Journal of Psychosomatic Research 71 (2011) 277–281

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Journal of Psychosomatic Research

Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium☆

Sandeep Grover ⁎, Vineet Kumar, Subho ChakrabartiDepartment of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh, India

☆ Conflict of interest: none.⁎ Corresponding author. Department of Psychiatry, Po

Education & Research, Chandigarh 160012, India. Tel.: ++91 172 2744401, 2745078.

E-mail address: drsandeepg2002@yahoo.com (S. Gro

0022-3999/$ – see front matter © 2011 Elsevier Inc. Aldoi:10.1016/j.jpsychores.2011.01.019

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 30 November 2010Received in revised form 1 January 2011Accepted 30 January 2011

Keywords:DeliriumEfficacyAtypical antipsychoticsOlanzapineRisperidone

Objective: The objective of the study was to assess the efficacy and safety of second-generation antipsychoticsolanzapine and risperidone vs. haloperidol in patients of delirium admitted to medical and surgical wards.Methods: Prospective follow-up single-blind randomized controlled trials were performed. Consecutivepatients with delirium referred to the consultation–liaison psychiatry team were eligible for the study. Thestudy sample comprised 64 patients, with 20 subjects in the haloperidol group, 21 subjects in the risperidonegroup and 23 subjects in the olanzapine group. A flexible dose regimen (haloperidol −0.25 to 10 mg;risperidone −0.25 to 4 mg; olanzapine −1.25 to 20 mg) was used. Delirium Rating Scale-Revised-98 (DRS-R98) was used as the primary efficacy measure, and mini mental status examination (MMSE) was used as asecondary efficacy measure.Results: There was no significant difference in mean baseline DRS-R98 severity scores and MMSE scores

between the three groups. However, there were a significant reduction in DRS-R98 severity scores and asignificant improvement in MMSE scores over the period of 6 days, but there was no difference between thethree groups. Four patients in the haloperidol group, six subjects in the risperidone group and two subjects inthe olanzapine group experienced some side effects.Conclusions: Risperidone and olanzapine are as efficacious as haloperidol in the treatment of delirium.

© 2011 Elsevier Inc. All rights reserved.

Introduction

Delirium is a common neuropsychiatric disorder among medicallycompromised patients. It is characterized by disturbance of con-sciousness, attention, cognition and perception and can also affectemotions, sleep and psychomotor activity [1]. The treatment ofpatients with delirium involves identifying and treating the etiologyof the delirium, ensuring safety and improving the patient'sfunctioning. In terms of pharmacological treatment, antipsychoticmedications and benzodiazepines are the commonly used agents.Among the antipsychotics, haloperidol continues to be the mostcommonly used [2]. However, haloperidol can also lead to extrapy-ramidal symptomswhich are more likely to occur in delirious patientsbecause delirium ismore common in elderly and severelymedically illpatients. In the last decade or so, many researchers have evaluated theusefulness of second-generation antipsychotics in delirium; however,most of the data are in the form of case reports/case series and open-label trials [3–4]. Although some randomized controlled trials areavailable evaluating the role of various atypical antipsychotics indelirium [5–14], the data are still limited. These trials have compared

stgraduate Institute of Medical91 172 2756807 (Office); fax:

ver).

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an antipsychotic agent with haloperidol [5–8,10] or two atypicalagents [11,14], and only few trials had placebo-controlled design[8,12] for treatment of delirium. One trial compared haloperidol withchlorpromazine and lorazepam [9]. In general, these trials have shownthat there is no significant difference between the efficacy ofhaloperidol and atypical antipsychotics in the treatment of delirium.However some of these trials have included only subjects admitted tointensive care units who were mechanically ventilated [13], whereasothers have been focused on geriatric population. However, deliriumis a heterogeneous disorder, arising due to multiple etiologies, and inour setting is seen more frequently in nonelderly population [15].Hence, the findings of some of the above studies cannot begeneralized to this population. Hence, there is a need to evaluatethe effectiveness of atypical antipsychotics in delirium inpatients whoare relatively young. This prompted the present randomized con-trolled trial, which assessed the efficacy and safety of second-generation antipsychotics olanzapine and risperidone vs. haloperidolin patients of delirium admitted to medical and surgical wards.

