Is there any evidence that quetiapine is more efficacious or safer than haloperidol for ICU delirium treatment?

Comment by InpharmD Researcher

Available literature does not show there are any differences in efficacy or safety between quetiapine and haloperidol for the treatment of delirium. Studies did not exclusively evaluate delirium in ICU patients. One meta-analysis found quetiapine to have a significant response rate when used to treat ICU delirium; however, haloperidol did not (low strength of evidence).

Background

A 2019 systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults included 16 randomized controlled trials (RCT; n= 1,768) and 10 observational studies (n= 3,839) of hospitalized adults. Two of the included RCTs involved a direct comparison between haloperidol and quetiapine (Tables 1 and 2). Overall with low to moderate strength of evidence, no differences in sedation status, delirium, hospital length of stay, mortality, delirium severity, and cognitive function between haloperidol versus second-generation antipsychotics were noted. Notably, most of the RCTs excluded patients with underlying neurologic or cardiovascular issues, which potentially underestimated the harms associated with routine antipsychotic use in treating delirium. A quantitative synthesis of the included studies is limited by heterogeneity in drug dose, frequency, route of administration, outcomes evaluated, and the measurement instruments. Antipsychotics for the treatment of delirium in adult inpatients did not improve patient outcomes, with little evidence of neurologic harms but a tendency for more frequent potentially harmful cardiac effects. [1]

A 2020 meta-analysis compared the efficacy and tolerability of various pharmacologic interventions for the treatment of patients with delirium in the intensive care unit (ICU). One-hundred and eight RCTs were included with the majority observing prevention of delirium versus treatment (N= 29,935). The response rate for quetiapine was found to be significant for ICU delirium with a reported odds ratio (OR) of 8 (95% confidence interval [CI] 1.41 to 45.41) but the strength of evidence was deemed to be low; quetiapine only has a single study supporting its use. By comparison, haloperidol was not statistically beneficial with an OR of 1.01 (95% CI 0.72 to 1.44). None of the agents were significantly beneficial in the non-ICU setting. [2]

The Society of Critical Care Medicine (SCCM) 2018 clinical practice guidelines for prevention and management of delirium in adult patients in the ICU suggest not routinely using haloperidol or an atypical antipsychotic (e.g., quetiapine) to treat delirium (conditional recommendation, low quality of evidence). This recommendation is based on evidence that suggests the use of haloperidol or an atypical antipsychotic is not associated with a shorter duration of delirium, reduced duration of mechanical ventilation or ICU length of stay, or decreased mortality. Although this recommendation discourages the “routine” use of antipsychotic agents in treatment of delirium, patients who experience significant distress secondary to symptoms of delirium or who are agitated and may be physically harmful to themselves or others may benefit from short-term use of haloperidol or an atypical antipsychotic until distressing symptoms resolve. It is stated the undesirable effects of haloperidol and atypical antipsychotics remain uncertain, given the small sample sizes of available studies. A consensus regarding the comparative efficacy and safety of quetiapine and haloperidol is not given. [3]

References: [1] Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med. 2019;171(7):485-495. doi:10.7326/M19-1860
[2] Kim MS, Rhim HC, Park A, et al. Comparative efficacy and acceptability of pharmacological interventions for the treatment and prevention of delirium: A systematic review and network meta-analysis. J Psychiatr Res. 2020;125:164-176. doi:10.1016/j.jpsychires.2020.03.012
[3] Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any evidence that quetiapine is more efficacious or safer than haloperidol for ICU delirium treatment?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-3 for your response.

 

Comparative Effectiveness of Quetiapine and Haloperidol in Delirium: A Single Blind Randomized Controlled Study

Design

Single-blind, randomized controlled study

N= 63

Objective

To evaluate the effectiveness of quetiapine and haloperidol in patients of delirium referred to psychiatry consultation liaison services

Study Groups

Haloperidol (n= 32)

Quetiapine (n= 31)

Inclusion Criteria

Age >18 years with a diagnosis of delirium according to the Diagnostic and Statistical Manual, 4th Revision

Exclusion Criteria

Delirium associated with alcohol or benzodiazepine withdrawal; poisoning due to overdose; delirium associated with dementia; unresponsive to any verbal or physical stimulus; history of aphasia; profound hearing or visual loss; prolonged QTc interval (> 500 ms); history of hypersensitivity to any study drugs; developed neuroleptic malignant syndrome; comorbid Parkinson's disease, psychotic or mood disorders; terminal illnesses

Methods

A flexible dosing regimen (haloperidol 0.25 to 10 mg and quetiapine 12.5 to 75 mg/day) was used and could be adjusted as per the clinical judgment. Haloperidol was usually dosed at 0.25 mg two to three times daily and titrated as per the requirement, and the majority of patients were managed with 0.75 to 2.5 mg of haloperidol per day. A dose of 1.25 to 2.5 mg was given intravenously and repeated as needed for agitation. For quetiapine, a regimen of 12.5 mg/day was started and increased to 75 mg/day depending on patients' needs. If delirium improved, the dose used on the previous day was continued until the end of the trial.

