|Year : 2020 | Volume
| Issue : 2 | Page : 226-229
COVID-19: Neuropsychiatric manifestations and psychopharmacology
Harpreet Singh Dhillon1, Shibu Sasidharan2, Gurpreet Kaur Dhillon3, Vijay Singh2, M Babitha4
1 Department of Psychiatry, Level III Hospital, Goma, DRC
2 Department of Anaesthesiology and Critical Care, Level III Hospital, Goma, DRC
3 Department of Paediatrics, 166 Military Hospital, Jammu, Jammu and Kashmir, India
4 Consultant Radiologist, Ojas Hospital, Panchkula, Haryana, India
|Date of Submission||29-Jul-2020|
|Date of Decision||12-Sep-2020|
|Date of Acceptance||21-Sep-2020|
|Date of Web Publication||25-Nov-2020|
Dr. Harpreet Singh Dhillon
Department of Psychiatry, Level III Hospital, Goma
Source of Support: None, Conflict of Interest: None
The COVID-19 pandemic has emerged as one of the major global health crises of recent times. It has posed adverse consequences for people with mental illnesses with its potential to infect patients with existing psychiatric disorders on psychotropic drugs and additionally, spawning psychiatric symptoms in patients infected with COVID-19. To add to the miseries, there have been a multitude of experimental treatments in the form of antivirals, immune-modulators, corticosteroids, etc., which can have serious interactions with psychotropic drugs. In this review, we intend to provide recommendations for pharmacotherapy to address the neuropsychiatric morbidity in COVID-19 patients.
Keywords: COVID-19, neuropsychiatric manifestations, psychotropics
|How to cite this article:|
Dhillon HS, Sasidharan S, Dhillon GK, Singh V, Babitha M. COVID-19: Neuropsychiatric manifestations and psychopharmacology. Ann Indian Psychiatry 2020;4:226-9
|How to cite this URL:|
Dhillon HS, Sasidharan S, Dhillon GK, Singh V, Babitha M. COVID-19: Neuropsychiatric manifestations and psychopharmacology. Ann Indian Psychiatry [serial online] 2020 [cited 2021 Jan 27];4:226-9. Available from: https://www.anip.co.in/text.asp?2020/4/2/226/301441
| Introduction|| |
Psychological distress and accentuation of mental illnesses with increase in health-related anxiety is an expected outcome during a rapidly spreading pandemic like COVID-19. There are other factors such as uncertainty about the disease, social isolation, misinformation in the social media platforms, dwindling economy, fear, and panic, leading to hoarding behavior, etc., which only add onto the psychological burden and takes a toll on the already-limited mental health resources. The WHO (2020) reiterated the same in their guidance note, “the main psychological impact to date is elevated rates of stress or anxiety,” and also warned regarding elevated levels of depression and substance use in harmful pattern especially due to quarantine and its consequences on socio-occupational routines. The symptoms of neurological manifestations can be classified into central (headache, dizziness, altered sensorium, and cerebrovascular events), peripheral (reduced smell and taste), and skeletal. The psychological symptoms can range from anxiety, adjustment issues, depression, and rarely self-harm ideation. Headache and myalgia are the most common symptoms, while life-threatening symptoms such as seizures and delirium are relatively rare except in patients with severe respiratory compromise (acute respiratory distress syndrome [ARDS])/other significant comorbidities.
The prevalence of neuropsychiatric symptoms was found to be 22.5% (n = 9086) in a sample of 40,469 COVID-19 patients. Headache (3.7%) was the most common neurologic symptom followed by sleep disturbances (3.4%), encephalopathy (2.3%), myalgia (2.0%), loss of taste and smell (1.2%), stroke and transient ischemic attack (1.0%), and seizures 258 (0.6%). The most prominent psychiatric symptoms included anxiety and related disorders (4.6%), mood disorders (3.8%), and suicidal ideation (0.2%). Confusion and delirium were reported as the most common neuropsychiatric features of SARS and Middle East respiratory syndrome-corona virus, in a systematic review and meta-analysis by Rogers et al. Neurocognitive impairment was noticed in patients who survived severe illness after intensive care unit (ICU) admission. During the postillness phase, the point prevalence of anxiety and depressive disorders was 14.8% (95% confidence interval [CI]: 11.1–19.4); and 14.9% (95% CI: 12.1–18.2), respectively, followed by chronic fatigue.
