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CLINICAL TRIAL OF LITHIUM WITH OLANZAPINE vs. LITHIUM WITH RISPERIDONE FOR THE
TREATMENT OF ACUTE PHASE MANIA IN BIPOLAR AFFECTIVE DISORDER
THESIS
SUBMITTED TO THE FACULTY OF MEDICINE DEPARTMENT OF PSYCHIATRY
B.P.KOIRALA INSTITUTE OF HEALTH SCIENCES IN THE PARTIAL FULFILLMENT OF THE REQUIREMENT
FOR THE DEGREE OF DOCTOR OF MEDICINE (MD) PSYCHIATRY
SUBMITTED BY Dr. Ashish Dutta Junior Resident
Department of Psychiatry B.P. Koirala Institute of Health Sciences
2012 July
DEPARTMENT OF PHYCHIATRY B.P. KOIRALA INSTITUTE OF HEALTH SCIENCES, DHARAN, NEPAL
CERTIFICATE
This is to certify that Dr. Ashish Dutta has conducted this original
research work titled "CLINICAL TRIAL OF LITHIUM WITH
OLANZAPINE VS LITHIUM WITH RISPERIDONE FOR THE
TREATMENT OF ACUTE PHASE MANIA IN BIPOLAR AFFECTIVE
DISORDER" under our direct supervision and guidance in the
Department of Psychiatry, B. P. Koirala Institute of Health Sciences,
Dharan, Nepal.
This research was completed in partial fulfillment of his training for
the degree of MD.
________________________________________ DR. ARUN KUMAR PANDEY
ASSOCIATE PROFESSOR HEAD OF DEPARTMENT
DEPARTMENT OF PSYCHIATRY BPKIHS, DHARAN
Department of psychiatry B.P. Koirala Institute of Health Sciences
DECLARATION
This is to certify that the thesis entitled "CLINICAL TRIAL OF LITHIUM WITH OLANZAPINE VS LITHIUM WITH RISPERIDONE FOR THE TREATMENT OF ACUTE PHASE MANIA IN BIPOLAR
AFFECTIVE DISORDER" was done by me under the supervision and guidance of Professor Dr Pramod M. Shyangwa and Assistant professor Dr Baikuntha Raj Adhikari for the partial fulfillment of the requirement for the degree of Doctor of Medicine (Psychiatry).
……………………………………….. Dr. ASHISH DUTTA Junior Resident
Department of Psychiatry BPKIHS July, 2012
ACKNOWLEDGEMENT
I would like to express sincere gratitude to my chief guide Dr. pramod m
shayangwa, Professor and head of department for his support and
encouragement for the successful completion of my study. I would like to
express my deep gratitude to my co- guide Dr Baikuntha Raj Adhikari
for his constant inspiration, support and guidance.
I would also like to thank Associate Professor Dr Arun K Pandey,
Dr. Dhana Ratna Shakya , Assistant Professor Dr. Nidesh Sapkota,
Dr Liton Mallick for the encouragement and support.
I am also thankful to Senior Resident Dr Rinku Gautam, Dr. Rachana
Sharma, Dr. Mausami Thapa, Dr. Neena Rai, Dr. Madhur Basnet,
Dr. Sulochana Joshi, Dr Sandeep Verma, Dr Parashar Koirala and
Dr Lata Gautam.
I would also like to appreciate Mr. Surya Raj Niroula’s support in my
statistical and database works.
I would like to thank my parents, my in- laws, my brother, sisters for the
constant love, support and encouragement.
Last but not the least I would like to thank my wife Mrs. Babita Das
Dutta and my little princess Aastha for their support, encouragement and
for always being there in the time of need.
Dr. ASHISH DUTTA
ABBREVIATIONS
APA American Psychiatric Association
BMI Body Mass Index
BPAD ‐ Bipolar Affective Disorder
BPKIHS ‐ B. P. Koirala Institute of Health Sciences
CGI –BP Clinical Global Impression – Bipolar Version
CSOM Chronic Suppurative Otitis Media
DM Diabetes Mellitus
DSM‐IV ‐TR Diagnostic and Statistical Manual of Mental
Disorder 4th Edition, Text Revision
ECA Epidemiologic Catchment Area.
EPS Extrapyramidal Side Effects
HTN Hypertension
ICD‐10 International statistical Classification of
Disease 10th revision
Kg kilogram
Meq Miliequivalent
Mg Miligram
NPR Nepalese Rupees
PS Psychotic Symptom
RBS Random Blood Sugar
RCT Randomized Controlled Trial
SD Standard Deviation
SPSS Statistical Package for the Social Sciences
Vs Versus
Wt Weight
WHO World Health Organization
YMRS Young Mania Rating Scale
CONTENT
TABLE OF CONTENTS PAGE NO.
1. INTRODUCTION 14
2. RATIONALE OF THE STUDY 58
3. AIMS AND OBJECTIVES 9
4. REVIEW OF LITERATURE 1020
5. MATERIALS AND METHODS 2135
6. RESULTS 3654
7. DISCUSSION 5577
8. SUMMARY AND CONCLUSION 7880
9. REFERENCES 8188
INTRODUCTION
Introduction
INTRODUCTION
Bipolar disorder is generally an episodic, lifelong illness with a
variable course. The first episode of bipolar disorder may be
manic, hypomanic, mixed, or depressive. Men are more likely than
women to be initially manic, but both are more likely to have a first
episode of depression. Patients with untreated bipolar disorder
may have more than 10 total episodes of mania and depression
during their lifetime, with the duration of episodes and inter-
episode periods stabilizing after the fourth or fifth episode .1
EPIDEMIOLOGY:
Bipolar I disorder affects approximately 0.8% of the adult
population, with estimates from community samples ranging
between 0.4% and 1.6%. Bipolar II disorder affects approximately
0.5% of the population While bipolar II disorder is apparently more
common in women , bipolar I disorder affects men and women
fairly equally.
The Epidemiologic Catchment Area (ECA) study reported a mean
age at onset of 21 years for bipolar disorder, suggesting that the
illness begins at a relatively young age and severe consequences.
Evidence from epidemiological and twin studies strongly suggests
that bipolar disorder is a heritable illness. First-degree relatives of
patients with bipolar disorder have significantly higher rates of
mood disorder than do relatives of nonpsychiatrically ill
Introduction
comparison groups. However, the mode of inheritance remains
unknown. 1
PRINCIPLES OF TREATMENT
Bipolar disorder is a debilitating illness characterised by drastic
swings in mood, energy and functional ability. Effective and rapid
control of acute mania is required to prevent potential harm to
patients, their families and society at large. Without consistent
long-term treatment, bipolar disorders are potentially very
disruptive. Patients often experience a chronic and chaotic course,
in and out of the hospital, with psychotic episodes and relapses.
Thus, stabilizing bipolar disorders with mood stabilizers, atypical
antipsychotics, is increasingly important not only in returning these
patients to wellness but in preventing unfavorable long-term
outcomes.2
The goal of treatment in bipolar disorder is to stabilise mood.
Treatment is divided into 3 phases-acute, continuation and
maintenance3
Acute –aims at full symptom remission and restoration of full
function.
Continuation treatment aims to sustain those gains, thereby
preventing the return of the index episode.
Maintenance treatment is designed to prevent a new episode
(recurrence).
Introduction
Acute treatment is guided by:
Estimate of imminent suicidal risk.
Capacity of patient to recognise and adhere to
recommendations.
Level of psychosocial support.
Psychosocial stress and functional impairment.
It is essential to reach full remission in acute treatment whenever
possible as it is associated with better prognosis (i.e,lower relapse
rates) in continuation treatment and when treatment is
discontinued.
Patient adherence is essential and can be enhanced by patient
education and shared decision making.3
PSYCHIATRIC MANAGEMENT1
Perform a diagnostic evaluation.
Evaluate the safety of the patient and others and determine a
treatment setting.
Establish and maintain a therapeutic alliance.
Monitor treatment response.
Provide education to the patient and to the family.
Enhance treatment compliance.
Promote awareness of stressors and regular patterns of activity
and sleep.
Introduction
Work with the patient to anticipate and address early signs of
relapse.
Evaluate and manage functional impairments.
RATIONALE OF THE STUDY
Rationale of the Study
RATIONALE OF THE STUDY
The burden of bipolar affective disorder is overwhelming in Nepal,
which is based on the observation of the number of patients
suffering from this illness frequenting the psychiatric services of
BPKIHS,DHARAN. The magnitude of the disease in this country is
not known exactly (as there have been almost no scientific,
evidence based studies). Approximately 28% (source: ward
registers) of patients admitted to psychiatry ward of BPKIHS
constitute patients with bipolar illness, which reflects that a
significant number of people are suffering with this illness ,and the
number of people seeking treatment for such illnesses are rising.
Drugs are the first line treatment for acute mania. A number of
different drugs are used in the treatment of mania - either as
monotherapy or in combination. Thus, stabilizing bipolar disorders
with mood stabilizers, atypical antipsychotics, is increasingly
important not only in returning these patients to wellness but in
preventing unfavorable long-term outcomes.2
All drug treatments for mania are potentially associated with
serious adverse effects and a risk of precipitating depression.
Lithium has been used to treat mania for many years and has
been shown to be effective (Goodwin 1990). Antipsychotics have
been used for many years, particularly when mania is
accompanied by psychosis. Lithium therapy has been effectively
and acutely used for patients with pure or elated mania and its
prophylaxis. However mixed mania, rapid cycling type patients and
Rationale of the Study
bipolar disorder associated with substance abuse do not respond
well to lithium therapy. In addition to the lithium therapy, guidelines
recommend the use of antipsychotic agents in respect of patients
with bipolar disorder during both the acute and maintenance
phases of treatment.
Antipsychotic agents have been used for almost forty years and
are used in combination with a lithium therapy. Compared to
lithium, antipsychotics are sometimes considered to possess a
wider ratio between doses that confer efficacy and those that
induce side-effects and this is important in the treatment of
patients with mania. Conventional antipsychotics are effective but
they may induce late dyskinesia, weight gain, sedation, sexual
dysfunction and depression. According to the American Psychiatry
Association the first-line pharmacological treatment for severe
manic or mixed episodes is the initiation of either lithium plus an
antipsychotic or valproate plus an antipsychotic.
Atypical antipsychotics are preferred over typical antipsychotics
because of their more benign side effect profile with most of the
evidence supporting the use of olanzapine or risperidone.
Risperidone and olanzapine are effective in reducing manic
symptoms both as monotherapy and as an adjunctive treatment to
lithium.15
Olanzapine causes fewer movement disorders but greater weight
gain than conventional antipsychotics and it may increase the risk
of diabetes (Koro 2002).
Rationale of the Study
Risperidone causes less movement disorders and relatively less
weight gain compared to olanzapine.
Risperidone reaches its peak plasma level within 1 hour, has a half
life of 20hrs and it reaches a steady state concentration in
5days(range of 1-5 days)indicating an earlier onset of action as
compared to olanzapine which reaches its peak plasma level in 5
hrs, has a half life 31hrs and reaches a steady plasma
concentration in about 7 days. Studies indicate that risperidone
has a lower risk of hyperglycemia and diabetes mellitus than some
of the other atypical antipsychotics ,in particular olanzapine .
Though weight gain and metabolic side effects are more
commonly seen with the olanzapine group, routine practice in our
setting is the use of combination of lithium with olanzapine in
patients presenting with bipolar affective disorders in acute phase
mania in out-patient/in-patient setting .This can lead to a life long
disability to patients with an overwhelming increase in total cost of
medications, lifelong use of hypoglycemics ,widespread organ
damage over a period of time(due to metabolic syndromes) which
is painstakingly an extra burden to a person who is already
suffering from a chronic ,debilitating mental illness.
So using an atypical antipsychotic like risperidone with its
relatively less disabling side effects(in terms of metabolic
syndromes), lesser cost could prove to be more effective than
using olanzapine for the acute phase of mania.