Duration

6 days

Outcome Measures

Primary outcome: Delirium Rating Scale-Revised-98 (DRS-R-98; 16-item scale with 13 severity and 3 diagnostic items, 0 [absent/normal] to 2/3 [severe impairment]; high scores [0], [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39] indicated more severe delirium)

Secondary outcome: Mini mental status examination (MMSE)

Baseline Characteristics

  

Haloperidol (n= 32)

Quetiapine (n= 31)

  

Age, years

 44.4 ± 16.76 48.51 ± 19.75  

Male

 28 (87.5%) 21 (67.74%)  

Duration of delirium prior to assessment, days

 2.38 ± 1.81 2.83 ± 2.32  

Total IQCODE

 3.01 ± 0.053 3.13 ± 0.4  

Delirium subtype as per amended DMSS

Hyperactive

Hypoactive

Mixed


28 (87.5%)

3 (9.37%)

1 (3.12%)


27 (87.09%)

2 (6.45%)

2 (6.45%)

  

Mean dose, mg/day (range)

0.67 ± 0.35 (0.25 to 1.25)

26.63 ± 15.61 (12.5 to 75)

  

DRS-R-98 total score

31.21 ± 2.4

31.83 ± 4.1

  

DRS-R-98 severity items only score

24.81 ± 2.19

25.48 ± 3.6

  

MMSE score

7.5 ± 3.83

6.83 ± 4.45

  

There was no statistically significant difference between groups for any baseline variables. 

IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly; DMSS, Delirium Motor Subtype Scale

Results

Endpoint

Haloperidol (n= 32)

Quetiapine (n= 31)

p-value

DRS-R-98 severity items only scores

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

 

20.46 ± 3.93

15.43 ± 6.19

11.46 ± 6.58

8.65 ± 6.73

6.46 ± 6.06

5.43 ± 5.84

 

19.54 ± 6.4

13.54 ± 7.67

9.51 ± 7.29

7.83 ± 7.42

6.48 ± 6.84

5.58 ± 5.84

 

0.49

0.28

0.26

0.64

0.749

0.679

MMSE scores

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

 

11.31 ± 5.91

15.5 ± 5.16

18.28 ± 0.73

20.34 ± 5.72

21.93 ± 5.01

23 ± 4.75

 

11.8 ± 6.02

16 ± 6.37

18.38 ± 6.26

20.67 ± 6.41

21.58 ± 5.74

22.54 ± 5.34

 

0.74

0.73

0.94

0.828

0.794

0.724
Endpoint Haloperidol group Quetiapine group p-value for haloperidol, quetiapine

Improvement in DRS-R-98 severity scores

Day 0 and day 1

Day 0 and day 2

Day 0 and day 3

Day 0 and day 4

Day 0 and day 5

Day 0 and day 6

Day 3 and day 6

 

7.1

9.48

11.69

14.08

17.63

4.94

4.7

 

5.12

8.6

11.68

12.9

4.86

4.86

3.98

 

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

Improvement in MMSE

Day 0 and day 1

Day 0 and day 2

Day 0 and day 3

Day 0 and day 4

Day 0 and day 5

Day 0 and day 6

Day 3 and day 6


3.83

8.53

9

10.07

11.68

12.38

6.5


4.81

7.4

8.66

9.45

10.55

12.23

5.66


0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

< 0.001, < 0.001

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Quetiapine is as effective as haloperidol in the management of delirium.

InpharmD Researcher Critique

Consecutive patients were screened for eligibility instead of using convenience sampling, which may have prevented potential sampling bias. The DRS-R-98 severity scale and total scale are the validated scales for adequately measuring the primary efficacy endpoint. Overall, the results show haloperidol and quetiapine are effective treatment strategies for delirium; however, there do not appear to be any differences in efficacy. Safety was not evaluated in this study.



