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INTRODUCTION
Delirium is defined as an alteration in mental status that is characterized by disturbance of
consciousness and attention, cognition, and perception for a brief period of time and tends to
fluctuate during the course of the day. A systematic review of delirium in general medical
inpatients showed that estimates of delirium prevalence on admission ranged from 10 to 30%.1
The highest prevalence of delirium (often 70% to 87% of patients) is generally seen in critically
ill patients in the intensive care unit (ICU).2 On the basis of motor subtypes it has been classified
into hypoactive, hyperactive and mixed variety.3 Hypoactive delirium is characterized by
decreased responsiveness, withdrawal and apathy; whereas hyperactive is characterized by
agitation, restlessness and emotional lability. Pure hyperactive delirium is rare (
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as constipation, dehydration and poly-pharmacy), as well as providing adequate lighting, signage
and ways to tell the time, may prevent delirium. It is thought that 3040% of all cases of delirium
could be prevented if interventions were done on time.6
The standard approach to managing delirium in the medically ill includes a search for underlying
causes, correction of those factors, and management of the symptoms of delirium. 7 The
management of the symptoms of delirium involves the use of both non pharmacological and
pharmacological interventions. Non pharmacological or supportive interventions alone are often
not effective in controlling all the symptoms of delirium and symptomatic treatment with
neuroleptics or antipsychotic medications is necessary. Antipsychotic medications have been
regarded as the treatment of choice for delirium.8 Haloperidol is most frequently used because of
its effectiveness and low incidence of anti cholinergic side effects. However, haloperidol is
associated with significant side effects such as extra pyramidal symptoms (EPS), QT
prolongation and neuroleptic malignant syndrome (NMS). These side effects are more frequent
in elderly and seriously medically ill patients, who are most vulnerable to delirium. Since last
decade of 20th
century, some physicians have reported treating clinical cases of delirium withatypical antipsychotic drugs such as risperidone, olanzapine and quetiapine.
But the literature on the use of atypical antipsychotics e.g. olanzapine for the treatment of
delirium is quite limited in terms of methodology and the number of patients studied. Moreover
we could not find any study regarding use of atypical antipsychotics olanzapine for delirium
from India.
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REVIEW OF LITERATURE
Delirium is characterized by an acute decline in both the level of consciousness and cognition
with particular impairment in attention. The prevalence of delirium at hospital admission range
from 14 to 24 percent, and the incidence of delirium arising during hospitalization range from 6
to 56 percent. Delirium is commonly encountered across healthcare professionals but most of the
cases go unrecognized because of lack of awareness among them regarding this life threatening,
yet potentially reversible disorder of central nervous system.5 The development of delirium has
been associated with increased morbidity, persistent functional decline, increased nursing time
per patient, higher per-day hospital costs, increased length of hospital stay, higher rates of
nursing home placement and increased mortality. Recent studies indicate that mortality rates
among hospitalized patients with delirium range from 22% to 76%.2 The severity of this problem
becomes plainly evident when noting that mortality rates for patients with delirium are
equivalent to mortality rates of patients with acute myocardial infarction or sepsis. 2 Delirium is
also a problem in patients presenting from long-term care facilities. In an American study9 it was
found that average costs per day among patients with delirium were more than 2.5 times the
costs among patients without delirium. It also calculated that national burden of delirium on the
health care system ranges from $38 billion to $152 billion each year, rivaling the health care
costs of falls and diabetes mellitus.
