While the COVID-19 pandemic remains a major global health challenge, research has advanced in understanding the highly heterogeneous and multisystem manifestations of the infection. Neuropsychiatric symptoms in patients with COVID-19, either as new-onset manifestations or exacerbations or relapses of preexisting conditions, have been repeatedly reported (1–4). Those are thought to be caused by the direct and indirect effects of the virus on the brain and by the psychosocial stressors brought up by the pandemic and containment measures (5, 6). Estimates of the prevalence of neurological and psychiatric symptoms in patients with COVID-19 are one-fifth and one-half, respectively (3). The neuropsychiatric manifestations of COVID-19 have been categorized into three distinct groups: olfactory symptoms; headache and limb force reduction; photophobia, hallucinations, mental state change, vision and speech problems, seizure, stroke, and ataxia (7). New-onset psychiatric illness has been identified in 5.8% of COVID-19 survivors within 14–90 days since the COVID-19 diagnosis (8).

Bipolar disorder (BD) is a spectrum of chronic, episodic, and highly disabling mood disorders with a lifetime prevalence of about 2.4% (9, 10) and is associated with poor health and reduced life expectancy due to psychiatric and general medical conditions, including suicide, respiratory and cardiovascular diseases, and cancer (11–13). A typical presentation of new-onset BD is first-episode mania, in which people without a previously known history of BD exhibit symptoms such as elevated or dysphoric mood, grandiosity, irritability, increased psychomotor activity, behavioral disinhibition, decreased need for sleep, distractibility, and, severe cases of, psychotic features such as delusions and hallucinations congruent with the mood (14). There have been increasing reports of first manic episodes in people within days after being infected by SARS-CoV-2 (15–22). While actual the causality, correlation, and pathophysiology of mania following COVID-19 are not yet understood, previous research associating BD with immune and inflammatory dysfunctions (23, 24) shows a way to study mania after COVID-19 as a possible result of direct and indirect brain effects of the virus.

Being first-episode mania, and consequently new-onset BD, a potential, rare yet very severe complication of COVID-19, it is paramount to identify affected individuals and characterize its manifestations and course. This study presents an original case series of 12 individuals presenting with first-episode mania within a month of being infected with COVID-19. It includes an overview of the series showing the most remarkable demographic and clinical details (symptoms, medical workup, treatment, etc.) of each case alongside two illustrative detailed cases. The series is accompanied by a compilation of other case reports previously published in international scientific literature to provide a more comprehensive and global understanding of the phenomenon and promote further discussion, data sharing, and research on the topic.

This original case series aimed to document the clinical presentation, associated stressors, family aggregation patterns, and brain imaging and electroencephalographic correlates in hospitalized patients with post-COVID first-episode mania. Patients’ records were included in the series if they had their first manic episode within a month of COVID-19 infection and were excluded if patients were abusing substances or had any past medical history of a psychiatric or neurological disorder.

Twelve patients were included; they had attended Rasool-e-Akram hospital and Iran psychiatric hospital, two tertiary medical centers in Tehran, Iran, and were diagnosed with bipolar disorder type 1 (currently in the first episode of mania) by an experienced psychiatrist after a complete psychiatric assessment. COVID-19 had been diagnosed by an infectious disease specialist based on a positive RNA test and/or a spiral chest computerized tomography (CT) scan, these findings were reported by an experienced radiologist. Nine out of 12 patients had agreed to undergo brain magnetic resonance imaging (MRI) during hospitalization. Additional demographic and clinical data were collected by psychiatry residents through face-to-face interviews with the patients and their families during their hospitalization and through chart reviews of patients’ records. Information of interest included demographic details, past medical, psychiatric, substance, drug, family history, COVID-19 symptoms and diagnostic methods, treatment records, and paraclinical data. Descriptive statistics were obtained using SPSS v.16.0 software (SPSS Inc., Chicago, IL, United States).

Informed consent for inclusion in the reported series was obtained from all patients and their families, and the study follows the Helsinki Declaration (current version, 2013).

This case series included 12 patients with a mean age of 44 (median: 43, range: 32–69) including seven men and five women. Patients’ characteristics are presented in Tables 1-1 and 1-2. The interval between the onset of symptoms of COVID-19 and mania ranged between 0 and 28 days (mean: 16.25 days, median: 14 days). Five out of 12 patients had a family history of mood disorders (cases 2, 4, 6, 7, and 8; see tables for correspondence), and eight out of 12 patients had received corticosteroids as a treatment for COVID-19 (cases 1, 2, 3, 6, 7, 8, 11, and 12; see tables for correspondence). None of the patients had a previous personal psychiatric history and only one had past substance use (methamphetamine). Findings from neurological examination and imaging were unremarkable for all patients. There was no observed relevant difference between men and women regarding the long interval between the onset of symptoms of COVID-19 and mania onset (mean: 15.43 days for men, and 17.4 for women).

Patients with a family history of mood disorders had an observed shorter average interval (mean: 13.2, median: 14 days) compared to those with a negative family history (mean: 18.43, median: 21 days). The median interval between COVID-19 symptoms and mania onset was similar in patients with and without corticosteroid treatment and in those with a mood disorder family history (the median for all three groups was 14 days), while individuals without a mood disorder family history had a longer median interval of 21 days.

The Mann–Whitney U test was chosen from the nonparametric tests. There was no significant relationship between the family history of mood disorder and the distance between the onset of mania and COVID-19 (p value = 0.722), as well as the use or non-use of corticosteroids. There was no significant relationship between the time interval between the onset of mania and COVID-19 (p value = 0.308).

