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THE ASSOCIATION BETWEEN VERBAL WORKING MEMORY, VISUAL SPATIAL WORKING MEMORY AND

EXECUTIVE FUNCTIONING WITH FUNCTIONAL OUTCOMES IN PATIENTS WITH SCHIZOPHRENIA

DR. SASITHARAN S/O MOORTHI

DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF PSYCHOLOGICAL MEDICINE

DEPARTMENT OF PSYCHOLOGICAL MEDICINE FACULTY OF MEDICINE

UNIVERSITY OF MALAYA KUALA LUMPUR

2017

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This is to certify that the thesis titled ' The Association Between Verbal Working Memory, Visual Spatial Working Memory and Executive

Functioning With Functional Outcomes In Patients With Schizophrenia was done by DR. SASITHARAN MOORTHI

and to the best of my knowledge, this thesis is entirely his original work.

Sign;

ASSOCIATE PROFESSOR DR. JESJEET SINGH GILL S/O JESWANT SINGH

CONSULTANT PSYCHIATRIST,

DEPARTMENT OF PSYCHOLOGICAL MEDICINE, UNIVERSITY OF MALAYA

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This is to certify that the thesis titled ' The Association Between Verbal Working Memory, Visual Spatial Working Memory and Executive

Functioning With Functional Outcomes In Patients With Schizophrenia was done by DR. SASITHARAN MOORTHI

and to the best of my knowledge, this thesis is entirely his original work.

Sign;

PROFESOR DR. AHMAD HATIM BIN SULAIMAN

CONSULTANT PSYCHIATRIST,

DEPARTMENT OF PSYCHOLOGICAL MEDICINE, UNIVERSITY OF MALAYA

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ABSTRACT

THE ASSOCIATION BETWEEN VERBAL WORKING MEMORY, VISUAL SPATIAL WORKING MEMORY AND EXECUTIVE FUNCTIONING WITH

FUNCTIONAL OUTCOMES IN PATIENTS WITH SCHIZOPHRENIA

Introduction:

Cognitive impairment in schizophrenia patients has been identified from the early description of the illness. Cognition plays an important role in recovery process of schizophrenia. Recovery has been the vision of treatment outcome in schizophrenia patients in this current era. Functionality among schizophrenia has been a major factor and determinant of recovery and success of rehabilitation programmes. The association between cognition and functionality is being actively studied globally. However, the connection between cognition and functionality is still very new and not explored in Malaysia.

Objectives:

This study is aimed at studying the association of Verbal Working Memory, Visual Spatial Working Memory and Executive Functioning with functionality among stable patients with schizophrenia as well as socio-demographic factors associated with cognitive impairment and functionality.

Methods:

Outpatients with well-established diagnosis of schizophrenia are recruited from outpatient clinic of Hospital Bahagia Ulu Kinta, Perak. Socio-demographic data are obtained. The Verbal Working Memory will be assessed using Digit Span test

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from WAIS IV, Visual Spatial working Memory will be assesed using Letter Number Sequencing from WAIS IV and Executive Functioning will be assessed using the MCCB Maze subtest. The functionality will be assessed using the WHO DAS 2.0 scale.

Results:

Total of 134 stable patients with schizophrenia was recruited for this study.

Participants in this study generally performed poorly in all the three cognitive test based on published studies and data elsewhere. The mean score for digit span test was 5.28, for letter number sequencing was 4.37 and the mean score for MCCB Maze subtest was 3.93. The mean percentage of disability in domain 1 of WHO DAS was 54.74, domain 3 was 12.86, domain 4 was 41.22, domain 5 was 69.66 and domain 6 was 54.16. The overall percentage of disability based on WHO DAS scale was 38.77.

The level of education plays an independent factor in predicting a good performance in verbal working memory and visual spatial working memory. Age is an independent factor in prediction of a good performance in executive functioning.

Severity of negative symptoms, cognitive symptoms and overall severity of illness affects the cognitive performance and functionality among schizophrenia patients.

Conclusion:

Verbal Working Memory, Visual Spatial Working Memory and Executive Functioning are associated with functionality among stable patients with schizophrenia. Cognitive enhancement should be considered in tailoring treatment and rehabilitation programmes for schizophrenia patients.

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ABSTRAK

FAKTOR HUBUNGKAIT DIANTARA FUNGSI KOGNITIF MEMORI KERJA LISAN, MEMORI VISUAL RUANG DAN FUNGSI EKSEKUTIF DENGAN FUNGSI HARIAN DIKALANGAN PESAKIT SKIZOFRENIA.

Pengenalan:

Kemerosotan fungsi kognitif di kalangan pesakit skizofrenia telah di kenalpasti dari mula lagi. Kognitif memainkan perana yang penting dalam proses pemulihan daripada penyakit skizofrenia. Pemulihan penuh daripada penyakit skizofrenia telah menjadi visi and objektif dalam proses perubatan penyakit ini di masa kini. Fungsi harian telah menjadi faktor utama dalam menentukan proses pemulihan dan kerberjayaan perubatan penyakit skizofrenia. Faktor hubungkait diantara fungsi kognitif dan fungsi harian telah menjadi topik kajian pada masa kini di seluruh dunia. Walaubagaimanapun, faktor hubungkait ini masih belum lagi popular di Malaysia.

Objektif:

Kajian ini adalah bertujuan untuk mengkaji faktor hubungkait diantara Fungsi Kognitif Memori Kerja Lisan, Memori Visual Ruang Dan Fungsi Eksekutif dengan fungsi harian dikalangan Pesakit Skizofrenia. Faktor-faktor socio-demografi yang berhubungkait juga akan dikaji.

Kaedah:

Pesakit luar dengan diagnosis skizofrenia di pilih di kalangan pesakit luar di Hospital Bahagia Ulu Kinta. Maklumat mengenai faktor sosio-demografi diperolehi.

Fungsi kognitif diuji dengan 'Digit Span', 'Letter Number Sequencing' dan 'Maze'.

Fungsi harian diuji dengan WHO DAS 2.0.

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Keputusan:

Seramai 134 pesakit mengambil bahagian di dalam kajian ini. Kesemua peserta mendapat skor yang rendah dalam kesemua ujian kognitif. Skor purata untuk ujian 'digit span' adalah 5.28, untuk ujian 'letter number sequencing' adalah 4.37 dan untuk ujian 'maze' adalah 3.93. Purata peratus ketidakupayaan bahagian 1 WHO DAS adalah 54.74, untuk bahagian 3 adalah 12.86, bahagian 4 adalah 41.22, bahagian 5 69.66 dan bahagian 6 adalah 54.16. Purata peratus ketidakupayaan secara keseluruhan adalah 38.77. Tahap pendidikan menjadi faktor penentu dalam menentukan tahap fungsi kognitif memori kerja lisan dan memori kerja visual ruang.

Umur pula menjadi faktor penentu dalam menentukan fungsi eksekutif. Keterukan simptom negatif, simptoms kognitif dan keterukan klinikal keseluruhan mempengaruhi fungsi kognitif dan fungsi harian.