Studies have been conducted comparing the efficacy of
risperidone alone or in combination with lithium for the treatment of
Rationale of the Study
acute phase of mania. Similarly studies have been conducted
comparing the efficacy of olanzapine alone or in combination with
lithium for the treatment of acute phase of mania but to our best
knowledge we didn’t come across studies comparing the
effectiveness of lithium with olanzapine and lithium with
risperidone. Furthermore the abovementioned studies have
mostly been done in the western setup. How applicable are the
results of these studies in our setup is a matter of research!
As of now there are no proper database available for the use of
antipsychotics and mood stabilizers for treatment of acute mania
in Nepal .We follow and rely upon guidelines provided by western
countries and various guidelines give different opinions in their
usage which creates dilemmas on the proper implementation of
such drugs. Thus we take a small effort towards examining the
data on the usage of lithium, olanzapine and risperidone which
may guide us through the clinical practices in our setting with
regards to which combination(out of the two) is more effective ,if
they are to be used in culturally and climatically different region of
the globe.
Hence we take this endeavour with the following aims and
objectives:
AIMS AND OBJECTIVES
Aims and Objectives
AIMS AND OBJECTIVES:
To compare the effectiveness of lithium and olanzapine vs
lithium and risperidone in the treatment of acute phase mania
of bipolar affective disorder.
To compare the Cost of psychotropics used ,cost of ward
stay ,average dose of co-interventions and magnitude of drug
related adverse events in each category.
RESEARCH HYPOTHESIS:
Lithium - lithium has been employed as an internal
comparator in phase III approval studies, thus allowing a
judgment of its efficacy.
Hypothesis- lithium with olanzapine vs lithium with risperidone
is equally effective in the treatment of acute manic phase of
bipolar affective disorder.
REVIEW OF LITERATURE
Review of Literature
REVIEW OF LITERATURE:
A number of mood stabilizers are reported to have an acute
antimanic effect, but the Expert Consensus Guideline on the
Treatment of Bipolar Disorder advocated either lithium or valproate
as the drugs of first choice. Valproate is preferred for patients with
mixed states or rapid cycling disorder. Response to lithium or
valproate is usually delayed by 7 to 14 days, so most clinicians
also use other drugs such as neuroleptics or atypical
antipsychotics.4
Classical neuroleptics (such as haloperidol, chlorpromazine) have
long played a role in the treatment of agitation and the psychosis
of mania. More recently, the atypical antipsychotics (such as
risperidone, olanzapine and quetiapine) have begun to replace the
older neuroleptics and assume an important adjunctive role in the
treatment of bipolar disorders. Currently, the atypical
antipsychotics are becoming more widely used for management of
the manic phase of bipolar disorder.2
Lithium, carbamazepine and valproate are well established and
FDA-approved treatments of acute mania. All drugs for treatment
with schizophrenia, including typical and atypical antipsychotics,
have demonstrated antimanic effects and, in some cases, the
magnitude of clinical effects in bipolar patients exceeds that for
patients with schizophrenia.3
Review of Literature
Evidence and research based studies in developed countries
have formulated their own guidelines for the treatment of
acute mania:
According to the American Psychiatry Association guidelines
the first-line pharmacological treatment for severe manic or mixed
episodes is the initiation of either lithium plus an antipsychotic or
valproate plus an antipsychotic. For less severe patients,
monotherapy with lithium, valproate, or an antipsychotic such as
olanzapine may be sufficient.1
Atypical antipsychotics are preferred over typical antipsychotics
because of their more benign side effect profile with most of the
evidence supporting the use of olanzapine or risperidone.
Olanzapine was superior to placebo in the treatment of acute
bipolar mania in four double blind placebo controlled monotherapy
studies1.
Lithium has been used for the treatment of acute bipolar mania for
over 50 years. In active comparator trials, lithium displayed
efficacy comparable to that of carbamazepine ,risperidone ,
olanzapine, and chlorpromazine and other typical antipsychotics .
Active comparator-controlled studies indicate that lithium is likely
to be effective for treatment of pure or elated mania but is less
often effective in the treatment of mixed states.1
Lithium is the most extensively studied mood stabilizer and has
the best overall efficacy for the prophylactic treatment of bipolar
disorder. Recent meta-analyses show it to be superior to placebo
Review of Literature
in the prevention of relapse and to reduce the risk of relapse 3.6-
fold 36.
The National Institute For Clinical Excellence(2006) licensed
lithium, olanzapine, quetiapine, risperidone and sodium valproate
for the treatment of acute mania in the UK. According to this
guideline if a patient develops acute mania when not taking
antimanic medication, treatment options include starting an
antipsychotic, valproate or lithium. They also recommend to take
into account the future prophylactic use, the side-effect profile, and
consider prescribing an antipsychotic if there are severe manic
symptoms or marked behavioural disturbances as part of the
syndrome of mania .5
The Australian prescriber (2008) mentions the following drugs as
first ,second and third line in the treatment of aute mania.6
• First-line – lithium
– Valproate
– carbamazepine
– second generation antipsychotics (olanzapine,
risperidone,quetiapine, aripiprazole ,ziprasidone)
• Second-line
‐ second generation antipsychotic plus lithium or
valproate
‐ lithium plus valproate
Review of Literature
• Third-line
- electroconvulsive therapy
- clozapine
According to the Texas guidelines( 2007),the algorithm for
treatment of BDI – Currently Hypomanic/Manic, presenting with
euphoric mania/hypomania or psychotic mania, the medication
choices are lithium, valproate, aripiprazole, quetiapine, risperidone,
and ziprasidone. For dysphoric or mixed mania, the
recommendation is to use any one of the following drugs-
valproate, aripiprazole, risperidone or ziprasidone. The consensus
panel placed olanzapine and carbamazepine as potential
monotherapy options . These medications have greater potential
adverse events and complexities associated with treatment.7
To date a total of 29 published or presented studies have
evaluated the acute antimanic efficacy of lithium. Lithium therefore
has clearlythe largest pool of studies.8
Both lithium and valproate were significantly more effective than
placebo. Subsquently, lithium has also been employed as an
internal comparator in other phase III approval studies, thus
allowing a judgement of its efficacy. Lithium was superior to
placebo in a study with quetiapine as investigational drug (Bowden
et al. 2005), in two studies with topiramate as investigational drug
(Kushner et al. 2006), and in one study with aripiprazole as
investigational drug(Keck et al. 2007).8
Review of Literature
Lithium has been used as the “gold standard” in RCTs of some of
the newer antimanic treatments.9
Atypical antipsychotics (other than clozapine) are now rated as
first-line agents for adjunctive treatment of mania because they
produce less adverse side effects. Atypical antipsychotics are also
rated as first-line agents for combined treatment of psychotic
depression and they are strongly preferred when an antipsychotic
is required for long-term maintenance. Many studies report the
combination of mood-stabilizing agents with conventional
antipsychotics and atypical antipsychotics. Combination therapies
produce a number of adverse side effects1.
Recent randomised, double-blind, placebo-controlled studies have
shown clozapine, risperidone and olanzapine to be effective with
antimanic and antidepressive effects, both as monotherapy and as
add-on maintenance therapy with lithium or valproate. They also
have a favourable side effect profile and a positive effect on overall
functioning. Similarly, valproate combined with antipsychotics
provides greater improvement in mania than antipsychotic
medication alone and results in lower dosage of the antipsychotic
medication. There is currently no double-blind study regarding the
use of clozapine for bipolar disorders.
Two recent double-blind studies of acute mania found olanzapine
to be more effective than placebo. Based on these two studies,
olanzapine has recently been approved for the indication of mania.
The olanzapine treatment group had significantly greater mean
improvement of mania ratings and a significantly greater proportion
Review of Literature
of patients achieving protocol-defined remission. Significantly more
weight gain and cases of dry mouth, increased appetite and
somnolence were reported with olanzapine.10
In comparator studies without a placebo arm, the antimanic
efficacy of lithium was tested versus various antipsychotics, two
studies were versus olanzapine .11
A multicenter, double-blind, randomized, controlled study
conducted in China examined the efficacy and safety of olanzapine
versus lithium in the treatment of patients with bipolar manic/mixed
episodes. A significantly greater mean change was observed in the
olanzapine group in CGI-BP (Overall Severity) ,YMRS, BPRS and
CGI-BP (Severity of Mania)scores. More olanzapine than lithium
taking patients experienced at least one adverse event possibly
related to study drug .More olanzapine patients had a clinically
significant weight increase (7% of baseline weight) compared to
lithium patients. More olanzapine patients completed the study
than lithium patients, although this difference was not statistically
significant (olz, 91.3%; lith, 78.9%; P = 0.057). Results showed
olanzapine has superior efficacy to lithium in the acute treatment of
patients with bipolar mania over a 4-week period. However,
adverse events were experienced by a greater number of
olanzapine patients than lithium patients.12
The comparison of olanzapine with lithium for the treatment of
mania has also been the subject of a double-blind randomized
controlled trial. That study shows no differences between the two
drugs. While these studies support the idea that olanzapine has
Review of Literature
direct acute anti-manic effects, a number of authors are of the
opinion that olanzapine may have specific prophylactic mood-
stabilizing properties. Olanzapine would appear to be effective in
the maintenance treatment, as it exhibited both antimanic and
antidepressant effects.
Symptomatic relapse/recurrence (score ≥15 on either the Young
Mania Rating Scale or Hamilton depression scale) occurred in
30.0% of olanzapine treated and 38.8% of lithium-treated patients.
Secondary results showed that compared with lithium, olanzapine
had significantly lower risks of manic episode and mixed episode
relapse/recurrence. 13
In a study done over 47 weeks, mean improvement in Young
Mania Rating Scale score was significantly greater for the
olanzapine group. Median time to symptomatic mania remission
was significantly shorter for olanzapine, 14 days, than for
divalproex, 62 days. There were no significant differences between
treatments in the rates of symptomatic mania remission over the
47 weeks (56.8% and 45.5%, respectively) and subsequent
relapse into mania or depression (42.3% and 56.5%). Treatment-
emergent adverse events occurring significantly more frequently
during olanzapine treatment were somnolence, dry mouth,
increased appetite, weight gain, akathisia,and high alanine
aminotransferase levels;those for divalproex were nausea and
nervousness.14
Data from the EMBLEM(European mania in bipolar longitudinal
evaluation of medication) Study, a 2-year, prospective,
Review of Literature
observational study of health outcomes associated with acute
treatment of patients experiencing a manic/mixed episode of
bipolar disorder, was used to compare the effectiveness of
olanzapine monotherapy versus risperidone monotherapy.
Symptom severity measures included the Young Mania Rating
Scale (YMRS), the 5-item Hamilton Depression Rating Scale, and
the Clinical Global Impression-Bipolar Disorder Scale. A total of
245 EMBLEM inpatients were analyzed with YMRS ≥20:
olanzapine (n=209), risperidone (n=36). Both the treatment groups
had similar improvements in YMRS from baseline to 6 weeks, but
there was a significantly greater improvement in 5-item Hamilton
Depression Rating Scale in the olanzapine group. There was a
similar improvement in Clinical Global Impression-Bipolar Disorder
Scale in both the groups and the occurrence of treatment-
emergent adverse events and weight gain did not differ between
the treatment groups. The EMBLEM results partly support those of
the randomized controlled trial, which suggests olanzapine and
risperidone have similar improvements in mania but that
olanzapine monotherapy may be more effective than risperidone
monotherapy in the treatment of depressive symptoms associated
with mania.
A population-based case-control study evaluating 19,637 patients
in the united kingdom concluded that risperidone use was
associated with a nonsignificant increased risk of developing
diabetes vs no antipsychotic treatment. Another study analyzing
4308 patients taking antipsychotic medications concluded that the
frequency of new onset diabetes type -2 was not significantly
Review of Literature
different in patients treated with risperidone vs untreated
patients(N=3625) .Results from the CATIE(clinical antipsychotic
trial of interventions effectiveness)17 study indicate that risperidone
produced changes in glucose level comparable to perphenazine
and quetiapine, with an increase lower than that with olanzapine
treatment and higher than that with ziprasidone treatment. The
CATIE data demonstrates little or no change in lipid parameters
with risperidone treatment.In the CATIE study the percentage of
patients gaining over 7 % of their body weight was 18% vs 9% for
placebo.
