key: cord-0917626-bi091gip
authors: Arbelo, Nestor; López-Pelayo, Hugo; Sagué, María; Madero, Santiago; Pinzón-Espinosa, Justo; Gomes-da-Costa, Susana; Ilzarbe, Lidia; Anmella, Gerard; Llach, Cristian-Daniel; Imaz, María-Luisa; Cámara, María-Mercé; Pintor, Luis
title: Psychiatric Clinical Profiles and Pharmacological Interactions in COVID-19 Inpatients Referred to a Consultation Liaison Psychiatry Unit: a Cross-Sectional Study
date: 2021-01-07
journal: Psychiatr Q
DOI: 10.1007/s11126-020-09868-6
sha: f777cd94bc341b122a63174f41b24365ac716f3e
doc_id: 917626
cord_uid: bi091gip

The Coronavirus Disease 2019 (COVID-19) can affect mental health in different ways. There is little research about psychiatric complications in hospitalized patients with COVID-19. The aim of the study was to describe the psychiatric clinical profile and pharmacological interactions in COVID-19 inpatients referred to a Consultation-Liaison Psychiatry (CLP) unit. This is a cross-sectional study, carried out at a tertiary hospital in Spain, in inpatients admitted because of COVID-19 and referred to our CLP Unit from March 17,2020 to April 28,2020. Clinical data were extracted from electronic medical records. The patients were divided in three groups depending on psychiatric diagnosis: delirium, severe mental illness (SMI) and non-severe mental illness (NSMI). Of 71 patients included (median [ICR] age 64 [54–73] years; 70.4% male), 35.2% had a delirium, 18.3% had a SMI, and 46.5% had a NSMI. Compared to patients with delirium and NSMI, patients with SMI were younger, more likely to be institutionalized and were administered less anti-COVID19 drugs. Mortality was higher among patients with delirium (21.7%) than those with SMI (0%) or NSMI (9.45%). The rate of side effects due to interactions between anti-COVID19 and psychiatric drugs was low, mainly drowsiness (4.3%) and borderline QTc prolongation (1.5%). Patients affected by SMI were more often undertreated for COVID-19. However, the rate of interactions was very low, and avoidable with a proper evaluation and drug-dose adjustment. Half of the patients with SMI were institutionalized, suggesting that living conditions in residential facilities could make them more vulnerable to infection.

This cross-sectional study was carried out at a tertiary general university hospital in Barcelona, Spain, on inpatients admitted because of COVID-19 to medical wards, and referred to our CLP Unit from March 17, 2020 to April 28, 2020.

Selection criteria was: patients confirmed as a case of COVID-19 on polymerase chain reaction (PCR) analysis of nasopharyngeal or throat swab specimens, as per the hospital protocol. There was no exclusion criteria.

The study was performed in accordance with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of Hospital Clinic, Barcelona, Spain, under resolution number HCB/2020/0496.

We reviewed electronic medical records and laboratory findings from all patients and collected data on the following variables:

& Sociodemographic variables: age, sex, institutionalization, social support. & Medical and psychiatric history: presence of severe comorbidities (defined as severe chronic lung, kidney, liver or heart disease, neoplasm or ischemic brain disease), psychiatric history (diagnosis according to , previous psychiatric medication. & Hospitalization variables: Date of admission, Intensive Care Unit (ICU) admission, incidental SARS-CoV-2 diagnosis (asymptomatic inpatients with a positive test for SARS-CoV-2 and admitted for other reasons), reason for referral, prolonged weaning, current DSM-5 diagnosis, clinical features of delirium (hyperactive, hypoactive, mixed, presence of hallucinations, delusions or mood disturbances such as depression or mania), COVID-19 therapies (HCQ, LPV/r, AZT, tocilizumab, corticosteroids or others), side effects due to interaction between COVID-19 and psychiatric medication (drowsiness, confusion, extrapyramidal effects or others), requirements of psychiatric drug dose adjustment, QTc interval before and after consultation, date of discharge, total days of stay, outcome at discharge (death, home, nursing homes and others).

