DOI: 10.5958/2319-5886.2015.00092.

International Journal of Medical Research

&
Health Sciences

[Link]
Volume 4 Issue 3
Received: 20th April 2014
Research article

Coden: IJMRHS
Copyright @2014
ISSN: 2319-5886
Revised: 10th Jan 2015
Accepted: 18th April 2015

A COMPARATIVE STUDY OF ORAL OLANZAPINE AND ORAL HALOPERIDOL ON GLUCOSE

TOLERANCE LEVELS IN PATIENTS WITH SCHIZOPHRENIA
*G N S Sangeetha Lakshmi
Asst Professor, Dept of Pharmacology, Osmania University, Hyderabad
*Corresponding author email: asangeethalakshmi@[Link]
ABSTRACT
Background: Schizophrenia is a mental disorder characterized by persistent defects in the perception, thinking or
the expression of reality. The term "schizophrenia" translates roughly as "shattered mind," and comes from the
Greek (schizo, "to split" or "to divide") and (phrn, "mind"). Material and Methods: The study was designed to
be a prospective control study. Schizophrenic patients taking Olanzapine and Haloperidol were selected and
follow up at three weeks and six weeks was done. Results: In this prospective control study, Olanzapine and
Haloperidol were associated with an increase in Blood Glucose Levels. The mean changes in Glucose remained
within clinically normal range in this six week study. Conclusion: Antipsychotic treatmemt leads to the
development of Diabetes mellitus in a significant 10.1% of patients within 6 weeks. Given the serious
implications for morbidity and mortality attributable to diabetes mellitus, clinicians need to be aware of these risk
factors when treating patients with chronic schizophrenia
Keywords: Schizophrenia, Olanzapine, Haloperidol, Blood Glucose levels
INTRODUCTION
Schizophrenia is often described in terms of
"positive" and "negative" symptoms. Positive
symptoms include delusions, auditory hallucinations
and thought disorder and are typically regarded as
manifestations of psychosis. Negative symptoms are
so named because they are considered to be the loss
or absence of normal traits or abilities, and include
features such as flat, blunted or constricted affect and
emotion, poverty of speech and lack of motivation.
Some models of schizophrenia include formal
thought disorder and planning difficulties in a third
group, a "disorganization syndrome."[1]
The most commonly used criteria for diagnosing
schizophrenia are from the American Psychiatric
Association's Diagnostic and Statistical Manual of
Mental Disorders (DSM) and the World Health
Organization's International Statistical Classification
of Diseases and Related Health Problems (ICD). The
most recent versions are ICD-10. [2]

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Cause: Genetic: Some researchers estimate

schizophrenia to be highly heritable (some estimates
are as high as70%). Environmental [3] . There is also
considerable evidence indicating that stress may
trigger episodes of schizophrenia psychosis.
Neurobiological influences: Role of dopamine: In
adult life, particular importance has been placed upon
the function (or malfunction) of dopamine [4] in the
mesolimbic pathway in the brain. This theory, known
as the dopamine hypothesis of schizophrenia, largely
resulted from the accidental finding that a drug group
which blocks dopamine function, known as the
phenothiazines, reduced psychotic symptoms. These
drugs have now been developed further and
antipsychotic medication is commonly used as a first
line treatment. Role of glutamate and the NMDA

receptor: Interest has also focused on the

neurotransmitter glutamate and the reduced

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function of the NMDA glutamate receptor in the

