Post Graduate Student in Pharmacology (M.D)

From, Date: 24.09.2012. DR. SWATHI ACHRAYA. Post graduate student in Pharmacology (M.D), Department of Pharmacology, VIMS, Bellary.

To, The Principal Vijayanagar Institute of Medical Sciences, Bellary. THROUGH PROPER CHANNEL

Respected sir,

Sub: Submission of synopsis – reg. ------In accordance with the above subject I, the undersigned, studying in Medical P.G course in M.D Pharmacology have been allotted the dissertation topic, A COMPARATIVE STUDY OF THE EFFICACY, TOLERABILITY AND SAFETY PROFILE OF “ILOPERIDONE WITH RISPERIDONE IN PATIENTS WITH SCHIZOPHRENIA IN VIMS, A TERTIARY CARE HOSPITAL- BELLARY”, from January - 2013 to March - 2014 under the guidance of DR. V. SRINIVAS, Professor and Head of the Department, Department of Pharmacology, VIMS, Bellary. I request your kindself to accept and forward the same to the Registrar of RGUHS University for Registration. Thanking you, Yours faithfully,

(DR. SWATHI ACHARYA)

Signature of the Guide Signature of the Co - Guide

Dr. V. Srinivas Dr. S. Kotresh Professor and HOD, Associate Professor, Dept of Pharmacology, Dept of Psychiatry, VIMS, Bellary 583104. VIMS, Bellary

Dr. V. Srinivas Professor and HOD, Dept of Pharmacology, VIMS, Bellary 583104. From, Date: 24.09.2012. The Professor and Head of the Department, Department of Pharmacology, VIMS, Bellary.

To, The Registrar, Rajiv Gandhi University of Health Sciences, Bangalore.

THROUGH PROPER CHANNEL

Respected Sir, As per the regulation of the university for registration of dissertation topic, the following Post Graduate Student in M.D (Pharmacology) has been allotted the dissertation topic as follows by the official registration committee of all the qualified guide of the department of Pharmacology .

Name Topic Guide DR. SWATHI ACHARYA A COMPARATIVE STUDY OF P.G. STUDENT IN THE EFFICACY, DR. V. SRINIVAS M.D (PHARMACOLOGY) TOLERABILITY AND PROFESSOR & DEPARTMENT OF SAFETY PROFILE OF HOD, PHARMACOLOGY “ILOPERIDONE WITH DEPARTMENT OF VIMS, BELLARY. RISPERIDONE IN PATIENTS PHARMACOLOGY, WITH SCHIZOPHRENIA IN VIMS, BELLARY. VIMS, A TERTIARY CARE HOSPITAL- BELLARY”

Therefore I kindly request you to communicate the acceptance of the dissertation synopsis to the P.G. student at an early date.

Thanking you, Yours faithfully,

Place: Bellary Date: Dr. V. SRINIVAS Professor and Head of the Department Dept of Pharmacology VIMS, BELLARY. Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 Name of the Candidate DR. SWATHI ACHARYA. and Address POST GRADUATE STUDENT IN M.D., (in block letters) PHARMACOLOGY VIMS, BELLARY- 583104. 2 Name of the Institution Vijayanagara Institute of Medical Sciences, Bellary. 3 Course of study and subject M.D. Pharmacology.

4 Date of admission to course 14.07.2012.

5 Title of the Topic A COMPARATIVE STUDY OF THE EFFICACY, TOLERABILITY AND SAFETY PROFILE OF “ILOPERIDONE WITH RISPERIDONE IN PATIENTS WITH SCHIZOPHRENIA IN VIMS, A TERTIARY CARE HOSPITAL - BELLARY”.