The patients were divided in three groups depending on psychiatric diagnosis after assessment by the CLP unit: (1) patients affected by delirium, (2) patients affected by severe mental illness (defined as psychotic disorder [including schizophrenia, schizoaffective disorder and other types of psychosis], bipolar disorder, severe major depressive disorder, severe autism spectrum disorder or intellectual disability and severe chronic organic mental disease), and (3) patients affected by non-severe mental illness (defined as mild-moderate major depressive disorder, dysthymic disorder, anxiety disorder, adjustment disorder, substance use disorder, personality disorder or others) or without any DSM-5 diagnosis. If a patient met criteria for more than one group, delirium prevailed over the other two groups and severe over non-severe mental illness.

The electrocardiogram (ECG) QTc interval was evaluated at two timepoints: Baseline ECG and control ECG after psychiatric drug dose adjustment. It was interpreted as "pathological" when there was a prolongation greater than 450 milliseconds (ms) in men and 470 ms in women [19] . QTc intervals of 431-450 ms in men or 451-470 ms in women were interpreted as "borderline" [19] .

Descriptive statistics were calculated to summarize the sociodemographic and clinical characteristics of the sample. The distribution was non-parametric. Categorical variables were expressed by using frequencies and percentages, while medians and interquartile ranges were used for continuous variables. The chi-square-test (χ 2 ) or Fisher's exact test where appropriate were used to analyse categorical data. Mann-Whitney U-test was used to compare quantitative data between two groups, and for more than two groups, the Kruskal-Wallis test by ranks was used instead. Significance was pre-assigned at p < 0.05. Missing cases were excluded from analysis using pairwise deletion. Statistical evaluation was performed using IBM SPSS Statistics software package ver. 25. [20] Results

A total of 71 patients were included in the final analysis. There were 25 patients (35.2%) in the Delirium group, 13 patients (18.3%) in the SMI group and 33 patients (46.5%) in the NSMI group.

The median age of the sample was 64 years (IQR: 54-73). The SMI group (median age: 48 years) was younger than the Delirium (median age: 69 years; p = 0.002) and NSMI group (median age: 67 years; p = 0.001).

The sociodemographic and clinical characteristics of all the sample and each clinical group of patients, just as the main differences among the three groups, are summarized in Table 1 .

About three-quarters (n = 53; 74.6%) of the sample had at least one previous psychiatric diagnosis, and 63.4% (n = 45) were taking at least one psychiatric drug; the most common were antidepressants (n = 30; 42.3%) ( Table 2) .

The most common reason for referral was psychiatric drug dose adjustment (38.8% of all consultations), whereas suspected substance abuse was the least (1.4%). Difficult weaning was present in 14.1% of the sample (mainly those with delirium) and was related mostly to confusion (50%) or agitation (20%). (Table 3) .

The most common type of delirium was mixed (48%), followed by hyperactive (32%) and hypoactive (20%). The symptomatology also included persecutory delusion in 12% (n = 3), mood disturbances in 12% (n = 3) and visual hallucinations in 4% (n = 1). 

The most common therapies were HCQ, AZT and LPV/r, usually in combination. The rate of patients receiving any drug was statistically significantly lower in the SMI-group than the others, especially in the case of LPV/r and HCQ (Table 4) .

Some patients with prior psychiatric treatment required dose adjustment: antipsychotics were reduced in 37.5% and stopped in 18.8%, antidepressants were reduced in 17.2% and stopped in 10.3%, benzodiazepines were stopped in 41.7% and reduced in 4.2%, while anticonvulsants were reduced or stopped only in 7.7%.

Moreover, almost two-thirds of the sample (n = 44; 62%) were started on new medication, mostly olanzapine (n = 12; 17.1%) and intravenous haloperidol (n = 6; 8.6%). 