Methodology

Approval/consent

The plan of the study was approved by the research and ethicscommittees of the institute (Post Graduate Institute of MedicalEducation and Research, Chandigarh, India) where it was conducted.Written informed consent was taken from the patients' primary

278 S. Grover et al. / Journal of Psychosomatic Research 71 (2011) 277–281

caregivers prior to randomization. Prior to randomization, thepurpose of the study and the pharmacological interventions whichare currently available were explained to them. If their patientparticipates in the trial, they were also told about what options will beused along with data available in the literature for the efficacy of theagents and the adverse effect profile. The primary caregivers had theright to withdraw consent at any stage of the study.

Study design

This was single-blind randomized controlled trial. Consecutivepatients with delirium referred to the consultation–liaison psychiatryteam were eligible for the study. Patients were randomized accordingto a computer-generated randomization table.

Selection criteria

To be included in the study, participants were required to have adiagnosis of delirium (based on the diagnostic items of the DeliriumRating Scale-Revised-98 [DRS-R98] [16] and the Confusion Assess-ment Method scale [CAM] [17]) and be older than 18 years. Subjectswith delirium due to alcohol or benzodiazepine withdrawal, thosewith associated dementia (based on clinical history), those who wereunresponsive to any verbal or physical stimulus, those suffering froma terminal illness (based on the clinical history and information fromthe primary treating physician or surgeon) or those who hadcomorbid psychotic or mood disorders were excluded (based on thedetailed clinical history). Subjects with history of profound hearing orvisual loss, aphasia, Parkinson's disease, history of neurolepticmalignant syndrome, prolonged QTc interval (N500 ms) and pasthistory of hypersensitivity to any of the drugs were also excluded.

Fig. 1. Consort diagram showing the inclusion of p

Randomization and treatment groups

One hundred and fifteen patients were assessed for the trial, ofwhich 25 were excluded because they did not fulfill the inclusion and/or exclusion criteria for the study (Fig. 1). Primary caregivers of the 90patients who fulfilled the inclusion and exclusion criteria wereapproached for the consent. Written informed consent was providedby 74 primary caregivers, and these patients were randomized totreatment with either olanzapine (n=26), risperidone (n=22), orhaloperidol (n=26). Of the 74 patients randomized, 64 completed thetrials, and 6 could not be assessed at least once after the initialassessments because of further worsening of the clinical picture (3subjects went into coma, and 3 were shifted to intensive care unit)during the subsequent day; for four subjects, data were available foronly 2 days because they left the hospital against the medical advice.The final sample comprised 64 patients, with 20 subjects in thehaloperidol group, 21 subjects in the risperidone group and 23subjects in the olanzapine group (Fig. 1).

Doses and titration

The doses and duration of treatment were guided by standardrecommendations and adjusted according to clinical judgement on adaily basis based on overall clinical picture of delirium. A flexible doseregimen (haloperidol −0.25 to 10 mg; risperidone −0.25 to 4 mg;olanzapine −1.25 to 20 mg) was used. As a practice in ourconsultation–liaison psychiatry practice, in most cases, patients arestarted on haloperidol 0.25mg twice or thrice daily which is graduallyincreased according to the necessity, and most patients are managedwith 1.5 to 2.5 mg of haloperidol daily. However, when the patient isagitated, a dose of 1.25 to 2.5 mg is given intravenously, anddepending on the requirement, the intravenous injections are

atients during the various phases of the trial.

279S. Grover et al. / Journal of Psychosomatic Research 71 (2011) 277–281

repeated. For risperidone, patients are usually started on 0.25 to 0.5mg/day, and the usual starting dose of olanzapine is 1.25 to 5 mg/day.The dose increment is done according to requirement, and mostpatients require a dose of 0.5 to 1.5 mg/day of risperidone and 1.25 to7.5 mg/day of olanzapine. Whenever olanzapine is used in parenteralform, it is given in a dose of 2.5 to 5 mg/day, and the same is repeatedas per the requirement. Whenever rescue medication was required tomanage agitation, the same drug was used in the injectable form forthe haloperidol and olanzapine groups. For the risperidone group,injectable benzodiazepine (lorazepam) or haloperidol was used asrescue medication. The doses were titrated after daily clinicalassessment; however, if the patient was agitated, titration was alsodone more than once per day.

Blinding

Randomization and dose adjustments were carried out by one ofthe investigators (S.G.), and all the assessments were carried out byanother investigator (V.K.) whowas blind to the drug treatment beingadministered.