6 6.1 NEED FOR THE STUDY:

Schizophrenia is a severe form of mental illnesses affecting about seven per thousand of adult population, mostly at the age group 15-35 years. The lifetime prevalence of schizophrenia is between 0.4 and 1.4% .In India there are an estimated four million people with schizophrenia.[1] It is a clinical syndrome of variable but profoundly disruptive psychopathology which involves thought perceptions, emotions, cognitive function and behavior. It is a leading health problem that exacts enormous personal and economic cost world wide, affecting around 1% of population.[2]Persons suffering from Schizophrenia ,suffer from increased morbidity and mortality compared with general population , having life expectancy of 20% shorter.[3]

Optimal treatment of disease can lessen this burden.[4]In the treatment of Schizophrenia , choice of antipsychotic agent is based on avoidance of adverse effects. Since schizophrenia is a life long disease, the goal of treatment is to maximize functional recovery by decreasing positive symptoms and their behavioral influences, improving negative symptoms, decreasing the social withdrawal, and remediating cognitive dysfunctions.[5]

Although many antipsychotics are currently available, the treatment varies widely. A study has shown that antipsychotic treatment is marked by poor compliance, drug discontinuation and frequent switching attributable to lack of efficacy and recently introduced atypical antipsychotics. Hence the field is in need of better agents, which can improve antipsychotic agent property, a lower rate of refractory illness and reduced metabolic and neurological side effects.[6]

Among the atypical antipsychotics, Risperidone most widely studied drug, has shown to improve positive and negative symptoms of psychosis with reduced risk of relapse and lower liability for movement disorders.[7]

Iloperidone, a new dopamine type2/Serotonin type 2A (D2/5HT2A) antagonist structurally related to Risperidone, is expected to give better efficacy [8] with lesser extrapyramidal symptoms than the D2 receptor antagonists.

Hence the present study has been planned to compare the efficacy, tolerability and safety profile of Iloperidone, a novel antipsychotic with that of Risperidone, an atypical antipsychotic in department of psychiatry in collaborations with department of pharmacology in VIMS, Bellary.

6. 2 REVIEW OF LITERATURE:

Dopamine hypothesis for Schizophrenia is essential for understanding the mechanism of all antipsychotic agents. Other non-dopaminergic receptors like Serotonin receptors (5HT2A) are also involved. 5HT2A receptor subtype mediates the synergistic effects and protects against extrapyramidal consequences of D2 antagonism .So the current research is directed towards development of compound that acts on several transmitter receptor systems.[9]

Among atypical antipsychotic agents, Risperidone is a benzisoxazole agent which is an antagonist at D2 receptor, which is claimed (to produce lower incidence of extrapyramidal symptoms) and to have efficacy against both positive and negative symptoms of Schizophrenia. However, it causes common adverse effects like insomnia, headache, anxiety, dyspepsia, blurred vision, constipation, nausea, vomitting, abdominal pain and sexual dysfunction.[10]

Systematic review suggested that Risperidone has an advantage over Haloperidol as it causes faster onset of action, has lower incidence of extrapyramidal symptoms and shows greater efficacy against negative symptoms of Schizophrenia.[11] One study has showed Risperidone to be more acceptable to schizophrenia patients compared to typical antipsychotics and increases the odds of moderate clinical improvement [12].

A Study conducted comparing the effects of Chlorpromazine and Risperidone showed that Risperidone was superior compared to chlorpromazine in controlling negative symptoms and reduction in negative symptoms was 30% for Chlorpromazine and 74% for Risperidone.[13]The fact that risk of extrapyramidal symptoms of Risperidone appears to be dose dependent, was established by a study. [14] Another study showed that Risperidone is the only atypical antipsychotic to have shown significant lower relapse rate compared with Haloperidol.[15]. The median time of relapse was longer for Risperidone (466 days) when compared to Haloperidol (205 days).[16]

A review concluded that, there was little difference between Olanzapine and Risperidone apart from their adverse effects. Risperidone was partly associated with movement disorder and sexual dysfunction while Olanzapine induced rapid weight gain.[17]

Iloperidone was introduced in May 2009 and approved by FDA for treatment of Schizophrenia belongs to the piperidinyl benzisoxazole derivatives.[18] Its mechanism of action involves high affinity antagonism of serotonergic (5HT2A), alpha 1 and alpha 2 adrenergic receptors and D2 and D3 dopeminergic receptors. It [19] is most potent at D3 receptors. D3> alpha 2c> 5HT1A> D2 5HT6.