A 5.9% (n = 4) of the sample had a pathological QTc interval at admission, before starting any medication for COVID-19, and none in the SMI-group. Only one patient, with asymptomatic COVID-19, was admitted for Torsades de Pointes due to intoxication with methadone 400 mg. After adjusting the dose or starting a new psychiatric drug, the QTc interval remained without any significant change in most of the sample (n = 62; 95.4%), and 100% of the SMIgroup. Normalization of QTc interval was present in 3,1% (n = 2) of the sample. Only one patient (1.5%) had a borderline prolongation of the QTc interval, probably due to the interaction between three antidepressants (vortioxetine 10 mg/day, trazodone 50 mg/day and venlafaxine 225 mg/day) and LPV/r/HCQ/AZT.

Other probable adverse effects secondary to interaction between psychiatric and COVID-19 medications were drowsiness (n = 3; 4.3%) and confusion (n = 1; 1.4%). They were secondary to the combination of LPV/r (dose 200/50 mg 2 U/12 h) and one of the following sedative drugs: quetiapine 300 mg/day (the patient was in antipsychotic therapy before starting LPV/r, and because he presented both drowsiness and confusion, LPV/r was immediately stopped), haloperidol 3 mg/day, and trazodone 50 mg/day.

The median length of stay for all patients was 12 days (IQR: 7-16.5); it was statistically significantly larger (p = 0.027) in the delirium-group (19 days) in comparation with the SMIgroup (9 days). There were not statistically significant differences when comparing any of the mentioned groups with the NSMI-group (13.5 days).

Hospital-to-home discharge was the intended destination in the majority of the patients (n = 32; 48.5%), while 39.4% (n = 26) were admitted to a low complexity center and 12.1% (n = 8) died. The mortality was higher among patients with delirium (21.7%) than those with SMI (0%) or NSMI (9.45%), although there were not statistically significant differences. The median number of days between onset of delirium and death was 7 (2.5-7.75). No patient with severe mental illness (including the SMI-group and patients with SMI in the delirium group) died.

To our knowledge, this is the first report analyzing the clinical features and outcomes of hospitalized patients with COVID-19 referred to a CLP unit.

The patients with delirium were older and had a more severe infection, as they were five more times admitted to ICU than the other groups, and almost a third had difficult weaning. The most common presentation of delirium was mixed, which is the usual presentation in elderly hospitalized patients [21] . Moreover, the rate of agitation seems to be higher in delirium associated with COVID-19, as suggested by other studies [22] . One-quarter of patients with delirium died at the hospital, approximately one week after the onset of delirium, which may indicate that acute confusional states implies a worse prognosis in COVID-19, as described in critically-ill patients [23] .

Patients with NSMI had a similar rate of severe somatic comorbidities compared to patients with delirium, and an intermediate age range and prognosis compared to the other groups. The most common problems were anxiety and depressive disorders, and they were usually referred for anxiety or dose adjustment.

Patients with SMI were younger and had less severe comorbidities than patients with delirium or NSMI. The most common diagnosis was psychotic disorder and almost half resided in long-term care facilities (LTCF). While the institutionalized elderly have been a constant subject of public attention because of their vulnerability to COVID-19 [24, 25] , little attention has been focused on institutionalized people with SMI. It has been suggested that people with mental health disorders are more susceptible to infections when epidemics arise [17] , and the semi-confined living conditions of LTCFs where some of them live may be one of the reasons. In LTCFs, residents live in close proximity under the care of often under-resourced nurse assistants, and viral infections, with high transmissibility via droplets and contact transmission, are easily brought in by people entering the facilities and widespread [24] .

The younger age, lower rate of comorbidities, and higher rate of incidental diagnosis may explain a better prognosis in the patients with severe mental illness, as they had a shorter hospitalization and none died.

The theorical risk of pharmacological interactions between COVID-19 therapies and psychiatric drugs promoted that drug dose adjustment was the most common reason for referral.