| Etiopathogenesis|| |
The etiology of neurological complications may be due to primary neuroinvasion by the coronavirus or a secondary bout of inflammation by activated immune and inflammatory mediators. The virus enters the nervous system either directly from olfactory neuroepithelium or is spread via hematogenous route and attaches onto the angiotensin-converting enzyme 2 receptors on the neuronal endothelium. The acute effects can trigger meningitis/encephalitis, leading to altered sensorium, delirium, seizures, and/or even coma. The direct invasion of medullary neurons in the brainstem is hypothesized to be responsible for severe respiratory failure. Various other factors such as hypoxia from respiratory failure, derangements in coagulation pathways, metabolic disequilibrium, multiorgan dysfunction, or even iatrogenic (drugs used during mechanical ventilation) can also lead to alterations in sensorium and delirium. The physiological and perceived psychological stress during the pandemic can also trigger the hypothalamo–pituitary–adrenal axis, leading to disequilibrium in steroid levels, and further derangements in the immune response, leading to nonspecific features of chronic fatigue, myalgias, and malaise.
The incidence of delirium in mechanically ventilated patients is up to 81%, which expectedly surges in a COVID-19 patient with ARDS. The common symptoms include confusion or disorganized thinking, fluctuation in the levels of consciousness, altered psychomotor activity including severe agitation, inattention, rapid fluctuation in emotions, and auditory and/or visual hallucinations. The symptoms can also present as a hypoactive delirium state with reduced motor activity and lethargy. Aggressive and disruptive behavior in a COVID-19-infected patient can violate the isolation protocol and hence needs to be managed with priority.
The risk factors include old age (>65 years), medical comorbidities, drugs (propofol, opioids, and high-dose benzodiazepines, which are routinely used during mechanical ventilation), and hydroxychloroquine. Personal protective equipment hides the reassuring and empathetic look on the doctor's face, accentuating the anxiety in an alien environment. This can add to the distorted perception of reality and worsen confusion.
| Investigations|| |
- Meningitis/encephalitis: It can be confirmed by detecting specific SARS-CoV-2 RNA in cerebrospinal fluid (CSF), however current evidence is from case reports only and warrants further research
- Acute cerebrovascular accidents: possibly due to deranged coagulation profile and hence the same needs to be evaluated 
- Nonconvulsive seizures (electroencephalography [EEG] can be done to confirm/rule out)
- Evaluation and management of general causes such as electrolyte imbalance, metabolic disturbances, substance use disorder, hydration status, polypharmacy (drug interactions/toxicity), other infections, vascular causes, and traumatic injury should be done.
The need for additional investigations such as CSF studies, magnetic resonance imaging (MRI) brain, and EEG is debatable in delirium considering isolation protocols, costs involved, trained workforce, and infrastructure requirements. There are no pathognomonic radiological signs, but leptomeningeal enhancement and bilateral fronto-temporal hypoperfusion have been described in MRI.
| Scales for Assessment of Delirium|| |
Because of strict isolation protocols, a live neuropsychiatric consult might not always be feasible and hence scales for assessing and monitoring the confusion status should be routinely used. The time-tested confusion assessment method for the ICU should be followed routinely. Other useful scales include Intensive Care Delirium Screening Checklist and the Stanford Proxy Test for Delirium.
| Management|| |
- Ensuring a comfortable ambient light in synchronization with the diurnal cycle.
- Ensuring pain-free spell of 6–8 hours of sleep without significant treatment-related disruptions.
- Regular cognitive stimulation and reorientation of the patient to time, place, and person (utilizing audio–visual aids for virtual communication with family members/other familiar people)
- Encouraging physical mobilization at the earliest.
- Providing all kinds of possible aids (glasses, hearing aids, mobiles, etc.) to convey a feeling of self-sufficiency and sense of control over the situation.
Melatonin may be used for regularizing the sleep–wake cycle in delirium. It has the advantage of short half-life, mild anti-inflammatory properties, and no respiratory depression. Suvorexant (orexin antagonist) has also been proved to be beneficial especially in conjunction with ramelteon in patients with acute poststroke delirium. Trazodone can also be used for sleep regulation as monotherapy or in combination with ramelteon. Benzodiazepines should be avoided (except in the cases of delirium tremens), as cumulative doses run the risk of respiratory depression and may cause paradoxical disinhibition. Hypnotics such as zolpidem are comparatively safer (minimal respiratory depression), but caution needs to be exercised when co-prescribed with ritonavir (blood levels are mildly elevated).
Acute agitation/disruptive behavior
Antipsychotic drugs such as haloperidol, olanzapine, quetiapine, and aripiprazole are found to be beneficial in the management of agitation. However, close monitoring of QTc interval, neurologic side effects extrapyramidal symptoms (EPS), and sedation is warranted. The risk of QTc prolongation gets further amplified, given the potential use of COVID-19-specific medications which themselves prolong QTc (hydroxychloroquine and azithromycin), leading to a potentially increased risk of torsades de pointes.