A large number of studies indicate that olanzapine is associated
with greater weight gain than other second generation
antipsychotics with the possible exception of clozapine. In the
NIMH(National Institute of Mental Health) CATIE study it was
observed that 56% of patients gained greater than 7% of baseline
weight. In the NIMH CATIE study the mean increase in
triglycerides in patients taking olanzapine was 40.5 g/dl.
The same study found greater elevations of in blood glucose on
olanzapine than on other antipsychotics.
Other studies have found that olanzapine is associated with an
increase in insulin resistance in both obese and non obese
patients.18
Ghaemi et al19 have reported that risperidone may be more
effective and better tolerated than conventional antipsychotics in
the treatment of bipolar disorder. In their survey, 64% of
risperidone-treated patients showed large improvements on the
Review of Literature
CGI, and Global Assessment of Functioning scores improved from
48.2 ± 4.9 to 58.0 ± 7.3 (p < .001). Treatment was well tolerated,
and no patient experienced worsening of mood symptoms while
receiving risperidone. In 1999, Ghaemi et al.20 concluded that
risperidone has bidirectional mood-stabilizing properties. They
reported that the mean response rate in 6 studies 19,21-25 of patients
with schizoaffective or bipolar disorder, both with and without
psychosis, was 51%. In 4 of these studies,19,21-23 in which
risperidone was an adjunct to mood stabilizers, there were no
reports of induction of mania.
Sachs et al.26 conducted a 3-week, double-blind, multicenter,
randomized trial comparing risperidone (1–6 mg/day) with placebo
as add-on therapy to lithium or divalproex in the acute
management of bipolar mania. Significantly greater improvement
in Young Mania Rating Scale (YMRS) scores was seen in patients
receiving risperidone and a mood stabilizer than in those receiving
placebo and a mood stabilizer (p = .009), with 57% of risperidone
patients showing at least a 50% reduction in YMRS score. Most
patients (76.5%) receiving risperidone and a mood stabilizer were
rated as much or very much improved on the CGI, compared with
57.4% of patients receiving placebo and a mood stabilizer. The
benefit of risperidone was apparent among patients with and
without associated psychotic features.
Only 3 other controlled trials 27-29 assessing the effects of atypical
antipsychotics in bipolar patients have been published.
Risperidone, haloperidol, and lithium were equivalent in efficacy in
a 28-day double-blind study involving 45 inpatients with mania.27 In
Review of Literature
a double-blind 3-week study, olanzapine was superior to placebo
for symptoms of acute mania in 139 patients who had failed
treatment with mood stabilizers.28 A 4-week replication study again
found olanzapine monotherapy superior to placebo in 115 patients
hospitalized for acute mania.29 Olanzapine has also demonstrated
efficacy similar to that of divalproex sodium in the treatment of
acute mania, although weight gain was significantly greater with
olanzapine than with divalproex (3.4 kg vs. 1.7 kg, p = .045).30 In a
recent study, Tohen et al.31 looked at patients who had achieved
symptomatic remission of bipolar disorder at the end of acute
therapy with olanzapine combined with lithium or valproate and
found that 55.3% of placebo-treated patients versus 36.7% of
olanzapine-treated patients relapsed into either mania or bipolar
depression during an 18-month trial (p = .149). Time to bipolar
relapse was significantly earlier in placebo- versus olanzapine-
treated patients.
MATERIALS AND METHODS
Materials and Methods
MATERIALS AND METHODS:
UNIVERSE OF THE STUDY:
Patients attending to psychiatric services of BPKIHS. Patients
diagnosed as bipolar affective disorder current episode mania
were recruited from Emergency ,OPD or Ward. Patients from
BPKIHS outreach clinics were also recruited.
SUBJECTS OF THE STUDY:
Any patient with a diagnosis of bipolar affective disorder (BAD)
fulfilling the following inclusion and exclusion criteria.
Inclusion criteria
• Patient with the clinical diagnosis of bipolar affective disorder
current episode mania with or without psychotic symptoms
according to ICD-DCR criteria.
• Patients of either gender.
• Age>=16 years.
• The primary caretakers or patients who give a written informed
consent.
Materials and Methods
Exclusion criteria
• Primary caretakers or patients who do not give the written
informed consent.
• Any disability in the patient hampering effective
communication.
• Patients with known history of diabetes mellitus,renal
pathology.
• If the clinical diagnosis of the patient changes during follow
up visits or during ward course ,the patient will be considered
as a “drop out”.
• Pregnant patients.
• Organic mania, or mania due to psychoactive substance
use(harmful use or dependence, as per ICD- 10).
ICD-10/DCR
F30.1 Mania without psychotic symptoms
For at least one week (or less, if hospitalised): Mood elevated,
expansive or irritable out of keeping with the patient’s
circumstances.
At least three of the following have to be present:
1. Increased activity or physical restlessness
2. Pressure of speech
3. Flight of ideas or racing thoughts
4. Loss of normal social inhibitions
Materials and Methods
5. Decreased need for sleep
6. Distractibility or constant changes in plans
7. Inflated self esteem with grandiose ideas and
overconfidence
8. Behaviour that is foolhardy and reckless
9. Marked sexual energy or indiscretion.
There are no hallucinations or delusions ,although perceptual
disorders may occur(e.g.,subjectivehyperacusis,appreciation
of colours as especially vivid)
Most commonly used exclusion criteria.The episode is not
attributable to psychoactive substance use or to any organic
mental disorder.
F30.2 Mania with psychotic symptoms
In addition to F30.1,
1. Delusions (usually grandiose) or hallucinations (usually of
voices speaking directly to the patient) are present,
2. The excitement, excessive motor activity, and flight of ideas
are so extreme that the subject is incomprehensible or
inaccessible to ordinary communication.
3. The episode does not simultaneously meet the criteria for
schizophrenia or schizoaffective disorder,manic type.
4. Most commonly used exclusion clause. The episode is not
attributable to psychoactive substance use or to any organic
mental disorder.
Materials and Methods
Specify whether the hallucinations or delusions are congruent or
incongruent with the mood:
With mood congruent psychotic symptoms(such as grandiose
delusions or voices telling the individual that he or she has
superhuman powers.)
With mood incongruent psychotic symptoms (such as voices
speaking to the individual about affectively neutral topics,or
delusions of reference or persecution).
STUDY DESIGN:
This is a 6 weeks long non randomised, comparator controlled,
non-blind clinical trial.
INTERVENTION ARMS:
Two arms : lithium with olanzapine
: lithium with risperidone
• Risperidone(2-6mg/day)
• Olanzapine(5-25 mg/day)
lithium(600-1500 mg/day) in a divided dose. Starting dose 300-
600mg/day.
Materials and Methods
SAMPLE SIZE:
Each arm consisted of 37 patients .The sample size calculated by
using the power and sample size programme, PS version 3.0.34,
based on following formulation:
According to the study done by Novick et al(2010),in the
comparison of olanzapine and risperidone in the treatment of acute
mania in a patient of bipolar affective disorder, the response within
each group was normally distributed with a standard deviation of
2.5. If the true difference in the mean change in YMRS between
the two groups is 1.65, 37 patients in olanzapine group and
another 37 patients in risperidone group need to be studied to be
able to reject the null hypothesis(H0) that the population change in
mean of two groups are equal with the probability 0.8(power of
test). The significance level(type 1 error) associated with the test of
null hypothesis is 0.05.
INVESTIGATIONS:
Random blood glucose.
Serum creatinine.
Complete blood count.
Na+/k+
NUMBER AND TIMING OF OBSERVATIONS:
First observation-0 weeks
Second observation-3 weeks±3 days.
Third observation-6 weeks±7 days.
Materials and Methods
INSTRUMENTS AND TOOLS:
For baseline assessment
Informed Consent form.
Self developed Semi-structured socio-demographic profile.
Self developed Semi-structured clinical profile.
Young mania rating scale.
Clinical global impression –bipolar version severity rating
scale.
In follow-up visits
Young mania rating scale.
Clinical global rating scale-bipolar version severity rating
scale.
Self developed semi structured Side effects check list.
Self developed semi structured follow-up checklist.
Random blood sugar at 6 weeks.
RATING SCALES:
YOUNG MANIA RATING SCALE(YMRS)
Developed by RC YOUNG et al, 1978. This scale is one of the
most frequently used rating scales in clinical as well as research
setting. Altogether there are 11 items, 4 items are graded on a 0-8
scale while remaining 7 items are graded on a 0-4 scale. Time
required to complete the scale is approximately 15-30 min. The
Strengths of this scale are its brevity, widely accepted use, ease of
Materials and Methods
administration. However there is a limitation to applying this scale
as it can be used only for cases of mania.
(Rating Scales In Mental Health,MARTHA SAJATOVIC,LUIS F
RMIREZ) THIS RATING SCALE HAS ALSO BEEN USED IN THE
DEPT. OF PSYCHIATRY (BPKIHS) ,IN PREVIOUS STUDIES OF
BIPOLAR DISORDERS.
CLINICAL GLOBAL IMPRESSION(CGI)
Developed at National Institute Of Mental Health
(NIMH,GUY,1976).This scale Measures overall illness severity and
response to treatment in psychiatric patients. It is a 3 item scale
(severity of illness:1-7,global improvement:1-7, Therapeutic
response). Therapeutic response is rated as a combination of
therapeutic effectiveness and adverse effects. In clinical and
research situations ,only the first two items are often utilized. Each
item is rated separately and there is no overall score. This scale is
useful in situations where change over time is to be assessed, and
since it is a general scale(not specific to a particular psychiatric
disorder),it is usually paired with a more specific psychopathology
scale. Approximate time required to complete the scale-<5
minutes.
CLINICAL GLOBAL IMPRESSION –BIPOLAR VERSION
The New CGI-Bipolar Version (CGI-BP) developed for rating
severity of manic and depressive episodes and the degree of
change from the immediately preceding phase and from the worst
phase of illness, to facilitate the reliability of these ratings of mania,
Materials and Methods
depression, and overall bipolar illness during treatment of an acute
episode or in longer-term illness prophylaxis. Interrater reliability of
the scale was demonstrated in preliminary analyses. Thus, the
modified CGI-BP is anticipated to be more useful than the original
CGI in studies of bipolar disorder. (1997 Elsevier Science Ireland
Ltd.)
DURATION OF STUDY:1 Year
PARAMETERS/VARIABLES:
SOCIODEMOGRAPHIC PROFILE.
WEIGHT,HEIGHT,ABDOMINAL GIRTH.
CLINICAL PROFILE.
RATING SCALES(YMRS,CGI-BP).
SIDE EFFECTS.
RANDOM BLOOD SUGAR.
EXPENDITURE DETAILS(WARD ,MEDICINE etc.).
FOLLOW-UP DETAILS.
STATISTIAL METHODS EMPLOYED:
Descriptive statistics was used to describe the quantitative
variables. Comparison between the continuos variables (scores)
were made by using t-test or suitable non parametric tests
depending upon the nature of data in between two groups.
Materials and Methods
Probablty of significance was set as 5% level of significance and
95% confidence limit.
TRIAL DISCONTINUATION CRITERIA:
Serious side effects related to treatment.
Unsatisfactory clinical improvement despite using maximum
recommended dose of study medication according to
respective treating team.
If the patient couldn’t tolerate the study medication .
If the diagnosis changed during the subsequent visits or ward
course.
CO-INTERVENTIONS ALLOWED:
Traditional healing without hampering the treatment regimen.
Physical restrain1 as decided by treating team.
Adjunct medication-Benzodiazepines and Inj.haloperidol
(Doses as per decision of treating team, record was
maintained on the amount and frequency of the adjunct
medications used).
Any medications for treating side effects like central
anticholinergics, antihistamines, beta blockers etc.
1 Physical restrain was implemented only when a patient carried a risk of harm to self or others, and no less restrictive alternative was available. Restrain was confined to specific, time limited period. The patients condition was regularly reviewed and documented during the restrain period.
Materials and Methods
OUTCOME MEASURES:
Primary
Mean decline in YMRS 2 and CGI 3 severity scale from
baseline.
