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A Randomized, Prospective Comparative Study to Evaluate A RANDOMIZED, PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE AND RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA Dissertation Submitted To THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY IN PARTIAL FULFILLMENT FOR THE AWARD OF THE DEGREE OF DOCTOR OF MEDICINE IN PHARMACOLOGY DEPARTMENT OF PHARMACOLOGY TIRUNELVELI MEDICAL COLLEGE TIRUNELVELI -11 MAY -2019 BONAFIDE CERTIFICATE This is to certify that the dissertation entitled “A RANDOMIZED, PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE AND RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA ” submitted by DR.T.BABY PON ARUNA to the Tamilnadu Dr. M.G.R Medical University, Chennai, in partial fulfillment of the requirement for the award of the Degree of Doctor of Medicine in Pharmacology during the academic period 2016-2019 is a bonafide research work carried out by her under direct supervision & guidance. PROFESSOR AND H.O.D DEAN Department of Pharmacology, Tirunelveli Medical college, Tirunelveli Medical college, Tirunelveli. Tirunelveli. CERTIFICATE This is to certify that the dissertation entitled “A RANDOMIZED, PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE AND RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA ” submitted by DR.T.BABY PON ARUNA is an original work done by her in the Department of Pharmacology, Tirunelveli Medical college, Tirunelveli for the award of the Degree of Doctor of Medicine in Pharmacology during the academic period 2016-2019. Place: Tirunelveli GUIDE Date: Department of Pharmacology, Tirunelveli Medical college, Tirunelveli. DECLARATION I solemnly declare that the dissertation titled “A RANDOMIZED, PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE AND RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA” is done by me in the Department of Pharmacology, Tirunelveli Medical College, Tirunelveli. The dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University in partial fulfillment for the award of the Degree of Doctor of Medicine in Pharmacology. Place: Tirunelveli DR. T.BABY PON ARUNA, Date: Post graduate student, M.D. Pharmacology, Department of Pharmacology, Tirunelveli Medical college, Tirunelveli -627011 ACKNOWLEDGEMENT First of all, I am grateful to the Almighty for the good health and wellbeing that were necessary to complete this research work. I am greatly indebted to Dr.S.M. Kannan M.Ch (Uro)., Dean, Tirunelveli Medical College and Dr.C.Revathy M.D., Vice Principal, Tirunelveli Medical College, Tirunelveli for their valuable support and generous permission for doing this research work. I wish to thank my guide Dr. J. Ezhil Ramya M.D., Associate Professor and Head of the Department of Pharmacology with due respect and deep gratitude for her inspiration, guidance and kind help rendered in completing this dissertation. I would like to express my deepest thanks to Dr. B. Meenakshi M.D., Associate Professor for giving kind advice, aspiring guidance, motivation and encouragement throughout the research. I would like to express my deepest thanks to Dr. K. Geetha D.C.H., M.D., Associate Professor for giving kind advice, aspiring guidance, motivation and encouragement throughout the research. I sincerely thank Dr.G.Ramanujam M.D., Professor and HOD, Department of Psychiatry for his support. With deep sense of gratitude, I thank the all faculty member of the Department of Psychiatry for sharing their implicit knowledge, support and encouragement during the course of this research work. I am immensely grateful to Dr.A.Dulcie celia D.C.H., M.D., Dr.M. Shanthi M.D., Dr. R. Nalini M.D., Dr. M.Prakash M.D., Dr.Y. Nisha Maheswari, M.D., Dr.M.Lakshmi Prabha M.D., Dr. T.J.Ainsy Goldlin M.D., Assistant Professors of my department for their support and advice provided during the research work. I would like to thank the post graduates of department of Pharmacolgoy, for their friendly advice and sharing their illuminating views related to this study. I also express my sincere thanks to my family members for their moral support and encouragement to carry out this research successful as a postgraduate. CERTIFICATE – II This is to certify that this dissertation work titled “A RANDOMIZED, PROSPECTIVE COMPARATIVE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE AND RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA” of the candidate DR.T.BABY PON ARUNA with registration Number 201616201 for the award of M.D. in the branch of Pharmacology. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion page and result shows 15 percentage of plagiarism in the dissertation. Guide & Supervisor sign with Seal. CONTENTS S.No TITLE PAGE No. 1. INTRODUCTION 1 2. REVIEW OF LITERATURE 3 3. AIM OF THE STUDY 47 4. METHODOLOGY 48 5. RESULTS 54 6. DISCUSSION 75 7. CONCLUSION 81 8. APPENDIX I. Informed Consent Form II. PANSS Scale III. Study proforma IV. Master chart V. Abbreviations 9. BIBILIOGRAPHY INTRODUCTION Schizophrenia is a type of functional psychoses in which severe personality changes and thought disorders occur with no evidence of organic cerebral damage. Although improvement is seen over a prolonged period of time for some patients, most of the patients experience some persisting symptoms despite treatment (1). To prevent relapse, maintenance treatment with antipsychotic drugs is obligatory for most patients who have schizophrenia. (2) Antipsychotic drugs are the cornerstone for the treatment of schizophrenia. First-generation antipsychotics, such as haloperidol, which mainly have dopamine D2 antagonist action, are effective against positive symptoms, but they are relatively less beneficial in treating negative and associated mood symptoms. (3) In addition, the D2 antagonists frequently induce extrapyramidal side effects (e.g., parkinsonism, dystonia, akathisia, and tardive dyskinesia) that are thought to reflect blockade of D2 receptors in the basal ganglia(4). Second-generation antipsychotics, which commonly have combined 5- hydroxytryptamine 2A (5- HT2A) and D2 blocking activity, may offer greater improvement in negative symptoms (5) , and have a more favorable tolerability profile with markedly reduced risk of EPS. However, several second-generation antipsychotics (e.g., clozapine, olanzapine) are associated with significant weight gain and metabolic dysfunction (6). Most of the atypical antipsychotics have relatively high affinity for 1 receptors, muscarinic receptors & H1 receptors. Some of the atypical antipsychoticsα produce weight gain, sedation and impairment in cognitive function by acting at these receptors (7) 1 Results from randomized, large, double-blind study showed that majority of chronic schizophrenia patients withdrawn their antipsychotic medications, because of either lack of efficacy of drug or intolerable adverse drug reactions (8). Considering these drawbacks we need a drug with good clinical efficacy and lower or absent extrapyramidal and metabolic side effects. Lurasidone is an atypical antipsychotic drug recently approved in India apart from other countries for the treatment of schizophrenia. It blocks D2, 5-HT2A and 5-HT7 receptors. It has partial agonistic activity on 5-HT1A receptor but has no effect on H1 and muscarinic receptors. As it has negligible activity at H1 and 5- HT2C receptors, lurasidone may produce lesser incidence of weight gain. The sedation is low due to very minimal action on H1 receptors. Risperidone is the second generation antipsychotic that gained approval of the Food and Drug Administration in 1994 and since then it is gaining rapid popularity. There are various studies which provide evidences that risperidone is as effective as second generation antipsychotics in treating positive symptoms and more effective in treatment of negative symptoms(10). This study is intended to find the clinical efficacy and safety profile of lurasidone comparing with risperidone, a drug in common use nowadays. 2 REVIEW OF LITERATURE SCHIZOPHRENIA - HISTORY It is very clear that psychotic disorders have been present and publicly recognized since ancient times because of their portrayals in old literatures like the madness of medea and the paranoia of Othello. Among the psychotic disorder schizophrenia is the most common disorder and devastating mental illness that affects 1% of population across all cultures (11). The ancient Greeks took a great interest in the human psyche and especially in madness. Plato who lived in the 5th and 4th centuries BC speaks about two kinds of madness, one with a divine origin and another with a physical origin. His descriptions on madness of divine origin closely coincide with the modern descriptions of schizophrenia (12). The influence from Hippocrates is obvious in the citation from Problemata. Hippocrate, the ‘father of medicine’, was partly a contemporary with Plato. He thought that the origin of the diseases as a disturbance of the balance of the humours that is the body fluids. This model groups the humours into blood, phledge, yellow bile and black bile. According to the humoural pathology, an imbalance of the body fluids may influence the brain and provoke madness (13). The earliest academic formulations of the concept of schizophrenia started in the mid-nineteenth century, especially in the work of Benedict- Auguste Morel and Karl Kahlbaum. Morel coined the term ‘demence precoce’ to 3 refer to a disorder that he observed in young people that was characterized by cognitive impairments associated with
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