Pathophysiology of delirium is poorly understood. The clinical manifestations of delirium appear
to represent a diffuse, reversible impairment of cerebral oxidative metabolism and
neurotransmission. The major neurotransmitter associated with delirium is hypothesized to be
acetylcholine, and the major neuroanatomical area is thought to be the reticular formation.10
Several studies have reported the relationship between delirium and decreased acetylcholine
activity in the brain. In fact, many medications with anticholinergic side effects can worsen or
induce delirium. The reticular formation in the brainstem is the principal area regulating attention
and arousal. A decrease in acetylcholine in the reticular formation, specifically the dorsal
tegmental pathway, appears to be strongly linked with delirium.9
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A multidisciplinary team approach is needed for the recognition, prevention and treatment of
delirium.6 A studyof medical inpatients older than 70 years reported a 40% reduction in odds of
developing delirium with intervention protocol, which included the following: repeated
reorientation, a provision of cognitively stimulating activities, a nonpharmacologic sleep
protocol to normalize sleep-wake cycle, early mobilization and range of motion exercises, timely
removal of catheters and restraints, addressing hearing and vision impairments and early
correction of dehydration.2 The next step in the management of patients with delirium should be
to correct modifiable contributing factors such as metabolic disturbances, including hypoxia,
hypercarbia and electrolyte abnormalities. Pharmacological treatment of delirium is considered
only after all other precipitating and contributing factors have been addressed and minimized.
Antipsychotics are the mainstay of treatment for delirious patients in most of the cases, exception
being delirium caused by alcohol or benzodiazepine withdrawal.8 Haloperidol is the agent most
often used to treat the psychotic symptoms of delirium because of its infrequent anticholinergic
side effects and few active metabolites and sedating effects. Haloperidol has the advantage of
being available in oral, intramuscular, and intravenous formulations. It was reported to be used in
the treatment of 67% of delirium patients and is the first-line drug for delirium in 97% of
medical institutions.11 Haloperidol does have significant disadvantages, including an increased
incidence of cardiac arrhythmias and an increased risk of extrapyramidal side effects.12 Patients
receiving haloperidol must be monitored for EKG (electrocardiogram) changes such as
prolongation of the QT interval, which can cause fatal heart arrhythmias such as torsades de
pointes and ventricular fibrillation. Extrapyramidal side effects such as parkinsonism, neuroleptic
malignant syndrome, dystonia, akathisia, and tardive dyskinesia are other risks of haloperidol.
Since the development of the atypical antipsychotics in the 1990s, many psychiatric conditions
that were previously treatable only with typical antipsychotics can now be managed with atypical
antipsychotics.
Atypical antipsychotics have similar rates of efficacy and a lower risk of extrapyramidal side
effects. Recent studies using atypical antipsychotics have shown some promise in being effective
in managing delirium. Studies have shown that risperidone, olanzapine and quetiapine at low
doses can be effective in controlling the aggression associated with delirium.13-19
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Efficacy of olanzapine and haloperidol in delirium was compared in a study in 1998.14 Eleven
elderly patients diagnosed with delirium received a mean dose of 8.2 3.4 mg of olanzapine
daily. The olanzapine group was compared with a cohort group of 11 patients with delirium who
had received 5.1 3.5 mg of haloperidol. Peak response time was similar in both groups. Five of
the 11 olanzapine patients showed significant improvement (50% score reduction) on theDelirium Rating Scale (DRS) and no patients had side effects, whereas 6 of the 11 control
subjects (haloperidol group) showed improvement on the DRS and 5 (45%) had extrapyramidal
symptoms or excessive sedation. The study concluded that olanzapine may be a useful
alternative to haloperidol for the treatment of delirium in hospitalized patients.
Breitbart et al in 2000 conducted an open, prospective trial of olanzapine for the treatment of
delirium in a sample of 79 hospitalized cancer patients.15 The mean age of patients was 60.6
years and all met the criteria for delirium based on the DSM-IV and Memorial Delirium
Assessment Scale. The mean starting dose of olanzapine was 3.0 mg a day and, at the end of the
study, the mean dosage had increased to 6.3 mg daily. 57 patients had complete resolution of
their delirium on olanzapine therapy, and no patients experienced extrapyramidal side effects,
however, 30% experienced sedation (usually not severe enough to interrupt treatment). The study
also found that patients older than 70 had a poorer response to olanzapine treatment. The study
concluded that olanzapine appears to be clinically effective and safe for the treatment of delirium
in the medically ill hospitalized patient.