Percentage of subjects achieving remission at end point(6
weeks).
Ancillary
Magnitude of drug related adverse events.
Average dose of co-intervention medication required.
Cost comparison(psychotropics,others related to mania,cost of
ward stay).
Sub group analysis on cumulative dose of the study
medications.
OPERATIONAL DEFINITIONS:
RESPONSE : 50% or less score on YMRS.
REMISSION- YMRS score < or = 9
- CGI-BP score<2 or =2
SERIOUS SIDE EFFECTS: -lithium toxicity
-cardiac arrhythmias
2 Young mania rating scale 3 Clinical global impression
Materials and Methods
DATA ANALYSIS:
Datas were analysed by “intention to treat analysis” and “per
protocol analysis”. For categorical or ordinal data comparison
was done by using chi-square test and by independent t-test for
continuation data.
ETHICAL CONSIDERATIONS:
• Signed informed consent was obtained from all participants.
• All patients and their attendants were informed about the study
in detail in a locally understandable language.
• All the patients received standard care whether he /she was a
participant of the study or not.
• Patients had the liberty to withdraw themselves from trial, any
time they wished to during the treatment.
• Regular monitoring of side effects and management
accordingly.
• Patient’s identity and all the information related to the patient
were kept confidential and were used only in the best interest of
the patient for management and treatment guidance.
Materials and Methods
STUDY PROCEDURE:
This 6-week, non randomized, comparator controlled, non-blind,
equivalence clinical trial compared the effectiveness of lithium
with olanzapine vs lithium with risperidone among hospital out
patients , inpatients and emergency patients who met ICD-DCR
criteria for bipolar affective disorder current episode mania,with or
without psychotic symptoms ..The study was conducted at
BPKIHS,DHARAN(NEPAL) .
After detail work up ,the diagnosis was confirmed by the consultant
psychiatrist .Patients were assigned medications in equal numbers
to recieve lithium with olanzapine or lithium with risperidone
alternately. After initiation of treatment (baseline), patients were
provided treatment on outpatient or in-patient basis. Socio
demographic and clinical profile were noted on a self developed
semi structured proforma. Treatment effectiveness was
determined primarily by the change from baseline to end-point in
mean decline on the Young Mania Rating Scale and CGI –BP
scale. Treatment emergent adverse events and vital signs were
assessed on alternate days for in-patients and during each follow
up visit for out-patients. The total dose of medication used in each
category, along with various other variables pertinent to the study
was recorded during follow-up visit on a self developed semi
structured follow-up check list. The primary outcome measure was
the mean decline in the Young Mania Rating Scale (YMRS)and
CGI-BP scale ,and percentage of subjects achieving respose at 3
weeks, and remission at 3 weeks and end point (6 WEEKS).
Patients who were not able to come for a follow up on specified
Materials and Methods
dates (owing to transportation or other problems )were considered
as “drop outs “ from the study) .Phone calls were made to the
patients 2 days prior to the schedule of follow –up whenever
possible to ensure timely follow-up.
LIMITATIONS:
• Non blind study.
• Non randomized.
• Use of adjunct medications could be the confounding factor.
ENSURING COMPLIANCE :
Psychoeducation regarding the nature of mental illness, the
long duration of treatment required.
Keeping vigilance over the patient.
Information about the importance of regular and adequate
dosing of the drugs was provided to the patient’s attendants.
Phone calls were made to the patients or their attendants 2
days prior to the schedule of follow-up.
RESULTS
Results
RESULTS
Group 1: Lithium with Olanzapine
Group 2: Lithium with Risperidone
Table 1
Caterogy Group 1 Group 2
P value
N % N % Age Mean±SD 29.3±9.8 28.65±9.3 0.764 Sex Male 13 25 0.007 Female 27 15 Religion Hindu 39 40 Muslim 1 0 Income <5000 17 19 5000-10000 9 5 >10000 1 8 Occupation House wife 13 7 Student 11 11 Farmer 2 4 Professional 3 3 Manual labourer 4 2 Unemployed 3 1 Others 4 12 Literacy Mean±SD 7.92±5.3 9.05±4.6 0.320
Marital Status Unmarried 11 27.5% 10 25% 0.968 Married 27 67.5% 28 70% Separated 2 5% 2 5%
Geographical Distribution
Terai 28 70% 34 85% 0.090 0.177
Mountain/Valley 12 30% 6 15%
Domicile Urban 8 20% 13 32.5%
Suburban 24 60% 24 60% Remote 8 20% 3 7.5%
Distance <100kms 7 17.5% 9 22.5% 0.627 100-200kms 17 42.5% 19 47.5% 200-500kms 16 40% 12 30% Diagnosis BPAD WITHOUT PS 13 32.5% 9 22.5% 0.227 BPAD WITH PS 27 67.5% 31 77.5%Psychiatric Comorbidity
Present 0 0% 0 0%
Absent 40 100% 40 100%
Results
Caterogy Group 1 Group 2
P value
N % N % Family History of Bipolar Illness
Present 15 37.5% 16 40% 0.5
Absent 25 62.5% 24 60% Family History of Medical Illness
Present 4 10% 9 22.5%0.112
Absent 36 90% 31 77.5%
Substance Use Use 6 15% 16 40% 0.011 Harmful Use 34 85% 24 60%
Physical Comorbidity
Present 9 22.5% 9 22.5% 0.605 Absent 31 77.5% 31 77.5%
Mode Abrupt 22 55% 20 50% 0.412 Acute 18 45% 20 50%
Stressor Present 31 77.5% 20 50% 0.010 Absent 9 22.5% 20 50%
Treatment received outside
None 1 2.5% 2 5% 1.00*
Faith Healing 39 97.5% 38 95%
Admission required
yes 29 72.5% 31 77.5% 0.398 No 11 27.5% 9 22.5%
Days of ward stay
Mean±SD 22.07±5.216 21.84±7.823 0.895
Duration of manic episode
Mean±SD 22.45±23.216 29.85±46.95 0.374
*Yates corrected x2 test
The mean age of patients in olanzapine group is 29.3±9.8 years
and in risperidone group is 28.65±9.3 yrs. The p value is 0.764
which is not statistically significant.
Results
The sex distribution is 13(32.5%) males and 27(67.5%) females in
olanzapine group, with 25( 62.5%)males and 15(37.5%) females in
risperidone group, with p value of 0.007, which is statistically
significant.
In olanzapine group 39(48.8%) patients followed hindu religion and
only 1 (1.2%)patient belonged to muslim community. whereas in
risperidone group all the patients belonged to hindu community
(50%). The p value is 0.5, which is not statistically significant.
Group 1 Group 2
AGE 29.3 28.65
28.2
28.4
28.6
28.8
29
29.2
29.4Axis Title
AGE(years)
Group 1 Group 2
Male 13 25
Female 27 15
0
5
10
15
20
25
30
Sex Distribution
Results
In olanzapine group , 17(42.5%) of the patients earned less than
Rs 5000, 9 (22.5%)patients earned between Rs 5000-10000 and
only 1(2.5%) patient had an income of >Rs 10000. Whereas
19(47.5%) patients earned <Rs 5000, 5 (12.5%)patients had an
income between Rs 5000-10000 and 8 (20%)patients earned >Rs
10000 in risperidone group. The p value is 0.048, which is not
statistically significant.
Occupationally, olanzapine group consisted of 13(32.5%)
housewives, 11(27.5%) students, 2 (5%) farmers, 3(7.5%)
professionals, 4 (10%) manual labourers, 3(7.5%) were
unemployed and 4 (10%) patients in others, whereas in
risperidone group there were 7(17.5%) housewives, 11(27.5%)
student, 4 (10%) farmers, 3(7.5%) professionals, 2(5%) manual
labourers, 1(2.5%) unemployed, 12(30%) others. The p value is
0.228, which is not statistically significant. overall 25% were
housewives, 27.5% were students, 7.5% were in farming, 7.5%
were manual labourers, 7.5% professionals, 5% unemployed.
<5000 5000‐10000 >10000
Group 1 17 9 1
Group 2 19 5 8
02468101214161820
Axis Title
Income(NPR)
Results
The literacy rate is as follows: In olanzapine group the mean
number of academic years spent by a patient is 7.92±5.3 yrs. In
risperidone group the value is 9.05±4.6 yrs. The p value is 0.32,
which is not statistically significant.
In olanzapine group 27(67.5%) patients were married , whereas
11(27.5%) were unmarried and 2(5%) separated. In risperidone
group , 28(70%) patients were married , 10(25%) unmarried and
2(5%) separated. The p value was 0.968, which is not statistically
significant.overall 68.75% patients were married.
House wife
student farmerprofession
alManual labourer
unemployed
others
Group 1 13 11 2 3 4 3 4
Group 2 7 11 4 3 2 1 12
02468
101214
Occupation Distribution
unmarried married separated
Group 1 11 27 2
Group 2 10 28 2
0
5
10
15
20
25
30
Axis Title
Marital Status
Results
In olanzapine group, 28 (70%) resided in terai region, 12(30%)
resided in mountains/valleys. In risperidone group 34(85%)
patients were from terai and 6(15%) belonged to mountain/
valley.The p value was 0.090 which is not statistically significant.
In olanzapine group, 8(20%) patients belonged to urban areas,
24(60%) belonged to suburban area, 8(20%) belonged to remote
area. In risperidone group, 13(32.5%) patients were from urban
area, 24(60%) from suburban area, and 3(7.5%) were from
remote area. The p value is 0.177, which is not significant
statistically.
The average distance of patients home(in kms) fromBPKIHS was
:In olanzapine group <100kms-7 patients(17.5%), 100-200kms-
17(42.5%)patients, 200-500kms-16(40%) patients. In risperidone
group, 9(22.5%) patients were within <100kms, 19(47.5%)
patients between 100-200kms and 12(30%) patients were within
200-500kms. The p value is 0.627 which is not statistically
significant.
Group 1 Group 2
terai 28 34
Mountain/valley 12 6
0
5
10
15
20
25
30
35
40
Axis Title
Geographical Distribution
Results
In olanzapine group, 13(32.5%) patients were diagnosed as
BPAD without PS, and 27(67.5%) patients were diagnosed as
BPAD with PS. In risperidone group, 9(22.5%) patients were
diagnosed as BPAD without PS whereas 31(77.5%) patients were
diagnosed as BPAD with PS. The p value is 0.227 which is not
statistically significant.
No psychiatric comorbidity was seen in either of the groups.
In olanzapine group, 15(37.5%) patients had a positive family
history of Bipolar illness. In risperidone group 16(40%) patients
had a positive family history. The p value is 0.5 which is not
statistically significant.
Group 1 Group 2
BPAD WITHOUT PS 13 9
BPAD WITH PS 27 31
0
5
10
15
20
25
30
35
Axis Title
Diagnosis
Group 1 Group 2
Present 15 16
absent 25 24
0
5
10
15
20
25
30
Axis Title
Family History of Bipolar Illness
Results
In olanzapine group, 4(10%) patients had a positive family history
of medical illness(Dyslipidemia, DM, HTN). In risperidone group,
9(22.5%)) patients had a positive family history of medical illness.
The p value is 0.112 which is not statistically significant.
In olanzapine group, 6(15%) patients were diagnosed as having
nicotine use, whereas 34(85%) patients were diagnosed as having
harmful use of nicotine. In risperidone grouop, 16(40%)patients
were in nicotine use and 24(60%)patients were in harmful use of
nicotine. The p value is 0.011, which is not statistically significant.
In olanzapine group, 9(22.5%) patients were having some type of
physical comorbidity ,out of which 75% had chronic suppurative
otitis media ,migraine headache in 5% patients, candidal intertrigo
in 15% , and menstrual irregularities in the rest 5%. In risperidone
group, 9(22.5%) has physical comorbidity ,mostly again in the
form of CSOM(85%) and candidal intertrigo in the remaining 15%.
The p value is 0.605 which is not statistically significant.