References:
[1] Grover S, Mahajan S, Chakrabarti S, et al. Comparative effectiveness of quetiapine and haloperidol in delirium: A single blind randomized controlled study. World J Psychiatry. 2016;6(3):365-371. doi:10.5498/wjp.v6.i3.365

 

Quetiapine versus Haloperidol in the Treatment of Delirium: A Double-Blind, Randomized, Controlled Trial

Design

7-day prospective, double-blind, randomized controlled trial

N= 52

Objective

To compare the efficacy and tolerability between quetiapine and haloperidol in controlling delirious behavior

Study Groups

Quetiapine (n= 24)

Haloperidol (n= 28)

Inclusion Criteria

All inpatients (aged 18–75 years old) with delirium diagnosis and needing consultation-liaison services from the psychiatric department 

Exclusion Criteria

Substance-induced delirium (e.g., alcohol-withdrawal delirium), known allergy or intolerance to quetiapine or haloperidol, pregnancy or breastfeeding, being on antipsychotic medication, renal or hepatic failure

Methods

Eligible patients were randomized (1:1) to receive either a flexible oral dose of quetiapine (25 to 100 mg/day) or haloperidol (0.5 to 2.0 mg/day) before bedtime and as needed. Starting with one capsule orally at bedtime, patients might receive one more capsule every 2-3 hours for agitation. The maximum dose was four capsules per 24 hours. Other psychotropic medications, including benzodiazepines, were prohibited.

Duration

From June 2009 to April 2011

Outcome Measures

Primary: Delirium Rating Scale-revised-98 (DRS-R-98) severity score 

Secondary: DRS-R-98 noncognitive and cognitive subscale scores, response rate, remission rate, total time of sleep, Clinical Global Impression-Improvement (CGI–I) scores, extrapyramidal side effects via Modified (nine-item) Simpson–Angus Scale (MSAS)

Baseline Characteristics

  

Quetiapine (n= 24)

Haloperidol (n= 28)

 p-Value

Age, years

 56.6 ± 12.0 57.0 ± 11.9 0.90

Male

15 (62.5%) 20 (71.4%) 0.49

Possible causes of delirium

Infection

Fluid-electrolyte imbalance

Trauma

CNS pathology

Hypoxia

Malnutrition or deficiency

Disorders of the endocrine system

Acute hemodynamic change

Toxin or drugs

Amitriptyline

Tramadol

Morphine

Steroid

Anticholinergic drug

Baclofen

Chemotherapy (ifosfamide)

Total numbers of drugs used

 

17 (70.8%)

19 (79.2%)

14 (58.3%)

11 (45.8%)

14 (58.3%)

17 (70.8%)

4 (16.7%)

7 (29.2%)

10 (41.7%)

6 (25.0%)

2 (8.3%)

2 (8.3%)

2 (8.3%)

0 (0%)

0 (0%)

1 (4.2%)

0.5 ± 0.9

 

25 (89.3%)

20 (71.4%)

19 (67.9%)

12 (42.9%)

18 (64.3%)

23 (82.1%)

7 (25.0%)

11 (39.3%)

11 (39.3%)

2 (7.1%)

1 (3.6%)

2 (7.1%)

0 (0%)

1 (3.6%)

1 (3.6%)

0 (0%)

0.3 ± 0.5

 

0.16

0.52

0.47

0.83

0.66

0.34

0.46

0.44

0.86

0.12

0.59

1.00

0.21

1.00

1.00

0.46

0.28 

Total possible causes of delirium

 5.3 ± 1.5 5.8 ± 1.6

0.25

Duration of delirium before enrolled, days

 3.3 ± 2.5 2.9 ± 2.8 0.16 

Baseline DRS-R-98 scores

 29.0 ± 4.4 29.7 ± 4.6 0.23 
CGI–S score 6.0 ± 0.8 6.1 ± 0.8 0.64 
Baseline total sleep time, hours 2.0 ± 2.7 1.1 ± 1.7 0.26 
Baseline MSASa 0.1 ± 0.5 0.2 ± 0.8 0.89 
aSome patients had prior movement disorder from Parkinson’s disease.