- Haloperidol, a potent dopamine receptor blocker with minimal anticholinergic and antihistaminic activity, is generally considered the first-line treatment; a dose of 2.5–5 mg can be used orally or intramuscularly. Intravenous (IV) administration should be accompanied by ECG monitoring. Recent research is investigating its role in treatment for COVID-19 due to its effects on sigma receptors,
- Olanzapine, 5–10 mg, can also be considered either orally or parenterally. In acutely disturbed patients, intramuscular (IM) is the preferred route of administration compared to IV route, and gluteal IM injections may be preferred over deltoid injections. This can afford better protection to health-care workers involved in the care of acutely disturbed patients. IM olanzapine has minimal effect on QTc interval and lesser risk for EPS compared to haloperidol.
- Quetiapine (25–50 mg) can be given orally.
- Dexmedetomidine is an alpha-2 agonist and reduces the release of noradrenaline and helps curtailing restlessness. Clonidine can also be used for the same reason and is more convenient as its available in skin patch form.
- Valproic acid is known for its neuroprotective potential and can be used to control impulsivity and extreme emotional fluctuations. It also gives a prophylaxis against the potentially epileptogenic state by increasing the seizure threshold, however liver function tests and platelets need to be constantly monitored.
- In extreme cases not responding to the above measures, only short-acting low-dose oral benzodiazepines (e.g., lorazepam 1 to 2 mg) may be considered with close monitoring for respiratory distress and respiratory failure.
- Mechanical restraint: Mechanical restraint should be used as a last resort for minimum possible time.
- Supplements: Vitamin C is being investigated for shortening the duration of mechanical ventilation in critically ill patients. Higher Vitamin D levels were found to be protective against delirium. In a randomized, double-blind, placebo-controlled clinical trial, omega-3 fatty acid supplementation (2 g/day) reduced the risk of delirium in patients undergoing mechanical ventilation.
Treatment of patients with preexisting psychiatric illness
Most psychiatric illnesses are remitting and relapsing in nature and generally require long-term prophylaxis. In the absence of a confirmed treatment for the management of COVID-19, a multitude of pharmacotherapeutic agents have been tried in recent past (e.g., hydroxychloroquine/chloroquine, antivirals, etc.) These trial treatments can have significant drug interactions with psychotropics. Hydroxychloroquine inhibits CYP2D6 and can alter the metabolism of aripiprazole, risperidone, paroxetine, several tricyclic antidepressants (TCAs), venlafaxine, vortioxetine, and atomoxetine. Ritonavir is a potent cytochrome P450 inhibitor and is contraindicated with clozapine, bupropion, and pimozide, while TCAs, selective serotonin reuptake inhibitors (SSRIs), phenothiazines, and carbamazepine warrant a 50%–70% dose reduction when given along with ritonavir to prevent toxicity. Hence, it is imperative to be mindful of such interactions.
Haloperidol, quetiapine, ziprasidone, etc., can prolong QTc interval. Therefore, other drugs such as hydroxychloroquine, chloroquine, and azithromycin, which also prolong QTc interval, can have a synergistic effect and should not be used together. Protease inhibitor antivirals such as sequinavir, lopinavir/ritonavir, and atazanavir can also cause QTc prolongation. The safer alternatives are lurasidone followed by aripiprazole, olanzapine, and risperidone.,
Antidepressants such as TCAs, citalopram, and mirtazapine can prolong QTc interval, which might be amplified when combined with chloroquine/hydroxychloroquine. SSRIs such as fluoxetine, fluvoxamine, paroxetine, and bupropion are CYP enzyme inhibitors, which can alter plasma concentration of antiviral agents. Certain antiviral medications such as lopinavir/ritonavir are also enzyme inhibitors and can increase the levels of SSRIs, endangering serotonin syndrome.
The safer alternatives are escitalopram and sertraline with lesser drug interactions.
The commonly prescribed anti-pyretics and anti-inflammatory agents (NSAIDs) especially COX-2 inhibitors (celecoxib and rofecoxib) can increase lithium levels, endangering toxicity. Valproate levels may be reduced with lopinavir/ritonavir.
Lorazepam is preferable in view of its shorter half-life and minimal drug interactions. Diazepam/clonazepam and other long-acting benzodiazepines may be avoided.
| The Way Forward|| |
The aim should be to provide affordable, effective, practical, and easily accessible mental health facilities, keeping in mind the strict isolation and other preventive measures. Digital platforms such as tele-psychiatry and computer-aided mental health services over the Internet should be utilized efficiently. The treatment protocol for patients with severe COVID-19 patients should comprise screening for symptoms of adjustment disorder, depression, anxiety, and suicidal ideation.
| Conclusion|| |
The COVID-19 pandemic is still evolving, and clinicians must be aware of the possibility of delirium, depression, anxiety, fatigue, posttraumatic stress disorder, and cognitive decline in the aftermath. Patients who are already on psychotropic medications can have cytochrome-related interaction and QTc prolongation when combined with COVID-19 treatment. Early identification, swift management, and optimal follow-up should be aimed at, to provide quick and effective patient care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al
. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:683-90.