Group 1 Group 2
present 9 9
absent 31 31
0
5
10
15
20
25
30
35
Axis Title
Physical Comorbidity
Results
The mode of onset was abrupt in 22(55%) patients, acute in
18(45%) patients in olanzapine group. In risperidone group,
20(50%) patients had abrupt onset of symptoms and remaining
20(50%) had acute onset of symptoms. The p value is 0.412 which
is not statistically significant.
In olanzapine group stressor was found to be present in 31(77.5%)
before the onset of illness. Stressors mainly in the form of non
compliance(as a precipitating factor) was seen in 20(64.51%)
patients, and psychosocial factor (as a stressor) was found in the
remaining 11(35.48%) patients. In risperidone group, 20(50%)
patients had a stressor in the form of noncompliance among
12(60%0 patients and psychosocial factor among the rest 8(40%)
patients. The p value is 0.010 which is statistically significant.
In olanzapine group, 39(97.5%) patients received faith healing
before coming to psychiatric services. In risperidone group,
38(95%) received faith healing. None of the patients in either
group received any type of medical treatment from outside before
coming to the psychiatric services.
29(72.5%) patients required admission to the psychiatry ward
among patients in olanzapine group whereas 31(77.5%) required
admission in the risperidone group. The p value is 0.398 which is
not statistically significant.
The mean duration of stay in ward for patients in olanzapine group
was 22.07±5.216 days. In risperidone group the mean days of
admission was 21.84±7.823 days. The p value is 0.895 which is
not statistically significant.
Results
The mean duration of manic episode in patients among
olanzapine group was 22.45±23.216 days whereas in risperidone
group it was 29.85±46.95 days. The p value is 0.374 which is not
statistically significant.
Table 2:
Caterogy Group 1 Group 2 P value
N N YMRS 0 week 33.12±8.416 32.55±7.317 0.745 3 weeks 13.91±5.145 12.80±4.52 0.353 6 weeks 4.78±4.117 4.6±3.657 0.841 CGI-BP 0 week 0.803 Mildly ill 2
5% 2
5%
Moderately ill
13 32.5%
11 27.5%
Markedly ill 13 32.5%
14 35%
Severely ill 9 22.5%
12 30%
Very severely ill
3 7.5%
1 2.5%
3 weeks 0.462 Normal,not
ill 15 48.38%
15 44.11%
Minimally ill 16 51.61%
19 55.88%
6 weeks Normal,not
ill 28 70%
30 75%
0.401
Minimally ill 12 30%
10 25%
Results
The mean YMRS score in the olanzapine group at the time of first
contact was 33.12±8.416. The mean score in risperidone group
was 32.55±7.317. The p value was 0.745 which is not statistically
significant.
The mean YMRS score at 6 weeks in olanzapine group was
4.78±4.117 and in risperidone group was 4.6±3.657. The p value
is 0.841 which is not statistically significant.
The mean decline in YMRS score between 0 week and 6 weeks in
the olanzapine group was found to be 86.97%. The mean decline
in YMRS score between 0 week and 6 weeks in risperidone group
was 85.63% .the p value was 0.600 which is not statistically
significant.
The response rate at 3 weeks was found to be 100%( data was
available for 67 patients).
The response rate at 6 weeks was 100%.
0 week 3 weeks 6 weeks
Group 1 33.12 13.91 4.78
Group 2 32.55 12.8 4.6
0
5
10
15
20
25
30
35
Axis Title
YMRS score(Mean)
Results
Altogether 22 (27.5%) patients reached remission at 3 weeks, out
of which 10(12.5%) belonged to olanzapine group and the rest
12(15%) belonged to risperidone group. the p value was 0.401
which is not significant statistically.
The remission rate at 6 weeks was as follows: Total 70(87.5%)
patients reached remission at 6 weeks out of which 35(43.8%)
patients belonged to olanzapine group and the rest 35(43.8%)
belonged to risperidone group.the p value was 0.631, which is not
statistically significant.
In the CGI-BP rating scale at first contact, among the olanzapine
group, 2(5%) patients were mildly ill, 13(32.5%) patients were
moderately ill, 13(32.5%) patients were markedly ill, 9(22.5%) patients
were severely ill, 3(7.5%) patients were very severely ill. Among the
risperidone group, 2(5%) patients were mildly ill, 11(27.5.5) patients
were moderately ill, 14(35%) patients were markedly ill, 12(30%)
patients were severely ill, 1(2.5%) patient was very severely ill. The p
value is 0.803 which is statistically insignificant.
Mildly ill Moderately ill Markedly ill Severely illVery severely
ill
Group 1 2 13 13 9 3
Group 2 2 11 14 12 1
0
2
4
6
8
10
12
14
16
Axis Title
CGI‐BP 0 week
Results
At 6 weeks CGI-BP rating scale revealed 28(70%) patients
normal,not ill in olanzapine group. In the same group minimally ill
were 12(30%) patients. In risperidone group, 30(75%) patients
were normal,not ill. Whereas 10(25%) patients were minimally ill.
The p value is 0.401 which is statistically insignificant.
Group 1 Group 2
Normal,not ill 15 15
Minimally ill 16 19
02468
101214161820
Axis Title
CGI‐BP‐3 weeks
Group 1 Group 2
Normal,not ill 28 30
Minimally ill 12 10
0
5
10
15
20
25
30
35
Axis Title
CGI‐BP 6weeks
Results
Table 3:
Caterogy Group 1 Group 2 P value
N N Body Mass Index
0 week 19.4661±2.555 20.0468±3.521 0.401 6 weeks 20.9695±2.699 21.0622±3.645 0.89
Random Blood Sugar(mg)
0 week 85.62±19.67 90.65±24.19 0.311 6 weeks 95±20.454 95.10±16.584 0.981
The mean BMI at first contact in olanzapine group was
19.4661±2.555 and in risperidone group was 20.0468±3.521. The
p value is 0.401 which is statistically insignificant.
The mean BMI at 6 weeks in olanzapine group was 20.9695±2.699
and in risperidone group was 21.0622±3.645 with a p value of
0.89 which is statistically insignificant.
The mean change in BMI within the olanzapine group, between
first contact and 6 weeks was 7.06±5.33 and test reveals a p value
Group 1 Group 2
0 week 19.4661 20.0468
6 weeks 20.9695 21.0622
18.5
19
19.5
20
20.5
21
21.5
Axis Title
BMI(kg/m2)
Results
of 0.001 which means the increment in bmi is significant for
subjects receiving olanzapine.
The mean change in BMI within risperidone group between first
contact and 6 weeks was 4.71±4.78 and the test reveals a p value
of 0.001 which means that the increment in BMI is significant for
subjects receiving risperidone.
The overall comparison between the two groups regarding the
mean change in BMI reveals a p value of 0.041 which is
statistically significant.
The mean random blood sugar at first contact in the olanzapine
group was 85.62±19.67 mg and in risperidone group was
90.65±24.19 mg with a p value of 0.311 which is statistically
insignificant.
The mean random blood sugar at 6 weeks in olanzapine group
was 95±20.454 mg and in risperidone group was 95.10±16.584
mg with a p value of 0.981 which is statistically insignificant.
Group 1 Group 2
0 week 85.62 90.65
6 weeks 95 95.1
80
82
84
86
88
90
92
94
96
Axis Title
RBS(Mg)
Results
The mean change in RBS within olanzapinr group between first
contact and 6 weeks was 9.38 mg and test reveals a p value of
0.002 which means the increment in RBS is significant for subjects
receiving olanzapine.
The mean change in RBS within the risperidone group between
first contact and 6 weeks was 4.45 mg and test reveals a p value
of 0.194 which means the increment in RBS is not significant for
subjects receiving risperidone.
Table 4
Caterogy Group 1 Group 2
P value
N % N %
0.136Side effects
Weight gain(kg) 16 20 8 10
EPS 0 0 2 2.5
None 4 5 5 6.2
Both 1 1.2 2 2.5
Sedation 7 8.8 5 6.2
Wt gain+EPS+Sed 2 2.5 0 0
Wt gain +Sed 10 12.5 18 22.5 Medication for side-effect
Anticholinergic(mg) 27±4.24 26±2.82 0.808
Beta blocker(mg) 840 0
Investigations
RBS 1st contact(mg)
85.62±19.671 90.65±24.191 0.311
RBS 6 weeks(mg) 95.00±20.454 95.10±16.584 0.981Serum lithium(Meq/lit)
0.8529±0.100 0.8579±0.126 0.898
Serum creatinine 0.824±0.1874 0.764±0.1640 0.13
Results
In the side effect profile ,among patients receiving olanzapine,
16(20%) had weight gain only, 2(2.5%) patients had weight gain
+EPS+sedation, 7(8.8%) patients had only sedation , 1(1.2%)
patient had both weight gain and EPS, 10(12.5%) patients had
weight gain +sedation, 4 (5%) patients had no side effects. Among
patients receiving risperidone, 8(10%) patients had weight gain,
2(2.5%) patients had EPS, 2(2.5%) patients had both weight gain
and EPS, 5(6.2%) patients had sedation, 18(22.5%) patients had
weight gain+sedation, 5(6.2%) patients had no side effect. The p
value was 0.136 which is statistically insignificant when compared
between the groups.
The mean weight at first contact in olanzapine group was
47.48±5.71kg and in risperidone group was 50.78±9.59 kg. The p
value was 0.066 which is not significant statistically. The mean
weight at 6 weeks in olanzapine group was 51.22±6.5 kg and in
the risperidone group was 53.25±9.33 kg. The p value was 0.267
which is not statistically significant.
Weight gain(kg)
EPS None Both SedationWt
gain+eps+sed
Wt gain +sed
Group 1 16 0 4 1 7 2 10
Group 2 8 2 5 2 5 0 18
02468101214161820
Axis Title
SIDE EFFECTS
Results
Within the group comparison of weight gain between first contact
and 6 wks in olanzapine group revealed a mean increase in weight
by 3.74 kg with a p value of 0.001, which means that increment in
weight is statistically significant in olanzapine group. The mean
increase in weight in risperidone group was 2.47 kg, with a p
value of 0.001 which again shows that the increment in weight is
significant in risperidone group.
All patients in both groups underwent routine investigations
including RBS, serum lithium(36 patients), and serum creatinine.
Among 36 patients who underwent s. lithium, mean level in
olanzapine group was 0.8529±0.10, and that in risperidone group
was 0.8579±0.126. The p value was 0.898 which is not
statistically significant.
The mean serum creatinine level in olanzapine group was
0.824±0.1874 and that in risperidone group was 0.764±0.1640.
The p value was 0.13 which is insignificant statistically.
2(5%) patients in olanzapine group required trihexyphenidyl ,mean
dose 27±4.24 mg and 2(5%) patients in risperidone group required
mean dose of 26±2.82 mg THP.the p value was 0.808 which is not
statistically significant. One patient in risperidone group required
840 mg of propanolol during the study period.
Results
Table 5:
Category Group 1(olanzapine converted to equivalent dose of risperidone)
Group 2 P value
N N Cost of Medicines (NPR)
PRIMARY Medicines:
Lithium 275.10±28.051 274.05±30.058 0.872Olanz/risp 402.15±188.302 247.380±85.387 0.000 ADJUNCTIVE: Lorazepam 78.795±59.2025 100.251±62.729
6 0.122
Haloperidol 99±76.94 90.95±75.29 0.776 MEDICINE FOR SIDE EFFECT
92.86±12.96 75.6±0.00 0.172
Cost was calculated in different categories in each group, namely
medicine cost (further subdivided into primary, adjunctive and
medicine for side effect), lab cost, travel cost and finally the total cost.
In olanzapine group patients had to spend a mean of Rs
275.10±28.051 on lithium and in risperidone group mean Rs
274.05±30.058 for lithium. The p value was 0.872 which is
statistically not significant. The mean cost of olanzapine in
olanzapine group was Rs 402.15±188.302 (converted to
equivalent cost of risperidone) and in risperidone group the mean
cost of risperidone was Rs 247.380±85.387. The p value was
0.001 which shows that there is significant difference in the money
spent on antipsychotic in olanzapine group.
Results
The mean cost of lorazepam in olanzapine group was Rs
78.795±59.2025 and Rs 100.251±62.7296 in risperidone group.
