Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care A Randomized Clinical Trial

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Agar MR, et al. "Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial". JAMA Internal Medicine. 2017. 177(1):34-42.
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Clinical Question

In patients with acute delirium, is the use of antipsychotics safe and effective in improving symptoms?

Bottom Line

In patients with acute delirium, the use of antipsychotic drugs is associated with greater incidence of symptoms and increased severity of delirium as compared to placebo.

Major Points

Treatment of delirium throughout the study included nonpharmacologic and pharmacologic measures with the goal of therapy being to reduce distress, maintain safety, and resolve delirium is possible. Despite limited supporting data, antipsychotic drugs are often used in inpatient settings to treat symptoms of delirium. There is no approved medication for symptomatic treatment of delirium, but clinical guidelines do recommend the use of antipsychotics in cases of severe distress of behavioral disturbance.

This study, published in January 2017, was a multi-site, double-blind, parallel- arm, dose-titrated, placebo-controlled randomized clinical trial. The trial was completed in conjunction with nursing staff at palliative care centers associated with the study. Patients included in the study were adults receiving hospice or palliative care with an advanced progressive disease that was no longer curable and required inpatient care by a specialist team.

The study concluded that antipsychotic drugs are not effective for the treatment of delirium. Management of symptomatic delirium should include screening techniques and support interventions. A recent meta-analysis similarly concluded that antipsychotics are ineffective at reducing severity or duration of delirium.

The study implemented pharmacologic intervention using oral solution dosage forms of haloperidol, risperidone, and placebo; the use of solutions led to the withdrawal of certain participants who developed dysphagia during the trial period. Doses used in the study were conservative in comparison to practice settings, which may misrepresent adverse effects of the therapy. There was no documented follow-up with the participants after the conclusion of the study


  • From the article:
    • Clinical guidelines recommend antipsychotic drugs to be reserved for severe distress or behavioral disturbance, when other strategies have been ineffective or are inappropriate, with consideration of patient safety.
  • Delirium: prevention, diagnosis and management
    • NICE. Delirium: prevention, diagnosis and management [Internet]. Delirium: prevention, diagnosis and management | Guidance and guidelines | NICE. NICE; 2010 [cited 2017 Apr 25]. Available from: https://www.nice.org.uk/guidance/cg103
      • Treatment:
        • Identify potential underlying cause(s)
        • If patient is distress/considered a risk to him/herself or others:
          • First use verbal + nonverbal de-escalation techniques
          • May consider short-term haloperidol or olanzapine starting at lowest clinical dose
        • Antipsychotics not appropriate for all patients (i.e. Parkinson’s, dementia)
  • Delirium, dementia, and depression in older adults: assessment and care
    • RNAO. Delirium, dementia, and depression in older adults: assessment and care. [Internet]. National Guideline Clearinghouse. Registered Nurses' Association of Ontario (RNAO); 2016 [cited 2017 Apr 25]. Available from: https://www.guideline.gov/summaries/summary/50477?f=rss&osrc=12
      • When prescribing and administering medications to the elderly, it is important to exercise caution
      • When treating delirium it is important to utilize multiple interventions tailored to the individual patient. The following interventions should be included in any delirium treatment regimen:
        • Treatment of the underlying causes of the delirium
        • Non-pharmacological interventions
        • Appropriate use of medications to alleviate the symptoms of the delirium


  • Multi-site, double blind, parallel arm, dose-titrated, placebo-controlled randomized clinical trial
  • N=249 patients
    • Risperidone (n=82)
    • Haloperidol (n=81)
    • Placebo (n=86)
    • Patients 65 years and younger received loading dose of 1.0mg, then maintenance dose of 0.5mg every 12 hours
      • Dose could be titrated by 0.25mg on the first day of treatment, then by 0.5mg on subsequent days to a maximum of 4.0mg/day
    • Patients over 65 years, loading doses, initial doses, and maximum doses were halved
    • As defined by protocol, subcutaneous midazolam hydrochloride 2.5mg was available as needed for patients experiencing illusions, hallucinations, or behavioral disturbances
    • Placebo solutions titrated to match volumes of intervention solutions
  • Setting: 11 inpatient hospice or palliative care services
  • Enrollment: August 13, 2008 to April 2, 2014
  • Mean follow-up: N/A
  • Analysis: Intention-to-treat (ITT)
  • Primary outcome: average of the last two delirium symptom scores on day 3, using the baseline score (average of the eligibility delirium symptom score and the score before the first dose of the study drug) as a covariate.
  • Secondary outcomes:
    • Daily MDAS score
    • Lowest delirium symptom score
    • Daily use of midazolam
    • Extrapyramidal symptoms (assessed by Extrapyramidal Symptom Rating Scale)
    • Adverse events
    • Survival


Inclusion Criteria

  • Inclusion criteria:
    • Delirium diagnosed via criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Re-vision)
    • Memorial Delirium Assessment Scale (MDAS) score of 7 or more
    • Presence of the target symptoms of delirium associated with distress, defined as a delirium symptoms score of 1 or more on the **Nursing Delirium Screening Scale [NuDESC] [severity range, 0-6]).