development of schizophrenia.
Treatment: Medication and hospitalization
The first line treatment for schizophrenia is usually
the use of antipsychotic medication. Therefore,
antipsychotic drugs are only thought to provide
symptomatic relief from the positive symptoms of
psychosis. The newer atypical antipsychotic
medications [5] (such as clozapine, risperidone,
olanzapine, quetiapine, ziprasidone and aripiprazole)
are usually preferred over older typical antipsychotic
medications (such as chlorpromazine
and
haloperidol) due to their favourable side-effect
profile.
While the atypical antipsychotics3 are
associated with less EPS and TD than the
conventional antipsychotics, some of the agents in
this class (especially olanzapine and clozapine)
appear to be associated with metabolic side effects [6]
such as weight gain, hyperglycemia and
hypertriglyceridemia that must be considered when
choosing appropriate pharmacotherapy.
Drugs: Haloperidol is a butyrophenone [7] with
general properties similar to those of the
phenothiazine, cholorpromazine.
It is an
antipsychotic with actions most closely resembling
those of phenothiazines with a piperazine side-chain.
Olanzapine is a thienobenzodiazepine atypical
antipsychotic.
It has affinity for serotonin,
muscarinic, histamine-H1 and adrenergic (a1)
receptors as well as various dopamine receptors.
Olanzapine is used for the management of
schizophrenia and for the treatment of moderate to
severe mania associated with bipolar disorder.
Olanzapine may share some of the adverse effects
seen with the classical antipsychotics, the incidence
and severity of such effects may vary. The most
frequent adverse effects with Olanzapine are
somnolence and weight gain; hyperprolactinaemia is
also common, but usually asymptomatic.
More
[8]
severe abnormalities of glucose homeostasis occur
uncommonly;
severe
hyperglycaemia,
or
exacerbation of pre-existing diabetes, sometimes
leading to ketoacidosis or coma, has been reported.
Clinical monitoring for hyperglycaemia [9] has been
recommended, especially in patients with or at risk of
developing diabetes. Olanzapine has been associated
with a low incidence of extrapyramidal symptoms
including tar dive dyskinesia although extrapyramidal
symptoms may be more likely at high doses.
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Neuroleptic malignant syndrome has been reported

rarely. [10]
Lambert BL [11] states that exposure to olanzapine is
associated with a 34-41% increase in the developing
of type 2 diabetes among recipients with
schizophrenia and compared with older generation
antipsychotics, exposure to olanzapine is associated
with an increased risk of hyperlipidemia among
people with schizophrenia. Still prospective,
randomized trials are needed to confirm these
retrospective, observational finding.
MATERIALS AND METHODS
A prospective study was conducted in the Psychiatry
department at Institute of Mental Health, Chennai on
patients admitted between October, 2005 to January,
2006. Patients who were newly started on Olanzapine
and Haloperidol and those who had been
antipsychotic free for the last six months formed the
sample of the study. The Olanzapine group had 38
patients and Haloperidol group had 25 patients.
Inclusion
Criteria:
Outpatient/Inpatient
in
Psychiatry department, Age 20 60 years, Patient
Sex-Male and Female Diagnosed by ICD-10 for
Schizophrenia, Patients taking oral Olanzapine 5-20
mg/day or Haloperidol 5-20 mg/day., Patients who
had given informed consent.
Exclusion Criteria:. Patients with other Mental
illness like bipolar mood disorders, Patients on
substance abuse or alcohol abuse, Pregnant or
lactating patients
Procedure: The study was a naturalistic study;
patients were diagnosed by the Consultant
Psychiatrist as suffering from Schizophrenia
according to ICD-10 [2].Informed consent was taken
from all the patients. Treatment was started and
monitored by a psychiatrist. The patients were
either s t a r t e d
on
Haloperidol
or
Olanzapine based on
the
psychiatrists opinion.
Patients could continue taking their concomitant drugs
like Benzhexol, Benzodiapines, and Multivitamins
and anti hypertensives.
After taking informed consent, a semi structured
proforma was used to collect information about
relevant socio demographic data details about family
history and previous medical history.
The duration of the study was six weeks. During the
study cases took only one antipsychotic drug i.e. oral