The p value was 0.122 which was insignificant statistically.
The mean cost of haloperidol in olanzapine group was Rs
99±76.94 and in risperidone group was Rs 90.95±75.29. The p
value was 0.776 which is statistically insignificant.
In olanzapine group mean lab costs were Rs 1012.52±150.22 and
in risperidone group the mean lab cost was Rs 1027.50±151.72.
The p value was 0.659 which is not statistically significant.
The mean travelling cost in olanzapine group was Rs
1460±1120.92 and in risperidone group was Rs 1240.75±891.030.
The p value was 0.338 which is not statistically significant.
Overall the mean of total cost in olanzapine group was Rs
6251.57±2531.44 and in risperidone group was Rs
5862.27±2334.86. The p value was o.477 which is not statistically
significant.
Group 1 Group 2
TOTAL COST 6251.57 5862.27
5600
5700
5800
5900
6000
6100
6200
6300
Axis Title
TOTAL COST(NPR)
Results
Table 6
Caterogy
Group 1(olanzapine converted to equivalent
dose of risperidone)
Group 2 P
value
n
n 0.748
Dose of Medicine(Mg)
Lithium 982.5±100.19 975±107.41
Olan/ris 5.97±2.39 3.7±0.88 0.000
Lorazepam 43.775±32.89 55.92±35.16 0.117
Haloperidol 27.50±21.37 25.26±20.91 0.776
In olanzapine group the mean dose of lithium required was
982.5±100.19 mg and in risperidone group mean dose was
975±107.41 mg .The p value was 0.748 which is statistically not
significant.The mean dose of olanzapine in olanzapine group was
5.97±2.39 mg (converted to equivalent dose of risperidone) and
mean dose of risperidone in risperidone group was 3.7±0.88 mg.
The p value was 0.001 which shows that there is significant
difference in the dose of antipsychotic required in olanzapine
group.
The mean dose of lorazepam in olanzapine group was
43.775±32.89 mg and 55.92±35.16 mg in risperidone group. The
p value was 0.117 which was insignificant statistically.
The mean dose of haloperidol in olanzapine group was
27.50±21.37 mg and in risperidone group was 25.26±20.91 mg.
The p value was 0.776 which is statistically insignificant.
DISCUSSION
Discussion
DISCUSSION:
Bipolar disorder is a chronic, recurrent mood disorder that is
associated with significant morbidity, functional impairment, and a
high rate of suicide (Angst and Sellaro, 2000)32.
Bipolar disorder is now recognised as a potentially treatable
psychiatric illness with substantial morbidity and mortality and high
social and economic impact 33. There is no cure, and every aspect
of its definition, mechanisms and treatment is subject to debate.
The lifetime prevalence of bipolar disorders is estimated at 1–4%
of the general population34 .
Though there is no officially published data on the prevalence of
this illness in Nepal, the number of patients brought with this
illness to the psychiatric services of this tertiary level teaching
hospital is increasing over the years(source:ward registers) .
Therapies address the control of acute episodes (manic,
depressed or mixed), and maintenance of remission of symptoms.
Drug treatments have included lithium, anticonvulsants, and
antipsychotics, but current therapies have proven inadequate for
many patients; only half of bipolar patients achieve remission over
two years, and half of these relapse within the two years 35. Issues
in drug treatment involve not only efficacy, but also tolerability.
Adverse events, including extrapyramidal symptoms and weight
gain, can be significant and influence adherence.
Discussion
The current trend is to use the combination of a mood stabilizer
with an antipsychotic for the treatment of acute phase of mania.
The first-line pharmacological treatment for patients with severe
mania is the initiation of either lithium plus an antipsychotic or
valproate plus an antipsychotic.(APA guidelines 2002)
The introduction of antipsychotic drugs in the 1950s heralded the
"golden age" of psychopharmacology. However, almost a half
century of experience has revealed their substantial limitations.
The advent of atypical antipsychotic drugs, with their potential for
enhanced efficacy and safety, has changed the risk/benefit profile
of this drug class. Although they were first developed for
schizophrenia, antipsychotic drugs are now broadly used for other
disorders, including behavioral signs and symptoms associated
with bipolar disorders, Alzheimer's disease and other dementias.
Despite their widespread use in these conditions, the overall
effectiveness and safety of these drugs remain unclear.
Short-term (mostly 3-week), randomized controlled trials (RCTs)
have established that atypical antipsychotics, such as olanzapine
and risperidone, are effective in the treatment of acute mania in
bipolar disorder when administered as monotherapy (Tohen et al.,
1999, 2000; Hirschfeld et al., 2004) or in combination with mood
stabilizers (Sachs et al., 2002; ). However, there have been few
head-to-head studies of olanzapine versus risperidone, or
comparisons of their effectiveness in clinical practice settings.
Moreover all the studies have been done in a western settings
,the results of which might not be applicable in a culturally and
Discussion
climatically different setting of ours. Keeping this in mind this study
was conducted .
The present study attempted to fill this gap (as there has been no
similar study in this country) .Although its findings are limited
because of non randomization, non blind nature and the small
number of patients derived from one particular teaching hospital
psychiatric unit in eastern nepal. Nevertheless, certain trends
regarding the usage of antipsychotics among patients with bipolar
disorder were discernible in this study.
In our setting trend is to use lithium with olanzapine for the
treatment of acute phase mania . There is an ample of literature
support for weight gain, diabetes mellitus leading to lifelong
physical comorbidity associated with olanzapine. Above all the
cost of olanzapine is almost twice that of olanzapine.
pharmacodynamically also they share different profiles with
risperidone having an earlier onset of action.
In our study Patients presenting to BPKIHS psychiatric
services(OPD, ward and emergency) with a diagnosis of manic
episode of BPAD were recruited and allocated medications
alternately with olanzapine and risperidone with all patients
receiving lithium. Datas were compiled at o week, 3 weeks ±3days
and 6 weeks ±7days. Primary and secondary outcome measures
were derived from baseline to endpoint at 6 week from SPSS
software. Descriptive statistics in terms of percentage were used
for categorical variables; Mean and SD were calculated for the
continuous variables. Group comparisons were done using
independent t-test for continuous variables and chi-square/Fisher
Discussion
exact test for categorical variables. Altogether 96 patients were
enrolled in the study ,among which full data was available for 80
patients, remaining 16 were not included because 9 of them didn’t
come for follow up, and the rest 7 who did come ,couldn’t show up
on the defined time frame of follow up visits.
Major findings of this study are:
Statistically significant difference in the
1. Mean Dose of Antipsychotic.
2. Mean Cost of of Antipsychotic.
3. Mean Weight Gain.
4. Mean change in BMI.
5. Sex distribution between the two groups.
6. Mean change in RBS in the olanzapine group between baseline
and 6weeks.
SOCIODEMOGRAPHIC PROFILE:
The mean age of patients in olanzapine group is 29.3±9.8 years
and in risperidone group I s 28.65±9.3 yrs. The p value is 0.764
which is not statistically significant. In one of the studies done in
india by Bharadwaj et al 37 the mean age of the patients was 36.2
(SD 14.08) years. The mean age of patients with affective disorder
in a study done by chakraworty et al 38 was 35.72 (SD 7.37) years.
The mean age of patients in a study done by Tohen M 29in 2000
was 39 years. In a study done by Morgan et al 39 (2005) the mean
Discussion
age at interview for men was 42 and for women 43. As compared
to other studies the mean age of patients in our study was
lesser(29 yrs).Patients in our study were relatively younger. Age
can be a factor for improvement, as younger patients have better
treatment response.
The sex distribution is 13(32.5%) males and 27(67.5%) females
in olanzapine group, with 25( 62.5%)males and 15(37.5%) females
in risperidone group, with p value of 0.007, which is statistically
significant. overall out of 80 patients enrolled in the study
38(47.5%) are males and rest 42(52.5%) are females. In a study
done by chakraworty et al males constituted the majority (about
62% in the affective disorder group). Approximately one half of the
bipolar sample was male (52.7%) in the study done by Morgan et
al. The census of Nepal revealed that the sex ratio i.e. males per
100 females was 99.8. In other words 49.95 percent of the total
population was male, while the females comprised 50.05 percent
of the population.In our study also the percentage of female
patients was higher as compared to the male patients which is
comparable to the higher female to male ratio of this country.
The mean age of bipolar 1 disorder is 30 years 40.There is an
equal prevalence of bipolar 1 disorder among males and females.
Manic episodes are more common in males and depressive
episodes more common in females .40
Income :In olanzapine group, 17(42.5%) of the patients earn less
than Rs 5000, 9 (22.5%)patients earn between Rs 5000-10000
and only 1(2.5%) patient has an income of >Rs 10000. Whereas
19(47.5%) patients earn <Rs 5000, 5 (12.5%)patients have an
Discussion
income between Rs 5000-10000 and 8 (20%)patients earn >Rs
10000 in risperidone group. The p value is 0.048, which is not
statistically significant. The Economic Survey 2011(Nepal) shows
the average income of a Nepali has increased this year. It says
Nepal’s per capita income jumped to $645 (Rs 46,020-approx-Rs
3800 per month) this FY, up from $561 (Rs 40,027) in the last FY.
This report is consistent with the findings of majority of patients
earning less than 5000 per month in our study.
Occupationally, the olanzapine group consists of 13(32.5%)
housewives, 11(27.5%) students, 2 (5%)farmers, 3(7.5%)
professionals, 4 (10%) manual labourers, 3(7.5%) are unemployed
and 4 (10%) patients in others, whereas in risperidone group
there are 7(17.5%) housewives, 11(27.5%) student, 4 (10%)
farmers, 3(7.5%) professionals, 2(5%) manual labourers , 1(2.5%)
unemployed, 12(30%) others. The p value is 0.228, which is not
statistically significant. Overall 4 patients (5%) were unemployed
,20(25%) were housewives ,22 students(27.5%), 6 (7.5%)were in
farming, 6(7.5%) in manual labour job ,6(7.5%) professionals. In a
study done by Morgan et al , 67.0% were unemployed at the time
of the interview . Compared with women, men were more likely to
be unemployed. One quarter (24.2%) were in professional or semi-
professional occupations, 46.3% were labourers or in elementary
clerical positions. In the Indian study done by chakraworty et al
about two thirds of the patients in affective group were employed
and were earning members of the family.
The literacy rate is as follows: In olanzapine group the mean
number of academic years spent by a patient is 7.92±5.3 yrs. In
Discussion
risperidone group the value is 9.05±4.6 yrs. The p value is 0.32,
which is not statistically significant. Overall 13(16.25%) patients
are illiterates . Altogether 8.48 is the mean number of academic
years spent by patients enrolled in this study. The percentage
without formal secondary school qualifications is 30.4% and is
similar for both men and women. In the study done by Bharadwaj
et al in India, mean number of completed academic years was
10.9±4.61 yrs. Most patients had less than 10 years of formal
education (73% in the affective disorder group) in the study done
by chakraworty et al in India. The census of 2001 has
indicated that currently the literacy rate among the population of 6
years or older in Nepal is 54 percent with male literacy rate of 65
and female literacy rate of 43. However in the census the details of
mean academic years completed by the population has not been
mentioned.
Marital status :In olanzapine group 27(67.5%) patients are
married , whereas 11(27.5%) are unmarried and 2(5%) separated.
In risperidone group , 28(70%) patients are married , 10(25%)
unmarried and 2(5%) separated. The p value is 0.968, which is not
statistically significant. In total 55(68.75%) were married. In the
study done by Chakraworty et al 81% patients were married. In a
study done by Morgan(Australia) et al just over one half of the men
and one-quarter of the women were single and had never been in
a long-term conjugal relationship. Bipolar disorder is more
common in divorced and single persons than among married
persons 40.
Discussion
Geographical distribution :In olanzapine group, 28 (70%)
patients reside in terai region, 12(30%) reside in mountains/
valleys. In risperidone group 34(85%) patients are from terai and
6(15%) belong to mountain/valley.The p value is 0.090 which is not
statistically significant. Nepal has three distinct ecological regions.