Results

Endpoint

Quetiapine Mean ± SD (95% confidence interval [CI])

 Haloperidol Mean ± SD (95% CI)

p-value

DRS-R-98 severity scores over the 7-day trial period

 −22.9 ± 6.9 (−26.9 to −19.0) −21.7 ± 6.7 (−24.7 to −18.6) 0.59

Noncognitive subscore

 −16.9 ± 5.5 (−20.1 to −13.7) −15.8 ± 4.7 (−18.0 to −13.7) 0.54 

Cognitive subscore

 −6.0 ± 3.2 (−7.9 to −4.1) −5.8 ± 3.6 (−7.5 to −4.2) 0.89 

Response rate

 79.2% 78.6% 0.97

Times to response, days

 1.7 ± 0.1 1.9 ± 1.6 0.51

Remission rate

 75.0% 67.9% 0.96
Times to remission, days 2.6 ± 1.9 1.8 ± 1.5 0.14
Clinical global impression-improvement −1.1 ± 1.0 (−1.7 to −0.6) −1.2 ± 1.4 (−1.8 to −0.5) 0.96 
Sleep time, hours 6.5 ± 3.0 (4.8 to 8.2) 6.1 ± 3.4 (4.6 to 7.7) 0.74 
MSAS scores 0.3 ± 0.7 0.3 ± 1.1 0.51

Side effects

Hypersomnia

Tremor

Nightmare

Rash

Akathisia

Ties

Quetiapine group number (%)

10 (41.7%)

0 (0)

1 (4.2%)

1 (4.2%)

0 (0)

0 (0)

Haloperidol group number (%)

8 (28.6%)

1 (3.6%)

0 (0)

1 (3.6%)

1 (3.6%)

1 (3.6%)

p-Value

0.32

1.00

0.46

1.00

1.00

1.00

Adverse Events

 See Results

Study Author Conclusions

Low-dose quetiapine and haloperidol may be equally effective and safe for controlling delirium symptoms.

InpharmD Researcher Critique

Despite its ideal study design (double-blind RCT), it is a small-scale study, which may in part explain the lack of differences in measured outcomes and adverse effects, and conducted in Thailand. The study further excluded vulnerable populations such as severely ill (e.g., renal or hepatic failure) delirious patients aged over 75. Inclusion of acute CNS pathology and other cognitive disorders such as dementia and relatively a long break between the identification of delirium and the study enrollment may have confounded the study results. 



References:
[1] Maneeton B, Maneeton N, Srisurapanont M, et al. Quetiapine versus haloperidol in the treatment of delirium: a double-blind, randomized, controlled trial. Drug Des Devel Ther. 2013;7:657-667. Published 2013 Jul 24. doi:10.2147/DDDT.S45575

 

Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium

Design

Single-center, prospective, comparative, observational study

N= 80

Objective

To compare the efficacy and safety of haloperidol versus three atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) for patients with delirium; to investigate whether response rate of haloperidol and three atypical antipsychotic medications differ depending on age, dividing the study cohort into two age groups, in the treatment of delirium

Study Groups

Haloperidol (n= 23)

Risperidone (n= 21)

Olanzapine (n= 18)

Quetiapine (n= 18)

Inclusion Criteria

Age ≥ 50 years; meets Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) diagnostic criteria for delirium; presenting with a mental status change; referred to a consultation-liaison psychiatric service at a tertiary level university hospital in Korea

Exclusion Criteria

Diagnosis of dementia or comorbid psychiatric disorder; terminal illness; history of prolonged QTc interval; hearing loss; neuroleptic malignant syndrome; use of antipsychotic medication before referral 

Methods

The initial starting dose was determined on the basis of age, degree of severity of delirium, and the general medical or post-surgical condition of the individual subject. A flexible dosing regimen (haloperidol: 0.5-10 mg, risperidone: 0.25-4 mg, olanzapine: 1–20 mg, quetiapine: 25–200 mg) was used.

Since strict restriction of rescue medication in subjects with a poor general medical condition would have been ethically problematic, rescue intramuscular injections of haloperidol or lorazepam were allowed and recorded.

Duration

6 days

Outcome Measures

Changes in Delirium Rating Scale-Revised-98 (DRS-K) and Korean version of the Mini-Mental Status Examination (K-MMSE) scores

Baseline Characteristics

  

Haloperidol (n= 23)

Risperidone (n= 21)

Olanzapine (n= 18)

 Quetiapine (n= 18) p-value 

Age, years

74 ± 9.9

70.1 ± 9.5

69.5 ± 15.9

 73.3 ± 10.7 0.522

Male

12 (52.2%)

8 (38.1%)

8 (44.4%)

8 (44.4%)

0.828

Definite cause of delirium

Metabolic/endocrine

Systemic infection

Systemic neoplasm

Cerebrovascular

Organ insufficiency

 

6 (26%)

4 (17.3%)

6 (26%)

3 (13%)

3 (13%)

 

8 (38%)

3 (14.2%)

1 (4.7%)

3 (14.2%)

3 (14.2%) 

 

4 (22.2%)