Kesimpulan:

Fungsi kognitif memori kerja lisan, memori kerja visual ruang dan fungsi eksekutif adalah saling berhubungkait diantara fungsi harian di kalangan pesakit skizofrenia yang stabil. Peningkatan fungsi kognitif perlu diambil kira semasa perawatan dan rehabilitasi pesakit dengan penyakit skizofrenia.

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ACKNOWLEDGEMENTS

All praise to the all mighty for granting me the energy and courage to continue and complete this thesis dissertation. My utmost and highest appreciation to Associate Professor Dr. Jesjeet Singh Gill and Professor Dr. Ahmad Hatim bin Sulaiman, my thesis supervisors for their continuous guidance and support until the completion of this thesis.

Millions of thanks to Associate Professor Dr. Ng Chong Guan for his guidance with statistical analysis in this project. I would like to extend my gratitude to Dr.

Kavitha from CRC Hospital Raja Permaisuri and clinical psychologist Miss Tunku Saara for all the cooperation and help she provided. Special thanks to Dr. Ong Lieh Yen and Dr. Lee Wen Jih as always being there as a friend and mentor for me at all times. My sincerest gratitude to my wife, my parents and my siblings, without whom I would not be who I am now, for their unconditional love and support since I began my journey in this Masters program. I would like to thank all my professors and lecturers in Department of Psychological Medicine and all the specialists and consultants of Hospital Bahagia Ulu Kinta for their non-stop support, whom guided me without any hesitations. Thanks to all my colleagues and friends in University Malaya for all their cooperation in making this dissertation a success.

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TABLE OF CONTENTS

1.0 INTRODUCTION 1

1.1 Epidemiology 3

2.0 LITERATURE REVIEW 7

2.1 Cognitive Overview 7

2.2 Cognitive Impairment in Schizophrenia 8

2.3 Functionality in Schizophrenia 11

2.4 Cognition and Functionality 12

2.5 Working Memory and Executive Functioning 15

3.0 AIMS AND OBJECTIVES 18

3.1 Aims 18

3.2 Objectives 18

3.3 Rationale of the Study 19

4.0 METHODOLOGY 20

4.1 Study Setting 20

4.2 Study Design and Sampling 20

4.2.1 Inclusion Criteria 21

4.2.2 Exclusion Criteria 21

4.3 Sample Size Calculation 22

4.4 Study Procedure 24

4.5 Instruments 23

4.5.1 Demographic Data Questionnaires 24

4.5.2 MINI International Neuropsychiatric Inventory (M.I.N.I) 25

4.5.4 Cognitive Assesment Tools 27

4.5.5 Functional Variables 29

4.6 Data Collection 29

4.7 Statistical Analysis 30

4.8 Ethics Approval and Consideration 31

5.0 RESULTS 32

5.1 Socio-Demographics 32

5.1.1 Socio-demographic Characteristics Of The Patients 34 5.2 Descriptive of Clinical Severity of the Illness 36

5.3 Descriptive of Type of Medication used 39

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5.4 Descriptive Analysis of the Cognitive Tests 40 5.5 Descriptive Analysis of WHO Disability Scale 41 5.6 Correlation between Cognitive Scales and WHO DAS 42 5.7 Association Analysis of Clinical Severity, Cognitive Tests, WHO DAS

with Socio-demographic Data 43

5.8 Multivariate Logistic Regression of Significant Socio-demographic data and digit span adjusted for CGI 5 – Overall Severity 55

6.0 DISCUSSION 69

6.1 Introduction 69

6.2 Socio-demographic Characteristics 69

6.3 Clinical Characteristics 70

6.4 Cognitive Characteristics 71

6.5 WHO DAS 2.0 Characteristics 72

6.6 CGI-SCH Severity Scale Domain 1, Socio-demographic Data And

Duration Of Illness 73

6.7 CGI-SCH Severity Scale Domain 2 and Socio-demographic Data 74 6.8 CGI-SCH Severity Scale Domain 4, Socio-demographic Data and

Duration of Illness 75

6.9 CGI-SCH Severity Scale Domain 5 and Socio-demographic Data 75

6.10 Digit Span and Socio-demographic Data 76

6.11 Letter Number Sequencing (LNS) and Socio-demographic Data 77 6.12 MCCB Maze subtest and Socio-demographic Data 78 6.13 Cognitive Tests, Functionality and Clinical Severity 79

7.0 STRENGTHS AND LIMITATIONS OF THE STUDY 82

7.1 Strengths 82

7.2 Limitations 82

8.0 CONCLUSIONS AND RECOMMENDATIONS 83

8.1 Conclusions 83

8.2 Recommendations 83

REFERENCES 85

LIST OF TABLES

Table 5.1.1 Socio-demographic Characteristics Of The Patients 34

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Table 5.2.1 Descriptive Analysis of Domain 1 – CGI-SCH 36 Table 5.2.2 Descriptive Analysis of Domain 2 – CGI-SCH 37 Table 5.2.3 Descriptive Analysis of Domain 3 – CGI-SCH 37 Table 5.2.4 Descriptive Analysis of Domain 4 – CGI-SCH 38 Table 5.2.5 Descriptive Analysis of Domain 5 – CGI-SCH 38 Table 5.3.1 Descriptive Analysis Of Participants On Typical

Antipsychotics 39

Table 5.3.2 Descriptive Analysis Of Participants On Atypical

Antipsychotics 39

Table 5.3.3 Descriptive Analysis Of Participants On Long Acting

Injections 40

Table 5.4.1 Descriptive Analysis Of Cognitive Tests 40 Table 5.5.1 Descriptive Analysis Of the Domains of WHO DAS 2.0 42 Table 5.6.1 Correlation between Clinical severity, Cognitive Tests and

WHO DAS 2.0 43

Table 5.7.1 Association Analysis Of SCH-CGI Item 1 Positive

Symptoms 44

Table 5.7.2 Association Analysis Of SCH-CGI Item 2 Negative

Symptoms 46

Table 5.7.3 Association Analysis Of SCH-CGI Item 4 Cognition

Symptoms 47

Table 5.7.4 Association Analysis Of SCH-CGI Item 1 Overal Severity 49 Table 5.7.5 Association Analysis of Digit Span 50 Table 5.7.6 Association Analysis of Letter Number Sequencing 51 Table 5.7.7 Association Analysis of MCCB Maze subtest 53 Table 5.7.8 Association Analysis of WHO DAS Overall Score 54 Table 5.8.1 Logistic Regression of Digit Span and Education Completed

adjusted for CGI Overall Severity 56

Table 5.8.2 Logistic Regression of Letter Number Sequencing and Age

adjusted for CGI Overall Severity 57

Table 5.8.3 Logistic Regression of Letter Number Sequencing and Race

adjusted for CGI Overall Severity 57

Table 5.8.4 Logistic Regression of Letter Number Sequencing and 58

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Education Completed adjusted for CGI Overall Severity Table 5.8.5 Logistic Regression of Letter Number Sequencing and

Employment adjusted for CGI Overall Severity 58 Table 5.8.6 Logistic Regression of Letter Number Sequencing and Race

adjusted for CGI Overall Severity 59

Table 5.8.7 Logistic Regression of Letter Number Sequencing and

Staying with adjusted for CGI Overall Severity 59 Table 5.8.8 Logistic Regression of Maze and Age adjusted for CGI