These are mountains, which are defined as area that lies between
the altitude of 4877 and 8848 meters comprise 35 percent of land
area, while hills are defined as area that lies between the altitude
from 610 to 4876 meters and comprises 42 percent of land area.
Altogether mountains and hilly regions comprise about about 52
percent of the total population in 2001. The Terai region lies below
the elevation of 610 meters. It contains nearly 48 percent of the
population. Most of the patients in our study belong to the terai
region.
Domicile : In our study we defined urban areas as those which
has been designated Nagarpalika/Mahanagarpalika, suburban as
those areas adjacent(within 10-15kms) from the National
highway/VDC and remote areas as the one which is atleast 24hrs
walk from the nearest national highway. In olanzapine group,
8(20%) patients belong to urban areas, 24(60%) belong to
suburban area, 8(20%) belong to remote area. In risperidone
group, 13(32.5%) patients are from urban area, 24(60%) from
suburban area, and 3(7.5%) from remote area. The p value is
0.177, which is not significant statistically. Altogether 21(26.25%)
patients belonged to urban area in this study. 70% of patients were
from an urban background in the study done by Chakraworty et al
in India. As per the Nepal census, the proportion living in
designated urban areas was 13.9 percent. As compared to both
Discussion
the datas from national census and the study from India
comparatively lesser patients were from urban area and more
were from suburban area in our study.
Overall in our study there is no significant difference in the two
groups with regards to Age , Religion, Income, Occupation, literacy
rates, Marital status, Geographical distribution, Domicile, which
matches with the findings of most of the international studies and
studies of southeast asia(India, Bhutan). However significant
difference in the sex distribution among the groups is found in our
study ,probably the reason for which can be non randomization of
the study participants and sociodemographic variables are not
matched before the study was conducted.
In both of the Indian studies(Bharadwaj et al, Chakraworty et al),
there was no significant difference between the groups under
study with regard to number of years of education, gender,
religion, and place of residence.
Even with the western studies no statistically significant differences
appeared in the demographic variables analyzed, such as marital
status, employment situation or sex or with the clinical variables,
such as age at onset, duration of illness, or number of admissions.
(Tohen M et al, Pillar Sierra, 2005,QOL in BPAD). Probably the
reason for this could be sociodemographic variables were already
matched before the studies were conducted so that a homogenous
sample of patients could be recruited to eliminate possible
confounding factors and avoid bias.
CLINICAL PROFILE:
Discussion
In olanzapine group, 13(32.5%) patients are diagnosed as BPAD
without PS, and 27(67.5%) patients are diagnosed as BPAD with
PS. In risperidone group, 9(22.5%) patients are diagnosed as
BPAD without PS whereas 31(77.5%) patients are diagnosed as
BPAD with PS. The p value is 0.227 which is not statistically
significant. Overall 57 patients met the criteria for BPAD Mania
with PS(delusion of grandiosity), and the rest 23 met the diagnosis
of BPAD Mania without PS. In the study done by Bharadwaj et al
40.3% patients met the criteria for BPAD with PS and 4.5% met
the criteria for BPAD without PS. In the study done by Chakraworty
et al 24 bipolar disorder-mania had psychotic symptoms(delusion
of grandiosity). In the study done by Morgan et al 47.6% patients
had psychotic symptoms(delusion of grandiosity) and only a
minority of bipolar patients (20.5%) had experienced hallucinations
in any modality, reported ever having had delusions, but in the
majority (59.0%) these were of short duration (<1 week). The most
frequent themes of delusions were grandiose (60.7%).In a study
done by Tohen M in 2000 ,55.7% were experiencing psychotic
symptoms.
No psychiatric comorbidity was seen in either of the groups.
Possibly the reason for this could be that assessment for ruling out
psychiatric comorbidity may not be adequate / or thorough. We
didn’t use any structured schedule/rating scale for this purpose.
We used brief interview/screening questions for other psychiatric
disorders. The most frequent co-morbid psychiatric disorders in
mood disorders are panic disorder, obsessive compulsive disorder,
and social anxiety disorders. The epidemiological catchment area
study showed the lifetime history of panic disorders(21%) and
Discussion
ocd(21%) was twice as high among patients with bipolar 1 disorder
than in patients with unipolar major depression40.
In olanzapine group, 15(37.5%) patients have a positive family
history of Bipolar illness. In risperidone group 16(40%) patients
have a positive family history. The p value is 0.5 which is not
statistically significant. Altogether 31(38.74%) had a positive family
history of bipolar disorder. As many as 38.4% reported a family
history of a psychiatric disorder other than schizophrenia (32.2% of
men and 45.3% of women). However, 14.3% reported a family
history of schizophrenia, with little difference in the percentages for
men and women in the study done by Morgan et al.
In olanzapine group, 4(10%) patients have a positive family
history of medical illness(Dyslipidemia, DM, HTN). In risperidone
group, 9(22.5%)) patients have a positive family history of medical
illness. The p value is 0.112 which is not statistically significant.
Substance use :In olanzapine group, 6(15%) patients are
diagnosed as having nicotine use, whereas 34(85%) patients are
diagnosed as having harmful use of nicotine. In risperidone group,
16(40%)patients are in nicotine use and 24(60%)patients are in
harmful use of nicotine. The p value is 0.011, which is
statistically significant. Overall 100% patients were found to be
using nicotine out of which 60% were using nicotine in the form of
smoking cigarettes and the rest 40% chewing tobacco . In our
study we excluded the patients with psychoactive substance use in
harmful use or dependence pattern(as per ICD-10) the reason
being :In patients with psychoactive substance use it would be
difficult to definitely rule out whether patients bipolarity is induced
Discussion
,or precipitated or independent. In the study done by Morgan et al
cigarette smoking was Prevalent: 61.0% of men and 54.7% of
women were current smokers and the average number of
cigarettes smoked per day was 26 for men and 29 for women. One
in three (32.1%) had a lifetime diagnosis of any substance or
alcohol abuse or dependence, 28.8% a lifetime diagnosis of
cannabis abuse/dependence and 11.9% a lifetime diagnosis of
other substance abuse/dependence. The most frequent substance
use disorder is alcohol harmful use or dependence. The lifetime
history of substance use disorders was found to be 61% with
bipolar 1 disorders as compared to unipolar major depression
(epidemiologic catchment area study) 40.
In olanzapine group, 9(22.5%) patients have some type of
physical comorbidity ,out of which 75% have chronic suppurative
otitis media ,migraine headache in 5% patients, candidal intertrigo
in 15% , and menstrual irregularities in the rest 5%. In risperidone
group, 9(22.5%) have physical comorbidity ,mostly again in the
form of CSOM(85%) and candidal intertrigo in the remaining 15%.
The p value is 0.605 which is not statistically significant. Altogether
18(22.5%) patients had some form of physical comorbidity and the
most commom among the groups was chronic suppurative otitis
media.In the study done by Bharadwaj et al one-fourth of the
patients with mania (23%) had a comorbid medical illness.
The mode of onset Is abrupt in 22(55%) patients, acute in
18(45%) patients in olanzapine group. In risperidone group,
20(50%) patients had abrupt onset of symptoms and remaining
20(50%) had acute onset of symptoms. The p value is 0.412 which
Discussion
is not statistically significant. In the study done by Morgan et al the
mode of onset was variable. In 25.0% of cases, onset was abrupt
or acute, occurring within the course of a week; in 24.1%, it was
moderately acute, occurring over the course of a month; in 25.9%,
it was gradual over 6 months; and in 25.0% of cases, it took place
insidiously over more than 6 months.
Admission :29(72.5%) patients required admission to the
psychiatry ward among patients in olanzapine group whereas
31(77.5%) required admission in the risperidone group. The p
value is 0.398 which is not statistically significant. Overall 75%
patients required admission .
The mean duration of stay in ward for patients in olanzapine
group is 22.07±5.216 days. In risperidone group the mean days
of admission is 21.84±7.823 days. The p value is 0.895 which is
not statistically significant. On average duration of ward stay for
patients is 21.5 days among all the patients recruited(n=80).
The mean duration of manic episode in patients among
olanzapine group is 22.45±23.216 days whereas in risperidone
group it is 29.85±46.95 days. The p value is 0.374 which is not
statistically significant. Among all the patients(n=80),on an average
the mean duration of presenting episode is 26.15 days. In the
study done by Bharadwaj et al the mean duration of hospital stay
was 65.6 days (SD=40.39) for patients with mania which is
significantly higher than the findings of our study.
Specific variables (outcome measures):
Discussion
Mean dose: In olanzapine group the mean dose of lithium
required is 982.5±100.19 mg and in risperidone group mean dose
is 975±107.41 mg .Th p value is 0.748 which is statistically not
significant. Masand et al reported patients in their olanzapine
group received significantly higher daily dose of concomitant
lithium(1211±186mg) whereas patients in risperidone group
required 750±150mg of lithium. The mean dose of olanzapine in
olanzapine group is 15.19±5.83(5.97±2.39 mg -converted to
equivalent dose of risperidone) and mean dose of risperidone in
risperidone group is 3.7±0.88 mg. The p value is 0.001 which
shows that there is significant difference in the dose of
antipsychotic required in olanzapine group. In a study done by
Masand et al the mean dose of olanzapine was 11.9±5.9mg and
that of risperidone was 3.5±3.6mg. In a study by Tohen et al 2003
mean dose of olanzapine was 9.7mg. Shelton et al reported the
mean requirement of dose of risperidone to be 2.15mg in his study
participants. In the emblem study mean modal dose of olanzapine
was 19.5±8.8mg and that of risperidone was 5.7±3.4mg.
The mean dose of lorazepam in olanzapine group is
43.775±32.89 mg and 55.92±35.16 mg in risperidone group. Our
study reveals an increased requirement of sedative in the
risperidone group as compared to the olanzapine group but the p
value is not statistically significant(p=0.117). In the emblem study
Use of benzodiazepine was frequently reported in both the groups
and was not significantly different (80.8% in olanzapine-treated
patients and 69.4% in risperidone-treated patients). Anticholinergic
use was reported significantly more frequently in the risperidone
Discussion
group than in the olanzapine group (13.9 vs. 3.4%, respectively,
P=0.019).
The mean dose of haloperidol in olanzapine group is
27.50±21.37 mg and in risperidone group is 25.26±20.91 mg. Our
study revealed slightly less requirement of the cumulative dose of
haloperidol in the risperidone group ,though the difference is not
statistically significant(p=0.776).
Cost is calculated in different categories in each group, namely
medicine cost(further subdivided into primary, adjunctive and
medicine for side effect), lab cost, travel cost and finally the total
cost.
In olanzapine group patients spent a mean of Rs 275.10±28.051
on lithium and in risperidone group mean Rs 274.05±30.058 for
lithium. The p value is 0.872 which is statistically not significant.
The mean cost of olanzapine in olanzapine group is Rs
402.15±188.302 (converted to equivalent cost of risperidone) and
in risperidone group the mean cost of risperidone is Rs
247.380±85.387. The p value is 0.001 which shows that there is
significant difference in the money spent on antipsychotic in
olanzapine group. Based on Masand et al study the whole sale
price of daily cost of risperidone was $5.81(Rs 20497.68 over a
period of 6 weeks and for olanzapine it was $11.84(Rs 41771.52
for 6 weeks).
The mean cost of lorazepam in olanzapine group is Rs
78.795±59.2025 and Rs 100.251±62.7296 in risperidone group.
The p value Is 0.122 which Is insignificant statistically.
Discussion
The mean cost of haloperidol in olanzapine group is Rs
99±76.94 and in risperidone group is Rs 90.95±75.29. The p value
is 0.776 which is statistically insignificant.
In olanzapine group mean lab costs are Rs 1012.52±150.22 and
in risperidone group the mean lab cost are Rs 1027.50±151.72.
The p value is 0.659 which is not statistically significant.
Laboratory investigations included complete blood count,
electrolytes, random blood sugar, serum creatinine, and serum
lithium.(serum lithium could be done for 36 patients only
depending on the affordability of the patients).
The mean travelling cost in olanzapine group is Rs
1460±1120.92 and in risperidone group is Rs 1240.75±891.030.