Primary efficacy measure

Delirium Rating Scale-Revised-98, which is a 16-item clinician-rated scale, was used as the primary outcome measure [16].

Secondary efficacy measure

Mini mental status examination (MMSE), which is a 30-pointcognitive test for bedside assessment of cognitive functions [18], wasused as a secondary outcome measure for the study.

Safety

Side effects were rated on the Simpson Angus Scale [19], AbnormalInvoluntary Movement rating scale (AIMS) [20] and Udvalg forKliniske Undersogelser (UKU) side effect rating scale [21].

Assessments

All the patients were assessed consecutively for 6 days, at aparticular time of the day (6:00–8:00 PM), on DRS-R98, MMSE,Simpson Angus Scale, AIMS and UKU side effect rating scale.

Other safeguards

Besides use of the trial medications, patients were continued ontreatment for the primary medical and surgical treatment. Anymedication that can cause delirium and/or was not essential for thecare of the patient was discontinued. The etiological causes identifiedfor delirium were treated with appropriate measures. The familymembers were advised to follow the behavioural management. Theseinterventions included providing optimal level of environmentalstimulation, reducing sensory impairments, making environmentmore familiar, providing environmental cues that facilitate orienta-tion and providing reassurance and information concerning deliriumso as to reduce fear or demoralization.

Analysis

Data were analysed using SPSS-14. Frequency–percentages andmean and standard deviation (S.D.) were calculated for the descrip-tive purposes. Student's t test/χ2 test and one-way analysis ofvariance (ANOVA) were used for comparison between the groups.As for the DRS-R98 and MMSE data which had nonnormaldistribution, these were compared by using nonparametric tests. For

the same, instead of paired t test, Wilcoxon sign rank test was used;for repeated-measure ANOVA, Friedman's two-way ANOVAwas used;and in place of MANOVA, Kruskal–Wallis test was used.

As there was significant difference in the Mauchly's test ofsphericity, Greenhouse–Geisser within-subject effect was taken intoconsideration while interpreting the f and P values.

Results

The mean age of all the three groups was in the mid-40s, and only three subjects inthe haloperidol group, two subjects in the risperidone group and 6 subjects in theolanzapine groupwere 65 years or older. Themean number of years of education variedfrom 9 to 9.35 years, with slightly higher mean for the risperidone group. Majority ofthe subjects in all the groups were males. However, no statistically significantdifference was noted between the three groups on the above variables (Table 1).

The mean duration of delirium prior to induction into the trial was longest for therisperidone group and least for the haloperidol group; however, this differencebetween the three groups was not significant. The mean dose of haloperidol used was0.88 mg (S.D. 0.98; range 0.25–5), that of olanzapine was 3.05 mg (S.D. 1.44; range1.25–10) and that of risperidone was 0.95 mg (S.D. 0.28; range 0.5–2). In terms ofchlorpromazine equivalent dose, there was no significant difference between the threegroups (Table 1).

All the subjects in the three groups fulfilled the criteria of inattention, acute onsetwith fluctuating course and altered level of consciousness on CAM. Disorganizedthinking was also present in more than 50% of subjects in the olanzapine andrisperidone groups but in only 19% of subjects in the haloperidol group, and thisdifference was statistically significant (Table 1).

Most cases had two (39%) or three (32.81%) identifiable etiologies for the delirium,and 10 cases (15.62%) had only one associated etiology. There was no significantdifference between the three groups on number of identifiable etiologies, with meanetiologies for each group being more than two (Table 1). The most common underlyingetiology in either of the group was a metabolic disturbance (haloperidol [n=17],risperidone [n=17], olanzapine [n=16]) and/or infections (haloperidol [n=10],risperidone [n=13], olanzapine [n=10]).

The mean baseline DRS-R98 severity score for the haloperidol group (21.85) wasless than that of the olanzapine (22.56) and risperidone (23.80) groups, but thedifference was not significant. Similarly, there was no significant difference betweenthe three groups on DRS-R98 scores at day 3 and day 6 and on MMSE scores at thebaseline, day 3 and day 6.

Various side effects experienced by patients are shown in Table 1. In total, fourpatients in the haloperidol group, six patients in the risperidone group and two patientsin the olanzapine group experienced some side effects. No significant difference wasfound between the haloperidol and risperidone groups in terms of number of subjectsdeveloping various side effects or each type of side effect (Fisher's Exact Test, PN.05).Similarly, no difference was found between the haloperidol and olanzapine groups(Fisher's Exact Test, PN.05) or the risperidone and olanzapine groups in terms ofnumber of subjects developing various side effects.

