147–62. https://doi.org/10.1002/ptr.6055.
Yadav B, Rai A, Mundada PS, Singhal R, Rao BCS, Rana R, et al. Safety and efficacy of Ayurvedic interventions and Yoga on long term effects of COVID-19: a structured summary of a study protocol for a randomized controlled trial. Trials. 2021;22(1):378. https://doi.org/10.1186/s13063-021-05326-1.
Thimmulappa RK, Mudnakudu-Nagaraju KK, Shivamallu C, Subramaniam KJT, Radhakrishnan A, Bhojraj S, et al. Antiviral and immunomodulatory activity of curcumin: a case for prophylactic therapy for COVID-19. Heliyon. 2021;7(2): e06350. https://doi.org/10.1016/j.heliyon.2021.e06350.
Soni VK, Mehta A, Shukla D, Kumar S, Vishvakarma NK. Fight COVID-19 depression with immunity booster: Curcumin for psychoneuroimmunomodulation. Asian J Psychiatr. 2020;53:102378. https://doi.org/10.1016/j.ajp.2020.102378.
Buemann B, Marazziti D, Uvnas-Moberg K. Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients? World J Biol Psychiatry. 2021;22(5):387–98; https://doi.org/10.1080/15622975.2020.1814408.
Thakur P, Shrivastava R, Shrivastava VK. Oxytocin as a potential adjuvant against COVID-19 infection. Endocr Metab Immune Disord Drug Targ. 2021;21(7):1155–62. https://doi.org/10.2174/1871530320666200910114259.
Benedetti F, Zanardi R, Mazza MG. Antidepressant psychopharmacology: is inflammation a future target? Int Clin Psychopharmacol. 2022;37(3):79–81. https://doi.org/10.1097/YIC.0000000000000403.
Cheng YC, Kuo PH, Su MI, Huang WL. The efficacy of non-invasive, non-convulsive electrical neuromodulation on depression, anxiety and sleep disturbance: a systematic review and meta-analysis. Psychol Med. 2022. https://doi.org/10.1017/S0033291721005560.
Dallaspezia S, Suzuki M, Benedetti F. Chronobiological therapy for mood disorders. Curr Psychiatry Rep. 2015;17(12):95. https://doi.org/10.1007/s11920-015-0633-6.
Sarris J, Ravindran A, Yatham LN, Marx W, Rucklidge JJ, McIntyre RS, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022. https://doi.org/10.1080/15622975.2021.2013041.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
None.
Conflict of interest
MGM, MP, SP, and FB declare that they have no conflicts of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Code availability
Not applicable.
Author contributions
MGM supervised the entire process, MGM and MP performed the literature search. MGM, MP, and SP drafted the manuscript. All authors critically revised the work. All authors have read and approved the final submitted manuscript, and agree to be accountable for the work.
Rights and permissions
About this article
Cite this article
Mazza, M.G., Palladini, M., Poletti, S. et al. Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment. CNS Drugs 36, 681–702 (2022). https://doi.org/10.1007/s40263-022-00931-3
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-022-00931-3