In one study involving 593 patients, 4 weeks double blind trial with Iloperidone 24mg/day was found to be effective, safe and was well tolerated in patients with acute exacerbation of schizophrenia than Ziprosidone (160mg/day). Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Iloperidone was associated with lower rates of many adverse effects like sedation (13%), somnolence (4%), extrapyramidal symptom (3%), akathisia (1%), agitation (3%), restlessness (4%) however it was associated with higher incidence of weight gain, tachycardia, hypotension, dizziness.[20]

Other studies comparing Iloperidone(4-24 mg/day) with Haloperidol (15mg/day), Risperidone (4-8mg/day) and placebo, showed better efficacy of Iloperidone compared to Risperidone and Haloperidol. At least 1 Iloperidone dosing group in each study demonstrated significantly better efficacy than placebo (Study 1, Iloperidone 12 mg/d [P = 0.047]; Study 2, 4-8 mg/d [P = 0.012] and 10- 16 mg/d [P = 0.001]; and Study 3, 20-24 mg/d [P = 0.010]). Risk of motor side effects were less with Iloperidone than with Risperidone and Haloperidol.[21]

In studies comparing Iloperidone (4-16 mg/day) with Haloperidol (5- 20mg/day), showed Iloperidone was found to be as effective as Haloperidol and the most common adverse events observed were insomnia (18.1%), anxiety (10.8%), and schizophrenia aggravated (8.9%) in Iloperidone group . Insomnia (16.9%), akathisia (14.4%), tremor (12.7%), and muscle rigidity (12.7%) were observed with haloperidol. The Extrapyramidal Symptoms Rating Scale scores improved with Iloperidone and worsened with haloperidol.[22]

A study done to assess the safety profile of Iloperidone showed that most common adverse effects were dizziness, drymouth, dyspepsia and somnolence. Statistically significant changes in vital signs particularly, orthostatic hypotension and tachycardia were noted in all Iloperidone treated group. Although corrected QT interval increased in all treatment groups no deaths or arrhythmias were attributable to it. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than Risperidone or Haloperidol groups. Patients taking Iloperidone experienced a mild weight increase (range, 1.5- 2.1 kg) similar to that of Risperidone (1.5 kg), No change in glucose or lipid profile seen, However a decrease in triglyceride level was observed. Discontinuation due to AEs was 4.8% for Iloperidone, 7.6% for Haloperidol, 6.2% for Risperidone, and 4.8% for placebo.[23]

6. 3 OBJECTIVES OF THE STUDY:

1. To compare the efficacy of Iloperidone and Risperidone.

2. To compare the tolerability & safety profile of Iloperidone and Risperidone.

7 MATERIAL & METHODS:

7.1 Source of data: Patients diagnosed with Schizophrenia according to ICD- 10 criteria, attending the Outpatient Department of Psychiatry, Vijayanagara Institute of Medical Sciences, Bellary form the material for our study. Inclusion and exclusion criteria are applied while registering the subjects for study. 7.2 Method of collection: The present study will be a prospective, randomized and open label study. A detailed history of all the registered patients will be taken. A thorough clinical examination will be done for all patients and so will be required laboratory investigations. A written/informed consent will be taken from all patients before subjecting them for study. Data collected will be entered in a specially designed Proforma (Case Recording Form) for study. Efficacy will be measured by PANSS (Positive and Negative Syndrome Scale), safety profile will be assessed by measuring incidence and severity of adverse effects that will be compared with adverse effect checklist prepared for both drugs separately. Extrapyramidal symptoms are assessed by ESRS (Extrapyramidal Symptom Rating Scale). The data collected will be transferred to a master chart which is then subjected to the statistical analysis using normal distribution tests for proportions.

Sampling size and Duration: The present study will be conducted during the period from January 2013 to March 2014. Eighty (80) Patients will be selected applying inclusion – exclusion criteria. These patients will be divided randomly into two groups. One group will be given Risperidone (4-8mg/day) & other group Iloperidone (6-24mg/day). The patients will be given treatment for 6 weeks and will be followed once in every 2 weeks. Periodic psychiatric assessment will be done at every visit by qualified psychiatrist. a) Inclusion criteria: - All patients diagnosed of schizophrenia according to ICD-10, in the age group of 18-65 yrs. Both male and females will be included in the study. b) Exclusion criteria: 1. Patients falling in the age group of <18 yrs and >65 yrs 2. Pregnant and lactating females. 3. Patients with history of hypertension, diabetes, hypercholesterolemia and cardiac diseases, hepatic disease, renal disease and terminally ill patients. 4. Patients with organic brain syndromes and drug abuse. 5. Patients already on other antipsychotic agents. 6. Drop outs will be excluded.

