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Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1 Name of the Candidate and Address (in block letters) 2 Name of the Institution 3 Course of study and subject DR. LAKSHMIPATHI B. S. POST GRADUATE STUDENT IN M.D., PHARMACOLOGY VIMS, BELLARY- 583104 Vijayanagara Institute of Medical Sciences, Bellary. M.D. Pharmacology 4 Date of admission to course 23-06-2011 5 Title of the Topic A comparative study of efficacy, tolerability and safety profile of Asenapine with Olanzapine in patients with schizophrenia in a tertiary care hospital. 6 6.1 NEED FOR THE STUDY: Schizophrenia is a clinical syndrome of variable, but profoundly disruptive, psychopathology that involves cognition, emotion, perception and other aspects of behavior1.Median lifetime prevalence of schizophrenia is about 0.7%–1.0%2.It causes recurring and progressive episodes of positive and negative symptoms, disturbed cognitive function and other abnormalities. This disorder is associated with an increased risk of mortality3, 4and imposes a huge financial burden on society,5 although with striking differences in the annual cost of care per patient between and within different countries.6Optimal treatment of the disease could lessen this burden but it is still challenging to develop effective and safe antipsychotic drugs7. Although many antipsychotics are currently available, the response to treatment varies widely. The lack of efficacy and intolerance in patients with schizophrenia for the older, conventional antipsychotics, commonly defined as “first-generation” antipsychotics8, resulted in the introduction of second generation drugs with the archetype Clozapine. These are now the mainstay of treatment in several countries. Even after the introduction of second generation antipsychotics, some drugs are likely to produce certain untoward effects like weight gain, hyperglycemia and dyslipidemia; drug-related cardiac changes (QTc prolongation) have also been reported9. In this direction efforts have been made to find out some drugs which can have more efficacy and better safety profile. Agents promising in second generation antipsychotics are being tried. Hence the present study has been planned to compare the efficacy, tolerability and safety profile of Asenapine, a novel, sublingual, atypical antipsychotic with Olanzapine, a Thienobenzodiazepine atypical antipsychotic. 6. 2 REVIEW OF THE LITERATURE: The immediate goals of acute antipsychotic treatment are the reduction of agitated, disorganized or hostile behavior, decreasing the impact of hallucinations, the improvement of organization of thought process and the reduction of social withdrawl10. Since schizophrenia requires long term treatment, antipsychotic agents with greater metabolic liabilities especially weight gain should be avoided as first line therapies 10. Existing typical and atypical antipsychotic medications are relatively equally effective in treating what are known as the positive symptoms of schizophrenia, as evidenced by the interpretation of the findings of the governmentfunded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study11. Thus, current treatment guidelines do not favour one class of antipsychotic over the other, rather suggest that “the choice of an antipsychotic medication and its dose, and subsequent decisions about changes in treatment, require careful initial consideration and ongoing, shared decision making between the patient and clinician”12. Asenapine was initially approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of acute schizophrenia. Sublingual administration of Asenapine results in a rapid absorption with peak plasma concentrations within 0.5–1.5 hours and moderate (35%) bioavailability. Oral dosing of Asenapine results in low bioavailability (<2%) due to first pass metabolism in the gut and the liver13. Consistent with other atypical antipsychotics, Asenapine exhibits a higher binding affinity for the 5HT2A receptor compared to D2 receptors. Moreover, Asenapine exhibits a broad range of effects on other neurotransmitter systems including 5HT2C, 5-HT7, 5-HT2B, 5-HT6, α2B, D3, H1, D4, α1A, α2A, α2C, D2L, D1, D2S, 5-HT1A, 5-HT1B, and H2 receptors14. One major difference between Asenapine and most other atypical antipsychotics (except Risperidone, Ziprasidone, and Aripiprazole) is that it exhibits little muscarinic receptor antagonist effects15, which may produce a less cognitively deleterious profile16, given that D2 receptor occupancy has been deemed as vital for antipsychotic efficacy 17. Asenapine appears to have relatively higher potency at serotonin receptors than at dopamine receptors, including the serotonin HT7 receptor, which has been studied regarding object discrimination in rats, and may be a therapeutic target for achieving antidepressant and memory-enhancing actions18. Olanzapine is a thienobenzodiazepine atypical antipsychotic. And it has affinity for serotonin, muscarinic, histamine (H1), and adrenergic (α1) receptors as well as various dopamine receptors. The most frequent adverse effects with Olanzapine are somnolence and weight gain. Hyperprolactinaemia is also common, but usually asymptomatic. The antimuscarinic effects of Olanzapine contra-indicate its use in patients with angle-closure glaucoma; caution is also advised in those with conditions such as benign prostatic hyperplasia or paralytic ileus19. . Different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. While Asenapine has a favourable effect on glucose and lipid metabolism, studies offer generally consistent evidence that Olanzapine treatment is associated with an increased risk of diabetes mellitus and dyslipidaemia20. 6. 3 OBJECTIVES OF THE STUDY: 1. To compare the efficacy of Asenapine with that of Olanzapine. 