Overall Severity 60

Table 5.8.9 Logistic Regression of Maze and Marital adjusted for CGI

Overall Severity 60

Table 5.8.10 Logistic Regression of Maze and Employment adjusted for

CGI Overall Severity 61

Table 5.8.11 Logistic Regression of Maze and Social Interaction adjusted

for CGI Overall Severity 61

Table 5.8.12 Logistic Regression of Maze and Staying With adjusted for

CGI Overall Severity 61

Table 5.8.13 Logistic Regression of Maze and Duration of Illness

adjusted for CGI Overall Severity 62

Table 5.8.14 Association Analysis of CGI-SCH Item 3 – Depressive

Symptoms 62

Table 5.8.15 Association Analysis of WHO DAS DOMAIN 1 - Cognition 63 Table 5.8.16 Association Analysis of WHO DAS DOMAIN 3 – Self Care 64 Table 5.8.17 Association Analysis of WHO DAS DOMAIN 4 – Getting

Along With People 65

Table 5.8.18 Association Analysis of WHO DAS DOMAIN 5 – Life

Activities 67

Table 5.8.19 Association Analysis of WHO DAS DOMAIN 6 -

Participation 68

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LIST OF ABBREVIATIONS

MCCB MATRICS Consensus Cognitive Battery LNS Letter Number Sequencing

DS Digit Span

WAIS Wechsler Adult Intelligence Scale

CGI-SCH Clinical Global Impression – Schizophrenia Scale CI Confidence interval

DSM Diagnostic and Statistical Manual of Mental Disorders M.I.N.I MINI International Neuropsychiatric Interview

NHMS National Health and Morbidity Survey OR Odds ratio

WHO DAS World Health Organization Disability Scale

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LIST OF APPENDICES

APPENDIX 1 Socio-demographic Questionnaire APPENDIX 2 WAIS IV – Digit Span Test

APPENDIX 3 WAIS IV – Letter Number Sequencing APPENDIX 4 MCCB Maze Subtest

APPENDIX 5 WHO Disability Scale (WHO DAS)

APPENDIX 6 Clinical Global Impression Scale – Schizophrenia APPENDIX 7 Information Sheet For Patient (English)

APPENDIX 8 Consent Form for Study (English) APPENDIX 9 Information Sheet For Patient (Malay) APPENDIX 10 Consent Form For Study (Malay)

APPENDIX 11 Medical Research and Ethics Committee Approval Letter APPENDIX 12 Approval Letter to do Research in HBUK

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1.0 INTRODUCTION

Mental illness has been existent in the history of mankind for many milleniums. The presence of mental disorder has been documented in the history of many civilizations [Neel Burton., 2012]. Mental disorder also has been seen across the world and in many parts of the world irrespective of culture, language or religion.

It is evident that mental illness is not confined to a particular race or culture. It happens across the world. It is a disease of the mankind. However, the early history of mental illness is not clear and not much evidence are available [Heinrichs., 2003].

In early years, during the era of ancient egypt, humans thought mental illness were disturbance of the nature and involvement of spiritual and supernatural forces [Foerschner., 2010]. The mental illnesses were never regarded as part of illness and was thought as possessions or spiritual superiority [Frith et al., 2003]. Many spritual practices were thought to be available in the early years to treat the mental ill patients.

The availability of ancient medicines for the treatment of mental disorders is not documented in the history of mankind. The fate of mental illness patients in the early years before the begining of modern era is also not clear and no evidence are available.

The view and believe of humans about mental illness had delayed in finding the cause and cure for the illness in the later years. It is stil evident to this date that mental illnesses or disorder is being labelled as disturbance of spirits and involvement of metaphysics aspects. Many other fields of medicine was well established as early as ancient egypt civilization or the Indian civilization. The has lead to discovery of many new medicines, treatment methods and surgical techniques in treating that

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disorders as early as 14 or 15th century [Butcher., 2009]. However, this was totally different in the field of psychiatry.

Humans started to realize about the presence of mental illness and the impact to the society in the later years during the 14th century [Butcher., 2009]. By then many other fields of medicine were already advanced and well established by this era.

Humans understanding about biological cause involved in mental illness only happened in the later years and started the spark in scientific reaserch into mental illnesses. Many researchers and clinicians started to describe the mental disorders in a more scientific way and many publications were published to report the findings or the mental illnesses [Simon., 2008].

Many mental disorders were identified and documented. However, due to the lack modern technology and lack of understanding into the illness, this mental disorders remained as unsolved puzzle to many reaserchers at that era. Among the many mental illnesses documented and found by the researchers, schizophrenia was among the earliest and first to be described by many clinicians and researches across their publications [Alexander., 1966]. The symptoms of schizophrenia was also documented in the ancient egypt and in many other early civilizations. This shows the prevalence of the illness across the time.

Schizophrenia is a chronic debilitating illness [ Alberti K. George 2004 ].

Schizophrenia was first identified by Emil Kraeplin back in 18th century and reported the illness as dementia precox. It is Bluelur whom coined the term schizophrenia later in the century [ Daisy Yuhas 2013 ]. Schizophrenia affects the patients in many of their life aspects. To date schizophrenia is still considered the serious mental illness among other mental illnesses. The understanding of the illness is growing day to day as new evidences and scientific findings are published and reported.

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1.1 Epidemiology

Mental health problems are one of the main cause of burden of diseases world wide [Vos, T et al., 2013]. 1 in 4 will experience mental health problems in UK [Ferrari et al., 2013]. Among the mental illnesses, schizophrenia affects many people gobally and locally in Malaysia. Based on the WHO report in 2016, schizophrenia affects almost 21 million people worldwide. Schizophrenia is a global burden of disease. The incidence of schizophrenia is about 15.2 in every 100, 000 people. The ratio of illness among gender is almost the same. Men are affected 1.4 times higher than females. The ratio male to female is 1.4 : 1.0. the median lifetime morbid risk for schizophrenia was 7.2/1000 people [John McGrath et al., 2008]. Based on the WHO report, patient with schizophrenia has 2 to 2.5 times more likely to die early compared to the general population.

In Malaysia, based on the National Mortality and Morbidity Survey 2015, prevalence of mental health among adults age 16 and above were 29.2% (95% CI : 27.9, 30.5). Mental health problems in Malaysia is showing an incresing trend. The prevalence of mental illness was 10.7% in 1996 and has increased to 29.2% in 2015.

Based on the same survey, the prevalence of mental illness was higher among other Bumiputras which was 41.1%. By gender, the prevalence of mental illness was slightly higher among females which was 30.8% compared to males which was 27.6%. Mental health problems were also highly prevalent among low income families compared to higher income families in Malaysia.

Schizophrenia occurs 1 in every 100 people in Malaysia based on the National Schizophrenia Registry. Based on Global Health Data Exchange, the annual years of

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healthy life lost per 100,000 people from schizophrenia in Malaysia has increased by 19.4% since 1990, an average of 0.8% a year.