Exclusion Criteria

  • Exclusion criteria:
    • Delirium due to substance withdrawal
    • History of neuroleptic malignant syndrome
    • Regular use of antipsychotic drugs within 48 hours (a single as-needed dose was allowed if administered more than 24 hours before the study for a non-delirium indication)
    • Previous adverse reaction to antipsychotic drugs
    • Extrapyramidal disorders
    • Prolonged QT interval
    • Clinician-predicted survival of 7 days or fewer
    • Cerebrovascular accident or seizure in the prior 30 days
    • Pregnancy or breastfeeding
    • Participants were required to speak English
    • Dysphagia.

Baseline Characteristics

  • Baseline demographics:
    • Age: 74.5 years
    • Female: 31 %
    • Mean delirium symptom score: 2.54
    • Age < 65 years : 22%
    • Cancer diagnosis: 93%
    • Performance status (Australia-modified Karnofsky Performance status score) : 40
    • Cumulative Illness Rating Scale score, median: 24
    • Cognitive impairment: 22%
    • Extrapyramidal Symptoms Rating Scale score, median: 5.0
    • MDAS score, median: 15.1
    • Opioid dose (Oral morphine equivalents in milligrams), median: 6.9
    • Patients receiving opioids: 48%
    • Benzodiazepines dose (oral diazepam equivalents in mg), median: 0
    • Informant Questionnaire on Cognitive Decline in the Elderly score, median: 4.1


  • Eligible participants were randomly assigned to receive risperidone, haloperidol, or placebo solutions at diagnosis of delirium for the control of target delirium symptoms
  • Dosing was based on prior controlled trials
  • Participants 65 years or younger received a 0.5 mg loading dose administered with the first dose of 0.5 mg, then 0.5 mg maintenance dose every 12 hours. Doses could be titrated by 0.25 mg on day 1 and by 0.5 mg thereafter to a maximum dose of 4 mg/d.
  • For participants older than 65 years, the loading, initial, and maximum doses were halved. The placebo solution was titrated similarly using matching volumes of solution for each dose level.
  • Study treatment duration was 72 hours. Participants were observed daily, with NuDESC (nursing delirium screening scale) scores measured every 8 hours. The last assessment performed 12 hours after the sixth dose.


Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

  • The primary outcome was the average of the last 2 delirium symptom scores on day 3, using the baseline score (average of the eligibility delirium symptom score and the score before the first dose of the study drug) as a covariate
Delirium Scores
*Risperidone vs. placebo group (on average 0.48 units higher; 95% CI, 0.09-0.86; p = 0.02)
  • Haloperidol vs. placebo group (on average 0.24 units higher; 95% CI, 0.06-0.42; p = 0.009)

Secondary Outcomes

Extrapyramidal effects
  • Risperidone (0.73; 95% CI, 0.09-1.37; p = 0.03)
  • Haloperidol (0.79; 95% CI, 0.17-1.41; p = 0.01)
MDAS score
*Risperidone vs. placebo group (mean difference of 0.96; 95% CI, 0.16-1.77; p<0.001)
  • Haloperidol vs. placebo group (mean difference of 0.75; 95% CI, -0.03 to 1.51; p = 0.06)

Subgroup Analysis

  • Mean lowest achieved score
    • Risperidone group 0.15 units higher vs. placebo (95% CI, -0.16 to 0.48; P = 0.31)
    • Haloperidol group 0.01 units lower vs. placebo (95% CI, -0.41 to 0.43; P = 0.95)

Adverse Events

  • Deaths
    • Participants in the placebo group had better overall survival than those receiving haloperidol (HR, 1.73; 95% CI, 1.20-2.50; p= .003
      • 73% increased chance of death with haloperidol vs. placebo
    • Survival rate differences were not significant for placebo vs risperidone (HR, 1.29; 95% CI, 0.91-1.84; p= .14).
      • 29% increased chance of death with risperidone vs. placebo


  • Did not include multiple comparisons between other drugs. The study only compared placebo vs. risperidone and placebo vs haloperidol.
  • Using just an oral solution lead to potential participants having to withdraw
  • Doses used in study may have underestimated the adverse consequences of using antipsychotic drugs to treat delirium in routine practice.
  • No documented follow-up.


The study was funded by the Australian Government’s Department of Health under the National Palliative Care Program, with individual site funding provided by grant NHMRC 480476 from the Australian National Health and Medical Research Council. Both funding sources had no role in design and conduct of the study.

Further Reading