The p value is 0.338 which is not statistically significant.
The mean ward cost in olanzapine group is Rs 3850(NPR) and
that in risperidone group is Rs 3675(NPR)
Overall the mean of total cost in olanzapine group is Rs
6251.57±2531.44 and in risperidone group is Rs
5862.27±2334.86. The p value is 0.477 which is not statistically
significant.
The mean YMRS score in the olanzapine group at the time of
first contact was 33.12±8.416. The mean score in risperidone
group was 32.55±7.317. The p value is 0.745 which is not
statistically significant.
Discussion
The mean YMRS score at 6 weeks in olanzapine group is
4.78±4.117 and in risperidone group is 4.6±3.657. The p value is
0.841 which is not statistically significant.
The mean decline in YMRS score between 0 week and 6
weeks in the olanzapine group is found to be 86.97%. The mean
decline in YMRS score between 0 week and 6 weeks in
risperidone group is 85.63%. The p value is 0.600 (not significant )
.The mean change in YMRS total score from baseline to week 6 is
not significantly different between the olanzapine and risperidone
groups ( – 23.45 vs. – 25.10, P=0.574).
Response is defined as 50% or greater reduction in YMRS total
score from baseline. Remission is defined as YMRS total score of
9 or less.
The response rate at 3 weeks is found to be 100%( data was
available for 67 patients). The response rate at 6 weeks is 100%.
There is no significant differences between treatment groups in the
rates of response or remission at 6 weeks. In the emblem study- A
total of 80.1% of the olanzapine-treated patients and 88.0% of the
risperidone-treated patients met the definition of response (Fisher
exact test, P=0.348). Similarly 56.9% of the olanzapine-treated
patients and 47.6% of the risperidone-treated patients met the
definition of remission (Fisher exact test, P=0.422). In studies
done by Ghaemi et al, Jacobson FM, Tohen M et al, Sajotovick et
al, the mean response rates in the risperidone group was 51% in
patients with schizoaffective or bipolar mania disorders with or
without psychotic symptoms. In a 3 week ,double blind, multicentre
RCT done by Sachs et al comparing risperidone with placebo or
Discussion
add on therapy with lithium or divalproex, in the acute
management of bipolar mania 57% patients showed response in
YMRS score.
Altogether 22 (27.5%) patients reached remission at 3 weeks, out
of which 12(54.54%) belongs to olanzapine group and the rest
10(45.45%) belongs to risperidone group.
The remission rate at 6 weeks in our study is as follows: Total
70(87.5%) patients reached remission at 6 weeks out of which
35(50%) patients belonged to olanzapine group and the rest
35(50%) belonged to risperidone group. In the Emblem study-
remission was achieved by about half the patients in both the
treatment groups (according to our definition of remission). The
remission rates in the 3-week RCT (Perlis et al., 2006b) were
38.5% for olanzapine and 28.5% for risperidone, but different
criteria were used to define remission and a high rate of remission
would not be expected within 3 weeks.
In our study the CGI-BP rating scale at first contact, among the
olanzapine group, 2(5%) patients are mildly ill, 13(32.5%) patients
are moderately ill, 13(32.5%) patients are markedly ill, 9(22.5%)
patients are severely ill, 3(7.5%) patients are very severely ill.
Among the risperidone group, 2(5%) patients are mildly ill,
11(27.5.5) patients are moderately ill, 14(35%) patients are
markedly ill, 12(30%) patients are severely ill, 1(2.5%) patient is
very severely ill. The p value is 0.803 which is statistically
insignificant. Masand et al reported that most patients(76.5%)
receiving risperidone and a mood stabilizer were rated much
improved or very much improved in CGI-BP ,compared with 57.4%
Discussion
of patients receiving placebo or mood stabilizer. In the emblem
study- there were no significant differences between the two
treatment groups in the changes in CGI-BP measures (mania,
depression, overall, overall in past year).
In our study at 6 weeks CGI-BP rating scale revealed 28(70%)
patients normal,not ill in olanzapine group. In the same group
minimally ill are 12(30%) patients. In risperidone group, 30(75%)
patients are normal,not ill. Whereas 10(25%) patients are
minimally ill. The p value is 0.401 which is statistically insignificant.
In a study done by Perlis et al in 2006 ,olanzapine-treated patients
had greater CGI-BP (p = .026) score improvement across the
study.
Weight gain in our study has been defined as any extent of
increase in weight from baseline.
The mean weight at baseline in the olanzapine group in our study
is 47.48±5.71kg, and that in risperidone group is
50.78±9.59kg.The p value is 0.066, which is not statistically
significant, which means that the baseline weight between the
groups are comparable. The mean BMI at first contact in
olanzapine group is 19.4661±2.555 and in risperidone group is
20.0468±3.521. The p value is 0.401 which is statistically
insignificant.
The mean weight at 6 weeks in olanzapine group in our study is
51.22±6.5kg and that in risperidone group is 53.25±9.33kg. The p
value is 0.267 which is insignificant statistically. The mean BMI at
6 weeks in olanzapine group is 20.9695±2.699 and in risperidone
Discussion
group is 21.0622±3.645 with a p value of 0.89 which is statistically
insignificant.
In a study done by Mayer JN in 2002, results revealed that patients
with concurrent use of lithium or valproate were associated with
greater weight gain in both drug groups, but this difference was
statistically significant only for the olanzapine cohort.
In a study done by Ghaemi et al in 2004 results revealed that
Weight gain occurred more frequently with olanzapine (57%) than
risperidone (13%). Risperidone and olanzapine appeared to have
similar real-world maintenance effectiveness for bipolar disorder,
but differed somewhat in side effects.
Perlis et al 2006 reported increase in weight (2.5 kg vs. 1.6 kg; p =
.004) in the olanzapine group more than the risperidone group.
The mean change in BMI in our study , within the olanzapine
group, between first contact and 6 weeks is 1.5 and test reveals a
p value of 0.001 which means the increment in BMI is significant
for subjects receiving olanzapine.
The mean change in BMI within risperidone group in our study
between first contact and 6 weeks is 1.02 and the test reveals a p
value of 0.001 which means that the increment in BMI is significant
for subjects receiving risperidone.
In the emblem study at baseline, mean weight was 70.4 kg
(SD=14.0) in the olanzapine group and 73.6 kg (SD=15.0) in the
risperidone group. The derived mean body mass index was 25.1
kg/m2 (SD=4.6) for the olanzapine group and 25.5 kg/m2 (SD=
Discussion
5.5) for the risperidone group. The differences in weight and body
mass index at baseline between treatment groups were not
significant. The weight gain from baseline to 6 weeks was similar
in the olanzapine and risperidone groups: mean 1.9 kg (SD=3.2)
versus 1.9 kg (SD= 4.3), respectively (P=0.633), as was the
proportion of patients with greater than 7% weight gain: 16.1
versus 25.0%, respectively (P=0.262). There was a similar weight
gain (1.9 kg, P=0.633) in the olanzapine and risperidone groups
over the 6-week period. In the 3-week RCT, Perlis et al. (2006b)
found that patients treated with olanzapine experienced
significantly greater weight gain than patients treated with
risperidone (2.46 vs. 1.60 kg, P=0.004).
The mean random blood sugar in our study at first contact in
the olanzapine group is 85.62±19.67 mg and in risperidone group
is 90.65±24.19 mg with a p value of 0.311 which is statistically
insignificant.
The mean random blood sugar at 6 weeks in olanzapine group
is 95±20.454 mg and in risperidone group is 95.10±16.584 mg
with a p value of 0.981 which is statistically insignificant.
The mean change in RBS within olanzapine group between
first contact and 6 weeks is 9.38 mg and test reveals a p value of
0.002 which means the increment in RBS is significant for subjects
receiving olanzapine.
The mean change in RBS within the risperidone group
between first contact and 6 weeks is 4.45 mg and test reveals a p
Discussion
value of 0.194 which means the increment in RBS is not significant
for subjects receiving risperidone.
In a study done by Mayer JM in 2002 findings suggested that
among the olanzapine patients (N = 37) experienced the mean
glucose level increased by +10.8 mg/dL versus +0.74 mg/dL
(risperidone) (p = .030).
In the side effect profile ,Among patients receiving olanzapine,
16(20%) had weight gain only, 2(2.5%) patients had weight gain
+EPS+sedation, 7(8.8%) patients had only sedation , 1(1.2%)
patient had both weight gain and EPS, 10(12.5%) patients had
weight gain +sedation, 4 (5%) patients had no side effects. Among
patients receiving risperidone, 8(10%) patients had weight gain,
2(2.5%) patients had EPS, 2(2.5%) patients had both weight gain
and EPS, 5(6.2%) patients had sedation, 18(22.5%) patients had
weight gain+sedation, 5(6.2%) patients had no side effect. The p
value was 0.136 which is statistically insignificant when compared
between the groups. Overall 85% patients had weight gain and
8.75% patients had EPS.
Within the group comparison of weight gain between 0wks
and 6 wks in olanzapine group revealed a mean increase in
weight by 3.74 kg with a p value of 0.001, which means that
increment in weight is statistically significant in olanzapine group.
The mean increase in weight in risperidone group is 2.47 kg, with
a p value of 0.001 which again shows that the increment in weight
is significant in risperidone group.
Discussion
In the study conducted by Ghaemi et al EPS was similar, and
tardive dyskinesia did not occur in both olanzapine and risperidone
group. In the emblem study the treatment-emergent events
observed in the olanzapine and risperidone groups between
baseline and week 6, there were no significant differences
between groups. The most commonly reported events in both
groups were sedation and memory loss/concentration difficulties.
Parkinsonism was higher in the risperidone group (22.6%) than in
the olanzapine group (8.9%), but the difference did not reach
statistical significance (P=0.054).
SUMMARY AND CONCLUSION
Conclusion and Summary
SUMMARY AND CONCLUSION
The major findings of this study are
Statistically significant difference in the
1. Mean Dose of Antipsychotic.
2. Mean Cost of of Antipsychotic.
3. Mean Weight Gain.
4. Mean change in BMI.
5. Sex distribution between the two groups.
6. Mean change in RBS in the olanzapine group between baseline
and 6weeks.
There is no significant difference in efficacy and effectiveness in
the two groups, however there is significant difference:
In the mean dose of the antipsychotic i.e. as compared to
olanzapine patients required lesser doses of risperidone to achieve
the desired symptom control. And hence forth the amount of
money spent was also less in the risperidone group(partly because
of the less dose requirements and partly because of cheaper price
of risperidone as compared to olanzapine.
In both the groups weight gain occured but mean weight gain in
olanzapine group was more than in the risperidone group and
hence the mean change in BMI between the groups was also
Conclusion and Summary
significantly different i.e., BMI increased more in the olanzapine
group.
The mean change in random blood sugar between the groups
revealed more increment in the olanzapine group.
Because of these differences we consider olanzapine and
risperidone treatment have similar (equally efficacious and safe
)improvements in manic symptoms in the treatment of acute
phase of mania in bipolar affective disorder ,however there is
difference in the dose requirements, cost effectiveness, side effect
profile (showing the superiority of risperidone in these regards)
which is similar to the findings of similar western studies done in
the recent years. Risperidone represents an opportunity for helping
patients with bipolar disorder and keeping them in long-term
remission when used as monotherapy or in combination with mood
stabilisers.
These findings must be interpreted conservatively given the non
random and non blind nature of the study.
The findings of this study cannot be generalized to the whole
population of this country.
The limitations of this study are:
Small sample size.
Sociodemographic profiles were not matched prior to the study.
Non randomization of the population of patients enrolled.
Non blind nature of the study.
Conclusion and Summary
During the study period follow ups have not been strictly
possible on allotted dates.
Possibility of errors while applying the rating scales.(rater’s bias,
interrater variability )
Depression has not been considered .
Mixed ,rapid cycling or hypomaic subtypes have not been
considered.
In the side effect profile CVS/GI/Hematologic changes have not
been considered.
Factors such as the total duration of illness, number and nature
of previous episodes, type of treatment received for previous
episodes, characteristics of the first episode, time elapsed since
last episode, suicidality have not been considered.
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