The outcome of schizophrenia is well studied in the field of psychiatry. As mentioned earlier in the paragraph, schizophrenia is a chronic debilitating illness. In the course of schizophrenia, patients will go through multiple relapses and remissions.

Based on the meta analysis done by Menezes et al, good outcome of schizophrenia patient was reported in 42% of cases, intermediate outcome in 35% of cases and poor outcome in 27% of cases [ Menezes et al., 2006]. The outcome of schizophrenia is dependent on many factors.

Due to the nature of the illness which involves multiple relapses and remissions throughout the course of schizophrenia, the impact of the illness is tremendous. The impact of schizophrenia is multilevel as it involves the individual himself, his surrounding family and social circle, health system and to the country.

Eventhough the prevalence of schizophrenia worldwide is low which is every 4 in 1000 persons [Saha et al., 2005], its health, social and economic burden is heavy. The burden of illness to the patients, caregivers and the wider society is also massive. The chronicity of the illness and chances of recovery is multifactorial, patients with schizophrenia suffer throughout their illness. Sociologist had pointed out the social drift among schizophrenic patients which leads them into unemployement and social distress.

Schizophrenia affects the person as whole and leads to functional deterioration [ Evelyn J Bromet et al, 1999 ]. Functional deterioration in schizophrenia patients are multifactorial and it involves duration of untreated psychosis (DUP), presence of negative and postive symptoms, types of antipsychotis being used and etc [ Bowie CR et al 2006 ]. Functional deterioration eventually leads to the disability among

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schizophrenia patients. Schizophrenia was ranked among the common causes of disability worldwide [Theo Vos et., 2015]. In the early years before the invention of antipsychotics, patients with schizophrenia were placed in mental asylums and instituitions which leads to the further deterioration of function among schizophrenia patients.

However, the invention of antipsychotics in the 1950's shed light to the symptomatic improvement of schizophrenia patients. In the later years, with better understanding of the illness and implementation of new mental laws and policies, leads to the down sizing of mental institution and introduction of community services which focuses on rehabilitation in schizophrenia patients [ Shorter et al 1997 ]. The treatment outcome of schizophrenia started to shift from symptoms improvement or remission which is complete absence of symptoms to recovery [ Robert Paul Liberman et al 2005]. Recovery is not solely absence of symptoms but functional recovery. Functional recovery can be understood as restoring the schizophrenia patient back to their premorbid functioning and being meaningful in their own community and family [ Maya Gupta et al., 2012 ]. On the other hand, functioning is understood as the ability of someone to be productive and to adapt to the need of family, personal, social and labor [ Guillermo Lahera et al., 2016 ]. Restoring back schizophrenia patients to their functionality has been the goal of schizophrenia treament in the current decade [ Gary Remington et al., 2010 ].

Cognitive impairment in schizophrenia has been the area of robust study in the current decade. Cognitive impairment has been recognized in major mental illness especially in schizophrenia [ Ronan O'Carroll et al., 2000 ]. The cognitive impairment has been observed by Kraepelin back in the early days of mental illness.

Dementia precox which was coined by Kraepelin clearly shows the involvement of

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cognitive dysfucntion in the process of mental illness [ Sharma T et al., 2003 ].

Cognitive impairment in schizophrenia has been recorded as high as 98% among schizophrenic patients [ Richard S.E Keefe., 2015 ]. Cognitive impairment in schizophrenia is multifactorial which involves the disease process itself, medication side effects and social factors [ Velligan DI et al., 1999 ]. However, it is disappointing to denote that cognitive impairment has not been stated or listed as one of the criteria or specifier in DSM V eventhough cognitive impairment is highly prevalent among schizophrenia patients.

Functionality and cognition is very closely related as cognition improvement can lead improvement in functionality [ Keefe RS et al., 2005 ]. Cognitive improvement in schizophrenia helps the patient to be back to their premorbid functioning and crucially helps them in recovery [ MF Green et al., 1996 ]. Absence of positive and negative symptoms is not enough in treating schizophrenia.

Improvement in cognitive function helps the patient to be more functional in their family and society. Thus cognition and functionality is closely related and it is important to study the association for a better understanding of the functionality and cognition.

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2.0 LITERATURE REVIEW

2.1 Cognition Overview

Cognitive involvement in schizophrenia has been topic of interest among many researchers starting from the 20th century. Schizophrenia itself is a heterogeneous disease with varying type of clinical symptoms and presentations.

Schizophrenia also presents with varying degree of severity. Apart from the common presentation of positive, negative, depressive symptoms and behavioral change in schizophrenia, cognitive impairment has been observed almost in all the patients with schizophrenia.

The advancement in neuroimaging studies made the study of neuro-cognition easier. The initial pictures of the brain of people of schizophrenia made the researchers to wonder whether the illness has involvement of neuronal cells and chemicals in the brain. The ventricles of patients with schizophrenia were larger than the normal population [Raz and Raz., 1990; Weinberger et al., 1979]. This finding gave an insight into the research of cognitive involvement in schizophrenia. Before the brain findings of patients with schizophrenia, researchers were trying to differentiate the organic and functional cause of schizophrenia [Green et al., 2014].

The large ventricles show that ventricles are accommodating to the loss of neuronal cells in the brain. This again points to the involvement of neural loop in the pathogenesis of schizophrenia. The earliest person in the field of psychology that considered schizophrenia as a cognitive disorder was Emil Kraeplin in the 19th century. Emil Kraeplin observed attention processing abnormalities in schizophrenia patients, which were known as dementia praecox at that era [Nuechterlein and

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Dawson., 1984]. Kraeplin divided the attention abnormalities into two, active attention and passive attention. In modern era active attention also known vigilance and passive attention as distractibility. This shows that there is degree of cognition involvement in schizophrenia.

2.2 Cognitive Impairment In Schizophrenia

Based on the meta-analysis done by Heinrichs and Zakzanis in 1998, moderate to large effect size was noted in all 22 neurocognitive test variables among patients with schizophrenia. Cognitive impairment was observed in varying degree of deficit in almost all the 22-neurocognitive tests [Heinrichs and Zakzanis., 1998]. Similarly Sharma et al, reviewed the cognitive impairment in schizophrenia patients and found that few domains of cognition was deficit. The main domains affected were attention, executive function, verbal and visual spatial working memory and learning and memory. As an addition, atypical antipsychotic was noted to improve the cognitive function among schizophrenia patients.

The cognitive impairment in schizophrenia can reach two standard deviations below the healthy control mean in many cognitive domains [Harvey and Keefe., 1997; Heinrichs and Zakzanis., 1998]. However in a study conducted by Palmer et al, about 27% of patients with schizophrenia were documented as not being impaired by clinical psychological assessment [Palmer et al., 1997]. In another study done by Keefe et al, among 50 healthy control versus 150 patient with schizophrenia, as high as 98% of patients with schizophrenia perform poorly in cognitive tests compared to their parents' education level [Keefe et al., 2005]. In this study, the subjects were exposed to 2.5 hours of cognitive battery, which involves the domains of verbal

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memory, motor functioning, working memory, information processing speed, attention and executive functioning. This study was conducted among in-patient with premorbid IQ was taken into account. Likewise, Blanchard and Neale, reported in their study that cognitive impairment was noted in motor, sensory, perceptual functioning, verbal and non verbal memory among schizophrenia patients compared to the normal population [Blanchard and Neale., 1994]. However, this study failed to support the difference in cognitive deficits in schizophrenia due to the limited psychometric tests. Tek et al also makes this point in his study. Visual perception and working memory are impaired in schizophrenia [Tek et al., 2002]. Bustini et al reported poor executive function among schizophrenia patients. In this study, the author used tower of Hanoi and Wisconsin Card Sorting Test to assess executive functioning among 28 patients with schizophrenia versus 28 controls [Bustini et al., 1999]. However, the study sample is very small and psychometric test Tower of Hanoi is not a common test to assess executive function.