3 (16.6%)

3 (16.6%)

0

8 (44.4%)

 

5 (27.7%)

4 (22.2%)

2 (11.1%)

3 (16.6%)

2 (11.1%)

 

0.759

0.957

0.26

0.328

0.059

Dose, mg/day

1.2 ± 0.4

1.1 ± 0.3

2.9 ± 1

47.9 ± 17.1

 -

Duration of medication, day

4.7 ± 1.6

5.1 ± 1.3

5.3 ± 1.1

4.8 ± 1.7

 0.655

Number of subjects assessed

Baseline

Day 2

Day 4

Day 6

 

23 (100%)

18 (78.2%)

16 (69.5%)

14 (60.8%)

 

21 (100%)

21 (100%)

18 (85.7%)

14 (66.6%)

 

18 (100%)

18 (100%)

15 (83.3%)

13 (72.2%)

 

18 (100%)

15 (83.3%)

12 (66.6%)

12 (66.6%)

 

-

-

-

-

Results

Endpoint

Haloperidol (n= 23)

Risperidone (n= 21)

Olanzapine (n= 18)

 Quetiapine (n= 18)

p-value

DRS-K

Severity score

Baseline

Day 2

Day 4

Day 6

 

 

17.4 ± 6.7

11.5 ± 7.1

8.5 ± 4.6

7.7 ± 5.4

 

 

18.9 ± 5.2

13.3 ± 5.8

9.8 ± 6.7

8.3 ± 7.1

 

 

17.5 ± 5.7

10.5 ± 6.6

8.8 ± 6

8.1 ± 5.5

 

 

17.5 ± 6.4

12.2 ± 5.4

7.6 ± 3.7

6.5 ± 4

0.779†

DRS-K

Cognitive subscale score

Baseline

Day 2

Day 4

Day 6

 

 

7.8 ± 3.8

5.7 ± 3.9

4.3 ± 2.4

4 ± 2.9

 

 

8.7 ± 3.4

6.5 ± 3.4

4.8 ± 3.6

4.1 ± 4

 

 

7.7 ± 3.6

5 ± 3

4.2 ± 3.2

4.2 ± 2.7

 

 

8.1 ± 3.2

5.6 ± 2.6

4 ± 2.5

3.2 ± 2.5

 0.718†
 

DRS-K

Non-cognitive subscale score

Baseline

Day 2

Day 4

Day 6

 

 

9.5 ± 3.5

5.7 ± 3.5

4.1 ± 2.6

3.7 ± 2.8

 

 

10.1 ± 3

6.5 ± 2.9

4.9 ± 3.8

4.2 ± 3.6

 

 

9.7 ± 3.3

5.5 ± 3.8

4.6 ± 3.5

3.9 ± 3.5

 

 

9.4 ± 4.2

6.6 ± 3.7

3.6 ± 2.2

3.3 ± 2

 0.918†

K-MMSE score

Baseline

Day 2

Day 4

Day 6

 

13.7 ± 6.5

19 ± 6.7

21.3 ± 4.7

22.4 ± 4.4

 

15 ± 5.8

18.3 ± 5.7

21.5 ± 5.3

22.4 ± 5

 

16.2 ± 5.4

21 ± 6.2

21.8 ± 5.8

23.1 ± 5.3

 

15.7 ± 6.3

20.2 ± 4.9

21.9 ± 3.7

23.4 ± 3.7

 0.63†

†p-values analyzed among groups by linear mixed model statistics

Each day-by-group interaction was not significant in all efficacy measures.

In all medication groups, the mean score of DRS-K severity, cognitive and non-cognitive subscale tended to decrease significantly over study period.

In all medication groups, the mean score of K-MMSE tended to increase significantly over the study period.

Adverse Events

Common Adverse Events: not disclosed

Serious Adverse Events: not disclosed

Percentage Discontinued due to Adverse Events: N/A

Study Author Conclusions

Haloperidol, risperidone, olanzapine, and quetiapine were equally efficacious and safe in the treatment of delirium. However, age is a factor that needs to be considered when making a choice of antipsychotic medication for the treatment of delirium.

InpharmD Researcher Critique

This study was limited by observational design, small sample size, and the lack of a placebo comparator group. Although the single-center nature of the study may limit the generalizability of the study, the real-world data may still be applicable as general guidance in practice.



References:
[1] Yoon HJ, Park KM, Choi WJ, et al. Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium. BMC Psychiatry. 2013;13:240. Published 2013 Sep 30. doi:10.1186/1471-244X-13-240