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Olanzapine and controls took oral Haloperidol along

with their concomitant treatment.
After the patients fulfilled the inclusion criteria,
Random Plasma Glucose was taken before the start of
treatment patients who had above normal random
blood glucose (Normal RBS-120-140 mg/dl.) were
not taken into the study.
After the patient was started on an antipsychotic i.e.
in the first week, Blood was taken for Fasting Blood
Glucose and Post Prandial blood glucose. When the
patient came for review after three weeks and again
after six weeks fasting blood glucose and post
prandial blood glucose was taken. At each visit 2ml
Blood was taken under aseptic conditions. From the
blood sample sent to the laboratory, serum was
separated immediately after clotting.
Fasting blood glucose and post prandial blood
glucose was estimated by standardized enzymatic
procedure (applying glucose oxidase peroxidase
method).
Enzymatic method yields maximum
specificity for the procedure. From the blood sample
sent to the laboratory, serum was separated
immediately after clotting. Samples were used on the
same day. Haemolysed or grossly contaminated
samples were not used.
The following reference values were used in the
Laboratory.
Random Blood Sugar =
120 140 mg/dl.
Fasting Blood Sugar
=
60 90 mg/dl.
Post prandial blood sugar =
140 160 mg/dl.
RESULTS
Basic Description of Data: A total of seventy
patients who satisfied the inclusion criteria and who
signed the consent form were selected for the study.
Seven patients were lost in the follow up.
The
remaining sixty three patients constituted the main
study group. The Olanzapine study group had 38
subjects (n=38) and the Haloperidol control group
had 25 subjects (n=25).
The mean age of study group was 34.5 9.9 years.
The mean age of Olanzapine group was 33.1 9.8
and the Haloperidol group was 35.6 + 10 years(Table
I). The Olanzapine group had Male 22 (57.9%) and
female 16 (42.1), Haloperidol group had male 11
(44%) and female 14 (56%). The Olanzapine group
had 5 subjects (13.2%) with family history of

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Diabetes Mellitus and Haloperidol group had 5

subjects (20%) with family history of Diabetes
Mellitus. There was no statistical difference with
regard to family history of Diabetes Mellitus between
the two groups. When Chi square test was done, p
was 0.500 (P<0.05 it is significant). Most of the
subjects belonged to low socio-economic status
(83.3%) and the rest middle socio-economic status
(16.7%). The most common diagnosis was Paranoid
Schizophrenia;
in
the
Olanzapine
group
Undifferentiated Schizophrenia (18.4%), Paranoid
Schizophrenia (55.3%) and chronic schizophrenia
(26.3%). In the Haloperidol group undifferentiated
schizophrenia (2%), Paranoid Schizophrenia (68%)
and Chronic Schizophrenia (24%).
The mean dose of Olanzapine used was 13 4.7
mg/day and the mean dose of Haloperidol that was
used in the study was 14 + 3.2 mg/day.
Table 1: Comparison Between Olanzapine and
Haloperidol Groups (Baseline Characteristics)
Student Independentt Test
Olanzapine Haloperidol p
Mean SD Mean SD Value
(n=38)
(n=25)
Age (Yrs.)
33.19.8
35.610.0
0.33
Height (cms.)
164.3 8.9 165.2 7.7
0.678
Weight (kgs.)
63.809.6
65.8 8.4
0.389
BM I
23.5 1.7
24.1 2.1
0.234
Random Blood
Glucose
99.5 15.1 101.1 23.0 0.74
(mg/ml)
P<0.05 Significant
There is no statistically significant difference between
the Olanzapine group and Haloperidol group in Age,
Weight or Random Blood Sugar levels.
Regarding the Change in Fasting Blood Glucose and
Post Prandial Blood Glucose between the Olanzapine
and Haloperidol groups there was no statistically
significant increase. The change in the Fasting Blood
Glucose for the 1st and 3rd week was P=0.434, for
the 1st and 6th week was P=0.805, for the 3rd and 6th
week was P=0.68. The change in the Post Prandial
Blood Glucose for the 1st week and 3rd week was
P=0.429, 1st and 6th week was P=0.922, 3rd and 6the
week was P=0.236 (Table 2)