Neil et al assessed the category fluency test to be an executive or semantic test among 40 schizophrenia patients versus 42 healthy controls. The study reported that semantic fluency test measures semantic memory function in schizophrenia patients.

However, the sample size of this study is small and the psychometric test used was not clearly delineated.

Meta analysis conducted by Fioravanti et al, found that cognitive deficits are apparent in almost all the cognitive domains among schizophrenia patients. In these meta-analysis of 113 studies from the year 1990 to 2003 was included. Only studies with patients and controls were selected [Fiovaravanti et al., 2005]. However, in this meta-analysis major issue highlighted was the heterogeneity among studies in many

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components. There were no standardized psychometric tests were used, heterogeneity in socio-demographic data and limited power of study.

In the second meta-analysis conducted by the same author Fioravanti et al, in 2012, 247 studies from the year 2010 with patient and control was included. 5 cognitive domains – memory, global cognitive functioning, language, executive functioning and attention was studied. Again, this meta-analysis echoed the findings of the meta-analysis conducted in 2005 by the same author Fiovaranti et al. All the 5 domains of cognitive functioning stated above was significantly impaired among schizophrenia patients compared to healthy controls [Fiovaranti et al., 2012]. High heterogeneity was also observed in this meta-analysis as compared to the analysis in 2005. Differences in age, sex, sample size, type of patients and type of measurement contributes to the severity of not-overlapping information reported by the single study.

As evidenced from the literature above, cognitive impairment is one of the core features in schizophrenia. However, many domains of cognitive functioning are involved in schizophrenia. Many cognitive tests are also available in assessing the cognitive functioning. This situation has lead to very high heterogeneity in studies conducted on cognitive function among schizophrenia patients. Meta analysis conducted by Nuechterlein et al, as the part of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) funded by National Institute of Mental Health (NIMH), looked into the varying type of cognitive domains impairment in schizophrenia and the availability of many types of psychometric tests [Nuechterlein et at., 2004]. Based on this meta-analysis, 7 major cognitive deficits in schizophrenia were identified. They were speed of processing, attention/vigilance,

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working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving and social cognition.

2.3 Functionality In Schizophrenia

Schizophrenia treatment outcome has substantially changed in the last few decades. In the era of institutionalization of schizophrenia patients and before the discovery of antipsychotics, treatment of schizophrenia patients were more to behavioral control rather than treating the real cause of schizophrenia. However, with the availability of antipsychotics, the treatment outcome had shifted from response to remission of symptoms. The social movement for the betterment of mentally ill patients and deinstitutionalization also contributed in the shift of the treatment outcome among mentally ill. In the recent decade, recovery has been the goal of treatment of schizophrenia patients [Anne Kary., 1999]. Improving in symptoms and achieving remission is not merely sufficient in the treatment of schizophrenia. Social reintegration and returning to premorbid functioning is crucial in the process of recovery in the schizophrenia [Liberman., 2005]. Although there are many facets of recovery in schizophrenia, functionality has been among the most important factor for recovery in schizophrenia [Jaaskelainen et al., 2013; Garcia., 2002].

Functionality refers to the ability to perform relevant skills such as that relevant to social, vocational and residential functions [Harvey et al., 2009; Mckibbin et al., 2004]. Karaday reported that quality of life improves with better functionality among schizophrenia patients [Karaday., 2011]. Anthony (1995) similarly mentioned that functionality is crucial in recovery process of schizophrenia and better quality of life. On the other hand, Apiquian et al reported that deficit in functionality in

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schizophrenia can happen during the early stage of the illness, during the relapse or as a part of the residual syndrome [Apiquian et al., 2009]. Honkonen et al mentioned that unemployment is a predictor of poor functioning in schizophrenia. Similarly, Haro et al mentioned that overall long duration of illness leads to poor functionality in schizophrenia patients.

Functionality is an umbrella term for many facets of function. Functionality includes the interpersonal relationship, social functioning, occupational functioning, participation in community and psychological functioning. In summary, functioning encompasses bodily functioning, activities and involvement in life activities [Ustun and Kennedy., 2009]. Based on the World Health Organization (WHO) Disability Scale, functionality involves 6 domains. The domains were – cognition, mobility, self-care, getting along with people, life activities and participation in community.

Cognition is the psychological functioning, mobility and self care would be physical functioning, getting along with people is the interpersonal functioning, life activities would be occupational functioning and participation would be social functioning [Ustun et al., 2010].

2.4 Cognition And Functionality

The introduction of antipsychotics in the 1950's lead to the reduction in psychotic symptoms in schizophrenia patients [Braslow., 1997]. The positive and negative symptoms of schizophrenia improved and patient achieved remission. The researchers expected the patient to have functional improvement and community integration. However, the functional improvement did not happen. The antipsychotics failed in community re-integration for schizophrenia patients [Hegarty

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et al., 1994]. It was only later cognition was recognized as crucial part in functionality and eventually plays important role in social integration and returning to premorbid functioning.

Based on the study done by Green et al, cognitive impairment is very closely correlated in determining functioning in schizophrenia and specific neuro-cognition correlates with functional outcome. Verbal memory, immediate memory and executive function closely related to the functional outcome in schizophrenia. [Green et al., 2000, 2004]. Similarly, McGurk et al reported executive functioning, attention, information processing speed and working memory is related to on job support.

Cognitive functioning is correlated to job performance. This study was done among 30 patients whom were newly enrolled in supported employment. Again, McGurk and Mueser (2004) strongly agrees with McGurk 2003 that cognitive functioning and symptoms were strongly related to work. Bowie and Harvey (2006) also makes the similar point that cognitive deficit has poor functional outcome and suggested that cognitive enhancement to be included in the goal of treatment. Likewise, Lysaker et al (1995) makes the case that level of cognitive impairment is associated with persistence of social skills deficits in schizophrenia. Green (1996) reported that verbal memory and vigilance are needed for adequate functional outcome. Similarly, Brekke et al reported that stroop test, digit symbol, verbal fluency and digit span correlated with independent living and work [Brekke et al., 1997]. Goldman et al also reported that digit span and trail making test predicted community functioning [Goldman et al., 1993]. However, this study was conducted on only 19 schizophrenia patients. The power of the study is poor. In another study by Meltzer et al, neurocognitive test, mazes and digit symbol coding correlated with global assessment scale and quality of life scale. This study was conducted among treatment resistant

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patients [Meltzer et al., 1996]. Likewise, Bell and Bryson (2001) and Bryson and Bell (2003) conducted a 6-month study on 96 schizophrenia patients. Their studies revealed that cognitive measures predicted rate of improvement in work performance.