Kim et al in 2001 performed an open trial of olanzapine in 20 Korean subjects (average age 45.8
18.3 years) with delirium.16 The patients were given olanzapine with doses of 5.9 1.5 mg a
day. The average duration of treatment was 8.8 2.2 days. Delirium was measured using the
DRS. Fourteen of the 20 patients (70%) showed significant improvement (50% score reduction)
of DRS scores. The study concluded that olanzapine is effective in reducing behavioral
disturbances and symptoms in delirium. Eleven of the 20 delirious patients in this study also had
leukemia, which may have affected the results (all 11 leukemia patients showed 50% or more
reduction in DRS scores).
Skrobik et al in 2001 conducted a prospective, randomized trial of 73 patients between the ages
of 18 and 75 years who were admitted to the medical and surgical ICU, from June 2000 to
September 2001.17 All patients enrolled in the study had the diagnosis of delirium using the
DSM-IV criteria. Patients were randomized to receive either enteral olanzapine or haloperidol.
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Haloperidol was initiated at a dose of 2.5 to 5.0 mg every 8 hours and olanzapine was started at
5.0 mg daily. Patients older than 60 received haloperidol 0.5 to 1.0 mg or olanzapine 2.5 mg.
Patients delirium severity and benzodiazepine use were monitored over a 5-day period. The
Delirium Index was noted to decrease significantly in both groups, as did the administration of
benzodiazepines. Clinical improvement was similar in both groups. The olanzapine group
reported no side effects, but 6 patients in the group receiving haloperidol exhibited
extrapyramidal side effects. The study concluded that olanzapine was a safe alternative to
haloperidol in the critically ill, delirious patient.
Hu in 2006 compared haloperidol and olanzapine in senile delirium.18 The author used parentral
haloperidol and oral olanzapine. There was no difference between haloperidol and olanzapine
groups in terms of response but patients on olanzapine showed significant shorter duration of
delirium as compared to patients taking haloperidol. The author found no significant difference
in incidence of the adverse effect of drowsiness; comparing olanzapine with haloperidol treated
patients, but noted a significant increase in dry mouth among haloperidol treated patients
compared with olanzapine treated patients. Extrapyramidal symptoms were also more frequent
among haloperidol treated patients than olanzapine treated patients.
Previous studies had serious methodological problems. Control groups were not used and
participants were not blinded. Two of the studies had sample size of 20 patients or less. The
current literature on atypical antipsychotics for the treatment of delirium is lacking in
randomized, controlled trials. As a significant proportion of patients show good response to
atypical antipsychotics in delirium with fewer side effects than typical antipsychotics, further
research in this regard is mandated which should assess the efficacy, tolerability, side effect
profile of olanzapine in patients suffering from delirium. Keeping this in mind, a comparative
study has been planned which intends to compare the efficacy of haloperidol and olanzapine in
delirium.
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AIMS AND OBJECTIVES
1. To compare the efficacy and tolerability of olanzapine and haloperidol in delirium.2. To compare the pattern of symptoms improvement with olanzapine and haloperidol in
delirium.
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MATERIAL AND METHODS
Study design and setting: This will be an interventional study. Study will be done on 100
patients of delirium admitted in medicine emergency ward and patients referred to consultation
liaison psychiatry.
Duration of study: Data collection will be completed within 6-12 months. Analysis of data,
written work and final submission will be completed within 2 years.
Method of recruitment: One hundred consecutive patients meeting DSM-IV criteria20 for the
diagnosis of delirium and assessed on CAM will be recruited. Diagnosis will be confirmed by
consultant-in-charge.
Inclusion criteria:
1) Age of patients should be more than 18 years.
2) Patient should be verbally responsive.
3) Patients or caregiver must give written consent for the study.
Exclusion criteria:
1) Mechanically ventilated or mute patients.
2) Alcohol withdrawal delirium.
