The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial Debanjan Mandal Dissertation submitted to The Tamil Nadu Dr. MGR Medical University, in part fulfilment of the requirement for MD Branch XVIII Psychiatry Final Examination to be held in May 2018 1 CERTIFICATE This is to certify that the dissertation titled “The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial” is the bonafide work of Dr. Debanjan Mandal towards MD Psychiatry Degree Examination of Tamil Nadu, Dr. M.G.R Medical University to be conducted in May 2018. This work has not been submitted to any university in part or full. Dr. Anna Benjamin Pulimood, M.D., PhD Dr. Mary Anju Kuruvilla M.D. Principal Professor and Head Christian Medical College Department of Psychiatry Vellore 632002 Christian Medical College Vellore 632002 2 CERTIFICATE This is to certify that the dissertation titled “The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial” has been initiated with Dr. Debanjan Mandal being the principal investigator and Prof. Prathap Tharyan as the guide. Dr. Prathap Tharyan retired from service on 1st August 2017 and Dr. Saumil Dholakia, Professor of Psychiatry, is the guide for this dissertation from 2nd August 2017 onwards. Dr. Anna Benjamin Pulimood M.D., PhD Dr. Mary Anju Kuruvilla M.D. Principal Professor and Head Christian Medical College Department of Psychiatry Vellore 632002 Christian Medical College Vellore 632002 3 CERTIFICATE This is to certify that the dissertation titled “The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial” is the bonafide work of Dr. Debanjan Mandal towards MD Psychiatry Degree Examination of Tamil Nadu, Dr. M.G.R Medical University to be conducted in May 2018. This study has been done under my guidance. This work has not been submitted to any university in part or full. Dr. Saumil Dholakia, MD Professor Department of Psychiatry Unit 2 Christian Medical College Vellore 632002 4 DECLARATION I hereby declare that this dissertation titled “The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial” is a bonafide work done by me under the guidance of Dr Saumil Dholakia, Professor of Psychiatry, Christian Medical College, Vellore. This work has not been submitted to any university in part or full. Dr. Debanjan Mandal, MBBS, DPM Post Graduate Registrar (MD) Department of Psychiatry Christian Medical College Vellore 632002 5 IRB APPROVAL LETTER 6 7 8 9 10 PLAGIARISM CERTIFICATE This is to certify that this dissertation work titled “The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial” of the candidate Dr. Debanjan Mandal with registration number 201628252 for the award of MD in the branch of XVIII Psychiatry. I personally verified urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows one percentage (1%) of plagiarism in the dissertation. Guide and Supervisor sign with seal 11 ACKNOWLEDGEMENTS Writing this dissertation has been an incredible learning experience for me in the field of medical research, and a mere “Thank you” in no way can adequately express my sincere gratitude to the following people without whom this work of research would not have been possible. Prof. Prathap Tharyan, for giving me the wonderful opportunity to work on my thesis under his guidance, it is truly an honour. Thank you for being a constant source of brainstorming scientific ideas, motivation, enthusiasm, immense knowledge, support and patience. Dr. Saumil Dholakia, for patiently guiding me through this project with constant moral support, inspiration, encouragement, for being there for me whenever I needed any help; and for all the innumerable instances where you were instrumental to completing this study. Dr Arnab Mukherjee, Dr Akhil Abhijnhan, Dr Sanmitra Dasgupta and Dr Munaf Nandyal, for being my co-guides, for on-field participation by recruitment and psychoeducation of participants; and for invaluable suggestions, constant support, help and encouragement throughout the study. Prof. Antony Devasia, Prof. Santhosh, Prof. Mukka, Dr. Partho Mukherjee, Dr.Johan Boaz, all from the department of Urology, for being my co-guides and helping in recruitment of patients. Prof. Deepa Braganza, Head of Unit 2, for being a constant source of moral support, encouragement and immense help throughout the study. 