In another study conducted by Fujii and Wylie (2003), trail making test, digit span, logical memory and finger tapping predicted functionality. This study was a 20-year retrospective study and has a large effect size. Fujii et al reported that executive functioning, working memory, and motor speed predicted objective indices of quality of life [Fujii et al., 2004]. In this study, digit span again was used to measure working memory. Similarly, Keshavan et al also used digit span to assess working memory and predicted the functional outcome in 2 years [Keshavan 3t al., 2003]. Again, Smith et al and Velligan et al reported that working memory measured using digit span shows correlation with functional outcome in schizophrenia patients [Smith et al., 2002; Velligan et al., 2000]. On the other hand, Robinson et al documented that executive functioning and visual spatial working memory predicted good outcome in functioning measured by social adjusment scale [Robinson et al., 2004]. Gold et al also makes this point by using the letter number sequencing test in the study.

However, Addington et al (1998) points out that no significant associations between cognitive measures and social functioning. Conversely, Johnstone et al (1990) argues that there was no neurocognitive measures predicted outcome in occupational functioning but ratings of social withdrawal did. Addington and Addington (1999) reported that neurocognitive battery measuring verbal ability, verbal and visual memory, verbal and visual memory, executive functioning, visual- spatial organization, vigilance and information processing showed negative findings with social functioning scale and quality of life scale. Again, Addington and Addington (2000) reported that multiple cognitive measures, which include digit span

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and verbal fluency test, did predict social functioning and quality of life but predicted social problem solving.

2.5 Working Memory And Executive Functioning

Assessing the cognitive function in schizophrenia imposes as great challenge to the patient and the examiner. Cognitive tests itself are complicated and time consuming. There are many cognitive domains involved in schizophrenia and as result there are many cognitive tests involves for each domain. Due to this variability in cognitive domains and availability of psychometric test, heterogeneity is easily observed in studies involving cognition.

Based on the MATRICS Consensus Cognitive Battery, 7 domain of cognition was identified to be deficit among schizophrenia patients [Neuchterlein et al., 2008].

Among the 7 domains identified, working memory and executive functioning plays a pivotal role in cognitive deficit among schizophrenia patients and commonly observed cognitive deficits in schizophrenia.

Working memory is defined as a temporary storage of memory and ability to manipulate information for gold directed activity [Baddeley., 1992]. Working memory can be divided into 3 domains, which were verbal memory, visual spatial memory and central executive. Based on the meta-analysis by Forbes et al, all 3 domains of working memory are affected in schizophrenia. However, there no clear difference across subdomains or between particular working memory tasks [Forbes et al., 2009]. Similarly, Zanello et al also reported that working memory is significantly affected in 1st episode and chronic schizophrenia patients [Zanello et al., 2009].

However, meta-analysis by Lee and Park (2005) points to working memory deficit in

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schizophrenia across different tasks and paradigms. The difference also modality independent [Lee and Park., 2005].

Working memory involves the Dorsolateral Prefrontal cortex (DLPFC) of normal humans. In schizophrenia patients, dysfunction of DLPFC and its connectivity to other part of brain leads impairment in working memory [Callicott et al., 2003]. Letter number sequencing task, which is considered as endophenotype of schizophrenia, is also part of working memory, which measures the circuit connection of DLPFC with other part of the brain [Greenwood et al., 2007].

On the other hand, executive function is defined as the ability of humans to voluntarily control their behavioral responses. Executive functions are set of subdomains that help us to make decision, to analyze problems, to solve problems and etc. in our life. Executive function (EF) is thought to involve the Prefrontal Cortex (PFC). Many parts of the PFC is deficit in schizophrenia patients. Braver et al in his study of executive function in schizophrenia reported that executive function is substantially affected in schizophrenia patients [Braver et al., 1999]. Similarly, Freedman and Brown (2011) mentioned in his study that impairment in EF is very commonly seen among schizophrenia patients and it is similar to the negative symptoms of schizophrenia [Freedman and Brown., 2011]. However, on the other hand, based on the meta-analysis by Fett et al, cognitive deficit in schizophrenia are across all the domains and there is not particular domain affected in the illness [Fett et al., 2011].

Cognitive impairment and functionality is an area of research globally. In Malaysia, there were very limited studies on cognitive impairment and functionality.

Midin et al conducted a cross sectional study among 95 schizophrenia patients and found that attention, working memory and executive functioning plays role in

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maintaining employment in patient with schizophrenia. In this study cognitive impairment was measured but no functionality was assessed.

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3.0 AIM AND OBJECTIVES

3.1 Aim

The aim of this study is to establish association between Verbal Working Memory, Visual Spatial Working Memory and Executive Functioning to Functional Outcomes in stable outpatients with Schizophrenia in Hospital Bahagia Ulu kinta.

3.2 Objectives

1. To examine the correlation and association between verbal working memory, visual spatial working memory, executive function, functionality and sociodemographic data

2. To determine the association between Verbal working memory and functionality among stable schizophrenia patients.

3. To determine the association between Visual Spatial working memory and functionality among stable schizophrenia patients.

4. To determine the association between executive functioning and functionality among stable schizophrenia patients

5. To exmine the correlation between verbal working memory, visual spatial working memory, executive function, functionality and severity of illness.

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3.3 Rationale of the Study

Cognitive impairment in schizophrenia has been observed and documented in the literature from the 18th century. Since the treatment outcome of schizophrenia shifted from remission to recovery, functionality among schizophrenia has been considered as the main factor for recovery and psychosocial rehabilitation. Cognition plays are very crucial and pivotal role in recovery process of schizophrenia patients.

The link between functionality and cognition has been the are of reasearch lately.

However, little is known about cognition and functionality in Malaysia.

Furthermore, there no study conducted on association between cognition and functionality in Malaysia. This area of study is still not yet largely explored in Malaysia. Studying the association of cognition and functionality in Malaysia, can improve the psychosocial rehabilitation programmes that is currently available in Malaysia. On the other hand, this study also can guide the policy makers in creating a hollistic approach in tackling mental illness in Malaysia.

This study will provide a clearer picture of cognition and functionality in Malaysia. Moreover, after completion, this study can be expanded to look into other ares of cognition among schizophrenia patients and other mentally ill patients.

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4.0 METHODOLOGY

4.1 Study Setting

The present study was conducted in outpatient clinic of Hospital Bahagia Ulu Kinta, Perak. Hospital Bahagia Ulu Kinta is the first mental instituition in Malaysia.

Anually thousands of patient from different race seek treatment from the outpatient clinic of Hospital Bahagia Ulu Kinta, Perak.

4.2 Study design and sampling method

This is a cross-sectional epidemiological study and samples are obtained using convenient sampling method. The locations of this study were also chosen by using convenient sampling method.

Subject will be selected from registration list of outpatient visit in psychiatric clinic of Hospital Bahagia Ulu. Patients whom attend the outpatient clinic in Hospital Bahagia Ulu Kinta will be given registration numbers by the counter staff starting from number 0001. First 5 patients with odd registration number will be selected to be included in the study. If any of the patients refuse to participate in the study, the next odd registration number will be selected. The study is conducted on outpatient clinic days which were on Monday to Thursday afternoon. If the inclusion and exclusion criteria's are met, the patient will be included in the study.