Our case series includes 12 patients with similar presentations of manic episodes within a month of being infected with COVID-19, which bears similarities with other cases reported in the international scientific literature. While inferences and generalizations cannot be made through the clinical description of a local, small sample, and an actual association between COVID-19 and mania cannot be confirmed beyond temporal concurrence, our observations provide valuable insights for the formulation of hypotheses and the design of future systematic observations and inferential research.

The emergence of psychopathology during a major infectious disease outbreak such as COVID-19 manifested as new-onset, relapse, or exacerbation is understood as possibly associated with direct and indirect neurotropic effects of pathogens and the immune response they trigger, as well as with the psychological stress produced by the trauma and social and economic impacts of the outbreak and containment measures (29–32). COVID-19 is a particular case of a global pandemic with a massive social impact caused by a virus with neurotropic potential (31, 33), which makes it plausible to trigger manic relapses in patients with BD and new-onset episodes in predisposed individuals, especially those with a family history of BD. In these regards, insights from scientific literature related to the neuropsychiatric effects of viral diseases and the mental health impact of disasters are relevant to contextualize the discussion of our case series.

Regarding potential neurotropic pathways for COVID-19 to trigger manic episodes, previous research has associated several viral infections with BD, including Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis B virus (HBV), and hepatitis C virus (HCV) (34–38). It has been hypothesized that an immune/inflammatory mechanism could induce changes in neurotransmitters at the limbic network (39), and several studies have found associations between BD and inflammation (34, 35, 40, 41). One study found increased C reactive protein during acute episodes of BD (42); another study reported a significant difference in peripheral blood lymphocytes which correlated with each phase of BD type 2, suggesting that cytotoxic T lymphocytes would migrate from blood to the brain in acute episodes of BD (43). As T cells are known for their defensive role against intercellular pathogens, especially viruses (44), these data support an underlying immune mechanism for BD and could help clarify the emergence of mania during acute infection by SARS-CoV-2. There has been a brain organoid study in which both indirect neuroinflammation and direct neuronal invasion of the virus have played a role in the neuropsychiatric manifestations of COVID-19 (33).

In terms of psychosocial stressors, Matsumoto et al. documented manic episodes in patients with BD in remission during the Great East Japan Earthquake and subsequent Fukushima nuclear disaster; notably, those BD relapses consisted more in manic rather than depressive episodes and were more observed in women than men (45). The COVID-19 pandemic unleashed a wide array of acute and chronic stressors including fear of being infected or infecting others, restrictive nationwide lockdown policies facilitating social isolation, domestic violence, boredom, inappropriate sleep hygiene, financial strain, trauma, and grief associated with the loss of loved ones, misinformation, insufficient social support of vulnerable populations, including the elderly with cognitive decline, social stigma, and limited access to care (46–48).

Patients with a family history of BD in our series had an earlier mania onset while they had normal or unremarkable paraclinical data. While speculative, it might be possible that psychosocial stress and treatment with corticosteroids would be the main triggers of acute mania in those with a family history, while neurotropic damage by the virus would have a more prominent role in cases without such evident genetic vulnerability. However, in previous case reports some patients with a family history presented abnormal neuroimaging findings (19, 25).

Corticosteroid therapy is one of the major components of the treatment of many cases of severe COVID-19, and it poses a well-known potential to induce acute neuropsychiatric conditions, including typically, mania, which gives them a possible relevant role in some of our cases. Corticosteroid-induced psychiatric symptoms are dose-dependent and tend to occur during the first weeks after initiation (49, 50). The main underlying mechanisms are unclear but there is evidence of disturbances in glucocorticoid stimulation and mineralocorticoid receptor stimulation which cause glutamate-induced neuronal toxicity (51). To note, there seemed to be no relevant difference in the interval between COVID-19 and mania onset in patients receiving those treatments in our series as compared to those not receiving them.

It is essential to note the main limitations of the evidence presented in this study. First of all, we had a small sample size and missing data, including clinical and imaging for some of our patients. Second, other than COVID-19, corticosteroids, and a family history of mood disorders, there could be many other factors playing a role in the emergence of mania in our patients that we have not contemplated or our data are not able to capture. Third, there was no follow-up for all patients after discharge. Finally, the nature of our study cannot present inferential evidence about the putative role of COVID-19 as a cause or a risk factor in the emergence of the first episode of mania. There is a great need for further research regarding the risk and protective factors for patients to present a first manic episode after COVID-19 infection, potentially identifying the high-risk groups that need closer follow-up.

While the pathophysiology of BD, involving complex interactions of genetic, epigenetic, and environmental predisposing and triggering factors, remains unclear (34, 39), future systematic research of the phenomenon of mania in the context of COVID-19 infection could provide valuable insights to inform the understanding and management of this disorder in contexts beyond COVID-19.

Our series provides observational, naturalistic evidence regarding the phenomenon of first-episode mania after an acute COVID-19 infection, and questions whether a family history of bipolar disorder and the use of corticosteroids could be triggering factors. Clinicians treating patients with COVID-19 should be aware of the possibility of the emergence of mania and other psychiatric disorders in the course of infection and its treatment, considering the putative roles of inflammation and pharmacological iatrogenic and trying to identify patients with potentially higher risk for those conditions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Research Committee of the Iran University of Medical Sciences with unique number IR.IUMS.REC.1399.080 and protocol number 17630. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

MS and TR: contribution in the design, acquisition of data, drafting, approval and agreement to be accountable for all aspects of the work. VP-S: contribution in the conception of data, interpretation of data, revising, approval and agreement to be accountable for all aspects of the work. MR, BS, SE, AS, and KA: contribution in the acquisition of data, drafting, approval and agreement to be accountable for all aspects of the work. BS and ME: contribution in the acquisition of data, revising, approval and agreement to be accountable for all aspects of the work. FM: contribution in the design and conception, acquisition of data, interpretation, revising. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor RF declared past collaborations with one of the authors VP-S.

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