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Table2: Comparison between Olanzapine and Haloperidol groups Student Independentt test
Olanzapine
Haloperidol
Blood Glucose
Time Point
P Valve
Mean SD
Mean SD
1st week
78.1 17.
84.1 19.2
0.211 (NS)
Fasting Blood
3rd week
84.8 17.0
88.8 17.2
0.372 (NS)
Glucose
6th week
88.3 16.7
95.0 17.9
0.132 (NS)
1st week & 3rd week
6.7 7.7
4.7 12.8
0.434 (NS)
Increase in Fasting
1st week & 6th week
10.2 7.6
10.9 14.0
0.805 (NS)
Blood Glucose
3rd week & 6th week
3.5 5.7
6.2 6.1
0.068 (NS)
1st week
108.7 22.0
113.7 31.9
0.465 (NS)
Post Prandial
3rd week
115.2 23.3
117.3 23.7
0.728 (NS)
Blood Glucose
6th week
121.323.6
126.8 29.9
0.420 (NS)
6.5 9.7
3.6 18.9
0.429 (NS)
Increase in Post Prandial 1st week & 3rd week
1st week & 6th week
12.6 7.4
13.1 24.5
0.922 (NS)
Blood Glucose
3rdt week & 6th week
6.1 9.8
9.512.5
0.236 (NS)
glucose.
For
fasting
blood
glucose
there was no
P < 0.05 Significant; NS-Non Significant
increase for 1st and 3rd week was P=0.237, the
increase for 3rd and 6th week was P = 0.003, 3rd and
There is no statistically significant difference between
6th week P = <0.001. For Post Prandial Blood
Olanzapine and Haloperidol group for Fasting blood
glucose and post prandial blood glucose between 1st
and 3rd week, 1st and 6th week and 3rd and 6th week.
Significant increase in Blood glucose was seen in the
Olanzapine group. In Fasting Blood Glucose, the
significant increase for 1st and 3rd week was
P=0.001, for 1st & 6th week was P=0.001 and for 3rd
and 6th week was P=[Link] Post Prandial Blood
Glucose the significant increase for 1st & 3rd week
was P=0.001, 1st & 6th week was P=0.001 and 3rd &
6th week was P=0.001
Table3: Comparison of Blood Glucose within
Olanzapine Group n=33 (between 1st, 3rd and 6th
week) Students Pairedt Test
Blood
Time Point
Change
P Valve
Glucose

MeanSD

(mg/dl)

glucose there was no significant increase for the 1st

and 3rd week P=1.000, there was significant increase
for 1st and 6th week P=0.039, and 3rd and 6th week
P=0.003.
Table 4: Comparison of Blood Glucose within
Haloperidol, Group n =25 (between 1st, 3rd and
6th week) Student Pairedt Test
Blood
Time Point
Change
P Valve
Glucose

MeanSD

(mg/dl)
Fasting

1st and 3rd week

4.7 12.8

0.237

blood

1st and 6th week

10.914.0

0.003*

Glucose

3rd and 6th week

6.2 + 6.1

<0.001*

Fasting Blood

1st and 3rd week

6.7 7.7

<0.001*

Post

1st and 3rd week

3.6 18.9

Glucose

1st and 6th week

10.2 7.6

<0.001*

Prandial

1st and 6th week

13.124.5

0.039*

3rd and 6th week

3.5 5.7

0.003*

Blood

3rd and 6th week

9.5 12.5

0.003*

Post Prandial

1st and 3rd week

6.5 9.7

<0.001*

Blood

1st and 6th week

12.6 7.4

<0.001*

Glucose

3rd and 6th week

6.1 9.8
<0.001*
*
P<0.05 Significant
There is statistically significant difference for
Olanzapine group for fasting blood glucose and post
prandial blood glucose for 1st and 3rd week, 1st and 6th
week and 3rd and 6th week (Table3). For Haloperidol
group there was a significant increase in blood
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Glucose
* P<0.05 Significant
There is statistically significant difference for
Halperiodol group for fasting blood glucose and post
prandial blood glucose between 1st and 6th week, and
3rd and 6th week. There is no statistically significant
difference between 1st and 3rd week for fasting blood
glucose and post prandial blood glucose within
Haloperidol
patients
group
(Table
4)

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Fig1: Mean change in Fasting Blood Glucose

between different time interval for Olanzapine
and Haloperidol group.

