Observational study of haloperidol in hospitalized patients with COVID-19

Abstract

Background Haloperidol, a widely used antipsychotic, has been suggested as potentially useful for patients with COVID-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2, possibly through sigma-1 receptor antagonist effect. Methods We examined the associations of haloperidol use with intubation or death and time to discharge home among adult patients hospitalized for COVID-19 at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. In the primary analyses, we compared these two outcomes between patients receiving and not receiving haloperidol using univariate Cox regression models in matched analytic samples based on patient characteristics and other psychotropic medications. Sensitivity analyses included propensity score analyses with inverse probability weighting and multivariable Cox regression models. Results Of 15,121 adult inpatients with a positive COVID-19 PT-PCR test, 39 patients (0.03%) received haloperidol within the first 48 hours of admission. Over a mean follow-up of 13.8 days (SD = 17.9), 2,024 patients (13.4%) had a primary end-point event and 10,179 patients (77.6%) were discharged home at the time of study end on May 1st. The primary endpoint occurred in 9 patients (23.1%) who received haloperidol and 2,015 patients (13.4%) who did not. The secondary endpoint of discharge home occurred in 16 patients (61.5%) who received haloperidol and 9,907 patients (85.8%) who did not. There were no significant associations between haloperidol use and the primary (HR, 0.80; 95% CI, 0.39 to 1.62, p = 0.531) and secondary (HR, 1.30; 95% CI, 0.74 to 2.28, p = 0.355) endpoints. Results were similar in multiple sensitivity analyses. Conclusion Findings from this multicenter observational study suggest that haloperidol use prescribed at a mean dose of 4.5 mg per day (SD = 5.2) for a mean duration of 8.4 days (SD = 7.2) may not be associated with risk of intubation or death, or with time to discharge home, among adult patients hospitalized for COVID-19.

Association Between Mood Disorders and Risk of COVID-19 Infection, Hospitalization, and Death

“…63 Moreover, lithium exerts substantial immune-modulating and anti-inflammatory effects, 64 and valproate has been associated with a lower risk of respiratory infections. 65 Preliminary results from controlled and observational studies [66][67][68][69][70] also suggest that conventional antidepressants provide protective effects against COVID-19 complications. The foregoing finding would be in accordance with preclinical work documenting anti-inflammatory and/or anti-SARS-CoV-2 replication effects of select selective serotonin reuptake inhibitors.…”

Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy

“… In vitro, In vivo and clinical trials should be done to confirm the activity [ 96 , 97 , 120 , 121 ] Hydroxychloroquine Anti-malarial drug with sigma-1 receptor agonist activity In vitro and some small uncontrolled studies suggested its efficacy in preventing SARS CoV-2 infection N/A Clinical studies showed little benefit to hospitalized patients treated with hydroxychloroquine which, however, could increase the risk of death in SARs CoV-2 hospitalized patients [ 123 , 126–130 ] PB28 Antagonist of the sigma-1 receptor Prevent the severity of SARS-CoV-2 infection PB28 binds to the Sigma-InsP3 receptor complex results in modulation of NSP6 activity leading to autophagosome activation In vitro, In vivo and clinical trials should be done to confirm the activity [ 61 , 133–135 ] Haloperidol Antipsychotic drug with sigma-1 (antagonist) and sigma-2 activity (agonist) Limit the severity of SARS-CoV-2 infection. Docking studies suggest haloperidol could effectively bind with NSP6 Activation of NSP6 could lead to activation of autophagy Clinical study has indicated that haloperidol treatment does not change the associated risk of intubation or death compared to patients not treated with haloperidol, nor does it affect time to discharge [ 61 , 136 , 137 ] Chlorpromazine Neuroleptic drug with sigma-1 receptor activity Prevent the severity of SARS-CoV-2 infection in monkey and human cells and in some patients Unknown Very few SARS-CoV-2 patients have taken chlorpromazine and more studies should be done [ 138 , 139 ] …”

“…Furthermore, docking analysis of haloperidol with the NSP6 protein shows haloperidol binds with an affinity score of −7.7 kcal/mol, which predicts a K D in the nano to the micromolar range [ 136 ]. However, it should be noted that an initial observational clinical study has indicated that haloperidol treatment does not change the associated risk of intubation or death compared to patients not treated with haloperidol, nor does it affect time to discharge [ 137 ].…”

COVID-19 in People With Schizophrenia: Potential Mechanisms Linking Schizophrenia to Poor Prognosis

“…Furthermore, recent reports on haloperidol on COVID-19 outcomes are varied. An observational study reported no association between haloperidol prescribing and risk of intubation, death or discharge time among patients hospitalised for COVID-19 (50). In contrast, neuroleptic malignant syndrome, which is typically associated with antipsychotics, has been reported in a case-study of a middle aged male with comorbid schizophrenia and severe COVID-19, who was prescribed haloperidol (51).…”