3) Patients having history of dementia.
4) Patients who had already been injected with antipsychotics in the emergency room or
intensive care unit.
5) Patients having hypersensitivity reaction to haloperidol or olanzapine in past.
Sampling technique: The study will be an open labeled, randomized control trial.
Tools:
1. Confusion Assessment Method (CAM)5
2. Memorial Delirium Assessment Scale (MDAS)213. Simpson-Angus Scale (SAS)23
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Methodology: Patients will be randomized in two equal groups of fifty each. Intervention will
be done on the basis of computer generated random number table. One group will be given
typical antipsychotic haloperidol; other group will be given atypical antipsychotic olanzapine.
Drugs will be given by enteral route either orally or by nasogastric tube. An attempt will be made
to keep dose of haloperidol between 1-4mg/day however in case it is required, dose will be
increased up to 10mg/day; and olanzapine will be used between 2.5-10mg/day. Doses will be
adjusted on the intent to treat basis.
Each patients socio-demographic and clinical variables will be recorded on proforma designed
for the study. Patients will be rated systematically with the MDAS as a measure of delirium
severity and phenomenology. Delirium severity will be assessed as mild delirium reflected by
MDAS score 15, moderate severity delirium by MDAS scores of 16-22 and severe delirium
as MDAS scores of 23-30. A score of 10 on MDAS will be taken as indicator of delirium
resolution.22
Response of treatment will be assessed on the basis of improvement on MDAS score every 24
hours till resolution of delirium. Follow up assessment of each patient will be done at the same
time of day at which he/she was first assessed. Pattern of symptoms improvement will be noted
and compared between both groups. Total time taken for the resolution of delirium will be noted
and compared.
Drug-related side effects will be recorded on the prescribed proforma designed for the study and
compared between both groups. Extra-pyramidal side effects will be assessed using SAS. Any
patient having serious side effects including hypersensitivity reaction during treatment will be
dropped from the study and will be managed accordingly. Any outcome other than resolution of
delirium will be noted separately. Reason for the same will be noted. Drugs of the standard
pharmaceutical companies approved by the drug committee of GMCH will be used.
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STATISTICAL ANALYSIS
Data will be entered on excel sheet, SPSS version 15 will be used for analysis. The following
measures of statistical analysis will be applied:
1) ANOVA with repeated measures.2) MANOVA with repeated measures.3) Chi square test.
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ETHICAL CONSIDERATION
The purpose and the design of the study shall be explained to the patient and a close family
member in the language they understand viz. Hindi, Punjabi. The family will be educated aboutavailable treatment alternatives. The costs incurred, if any, on the laboratory investigations will
be borne by the institution and no additional expenditure will be put on the patient. The defined
guidelines of central ethics committee for Biomedical Research on human subjects by ICMR will
be adhered to, in addition the principles enunciated in the Declaration of Helsinki. The patients
and the consenting family members will be informed that they can withdraw any time from the
study without having to give reasons for the same. In any case, they will receive appropriate
treatment for their condition. The confidentiality of the information obtained will be maintained
and will be revealed only to doctors/auditors of this study and if required, to the drug regulatory
authority.
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CONSENT PROFORMA
I,age.years S/O D/O W/O
.resident ofvoluntarily and of my own
free will, on behalf of my patient consent to participate in the research project
titled `Comparison of efficacy of haloperidol and olanzapine in the treatment of delirium being
conducted by Dr. Rajan Jain, who is the principal investigator, and is a Post graduate in the
department of psychiatry, GMCH sector -32, Chandigarh.
I have received the copy of the patient information pamphlet related to this project and read/it
has been read to me. The principal investigator has clarified my doubts to my satisfaction.
I have been informed by the principal investigator clearly, in a language that I can understand
that the main purpose of the project is to study the comparison of efficacy of haloperidol and
olanzapine in the treatment of delirium.
The study requires me to answer a questionnaire about my patient.