Our CLP unit has issued practical recommendations for the psychopharmacological management on the most representative identified case-scenarios on COVID-19 inpatients with psychiatric disorders based on the existing literature, including the Liverpool Interactions Drug Group recommendations [14] , and clinical experience [16] .

Although sometimes high-risk interaction drug discontinuation was not possible or intravenous haloperidol had to be used for agitated delirium, the incidence of side effects was very low. In fact, the QTc interval was not prolonged after dose adjusting or adding a new drug, in the 98,5% of the sample. Only one patient had a borderline QTc interval without any clinical repercussion, and was due to the interaction between three antidepressants (vortioxetine, trazodone and venlafaxine) and LPV/r/HCQ/AZT. The other probable side effect, with a low rate and reversible after dose adjustment, was drowsiness. It should be highlighted that concomitant administration of LPV/r and quetiapine should be avoided because it may increase considerably quetiapine concentration and its toxicity (coma in the worst-case scenario), and if coadministration is necessary, quetiapine dose should be reduced to 1/6 [14] . Overall, COVID-19 inpatients with psychiatric comorbidities should be managed on a personalized basis considering several clinical criteria and, should not be excluded from receiving COVID-19 treatments [16] .

This low rate of interactions contrasts with the fact that patients with SMI were undertreated (specially with LPV/r). The lack of familiarity with psychiatric medications in medical wards may have contributed to this. Furthermore, most of the recommendations for interactions with experimental COVID-19 therapies are based on theory, with a low evidence and do not quantify the changes in serum drug concentrations [14] .

The small size of the sample may have reduced the statistical power of the study. Because the study population was restricted to inpatients referred to a CLP unit, generalization of results is limited to patients affected by COVID-19 and having a psychiatric diagnosis admitted to the hospital, but gives practical information for the management of pharmacological interactions.

Our study suggests that the incidence of side effects due to interactions between psychiatric and COVID-19 treatments is low. However, patients with SMI were more often undertreated. In order to avoid undertreatment on people with mental illness and COVID-19, the role of consultation-liaison psychiatry is crucial during the pandemic, and further research is needed to determine the real impact of interactions on clinical practice.

Half of the inpatients with SMI were living on LTCF, which usually have semi-confined living conditions that make easier droplets and contact transmission. Therefore, in order to reduce the impact of the pandemic in this part of the population, improvement of COVID-19 prevention and control measures in mental health residential facilities is urgently needed.

Psychological influence of coronovirus disease 2019 (COVID-19) pandemic on the general public, medical workers, and patients with mental disorders and its countermeasures

Immediate psychological responses and associated factors during the initial stage of the 2019 Coronavirus disease (COVID-19) epidemic among the general population in China

Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019

Unravelling potential severe psychiatric repercussions on healthcare professionals during the COVID-19 crisis

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Predictors of emotional outcomes of intensive care

Neurologic manifestations of hospitalized patients with coronavirus disease

Psychiatric adverse effects of corticosteroids

Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article

Nervous system involvement after infection with COVID-19 and other coronaviruses

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

COVID-19: ICU delirium management during SARS-CoV-2 pandemic

Neurological and psychiatric adverse effects of antiretroviral drugs

Safe and informed prescribing of psychotropic medication during the COVID-19 pandemic

COVID-19 inpatients with psychiatric disorders: real-world clinical recommendations from an expert team in consultation-liaison psychiatry

Patients with mental health disorders in the COVID-19 epidemic

Consultation-liaison psychiatry in the age of COVID-19: reaffirming ourselves and our worth

Prolonged QTc interval and risk of sudden cardiac death in a population of older adults

Corp IBM. IBM SPSS statistics for windows. Armonk: IBM Corp

An empirical study of delirium subtypes

Neurocovid: pharmacological recommendations for delirium associated with COVID-19

Outcome of delirium in critically ill patients: systematic review and meta-analysis