12 Prof. Anju Kuruvilla, Head of our Department and Unit 1, Prof. Rajesh Gopalakrishnan, Prof. K S Jacob, for allowing me to recruit patients; and for their invaluable suggestions, support and encouragement. Prof. Suja Kuriyan, Head of Unit 3; for allowing me to recruit patients, and her support. Prof. Anna Tharyan, Ms Nandini Kathale, Mr Joseph Noel, my teachers, for their continuous encouragement and support throughout the tedious process. All my teachers and colleagues in our department, for rendering their support. Mr. Jayapaul, Mr. James, Dr Vivekanandan, Dr. Naveen Kolloju, Dr Saurav Naskar, Dr Ojas Gupta, Dr Abu Philip; for translation of various forms. Mr. Suresh, Mr. Palani and Mr. Jayapaul for formatting, printing and rendering help in conducting the study. Mr Richard Kirubakaran, our statistician, for helping in randomization process. Mr Ravi Nesan and other staffs from Pharmacy, for providing the participants with appropriate medication. Medical records department, for being of immense help throughout the study. I am indebted to all the study participants, who willingly and patiently agreed to take part in the study. I thank the research committee of Christian Medical College, Vellore for granting approval and funding of this project. 13 Heartfelt gratitude and special thanks to my family; my parents Mrs. Indrani Mandal and Mr. Arun Kumar Mandal, and my brother Nilanjan; and to my ever helpful friends- Dr(s).Madhu, Rosen, Deepthy, Abhinav, Raviteja, Abigail, Aishwarya, Poornima, Priyanka, Shilpa, Cheruba, Richa; and Gouri di; Arka, Saurav, Abhishek, and Prateep; for their constant encouragement, prayer and support to make this study possible. I thank God Almighty for being with us, and for giving us the strength to go through with this project. 14 Abstract Title of the abstract: The efficacy and safety of Clomipramine Hydrochloride versus Dapoxetine Hydrochloride in Married Heterosexual Men with Premature Ejaculation: A Pragmatic, Randomized Controlled Trial Department: Psychiatry Name of the candidate: Dr. Debanjan Mandal Degree and subject: MD, Psychiatry Name of the guide: Dr. Saumil Dholakia Background: Dapoxetine and Clomipramine are used in treating patients with premature ejaculation. Previous trials have demonstrated advantages for Dapoxetine compared to other SSRIs in increasing IELT (intravaginal ejaculatory latency time), and reducing distress due to premature ejaculation, but no head to head comparisons have been conducted against Clomipramine (tricyclic antidepressant) that has been shown to be effective in treatment of premature ejaculation. Objective: Objective of the study was to evaluate the efficacy and safety of six weeks of daily oral Clomipramine (25 to 50 mg) versus oral Dapoxetine on demand (30 mg; once a week for six weeks or for six doses) in the treatment of Premature Ejaculation in heterosexual, married men. 15 Methods: Design: The study was designed as a pragmatic, randomized, parallel group, allocation-concealed, assessor-blinded, active-controlled trial Setting: Urology, Andrology and Psychiatry department outpatient services of a teaching general and multi-specialty referral hospital in south India Participants: Eighteen married adults presenting with premature ejaculation as a result of a non-organic etiology and fulfilling selection criteria who provided written (and video-taped) informed consent for study participation. The target sample size is 120 and the study is ongoing. Interventions: Oral Clomipramine (25 mg daily for 1st week and 25-50 mg for subsequent 5 weeks, depending on participants’ preference) or oral Dapoxetine 30 mg on demand ( taken 1-3 hours prior to intercourse) for 6 doses (recommended once weekly for 6 weeks). Additional non-pharmacological interventions were delivered to each participant by the means of a structured psycho-education module. Main outcome measures: The primary outcome is the improvement of premature ejaculation at six weeks (or after the first six sexual encounters) which was measured by validated patient-reported measures (1) the Premature Ejaculation Profile (PEP) that measures changes in the participants subjective sense of control over ejaculation, distress related to PE, interpersonal difficulty and satisfaction with sexual intercourse, and (2) participant-reported Clinical Global Impression of Change (CGI-C). Secondary outcomes were adverse effects 16 of the interventions using the validated ASEC side effects rating