I have been informed that there is no risk/it is a routine established procedure with no additional
risk/it is a new procedure for which the risk for the participation is not more than minimal/the
risks have been explained to me and I have been informed that they are not more than minimal.
The alternative facilities available in this regard have been explained to me. I have being
informed that in case of procedures or other inventions including drug treatment, the procedure
will been conducted by medically competent doctors who meet the standards of care in
conducting this procedure and in case of a drug the detailed risks and benefits have been
explained to me. I may be called to the hospital for some additional tests. I have been informed
that the results of the study may or may not be of direct benefit to me but will enhance the
medical knowledge in the field and of benefit in medical care/for the benefit of society by
improving health care, monitoring health policies and filling gaps in knowledge .
1) I case I refuse to participate or withdraw consent at a later date, it will not jeopardize careof my patient, there will be no prejudice against me or my patient and I will continue to
receive the best available facilities for my patient at GMCH, Sector-32,Chandigarh.
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2) In case if any injury to my patient or any other adverse event to my patient related tostudy, I/patients dependence retain the right for compensation.
3) There is no extra cost involved from my/my patients side for my patients participation.4) I have been informed that the confidentiality of records will be maintained and in case of
the publication of the material, I will not be identified by name/image unless I give
written consent or if it is required by law/enforcement agencies/privileged
communication.
5) The material for the present study will not been used in other studies or for purposesother than defined in the present project or related to the present subject. If any such
material is to be used for other projects, the researcher will have to take my consent.
Strict confidentiality of record will be maintained.
6) The above have been explained to me in Hindi/Punjabi/Guajarati/French; the language Iunderstand. I have been informed that I can contact the project principal investigator
Dr. Rajan Jain at any time on mobile no. or phone no.
or in case of any other factor, the Director Principal or Professor- in-charge Academics,
GMCH -32 Chandigarh.
Kindly tick the appropriate box
Signature of participant Signature of witness
Name: Name:Address: Address:
Signature of principal investigator:
Date:
Understood Not understood May be explained
again
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REFERENCES
1. Johnson JC. Delirium in the elderly. Emerg Med Clin North Am 1990;8:255652. Inouye SK. Delirium in older persons. N Engl J Med 2006;354:115711653. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992;
161:843845
4. Cole MG, Primeau FJ. Prognosis of delirium in elderly hospital patients. CMAJ 1993;149:41-46
5. Inouye S, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifyingconfusion. The confusion assessment method: new method for detection of delirium. Ann
Intern Med1990;113:941-8
6. Inouye SK, Bogardus ST, Charpentier PA. A multi-component intervention to preventdelirium in hospitalized older patients. N Engl J Med 1999;340:669-676
7. American Psychiatric Association. Practice guideline for the treatment of patients withdelirium. Am J Psychiatry 1999;156:1-20
8. Schwartz TL, Masand PS. The role of atypical antipsychotics in the treatment ofdelirium. Psychosomatics 2002;43:1714
9. Douglas L, Edward R, Zhang Y, Linda Leo-Summers, Inouye S. One-Year health carecosts associated with delirium in the elderly population. Arch Intern Med 2008; 168:27-32
10.Brown TM. Basic mechanisms in the pathogenesis of delirium. In: Stoudemire A, FogelBS, Greenberg DB, eds. The Psychiatric Care of the Medical Patient, 2nd ed. New York:
Oxford University Press; 2000:571-80
11.Shingo M, Yamamoto K, Hoshino S. Comparison of the risk of adverse events betweenrisperidone and haloperidol in delirium patients. PsychiatryClinNeurosci 2007;61:275
282
12.Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de pointes associated withintravenous haloperidol in critically ill patients. Am J Cardiol 1998;81:238-240
13.Han C, Kim Y. A doubleblind trial of risperidone and haloperidol for the treatment ofdelirium. Psychosomatics 2004;45:297301
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14.Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics1998;39:42230
15.Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment ofdelirium in hospitalized cancer patients. Psychosomatics 2002;43:175182
16.Kim KS, Pae CU, Chae JH, Bahk WM, Jun T. An open pilot trial of olanzapine fordelirium in the Korean population. Psychiatry Clin Neurosci 2001;55:5159
17.Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treatingdelirium in a critical care setting. Intensive Care Med 2004;30:444-9
18.Hu H. Olanzapine and haloperidol for senile delirium: a randomized controlledobservation. Chin J Clin Rehab 2006;10:188-90
19.Sasaki Y, Matsuyama T, Inoue S. A prospective, openlabel, flexibledose study ofquetiapine in the treatment of delirium. J Clin Psychiatry 2003;64:13161321.
