We sought to address two Key Questions:

Key Question 1: What are the benefits and harms of antipsychotics compared with each other, placebo, or non-drug approaches to prevent delirium?

Key Question 2: What are the benefits and harms of antipsychotics compared with each other, placebo, or non-drug approaches to treat delirium?

For each Key Question, we first considered evidence about the overall population and then considered the following populations or settings:

• Persons aged 65 years or older
• Persons with dementia
• Patients in an intensive care unit
• Patients in a post-acute care facility
• Patients in palliative or hospice care
• Patients in postoperative care

This section provides information on how this AHRQ review relates to other systematic reviews of and clinical guidelines for antipsychotics for the prevention and treatment of delirium. Several systematic reviews have examined the risks and benefits of antipsychotic treatments for delirium but none of these existing reviews had the same scope as ours. For instance, we considered prevention and treatment studies separately and examined the evidence for specific subpopulations, in addition to looking at the data overall.

Related Review Findings

1. Other reviews have come to similar conclusions:
   • A systematic review of antipsychotics focused on antipsychotics for delirium prevention or treatment in adult surgical and medical inpatients, including the critically ill, concluded that "current evidence does not support the use of antipsychotics for prevention or treatment of delirium." The search for this systematic review ended in 2013; consequently, it excluded important, newer studies included in this report.
   • A recent Cochrane systematic review conclusion that "there is probably little or no difference between haloperidol and placebo for preventing ICU delirium" is consistent with findings in our review.
   • Similar to our review, another Cochrane review evaluating pharmacologic and non-pharmacologic interventions in non-intensive care unit hospitalized adults concluded that there was no evidence for the effectiveness of first-generation antipsychotics, such as haloperidol. However, we also concluded that there were no between-group differences for second-generation antipsychotics versus placebo in length of stay in hospital (low strength of evidence) and insufficient evidence to understand the impact on severity of delirium symptoms for both the postoperative subgroup and across all populations.


2. Reviews with dissimilar findings:
   • A review of antipsychotics for the treatment of delirium in adult patients concluded that antipsychotics are superior to placebo/usual care. That finding contradicts our findings and those of other more recent systematic reviews and guidelines that have concluded that there is no evidence that antipsychotics improve the outcomes among hospitalized adults with delirium. Although we included all of the published studies from this review, recently completed trials were also added to our synthesis and contributed to our conclusions.

Clinical Guidelines

1. 2018 clinical practice guidelines from the Society for Critical Care Medicine suggested not using haloperidol or a second-generation antipsychotic to prevent or treat delirium in critically ill adults (conditional recommendation, very low to low quality of evidence). This guideline focused on critically ill patients only.

Clinical Implications

• Across a range of cardiac and neurological effects, there was little evidence of increased serious harms related to antipsychotics compared with placebo or with other antipsychotics (i.e., drug-to-drug comparisons). However, across different types of cardiac events, the absolute number tended to be greater for antipsychotics compared to placebo, which may be clinically relevant.


• Moreover, inappropriate continuation of antipsychotics and associated long-term harms from inadvertent prolonged use were not evaluated in any studies that met our inclusion criteria. Given that observational studies of routine clinical practice demonstrate frequent inappropriate continuation of antipsychotics, this is an important issue.


• Given the lack of effectiveness of antipsychotics for the treatment of delirium, particularly in critically ill adults, and the lack of improved outcomes associated with the use of second-generation antipsychotics in preventing postoperative delirium, the use of other nonpharmacological therapies with low cost, burden, and harms warrants consideration for clinical practice as recommended by existing clinical practice guidelines.


• Future studies should include standardized, clinically meaningful measures of patient distress, subsequent memories of delirium, caregiver burden and distress, inappropriate continuation of antipsychotic therapy, and long-term cognitive and functional outcomes.

Policy Implications

• There is no Food and Drug Administration-approved medication for the prevention or treatment of delirium. Our findings do not support the use of antipsychotics for the routine treatment of delirium. While the use of second-generation antipsychotic medications may be associated with decreased incidence of postoperative delirium, this review did not identify improved outcomes associated with the use of these agents.

This review does not provide cost information.

Applicability

The overall results of this report may not be directly applicable to postoperative patients, older inpatients, and patients with dementia. Existing trials were often conducted in medical and surgical critically ill patients.

Any benefit and risk of antipsychotics for prevention or treatment of delirium within the context of critical illness may not be generalizable to other populations. Critically ill patients may:

• Have differing pathophysiological etiologies of delirium, as well as more severe physiological and metabolic derangements.
• Routinely receive relatively high doses of deliriogenic medications, such as sedatives (e.g., benzodiazepines and propofol).
• Be more susceptible to the potentially harmful effects of antipsychotics.

Limitations

• We were unable to conduct a network meta-analysis. Such an analysis could potentially provide important drug-to-drug comparison information that the current trials do not provide.
• There was insufficient or no evidence for many comparisons and outcomes.
• There was frequent unclear risk of bias related to missing outcome data and selective outcome reporting.
• Many studies were underpowered, with short duration.
• Study designs were fairly heterogeneous, using different dosing routes, and a range of doses and frequencies of different antipsychotics. Combining heterogeneous treatment and prevention approaches may bias the findings toward the null hypothesis. So, too, combining a range of dosing exposures may obscure adverse outcomes associated with higher doses of medications.