7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly: Yes. All the patients included in the study are subjected to the following investigations along with psychiatric assessment.

Investigations: All the patients included in the study are subjected to the following investigations.

1. Baseline/At 0 wk: Complete blood count. Blood Glucose level. Serum Cholesterol, Triglycerides. LFT, Urea, Creatinine. ECG, Body weight measurement and PANSS score. 2. Follow up at 2 weeks: PANSS score, side effect profiles and ESRS scale measured 3. Follow up at 4 weeks: PANSS score, side effect profiles and ESRS scale measured. 4. Follow up at 6 weeks: Blood Count, ECG, Cholesterol, Triglyceride, Blood Glucose level and Body weight measurements, PANSS score, side effect profiles and ESRS scale measured.

7.4 Has ethical clearance been obtained from your institution in case of 7.3? Yes, Ethical clearance has been obtained from the Institutional Ethics committee (IEC) of VIMS, Bellary.

8. LIST OF REFERENCES (BIBLIOGRAPHY): 1. India support people with schizophrenia: www.who.int/mental_health/ …./en/India-support-schizophrenia.pdf. 2. Kaplan & Saddock’s comprehensive text book of psychiatry 7th edition Vol I: 1096 – 1097. 3. Shiv Gautam, Parth Singh Meena, Department of Psychiatry S. M. S. Medical College, Jaipur ,Rajasthan, India; Drug Emergent metabolic syndrome in patient with schizophrenia receiving atypical antipsychotics. Indian Journal of Psychiatry Vol 53 Number 2 April-June 2011. Res 1992; 7:109-16. 4. Rossler W, Salize HJ, Van OS J, Riecher – Rossler A. size of burden of Schizophrenia and psychotic disorder, Eur Neuropsychopharmacol 2005; 15(4): 399-409. 5. Goodman and Gilman – The pharmacological Basis of Therapeutics 12th Edition. 418-455. 6. Liberman JA, Stroups TS, Mc Evoy JP, et al. Clinical Antipsychotic trials of Intervention effectiveness (CATIE) Investigators Effectiveness of antipsychotic drugs in patients with chronic Schizophrenia. N Eng J Med. 2005: 353: 1209-1223. 7. Donal EN Addington, Curistos pantelis, Mary Dineen, Isma Besmattia, Steven J Romano. Efficacy and Tolerability of Ziprosidone versus Risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: An 8 weeks double blind multicenter trial; J clinical psychiatry 65:12 Dec 2004. 8. Silvio caccia, Luca pasina and Alless audroNobili. New atypical antiphyschotics for schizophrenia: Iloperidone: Drug Des Devel ther 2010; 4: 33-48. 9. Basic and Clinical Pharmacology 12th Edition Katzung Masters Trevor: 502- 503. 10. Matrindale the complete drug references 37th Edition Vol. I 1130-1131. 11. Grant S, Fitton A: Risperidone A review of its psychopharmacology and therapeutic potential in the treatment of Scrizophrenia, Drugs 1994 Aug 48(2): 253-73. 12. Kennedy E, Song F, Hunter R, Clarke A, Gilbody S. Risperidone versus typical antipsychotic medications for Schizophrenia. Cochrane Database syst Rev 2003: (2): CD000440. 13. Amrita Prakash Singam, Abhishek Mamarde and Prakash B. Behere .A single blind comparative clinical study of the effects of chlorpromazine and Risperidone on Positive and Negative symptom in patients of Schizophrenia: Indian J psychol Med. 2011 July-Dec 33(2) 134-140. 14. Owens DGC, Extrapyramidal side effects and tolerability of Risperidone. A Review J clin Pscyhiatry 1994:55 (Suppl 5):29-35. 15. Pajonk FG. Risperidone in acute and long term therapy of Schizophrenic a clinical profile: Prog Neuropsychopharmacol Bio psychiatry. 2004 Jan; 28(1):15-23. 16. Schooler N et al. Rispenidone and haloperidol in the first episode of psychosis: a long term randamized trial. Am J psychiatry 2005, 162: 947-53. 17. Jayaram MB et al. Risperidone versus Olanzapine for schizophrenia available in cochrane Database of systemic review. Issue 2 Chichester John willey 2006. 18. Jonathan R Scarft MD and David A casey MD. New oral atypical antipsychotic agent: A review. P T. 2011 December; 36(12): 832-838. PMCID: PMC3278183. 19. Kalkman HO, Feuerbach D. Lotscher E, Schoeffter P. Functional characterization of the novel antipsychotic iloperidone at human D2, D3, alpha 2C ,5HT6 and 5HT 1A, receptors. Life sci 2003; 73(9): 1151- 1159. 20. Cutler AJ, Kalali AH, Weiden PJ, et al. Four week, double blind, placebo and ziprosidone controlled trial of Iloperidone in patients with acute exacerbations of schizophrenia. J clin psychopharmacol. 2008; 28 (2 suppl 1): S20-S28. 21. Potkin SG, Litman RE, Torres R, Wolfgang CD. Efficacy of Iloperidone in the treatment of schizophrenia: Initial phase 3 studies. J Clincal psychopharmacol. 2008; 28 (2 suppl 1): S4-S11. 22. Kane JM, Lauriello J, Laska E, et al. Long term efficacy and safety of Iloperidone: Result from 3 clinical trails for treatment of Schizophrenia.J clin psychopharmacol. 2008: 28(2 suppl 1)S29-S35. 23. Weiden PJ, Cutler AJ, Polymeropoulos MH, wolfgang CD, Safety profile of Iloperidone: A pooled analysis of 6 week acute phase pivotal trials: Journal clin Psychopharmacol .2008: 285 (2 suppl 1) S12-S19. 9 Signature of candidate:

(DR. SWATHI ACHARYA)

10 Remarks of the guide:

DR. V. SRINIVAS. M.D., 11 Name & Designation of PROFESSOR & HOD, (in block letters) DEPARTMENT OF PHARMACOLOGY, VIMS, BELLARY.

DR. V. SRINIVAS. M.D., 11.1 Guide

11.2 Signature

DR. S. KOTRESH. M.D., 11.3 Co-Guide (if any) ASSOCIATE PROFESSOR, DEPARTMENT OF PSYCHIATRY. VIMS, BELLARY. 11.4 Signature

DR. V. SRINIVAS. M.D., 11.5 Head of Department PROFESSOR & HOD, DEPARTMENT OF PHARMACOLOGY, VIMS, BELLARY.

11.6 Signature

12 12.1 Remarks of the Chairman & Principal

12.2 Signature VIJAYANAGAR INSTITUTE OF MEDICAL SCIENCES BELLARY – 583104, KARNATAKA STATE, INDIA.

Date: 25.09.2012. To, Dr. Swathi Acharya PG in Pharmacology, Department of Pharmacology, Vijayanagara Institute of Medical Sciences, Bellary – 583104.

Sub: VIMS IEC CLEARANCE CERTIFICATE

To Whomsoever it may concern, it is certified that the Dissertation Synopsis entitled, A COMPARATIVE STUDY OF THE EFFICACY, TOLERABILITY AND SAFETY PROFILE OF “ILOPERIDONE WITH RISPERIDONE IN PATIENTS WITH SCHIZOPHRENIA IN VIMS, A TERTIARY CARE HOSPITAL- BELLARY”, has been reviewed and approved by Institutional Ethics Committee of Vijayanagara Institute of Medical Sciences [Govt. Medical College] and the Director of VIMS, Bellary at it’s meeting held on Date:

The Dissertation Work may be commenced subject to the following conditions:

1. Informed / Written consent should be taken from each patient [or Legal guardian] participating in the study.

2. a) It is mandatory that a 3 monthly Interim Review Report on the Status of the Dissertation work is to be submitted to the Member Secretary of VIMS IEC.

b) On completion of the above Dissertation work the principal Investigator and Co- Investigators are responsible for submitting a brief summary of the results obtained to the Member Secretary of VIMS IEC through Chairperson / Principal / Director of VIMS.

With Best Wishes.

Member Secretary, Chairman, Institutional Ethics Committee, Institutional Ethics Committee, VIMS, Bellary. VIMS, Bellary.