In terms of both primary and secondary outcome measures, there was significantimprovement in all the three groups at day 3 and day 6 compared to the baseline. In allthe groups, there was significant reduction in DRS-R98 scores at days 3 and 6 comparedto the baseline, and there was significant improvement in MMSE scores at days 3 and 6compared to the baseline (Table 2). There was also no difference in the percentage ofpatients whose DRS-R98 score fell down to below 10 in all the three groups (Table 1). Inall the groups, besides the significant difference between day 3 and day 6 and baseline,there was significant difference in both primary and secondary outcome measuresbetween day 3 and day 6, indicating sustained improvement over time. None of the 64subjects expired. However, there was no significant difference between the threegroups on reduction of DRS-R98 at days 3 (Kruskal–Wallis test value 0.685, P=.710)and 6 (Kruskal–Wallis test value 2.53, P=.282) and on MMSE score at days 3 (Kruskal–Wallis test value 0.259, P=.879) and 6 (Kruskal–Wallis test value 0.130, P=.937),indicating that all the three are equally efficacious.

Discussion

Management of delirium involves ensuring safety, improvingfunctioning, identifying and treating the etiology of the delirium andusing antipsychotics to control symptoms. Haloperidol continues tobe the most commonly used antipsychotic in delirium. However, inrecent times, some data have emerged which suggest that atypicalantipsychotics may be as efficacious as haloperidol in the treatment ofdelirium.

The present study was a single-blind randomized controlled trialwhich evaluated the efficacy of haloperidol, risperidone and olanza-pine in subjects with delirium of mixed etiology in a samplepredominantly composed of young adult subjects (b65 years)

Table 1Sociodemographic, clinical profile, delirium subtype, DRS-R98 and MMSE ratings, side effects seen in the study sample

Variables Haloperidol n=21 mean (S.D.) Olanzapine n=23 mean (S.D.) Risperidone n=20 mean (S.D.) χ2/one-way ANOVA

Age (year) 44.09±16.84 (range 20–72) 45.39±19.18 (range 19–78) 46.50±14.51 (range 25–78) 0.102 (P=.903)Education (no. of years) 8.09±3.28 (range 3–15) 8.00±3.95 (range 0–15) 9.35±3.54 (range 2–15) 0.898 (P=.413)Male (n) 13 14 18 5.407 (P=.067)Duration of delirium prior to assessment (h) 41.71±22.96 64.00±60.51 77.20±58.96 2.574 (P=.084)Mean dose (mg/day) 0.88±0.98 (range 0.25–5) 3.05±1.44 (range 1.25–10) 0.95±0.28 (range 0.5-2) -Mean equivalent dose as chlorpromazine equivalent 44.34±49.09 61.05±28.91 47.70±14.19 1.49 (P=.232)CAM-acute onset with fluctuating course 21 23 20 -CAM-inattention 21 23 20 -CAM-disorganized thinking 04 13 14 11.58 (P=.003)CAM-altered level of consciousness 21 23 20 -Mean number of etiologies for delirium 2.42±0.74 (range 1–4) 2.30±1.01 (range 1–4) 2.55±0.94 (range 1–4) 0.387 (P=.681)DRS-R98 scores (severity items only)Day 0 21.85±4.77 22.56±4.49 23.80±5.16 0.856 (P=.430)Day 3 10.14±6.35 11.65±7.24 11.95±6.82 0.421 (P=.430)Day 6 6.09±7.19 9.17±8.65 8.00±7.27 0.870 (P=.424)DRS-R98 b10 on day 3 12 (57.14%) 14 (60.86%) 12 (60%) 0.068 (P=.967)DRS-R98 b10 on day 6 17 (81%) 16 (69.56%) 14 (70%) 0.906 (P=.636)

MMSE scoresDay 0 6.38±5.02 9.72±6.30 6.84±5.33 2.24 (P=.115)Day 3 17.90±7.37 17.77±7.53 17.57±6.22 0.011 (P=.989)Day 6 21.71±7.66 20.77±8.14 22.31±6.63 0.219 (P=.804)

Side effectsTremor 04 02 02Orthostatic dizziness - - 01Rigidity 03 - 02Constipation 02 - -Sleepiness/sedation 01 - 03Increased duration of sleep 01 - 01Increased salivation - - 01Lips and perioral movements - - 01Jaw movement - - 01Movements of tongue - - 02Total number of subjects who had side effects 04 02 06