Fig2: Mean change in Post Prandial Blood

Glucose between different time interval for
Olanzapine and Haloperidol group.
The relevant findings of the study are
Olanzapine produced significant increase in
fasting blood glucose and Post Prandial blood
glucose at 3rd week and 6th week
Haloperidol produced significant increase in
fasting blood glucose and Post Prandial blood
glucose at 6th week.
When Olanzapine and Haloperidol groups were
compared there was no statistically significant
difference between the increase in fasting and Post
Prandial blood glucose.
DISCUSSION
There is a re-emerging and controversial issue of
glycaemic control in schizophrenia and its possible
relationship to antipsychotic drug therapy. Obesity
and physical inactivity, which are common in patients
with schizophrenia, are known to increase the risk of
developing diabetes. It is reported a rate of diabetes
of 1.2% for persons age 18 to 44 years and 6.3% for
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persons age 45 to 64 years.

In patients with
schizophrenia, the prevalence of diabetes was 6 to 8%
in patients<45 years of age, 15 to 19% in patients 45
to 64 years of age, and 19 to 21% in patients>65
years of age. [12]
Case reports have also associated atypical
antipsychotic agents with exacerbation of pre-existing
diabetes,
new-onset
diabetes
and
diabetic
[13, 14]
ketoacidosis (DKA).
There are significantly
more reports associated with olanzapine.
In a pharmacoepidemiological study in >58,000
patients receiving a single antipsychotic, the overall
frequency of diabetes was about 3 times that found in
the reference general population. This result is very
similar to that found in studies to determine the rate
of diabetes in patients with schizophrenia done prior
to the widespread use of atypical agents.
In this report we are comparing the simultaneous
effect of two antipsychotic medications on a
important metabolic measure, indexing glucose in
patients with schizophrenia.
We found that
haloperidol was associated with significantly elevated
mean glucose levels after 6 week of treatment, that
olanzapine was associated wtih significantly elevated
glucose levels after 3 weeks of treatment. The mean
increases were modest and remained within clinically
normal ranges (one patient given Haloperidol
developed abnormally high glucose levels >125
mg/dl during the course of study treatment). The
Olanzapine-treated groups had significant elevations
in post prandial glucose levels when compared with
haloperidol-treated patients. Among antipschotics,
Olanzapine seems to have diabetogenic potential
when measured from baseline to endpoint.
Haloperidol fares better. [15, 16]
In our study, the typical antipsychotic haloperidol
was associated with an elevation of Blood glucose
levels within a clinically normal range. Haloperidol
has been reported to increase insulin resistance and to
be associated with higher fasting glucose levels in
obese women compared with control subjects.
Haloperidol has also been reported to be associated
with higher glucose levels in schizophrenia subjects.
Increased insulin resistance in peripheral tissues can
be caused by hyperprolactinemia and may be
involved in the mechanism underlying hyperglycemia
in patients treated with typical antipsychotics.

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Limitations:
Short follow up.
Confounding variables of co-medications.
Short duration requires 6th month or 1 year
follow up study.
More specific test can be used like Hydroxylated
Haemoglobin A (HbA) which will
give the blood
glucose level for the previous 6 weeks.
CONCLUSION
In this prospective study, Olanzapine and Haloperidol
were associated with an increase in Blood Glucose
Levels. The mean changes in Glucose remained
within clinically normal range in this six week study.
Given
the
concerns
regarding
endocrine
dysregulation in the context of treatment of
schizophrenia patients with antipsychotic medication
the baseline and 6th week monitoring of fasting
blood glucose and post prandial blood glucose levels
be obtained in routine clinical practice with both
antipsychotics in order to monitor the risk for
development of hyperglycaemia.
Given the serious implications for morbidity and
mortality attributable to diabetes mellitus, clinicians
need to be aware of these risk factors when treating
patients with chronic schizophrenia.
Acknowledgement: I thank the Director of Institute
of Mental Health,Chennai,[Link] and the
staff for helping me to do this study.
Conflict of interest: Nil
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