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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