key: cord-0963116-9dywuhkc authors: Noone, Rachel; Cabassa, Johanna A.; Gardner, Laura; Schwartz, Bruce; Alpert, Jonathan E.; Gabbay, Vilma title: LETTER TO THE EDITOR: NEW ONSET PSYCHOSIS AND MANIA FOLLOWING COVID-19 INFECTION date: 2020-08-08 journal: J Psychiatr Res DOI: 10.1016/j.jpsychires.2020.07.042 sha: 471bf481c9ff0da6c09797efbbbcff32da5c9d88 doc_id: 963116 cord_uid: 9dywuhkc nan Evidence suggests that acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) may be associated with neuropsychiatric symptoms, including delirium (Zubair et al. 2020; Rogers et al. 2020 ). Here we present two case reports of adult patients with COVID-19 infections who presented with severe psychosis and mania with no prior psychiatric history and in the absence of significant medical or pulmonary symptoms and an unremarkable neurological work-up. A 49 year old man (Patient-A) with hypertension, hyperlipidemia, and type 2 diabetes mellitus, but no personal or family psychiatric history and no substance use history or smoking, was brought to the psychiatric emergency department (ED) with an altered mental status and bizarre behavior. Clinical presentation: Patient-A presented with one week of insomnia and two days of altered behavior including confusion, decreased appetite, and grandiosity and making odd statements. Three weeks prior to his ED admission, Patient-A was diagnosed with presumed COVID-19, treated with oral azithromycin, and told to self-quarantine. He later presented to urgent care with a urinary tract infection and was treated with nitrofurantoin. His quarantine ended one week prior to his ED admission. In the ED, Patient-A appeared drowsy, was oriented only to the year, and endorsed hearing voices and delusions of grandiosity. On physical exam he had bilateral lower extremity weakness (proximal > distal) and numbness of the right calf and left anterior thigh affecting his ability to ambulate. Patient-A tested positive for COVID-19. Clinical management: Patient-A was admitted to medicine for work-up. Complete neurological work-up including brain computed tomography (CT), brain magnetic resonance imaging (MRI), electroencephalogram (EEG), lumbar puncture and urine toxicology were unremarkable (laboratories are presented in Table 1 ). Over the next 10 days, Patient-A remained disoriented, paranoid, and believed that he was the devil and stated that his family was in danger. He endorsed auditory hallucinations, confabulated episodes of violence at home and experienced insomnia, crying spells, hopelessness, sadness, guilt, inattentiveness, restlessness, ideas of reference, and passive suicidal ideation. He was treated with haloperidol 2mg as needed for agitation and received trials of olanzapine 2.5mg/day and then quetiapine up to 150mg/day and transferred to inpatient psychiatry for continued care. He remained psychomotor retarded, weak, wheelchair-bound, partially oriented to time and place, and with passive suicidal ideation. Over the following 2.5 weeks, Patient-A gradually improved and antipsychotic medications were tapered off. At discharge, Patient A continued to show residual increased speech latency and psychomotor retardation. A 34 year old woman (Patient-B) presented to the ED with altered mental status and new onset of psychosis. She had no prior personal or family psychiatric history, no significant medical or surgical history, and no history of substance use or smoking. Clinical presentation: Patient-B presented with bizarre behavior including disrobing in front of strangers, talkativeness, insomnia, and persecutory ideas about her landlord. She was carrying a knife, and believed she was being watched. Symptoms started two and half weeks prior to this ED admission when she was first seen in the ED due to severe agitation and anxiety. During the exam, she was screaming, not responding to questions and stated she did not feel safe. At that J o u r n a l P r e -p r o o f time, she tested positive for SARS-CoV-2. Chest x-ray and head CT were normal, and she was sent home to self-quarantine. Patient-B had two additional ED admissions due to shortness of breath and anxiety, and later increased paranoia and bizarre behavior including putting hand sanitizer in her food. Throughout these three ED presentations, there was no fever or signs of pneumonia on chest x-ray while tests for SARS-CoV-2 remained positive. Patient-B was sent again to self-quarantine leading to a fourth ED admission due to worsening of psychosis and bizarre behavior. Mental status exam was remarkable for psychomotor agitation, loud pressured speech, irritable mood, labile intense affect, circumstantial thought process, paranoid delusions, and impaired attention and concentration. Orientation was intact. Vital signs were within normal limits as was her physical exam. Urine toxicology was negative. Repeated head CT and chest xray were normal. Patient was started on risperidone 1mg at night and was admitted to medicine for a workup of acute altered mental status presumed to be secondary to SARS-CoV-2 infection. Clinical management: Neurological work: Brain MRI showed non-specific T2 hyperintensities and a lumbar puncture was unremarkable. An electroencephalogram showed greater focal cerebral dysfunction in the right frontal region than the left, with no epileptiform discharges or seizures. Detailed laboratory test results are included in Table 1 . Empiric treatment with acyclovir was initiated for possible encephalitis and risperidone was titrated up to 1mg twice daily. Patient-B continued to present with sleep disturbance, agitation, pressured speech, and paranoid ideation. After ten days, the patient was admitted involuntarily to a specialized COVID-19 positive psychiatric inpatient unit. A week after admission to inpatient psychiatry, manic symptoms resolved. Paranoid ideas and delusions remained though were more reality based. She was discharged with psychiatric outpatient follow-up. J o u r n a l P r e -p r o o f These cases illustrate an association of neuropsychiatric symptoms with COVID-19 infection, in the absence of personal or family history of psychiatric illness, as well as the absence of hypoxemia, cerebral infarction or significant pulmonary involvement. While vasculitis and encephalitis are possible mechanisms, work-up for both cases was not fully consistent with these diagnoses. Relatedly, a recent meta-analysis by Rogers et al., reported high rates of delirium, depression, and anxiety among patients with COVID-19 patients and possible residual executive dysfunction (Rogers et al. 2020) . A nation-wide surveillance study from the UK, using an online case report portal, yielded 23 cases (18%) with new onset neuropsychiatric syndromes, including 10 cases with psychosis, 6 cases with dementia-like symptoms, and 4 cases with affective disorders (Varatharaj et al. 2020) . A possible mechanism may involve immune system activation and its effect on the CNS. Importantly, inflammatory processes, including activation of the kynurenine pathway, have been implicated in a wide range of psychiatric presentations including psychosis, bipolar, depression and suicide. Such relationships have been documented in the absence of elevated blood CRP levels (Bradley et al. 2019; Reus et al., 2015; Tanaka et al. 2017; Schwarcz and Pellicciari 2002; DeWitt et al. 2018; Troyer, Kohn, and Hong 2020) . Follow-up studies should be carried out on the course, duration and treatment of psychiatric sequelae in these patients. Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms A pilot resting-state functional connectivity study of the kynurenine pathway in adolescents with depression and healthy controls The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities Infection and inflammation in schizophrenia and bipolar disorder Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f All authors declare no conflicts of interest.