Nalleballe K, Reddy Onteddu S, Sharma R, Dandu V, Brown A, Jasti M, et al
. Spectrum of neuropsychiatric manifestations in COVID-19. Brain Behav Immun 2020;88:71-4.
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;7:611-27.
Desforges M, Le Coupanec A, Brison E, Meessen-Pinard M, Talbot PJ. Neuroinvasive and neurotropic human respiratory coronaviruses: Potential neurovirulent agents in humans. Adv Exp Med Biol 2014;807:75-96.
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.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al
. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
Tassorelli C, Mojoli F, Baldanti F, Bruno R, Benazzo M. COVID-19: what if the brain had a role in causing the deaths?. European journal of neurology. 2020 Apr 25.
Dinakaran D, Manjunatha N, Naveen Kumar C, Suresh BM. Neuropsychiatric aspects of COVID-19 pandemic: A selective review. Asian J Psychiatr 2020;53:102188.
Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr., et al
. Delirium as a predictor of mortality in mechanically ventilated patients in the inten-sive care unit. JAMA 2004;291:1753-62.
Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry 2018;33:1428-57
Mascolo A, Berrino PM, Gareri P, Castagna A, Capuano A, Manzo C, et al
. Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: A review article. Inflammopharmacology 2018;26:1141-9.
Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, et al
. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 2020;94:55-8.
Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al
. Neurologic features in severe SARS-CoV-2 infection. N
Engl J Med 2020;382:2268-70.
Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, et al
. Evaluation of delirium in critically ill patients: Validation of the confusion assessment method for the intensive care unit (CAM-ICU). Crit Care Med 2001;29:1370-9.
van Eijk MM, van Marum RJ, Klijn IA, de Wit N, Kesecioglu J, Slooter AJ. Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med 2009;37:1881-5.
Maldonado JR, Sher YI, Benitez-Lopez MA, Savant V, Garcia R, Ament A, et al
. A study of the psychometric properties of the “Stanford Proxy Test for Delirium” (S-PTD): A new screening tool for the detection of delirium. Psychosomatics 2020;61:116-26.
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.
Kawada K, Ohta T, Tanaka K, Miyamura M, Tanaka S. Addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients. J Stroke Cerebrovasc Dis 2019;28:142-8.
Ishii T, Morimoto T, Shiraishi M, Kigawa Y, Narita K. Retrospective Study of Trazodone Monotherapy Compared with Ramelteon and Trazodone Combination Therapy for the Management of Delirium. J Psychiatry 21: 444. doi: 10.4172/2378-5756.1000444.
Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003;17:513-32.
Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 (Coronavirus disease 2019) treatment. Circulation 2020;141:e906-7.
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al
. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020;583:459-68.
Schetz JA, Perez E, Liu R, Chen S, Lee I, Simpkins JW. A prototypical sigma-1 receptor antagonist protects against brain ischemia. Brain Res 2007;1181:1-9.
Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. Valproic acid for treatment of hyperactive or mixed delirium: Rationale and literature review. Psychosomatics 2015;56:615-25.
Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: A meta-regression analysis. J Intensive Care 2020;8:15.
Bowman K, Jones L, Pilling LC, Delgado J, Kuchel GA, Ferrucci L, et al
. Vitamin D levels and risk of delirium: A Mendelian randomization study in the UK Biobank. Neurology 2019;92:e1387-94.
Naghibi T, Shafigh N, Mazloomzadeh S. Role of omega-3 fatty acids in the prevention of delirium in mechanically ventilated patients. J Res Med Sci 2020;25:10. [Full text]
Rani S, Grover S, Mehra A, Sahoo S. Psychiatric implications of the use of hydroxychloroquine in COVID-19 patients. Indian J Pharmacol 2020;52:229. [Full text]
Tseng AL, Foisy MM. Significant interactions with new antiretrovirals and psychotropic drugs. Ann Pharmacother 1999;33:461-73.
Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003;107:85-95.
Taylor DM, Barnes TR, Young AH. The Maudsley prescribing guidelines in psychiatry. Wiley: John Wiley & Sons; 2018.
Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 2003;64:1328.
Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999;24:347-55.
Ćosić K, Popović S, Šarlija M, Kesedžić I. Impact of human disasters and COVID-19 pandemic on mental health: Potential of digital psychiatry. Psychiatr Danub 2020;32:25-31.