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4.2.1 Inclusion criteria

• Patient’s age 20 years old to 59 years old

• Having an established diagnosis of schizophrenia according to DSM V criteria

• On maintenance treatment with antipsychotics

• Treatment remaining stable during the previous six months ( Silvia et al., 2015; Jarskog, L.F et al., 2015; Montemagni, C., 2014 )

• Subject who give informed consent

4.2.2 Exclusion criteria

• Subjects age less than 20 and above 59 years old

• Subjects who are suffering of an acute depressive episode at the time of selection

• Subjects who presents with severe or uncorrected auditory or visual sensory dysfunctions or psychomotor disturbances that would prevent the completion of cognitive tasks

• Subjects whom are severely ill based of CGI-S more than 4

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Patient who is not fit to give consent and family members are not contactable

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4.3 Sample Size Calculation

This study is a prevalence study. Based on the L. Naing et al, sample size calculation for prevalence study can be calculated based on the formulae given below :-

The following simple formula (Daniel, 1999) can be used:

n = Z 2 P (1 − P )

d2

where n = sample size,

Z = Z statistic for a level of confidence, P = expected prevalence or proportion d = precision

Z Statistic

In this study, the confidence interval (CI) is set at 95%. Therefore the conventional value for Z when CI is 95% will be 1.96.

P – Expected prevalence or proportion

P will be the expected prevalence of cognitive impairment in schizophrenia.

However, estimated prevalence of cognitive impairment is needed to calculate the sample size. Studies have shown varying percentage of cognitive impairment in schizophrenia. Based on the study done by O'Carroll Ronan et al , prevalence of

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cognitive impairment in schizophrenia is about 85%. For the purpose of this study, the P value which is the estimated prevalence will be set as 0.85.

d = Precision

Setting the precision for prevalence study can be difficult. There is no definite recommendation for determining precision (d) for a prevalence study. Based on L.

Naing et al, if the prevalence of the study is between 10% to 90%, precision (d) should be set at 5% which would be 0.05. For the purpose of this study, d is set at 0.05.

So, based on the values given above, sample size for this study would be :-

n = 1.96 2 0.85 (1 – 0.85 )

0.052

therefore n = 195

4.4 Study Procedure

All subject fulfilled the inclusion criteria will be explained about the study and given information about the purpose of the study in an information sheet. Patient who consented for the study will be participating in the study. They would be assured of

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their anonymity and the confidentiality of the data obtained. If the patient is not fit to give consent, consent will be taken from patient’s relatives.

Data were collected from clinical patient interview. Sociodemograhic data, clinical data and details about type of medications used is collected. In addition, sociooccupational status, functional status in different aspects of life and cognitive difficulties were assessed.

4.5 Instruments

This research used 7 tools to obtain data from the study sample, which is demographic data questionnaire, item A1 and A2 of Mini International Neuropsychiatric Inventory ( M.I.N.I ), Clinical Global Impression-Schizophrenia (CGI-SCH), Digit Span of WAIS IV [Weschler., 2001], Maze subtest of MATRICS Consensus of Cognitive Battery (MCCB) [Neuchterlein., 2008], Letter Number Sequencing of WAIS IV [Weschler., 2001] and World Health Organization Disability Scale version 2.0 (WHO DAS 2.0) [Janca et al., 1996].

4.5.1 Demographic data questionnaire

A questionnaire was developed to obtain the socio-demographic data that was intended to be used in this research. Questions include name, identity card number, age, gender, race, religion, marital status, completed education level, employment status, current employment, duration of illness, psychiatric co-morbidities, treatment adherence, social interaction with family, currently staying and medications.

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Name and identity card number was obtained to give an identification number during data analysis. Race and religion was subdivided into major races and religions in Malaysia. Marital status was subdivided into single, married, widow and divorced.

Education level was also subdivided into categories of no formal schooling, completed primary school, not completed primary school, secondary school SRP/PMR, secondary school up to SPM, Secondary school up to STPM, completed Matriculation/Pre university and diploma/degree. Employment status was subdivided into never been employed, not employed, working part time, self-employed, working full time, retired/SOCSO, housewife and student. Psychiatric co-morbdities was subdivided into presence of subtsance disorder, mood disorder, anxiety disorder and personality disorder. Treatment adherence was subdivided in yes and no. Social interaction was subdivided into on a daily basis or almost daily, one or twice per week, once or twice per month, every several month, rarely, never and unknown.

Currently staying is subdivided into staying with family, nursing home, day care centre and alone.

4.5.2 Mini International Neuropsychiatric Inventory ( M.I.N.I )

The Mini International Neuropsychiatric Interview (MINI) is a short diagnostic structured interview. The MINI was developed in France and United States to assist clinician in exploring 17 disorders according to Diagnostic and Statistical Manual (DSM III R) diagnostic criteria. MINI only focuses on the existence of current disorders in order to keep it short. One or two screening questions rule out the diagnosis when answered negatively for each disorder. 17 disorders are labeled in alphabets as modules in MINI. Module 'A' questions were related to major depressive disorder. There 6 major questions ranging from A1 to A6 in Module 'A'. Each major questions on depressive symptoms has sub questions to

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gather information on depression. Questions A1 and A2 in module 'A' of MINI is the screening question for depression. In this study, only question A1 and A2 used from module 'A' of Mini International Neuropsychiatric Inventory to screen for depression.

4.5.3 Clinical Global Impression – Schizophrenia (CGI-SCH)

The Clinical Global Impression-Schizophrenia (CGI-SCH) scale is a breif assessment instrument adapted and modified from the Clinical Global Impression (CGI) scale. The CGI-SCH scale is designed to assess the main symptoms dimensions in schizophrenia. CGI-SCH scale was adapted from the CGI scale and CGI-Bipolar patients (CGI-BP) scale. The CGI-SCH is simpler than the CGI and the CGI-BP scales. CGI-SCH consists only two categories which were severity of illness and degree of change. The severity of illness category evalutes the situation during the week previous to the assessment, while the degree of change category evaluates the change from previous evaluation [Haro et al., 2003]. For the purpose of this study, only severity category is used.

The severity category of the Clinical Global Impression – Schizophrenia (CGI-SCH) severity scale contains total of 5 subdomains. Domain 1 measures the positive symptoms, domain 2 measures negative symptoms, domain 3 measures depressive symptoms, domain 4 measures the cognition symptoms and domain 5 is the overall severity score. The severity of illness is divided into 7 domains ranging from normal or not ill to among the most severely ill.

The meaning of each of the ratings of the CGI-SCH is similar to the PANSS dimensions (positive, negative, depressive and cognitive).

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4.5.4 Cognitive Assessment Tools

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) review team [ Nuechterlein et al., 2008 ] had looked into the cognitive domains, which were closely related to functionality. Based on their published review, 9 domains of cognition were closely related to functionality. For the purpose of this study, the domains of cognition selected are verbal working memory, Visual spatial working memory and executive functioning.