Recommendations for protecting against and mitigating the COVID-19 pandemic in long-term care facilities

The coronavirus and the risks to the elderly in long-term care

Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

He is actually a third-year psychiatry resident in Hospital Clinic of Barcelona and has recently published one article as first author in an international journal (COVID-19 inpatients with psychiatric disorders: Real-world clinical recommendations from an expert team in consultation-liaison psychiatry). He has also presented two scientific posters at international conferences and one scientific poster at a national conference

His research has been focused on the treatment of alcoholism in patients affected by medical conditions (e.g. liver transplantation), the role of digital tools in the management of substance use (e.g. web-based interventions for risky alcohol use) and early diagnosis of cannabis use disorders and risky cannabis use

María Sagué is a medical doctor and fourth-year psychiatry resident in Hospital Clinic of Barcelona. At university, she was the highest-ranking student in her graduating class. She has a master's degree in Public Health. Her main focuses of interest are severe mental health disorders and public health policies

Santiago Madero is a medical doctor and fourth-year psychiatry resident in Hospital Clinic of Barcelona. He has a master's degree in Fetal Medicine. His main focuses of interest are psychosis and early diagnosis of cannabis use disorders and risky cannabis use

recently finished his Psychiatry residency at Hospital Clínic in Barcelona. He is currently working at Hospital Parc Taulí as an adult psychiatrist. He recently completed his MSc degree in Global Mental Health at the University of Glasgow. He does research primarily on psychotic disorders from multiple approaches, while also being interested in cultural and social aspects of psychiatry and global mental health. As per extracurricular activities, he serves as President of the Spanish Society of Psychiatry Trainees and as Chair of the Psychiatry

Psychiatrist (Hospital Clinic Barcelona, training 2009-2013) and PhD student at the University of Barcelona (UB) in the field of Nutritional Psychiatry and Bipolar Disorder

Lidia Ilzarbe is a medical doctor and third-year psychiatry resident in Hospital Clinic of Barcelona. She has presented two scientific posters at international conferences. Her research focuses on eating disorders

Since the beginning of his training period as a psychiatry trainee, he has engaged in various research projects regarding the study of several mental illness and especially Psychiatric Quarterly bipolar disorders. He has also been a fellow researcher in The Geelong Clinic and Barwon Health

He is a member of the executive board in the Spanish Psychiatry Trainee Association. He has participated in three publications indexed in Pubmed, two related to the field of Bipolar Disorders and the latter to the effect of COVID19 in our hospital

is psychiatrist in Hospital Clinic of Barcelona. Her research focuses on perinatal psychiatry, having a number of related publications in peer-reviewed journals

Cámara is a mental health nurse specialist (Advanced Practice Mental Health Nurse) of Consultation Liaison Psychiatry Unit in the Clinical Hospital of Barcelona

PhD is Head of Consultation Liaison Psychiatry Unit in the Clinical Hospital of Barcelona. He is also Associate professor in the Barcelona University, and his main research is about psychiatric and psychological disturbances in medically ill patients. Besides he is currently Director of the annual course

IDIBAPS, 170 Villarroel st

Fundació Clínic Recerca Biomèdica (FCRB), RETICS

IDIBAPS, CIBERSAM, 170 Villarroel st

Acknowledgements Dr. López-Pelayo has received funding from the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III through a 'Juan Rodes' contract (JR19/00025), with the support of the European Social Fund, and IDIBPAS is a CERCA Programme/Generalitat de Catalunya. Dr. Anmella's research is supported by a Pons Bartran 2020 grant (N°249566).Authors Contributions All authors contributed to the study conception, methodology, investigation and visualization. Formal analysis was performed by N. Arbelo, M. Sagué and H. López. Supervision and project administration were performed by H. López and L. Pintor. Resources were provided by L. Pintor. The first draft of the manuscript was written by N. Arbelo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.Data AvailabilityAll data and materials as well as software applications support our published claims and comply with field standards.