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admitted to various medical surgical wards. In the present study, theoutcome was evaluated on DRS-R98 and MMSE, both of which arevalid instruments for assessment of severity of delirium and havebeen reported to be useful for serial assessment of delirium [16]. Thesociodemographic profile (age and gender distribution) of thesubjects is similar to the profile of subjects with delirium seen inpsychiatry consultation–liaison services at our centre [22]. Fewretrospective or prospective trials in the past have compared eitherrisperidone [5,6,23,24] or olanzapine [7,8] with haloperidol. Thesestudies suggest that risperidone and olanzapine are as efficacious ashaloperidol in the treatment of delirium. Our study also supports theavailable research evidence in terms of efficacy of these agents indelirium. The dose of risperidone, olanzapine and haloperidol issimilar to that used in the previous studies and suggests thatantipsychotic in lower doses may be useful in controlling thesymptoms of delirium [6,7].

With respect to side effects, the current study also supports thefindings of previous studies which suggest that olanzapine leads tolesser number of side effects compared to haloperidol [7,8], although

Table 2Efficacy of haloperidol, olanzapine and risperidone

Day 0 Day 3 Day 6

Wilcoxon sirank testcomparingday 0 and d

HaloperidolDRS-R98 21.85±4.77 10.14±6.35 6.09±7.19 −4.018 (Pb.MMSE 6.38±5.02 17.90±7.37 21.71±7.66 −3.926 (Pb.

OlanzapineDRS-R98 22.56±4.49 11.65±7.24 9.17±8.65 −4.126 (Pb.MMSE 9.72±6.30 17.77±7.53 20.77±8.14 −3.722 (Pb.

RisperidoneDRS-R98 23.80±5.16 11.95±6.82 8.00±7.27 −3.922 (Pb.MMSE 6.84±5.33 17.57±6.22 22.31±6.63 −3.766 (Pb.

we did not find any statistically significant difference between the twogroups in terms of number of subjects developing side effects. Nosignificant difference was found between the haloperidol andrisperidone groups in terms of number of subjects developing variousside effects or each type of side effect [6].

The American Psychiatric Association guidelines for the treatmentof delirium [1] suggest that haloperidol should be used as the first lineof treatment for delirium because of potential advantages like lack ofsuppression of respiratory drive. However, haloperidol is associatedwith extrapyramidal symptoms and sedation. Atypical antipsychoticsare known to cause fewer extrapyramidal symptoms compared tohaloperidol. In view of the accumulating evidence, which our studyalso supports, atypical antipsychotics can be considered as areasonable alternative to haloperidol for the treatment of delirium.

Our study is limited by the small sample size, which may limit thegeneralizability of our findings, and the possibility of a type I errorcannot be ruled out. Our study also did not include a placebo controlarm. The rater was aware that all patients were on active treatment,and hence, this could have affected the ratings. Furthermore, our

gn

ay 3

Wilcoxon testcomparingday 0 and day 6

Wilcoxon testcomparingday 3 and day 6

Friedman's two-wayANOVA

001) −3.922 (Pb.001) −3.772 (Pb.001) 66.48 (df=5; Pb.001)001) −3.925 (Pb.001) 3.831 (Pb.001) 39.51 (df=5; Pb.001)

001) −4.078 (Pb.001) −3.113 (P=.002) 51.12 (df=5; Pb.001)001) −3.885 (Pb.001) −3.399 (P=.001) 32.34 (df=5; Pb.001)

001) −3.923 (Pb.001) −3.730 (Pb.001) 58.53 (df=5; Pb.001)001) −3.826 (Pb.001) 3.839 (Pb.001) 36.10 (df=5; Pb.001)

281S. Grover et al. / Journal of Psychosomatic Research 71 (2011) 277–281

sample only included those subjects who were referred to consulta-tion–liaison psychiatric services, and the treating physician was notblind to the drug; and this would have influenced the dose used.Hence, the findings of our study must be interpreted in thebackground of the above limitations.

To conclude, the present study suggests that olanzapine andrisperidone are as effective as haloperidol in the management ofdelirium. Furthermore, there is no significant difference in the sideeffect profile of the three medications in patients with delirium.

Acknowledgments

The study was funded by Institute Research Fund.

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