20.Kazmierski J, Kowman M, Banach M. Clinical utility and use of DSM-IV and ICD-10criteria and the memorial delirium assessment scale in establishing a diagnosis of
delirium after cardiac surgery. Psychosomatics 2008;49:73-6
21.Breitbart W, Rosenfeld B, Roth A. The memorial delirium assessment scale. J PainSymptom Manage 1997;13:128-37
22.Breitbart W, Tremblay A, Gibson C. The delirium experience: delirium recall anddelirium-related distress in hospitalized patients with cancer, their spouses/caregivers,
and their nurses. Psychosomatics 2002;43:183-194
23.Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects . Acta PsychiatrScand1970:11-19
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SOCIO- DEMOGRAPHIC AND CLINICAL PERFORMA
A. Socio-demographic
Name: Age: Sex:
Marital status: Education: Occupation
Residence: Total Monthly Income:
B. Clinical details
Chief Complaints:
Type of Onset:
Course of illness:
Total duration of illness:
History of present illness:
Past history:
Family history
C. Clinical Examination:
Pulse rate Blood pressure Respiratory rate
Temperature Icterus Cyanosis
Systemic examination (positive findings):
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D. Lab investigations:
Hemoglobin
Platelets
TLC
DLC
S. Sodium
S. Potassium
B. Urea
S. Creatinine
S. Bilirubin
Alkaline phosphatase
SGOT
SGPT
Total protein
S. Albumin
E. Radiological finding (if available):
F. Diagnosis:
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CONFUSION ASSESSMENT METHOD
1. Acute onset and fluctuating courseIs there evidence of an acute change in mental status from thepatients baseline? Did the behavior fluctuate during the day?
2. InattentionDid the patient have difficulty focusing attention, forexample, being easily distractible, or having difficultykeeping track of what was being said?
3. Disorganized thinkingWas the patients thinking disorganized or incoherent,
such as rambling or irrelevant conversation, unclear or
illogical flow of ideas, or unpredictable switching fromsubject to subject?
4. Altered level of consciousnessThis feature is shown by any answer other than alert to thefollowing question: How is this patients level ofconsciousness? (alert, vigilant, lethargic, stupor or coma)
The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4.
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MEMORIAL DELIRIUM ASSESSMENT SCALE (MDAS)
Serial
No.
Item Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1 Awareness
2 Disorientation
3 Short-term
memory
impairment
4 Impaired digit
span
5 Reduced
ability to
maintain and
shift attention
6 Disorganized
thinking
7 Perceptualdisturbance
8 Delusions
9 Decreased or
increased
psychomotor
activity
10 Sleep-wake
cycle
disturbance
TOTAL
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ANTIPSYCHOTICS INDUCED COMMON SIDE EFFECTS
Side effects Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Akathisia
Acute dystonia
Drug- inducedparkinsonism
Neurolepticmalignantsyndrome
Orthostatic
hypotension
Dry mouth
Constipation
Urinaryretention
Sedation
Dermatological
Others
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SIMPSON-ANGUS SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS
Serial
no.
Item Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1 Gait
2 Arm dropping
3 Shoulder
shaking
4 Elbow rigidity
5 Wrist rigidity
6 Legpendulousness
7 Head
dropping
8 Glabella tap
9 Tremor
10 Salivation
Total