Stop Prescribing Antipsychotics for Delirium

Diana Swift

September 05, 2019

Neither first- nor second-generation antipsychotics show a clear benefit over placebo for preventing or treating delirium in hospitalized adults, and their routine use should be discontinued, researchers from Johns Hopkins University in Baltimore, Maryland, report.

Second-generation antipsychotics, however, may have some benefit in the postoperative setting, according to two systematic reviews of 26 randomized controlled trials (RCTs) published online September 2 in the Annals of Internal Medicine.

As many as 50% of older inpatients hospitalized for acute illness or surgery experience delirium, which can impair awareness, attention, and cognition and may lead to potentially dangerous disorientation and confusion.

Data Do Not Support Routine Use for Prevention

In the first of two reviews, Esther S. Oh, MD, PhD, associate director of the Johns Hopkins Memory and Alzheimer's Treatment Center, and colleagues analyzed 14 RCTs involving 4281 patients that were published from 1999 to 2018. They compared the preventive benefits and harms of haloperidol vs placebo and atypical second-generation antipsychotics such as risperidone and quetiapine.

Little or no data emerged from the review to determine the effect of haloperidol on cognitive function, delirium severity, inappropriate continuation of medication, and sedation. Evidence suggested that second-generation antipsychotics may offer minimal benefit in the postsurgical setting.

Overall, the researchers conclude, "...evidence was insufficient to support the routine use of antipsychotics for preventing delirium in adult patients. Second-generation antipsychotics may lower delirium incidence in postoperative patients, but more research is needed to confirm this finding."

That conclusion is based on three RCTs that compared second-generation antipsychotics with placebo in postoperative settings. A statistically significantly lower pooled relative risk (RR) for incident delirium was found. In these studies, the pooled RR for delirium incidence with second-generation agents was 0.36 (95% confidence interval [CI], 0.26 – 0.50); for haloperidol, the RR was 0.94 (95% CI, 0.77 – 1.16).

In terms of safety, no statistically significant differences between haloperidol and placebo emerged regarding cardiac side effects such as arrhythmia and prolongation of the corrected QT interval (QTc). For six studies, the pooled RR of arrhythmias with haloperidol vs placebo was 1.27 (95% CI, 0.72 – 2.21). For seven studies, the RR of QTc was 1.11 (95% CI, 0.80 – 1.55).

Overall findings for cardiac events were similar for second-generation antipsychotics compared with placebo, but some trials found such events to be more frequent in antipsychotic recipients.


A second review, by Roozbeh Nikooie, MD, a postdoctoral research fellow at Johns Hopkins University School of Medicine, and colleagues, assessed 16 RCTs and 10 observational studies involving 5607 inpatients that were published from 2004 to 2018. This review weighed the benefits and harms of haloperidol and second-generation antipsychotics for treating delirium in hospitalized populations.

As with its prevention counterpart, the treatment review found no differences for haloperidol and second-generation antipsychotics compared with placebo regarding hospital length of stay, sedation status, delirium duration, or mortality. Evidence for their effects on cognitive functioning and delirium severity was insufficient or lacking.

Again, there were reports of more frequent cardiac side effects with antipsychotics, particularly prolongation of the QT interval, with second-generation antipsychotics compared with placebo or haloperidol. There was little evidence of antipsychotic-related neurologic harms.

Nikooie and associates note that for some clinically important outcomes and for subgroups such as older patients and palliative care patients, evidence was insufficient or absent, underscoring the need for continued research in this area.

The researchers write that future trials with standardized outcome measures are needed to clarify the impact of antipsychotics on multiple outcomes. These endpoints include agitation and distress, subsequent memories of delirium, caregiver burden and distress, inappropriate continuation of antipsychotic therapy, and long-term cognitive function.

In an accompanying editorial that focuses on treatment, Edward R. Marcantonio, MD, section chief for research in the Division of General Medicine and Primary Care at Beth Israel Deaconess Hospital in Boston, Massachusetts, notes that delirium is a strong predictor of adverse outcomes. These include in-hospital complications such as falls, functional and cognitive decline, and death. Delirium also leads to extensions of hospital stay and post-discharge institutional care, adding billions of dollars in annual costs to the US healthcare system.

Marcantonio agrees with the study authors that the routine practice of giving antipsychotics for delirium is not supported by evidence. "With regard to use of antipsychotics for broad treatment of delirium, I believe the findings presented are sufficient to stop this clinical practice," he writes.

Managing delirium for better short- and long-term outcomes should be an investigational priority. "Future research should focus on defining patient subgroups and settings (if any) in which the benefits of antipsychotics outweigh harms, such as short-term use for behavioral control of a patient who is a danger to themselves or others, and for whom behavioral strategies are insufficient," Marcantonio writes.

He supports a patient-centered, bundled approach to delirium that includes early diagnosis and that addresses underlying causes, prevention of complications, and promotion of functional recovery.

"Identifying which practices belong in this bundle, and how to deliver it in a standardized, high-quality, and sustainable way, should be a major focus of the next generation of delirium treatment research," Marcantonio concludes.

Both studies and several authors were financially supported by the Agency for Healthcare Research and Quality. Coauthor Karin J. Neufeld, MD, MPH, reports financial relationships with Merck and Hitachi outside the submitted work. Marcantonio has disclosed no relevant financial relationships.

Ann Intern Med. Published online September 2, 2019. Review 1, Full text; Review 2, Full text; Editorial

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