2. To compare the tolerability and safety profile of Asenapine with those of Olanzapine. 3. To note the adverse effects of Asenapine if any. 7 MATERIALS & METHODS: 1. Source of data: Patients diagnosed with schizophrenia, according to ICD-10, attending the outpatient Department of Psychiatry, Vijayanagar Institute of Medical Sciences, Bellary form the material for our study. 2. Method of collection: The present study is a prospective, randomized, open label study. A detailed history of all registered patients will be recorded. A thorough clinical examination will be done by the qualified psychiatrist for all patients and so will be the required laboratory investigations. A written/ informed consent will be taken from all patients before subjecting them to the study. Data collected will be entered into a specially designed proforma (CRF) for the study. Efficacy will be measured by Positive And Negative Symptom Scale (PANSS). Tolerability and safety will be assessed by measuring the incidence and severity of adverse effects that will be compared with the adverse effect check list prepared for both the drugs separately. The data collected will be subjected to statistical analysis using Normal Distribution Test for proportions. 3. Sampling size: The present study will be conducted during the period from January 2012 to March 2013.One hundred (100) patients will be selected applying inclusion –exclusion criteria. These patients will be divided randomly into two groups. One group will be given Tab Asenapine (4-8mg/day) & another group will be given Tab Olanzapine (2.5-5mg/day). The patients will be given treatment for 6 weeks and will be followed once every two weeks. Periodic psychiatric assessment will be done at every visit. 4. a) Inclusion Criteria: All patients diagnosed with schizophrenia according to ICD-10, in the age group of 19-60 years (both males and females) will be included in the study. b) Exclusion Criteria: 1. Patients falling in the age category <19 years and >60 years. 2. Pregnant and lactating mothers. 3. Patients with history of severe cardiac, hepatic and renal diseases. 4. Patients diagnosed with dyslipidemia. 5. Patients with comorbid illnesses like glaucoma, BPH and cancer. 6. Known cases of Pulmonary Tuberculosis, HIV – AIDS, Leprosy. 7. Patients with comorbid major psychiatric illness including intellectual difficulties and mental retardation. 8. Patients with late onset(onset after 40 yrs age) schizophrenia 9. Treatment resistant schizophrenia 10. Drop out cases will be excluded. [Patients who do not complete 6 weeks of treatment are considered as drop out cases] Investigations: All the patients included in the study are subjected to the following investigations. 1. Baseline / At O week: PANSS(for assessing the efficacy), Complete blood count, blood glucose levels, serum cholesterol levels, liver function tests, blood urea & serum creatinine & ECG. 2. PANSS, Complete blood count, liver enzymes will be repeated at 2nd, 4th & 6th weeks. 3. Blood glucose levels, serum cholesterol levels & ECG will be repeated at the end of the study (6th week). 8. 8. LIST OF REFERENCES: 1. Kaplan and Sodocks Synopsis of psychiatry. Tenth edition, Page 467. 2. Saha S, Chant D, Welham J, Mgrath J. A systematic review of theprevalence of schizophrenia.PLoS Med. 2005;2(5):e141. 3. Stahl SM. Symptoms and circuits, part 3: schizophrenia. J Clin Psychiatry. 2004;65:8–9. 4. Seeman MV. Symptoms of schizophrenia: normal adaptations to inability. Med Hypotheses. 2007;69:253–257. 5. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66:1122–1129. 6. Salize HJ, McCabe R, Bullenkamp J, et al. Cost of treatment of schizophrenia in six European countries. Schizophr Res. 2009;1 11(1– 3):70–77. 7. Rössler W, Salize HJ, van Os J, Riecher-Rössler A. Size of burden of schizophrenia and psychotic disorders. EurNeuropsychopharmacol. 2005;15(4):399–409. 8. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. 9. Luft B, Taylor D. A review of atypical antipsychotic drugs versus conventional medication in schizophrenia. Expert OpinPharmacother. 2006;7(13):1739–1748. 10. Goodman & Gillman’s, the pharmacological basis of therapeutics, 12th edition, page 422. 11. Carpenter WT, Buchanan RW. Lessons to take home CATIE.PsychiatrServ 2008;59(5):523– 525. [PubMed: 18451009]. 12. Parks J, Radke A, Parker G, Foti ME, Eilers R, Diamond M, et al. Principles of antipsychotic prescribing for policy makers, circa 2008. Translating knowledge to promote individualized treatment. Schiz Bull 2009;35(5):931–936. from 13. Expert OpinPharmacother. 2010 doi:10.1517/14656566.2010.506188. August; 11(12): 2107–2115. 14. Cosi C, Koek W. Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT(1A) receptors expressed in HeLa cells. Eur J Pharmacol 2001;433(1):55–62. [PubMed: 11755134]. 15. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996;124(1–2):57–73. [PubMed: 8935801]. 16. Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. Drugs 2008;68(16):2269– 2292. [PubMed: 18973393]. 17. Swerdlow NR, Braff DL, Taaid N, Geyer MA. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psych 1994;51 (2):139–154. 18. Ballaz SJ, Akil H, Watson SJ. The 5-HT7 receptor: Role in novel object discrimination and relation to novelty-seeking behavior. Neuroscience. 2007;149(1):192–202. [PubMed]. 19. Martin dale, 36th edition, the complete drug reference page 1013. 20. Newcomer JW.Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.CNS Drugs. 2005;19 Suppl 1:193. 9 Signature of candidate: 10 Remarks of the guide: 11 Name & Designation of (in block letters) DR. K. LAKSHMINARAYANA. PROFESSOR OF PHARMACOLOGY, VIJAYANAGAR INSTITUTE OF MEDICAL SCIENCES, BELLARY. 11.1 Guide 11.2 Signature DR. SRINIVAS. T. R. 11.3 Co-Guide (if any) 11.4 Signature 11.5 Head of Department 11.6 Signature 12 12.1 Remarks of the Chairman & Principal 12.2 Signature