The Wechsler Adult Intelligence Scale (WAIS IV) is an IQ test designed to measure intelligence and cognitive abilities in adolescence and adults. The original WAIS (Form 1) developed and published by David Wechsler in 1955. Currently the latest version of WAIS IV is used which was released in 2008. The WAIS IV contains 2 major domains which were the verbal IQ and performance IQ. Verbal IQ contains 7 tests which measures the verbal comprehension and working memory.

Performance IQ contains 6 tests which measures the perceptual organization and information processing speed. For the purpose of this study, only digit span and letter number sequencing tests were used to measure the different components of working memory.

Digit span from WAIS IV will be used to assess the verbal working memory, Letter number sequencing from WAIS IV will be used to assess the visual spatial working memory, Maze subtest from MATRICS consensus cognitive battery (MCCB) will be used to assess the executive functioning.

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Digit span of WAIS IV consist of 3 subtest. The forward, backward and sequencing test. Patients are given sequence of digits increasing in length and difficulty. For Digit Span Forward, the examinee is read a sequence of numbers and recalls the numbers in the same order. For Digit Span Backward, the examinee is read a sequence of numbers and recalls the numbers in reverse order. For Digit Span Sequencing, the examinee is read a sequence of numbers and recalls the numbers in ascending order. This subtest measures working memory, mental manipulation, cognitive flexibility, rote memory and learning, attention, and encoding. Each trial is given maximum score of 2. The total of forward, backward and sequencing will be the digit span total raw score. The raw score will be compared to the normative data published for the population and scaled score will be obtained for the given age group.

In Letter Number Sequencing, patients are given sequence of numbers and alphabets. They have to rearrange the given numbers and alphabets into numbers first and followed by alphabets. Each correct response will be given maximum score of 1.

The total score for letter number sequencing would be the raw score. The raw score will be compared to the normative data published for the population and scaled score will be obtained for the given age group.

MCCB subtest Maze contains 7 increasingly in complexity and difficulty of maze. Patient need to complete the maze in a given time period. The minimum score will be 0 and maximum score would be 5. If patient score 0 in consecutive maze, the test will be discontinued. The total score for maze will be the raw score. The raw score will be compared to the normative data published for the population and percentile score will be obtained for the given age group .

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It takes about 15 to 25 minutes for each subject to complete the test.

Subjects who were able to perform on all the test takes longer duration compared to other subjects.

4.5.5 Functional Variables

Subjects' functionality will be recorded using the WHO DAS 2.0 [ Janca A et al., 1996 ]. This assessment tool is a 36-item questionnaire, semi-structured interview designed to assess the functionality and disability from mental disorders. It includes the following domains: cognition, mobility, self-care, getting along with people, life activities and participation. Each domains are subdivided into subdomains. The score for each domain range from 1 – no disability, 2 – mild disability, 3 – moderate disability, 4 – severe disability and 5 – extreme disability. For the purpose of analysis, based on the WHO DAS manual, the severity score will be converted to 0 to 4. Score of 1 is equal to 0, 2 equal's to 1, 3 equal's to 2, 4 equal's 3, 5 equal's to 4.

The percentage of disability is calculated for each domain. Overall percentage of disability is calculated based on the domains given.

4.6 Data collection

Data collection for this study took about 4 months, from September 2016 till December 2016. Patients were selected randomly from the outptient clinic of Hospital Bahagia Ulu Kinta. Individuals who fulfilled the inclusion criteria were invited to participate in the study. Every individual who was interested to join the study was given an explanation on the aims of this research, following which the Patient Information Sheet was given. Every participant that agreed to join this research after

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being given the explanation was requested to sign the Patient Consent Form and confidentiality was assured to all. Participation in this study is totally voluntary.

After signing the consent form, the participants were asked on demographic questionnaire by the researcher, participants depressive symptoms were assesed using the item A1 and A2 of M.I.N.I, severity of illness was assesed using the CGI-SCH severity scale. Following which the participants undergo cognitive tests in order of digit span, maze subtest and letter number sequencing. After completing the cognitive tests, the reasearcher assess patients functionality and disability using the WHO DAS 2.0 36-item questionarre.

The participants were free to ask about any ambiguity related to the questionnaire. All data were kept in a confidential file, which is available for access only for the members of this research team.

4.7 Statistical Analysis

The clinician will rate all the scales. Raw scores for the cognitive 3 tests will be transformed into standardized scores, which are scalar scores based on the published normative data available. For the WHO DAS 2.0, the sum of the scores will be considered the measure of overall patient functional disability.

Data collected in this study was analyzed using Statistical Package for Social Science (SPSS) Version 22. The demographic data were summarized using descriptive statistics. Non Parametric test was done to analyze the association of demographic data (age, gender, race, religion, marital status, completed education, employment status, social interaction, staying and duration of illness) to clinical severity of illness, cognitive tests and disability scale (WHO DAS). As the variables are mixture of categorical and non-categorical, Mann Whitney U test was used.

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Spearman correlations used to describe the association between cognitive performance, clinical severity and functional disability results

Following this analysis, demographic profile that has significant correlation with clinical severity of illness, cognitive tests and disability scale (WHO DAS) were identified separately. Multiple binary logistic regression (multivariate) analysis was done to further assess the association of the earlier significant socio-demographic correlates with clinical severity of illness, cognitive tests and disability scale (WHO DAS).

4.8 Ethics Approval And Consideration

Before beginning collecting data for this study, ethical approval was obtained from Research and Ethics Committee of National Medical Research Register and ethics committe of Hospital Bahagia Ulu Kinta. All participants who participated in this research signed Patient Consent Form, following which a detailed explanation regarding the purpose of this study was given. All the participants were given an identification code for the use of data analysis later. If the subjects withdrew from the study, they will be still treated and followed up by the treating doctor. New subjects will be looked upon. All the subjects information will be kept in a locked cabinet.

Only the principal investigator has the access to the cabinet. Subjects will be not given access to the personal information and study data. Medical records will be kept in locked cabinet in the outpatient clinic of Hosp Bahagia Ulu Kinta. All the medical records will be kept by investigator for about 1 hour and will be returned to the officer in charge of the records on the same day. All data obtained was kept confidential.

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5.0 RESULTS

5.1 Socio-demographic

Total of 136 patients participated in this study. Table 5.1.1 shows that socio- demographic of the patients participated in this study. The mean age of the participants were 43.71 and standard deviation for the age were 10.02. The mean duration of illness was 19.68 years with standard deviation of 9.46.

Majority of the participants were male (n=94, 70.1%). The females were 29.9% (n=40) of the total participants. The race distribution among the participants follows the major race distribution in Malaysia. Malays were the majority among the 136 participants (n=68, 50.7%) followed by Chinese (n=52, 38.8%), Indians (n=13, 9.7%). Others races were only 0.7% (n=1) among the participants.

Since the Malays were the majority participants in this study, Islam was the highest practiced religion among the participants. 50.7% (n=68) of the participants were Muslims. Buddhist were 30% (n=22.4), Hindus were 7.5% (n=10) and Christians were 7.5% (n=10). Other religion such as Sikhism, Taois

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