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A Study on the Efficacy and Safety of Blonanserin in Indian Patients in Ahmedabad: a Randomized, Active Controlled, Phase III Clinical Trial

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A Study on the Efficacy and Safety of Blonanserin in Indian Patients in Ahmedabad: a Randomized, Active Controlled, Phase III Clinical Trial Lakdawala et al. : Efficacy and Safety of Blonanserin 359 Original Research Article A study on the efficacy and safety of Blonanserin in Indian patients in Ahmedabad: a randomized, active controlled, phase III clinical trial Bhavesh Lakdawala1, Mahemubin S. Lahori2, Ganpat K. Vankar3 1Associate Professor, Dept. of Psychiatry, AMC-MET Medical College and Sheth L.G. General Hospital, Ahmedabad, Gujarat, India. 2Assistant Professor, Dept. of Psychiatry, GMERS Medical College and General Hospital, Sola, Gujarat, India. 3Professor, Dept. of Psychiatry, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital Wardha, Maharashtra Corresponding author: Dr. Mahemubin Lahori Email – [email protected] ABSTRACT Introduction: Blonanserin is a novel atypical antipsychotic with higher dopamine D2 receptor occupancy and lower serotonin 5-HT2A receptor blocking activity as compared to the other atypical antipsychotics. The objective of this study was to compare the efficacy and safety of blonanserin with haloperidol in Indian patients with schizophrenia. Methodology: This was an 8 week, randomized, open label, active controlled, multicentre study. Patients diagnosed with schizophrenia according to the DSM-IV criteria were enrolled in the study. Patients were randomized to receive either blonanserin (16 mg/day) or haloperidol (4.5 mg/day). Patients were assessed on an out-patient basis after every 2 weeks for clinical efficacy [Positive and Negative Syndrome Scale (PANSS) total and factor scores], Clinical Global Impressions–severity CGI-S, Clinical Global Impressions–Improvement (CGI-I), Global Assessment of Efficacy (CGI-C), adverse events and drug compliance. Results: At our centre, total 60 patients were randomized in the study with 30 patients each in Blonanserin and Haloperidol group. Both blonanserin and haloperidol were effective in reducing the PANSS score at the end of the study as compared to the baseline (P<0.001). There was a significantly more decline in the mean total PANSS score from 78.5 ± 15.6 (range: 43-105) at baseline (Week 0) to 35.0 ± 8.8 (range: 14-54) at last assessment (Week 8) in the patients enrolled in Study Arm of Blonanserin; as compared to decline in the same from 67.7 ± 14.0 (range: 39-93) at baseline (Week 0) to 31.0 ± 5.7 (range: 21-43) at last assessment (Week 8) in Study Arm of Haloperidol. Blonanserin was superior to Haloperidol in control of negative symptoms of schizophrenia. On Clinical Global Impression for change in disease severity (CGI- S) at the end of treatment period; 10 (35.7%) patients had “much improvement” in Blonanserin group. On the other hand, 5 (17.2%) patients had “much improvement” in Haloperidol group. Blonanserin was well tolerated by the patients with the most common adverse event being extrapyramidal symptoms. Conclusion: Blonanserin was found to be non-inferior to haloperidol in the treatment of patients with schizophrenia and was superior to haloperidol for the treatment of negative symptoms of schizophrenia. Blonanserin has a great potential to be a new atypical first line drug for the treatment of schizophrenia. Key Words: Blonanserin, Haloperidol, India, Schizophrenia, Atypical antipsychotics (Paper received – 11th November 2017, Peer review completed – 25th November 2017) (Accepted – 28th November 2017) (Clinical Trials Registry of India: CTRI/2011/091/000140) Indian Journal of Mental Health 2017;4(4) Lakdawala et al. : Efficacy and Safety of Blonanserin 360 INTRODUCTION Schizophrenia is a complex heterogeneous psychiatric disorder with diverse manifestations including positive (e.g. hallucinations, delusions, agitations), negative (e.g. affective flattening, anhedonia, avolition, alogia) and disorganised (e.g. disorganised behaviour and speech, poor attention) symptoms; mood symptoms (e.g. depression) and cognitive impairments [1]. It affects about 7 per thousand of the adult population, mostly in the age group of 15-35 years, impairing their personal, social and occupational functioning [2]. Antipsychotic pharmacotherapy is the mainstay for the treatment of schizophrenia. Typical antipsychotics like haloperidol are effective in controlling the positive symptoms but have little effect on the negative symptoms and are often associated with severe adverse events like extrapyramidal symptoms (EPS) [1]. The development of atypical antipsychotics (e.g. risperidone, olanzapine and clozapine) has led to better control of negative symptoms with lesser propensity of inducing EPS. The enhanced efficacy and reduced adverse events of these atypical antipsychotics are thought to be due to their broader receptor binding profile including seroternegic, adrenergic and muscarinic receptors and weaker antidopaminergic activity [3]. Although the atypical antipsychotics are better than the first generation antipsychotics in the management of schizophrenia, they themselves are accompanied by adverse effects such as metabolic disturbances, weight gain and hyper-prolactinaemia [4]. Moreover, some patients are still only partially responsive to the treatment. Thus, there is a need for atypical agents with both good efficacy and improved tolerability [5]. Blonanserin is a novel atypical antipsychotic with a unique pharmacological receptor profile. It has higher dopamine D2 receptor occupancy and lower serotonin 5-HT2A receptor blocking activity as compared to the other atypical antipsychotics and is often called as “dopamine-serotonin antagonist”. It has lower affinity for serotonin 5-HT2C and adrenergic α2 receptors while it is almost devoid of histamine H1 and muscarinic M1 antagonistic activity. This selective receptor binding profile of blonanserin may minimize adverse events seen with other atypical antipsychotics. Moreover, blonanserin may have better effect on cognitive function due to its relatively high affinity for 5-HT6 receptors [6-8]. The efficacy and safety of blonanserin in the treatment of both positive and negative symptoms of schizophrenia has been demonstrated in various short term (upto 8 weeks) and long term (upto 6 years follow up) clinical studies in comparison to placebo and active comparators like risperidone and haloperidol [7.9]. However, there is dearth of data on the efficacy and safety of blonanserin in the Indian population. We report the results of a randomized, multicentre study comparing the efficacy and safety of blonanserin with that of haloperidol in Indian patients with schizophrenia in one centre of Ahmedabad. The aim of the study was to assess the comparative efficacy and safety of Blonanserin and Haloperidol in Indian patients with schizophrenia. METHODOLOGY The study was started after approval by the Licencing Authority (Drugs Controller General of India) and the Institutional Ethics Committees of the centre. Study was conducted at B.J. Medical College and New Civil Hospital, Ahmedabad. It was conducted in compliance with the Good Clinical Practise Guidelines, the local regulatory requirements and the ethical principles of the Declaration of Helsinki. The study was registered on Clinical Trials Registry of India (CTRI/2011/091/000140). Written informed consent was obtained from all the patients before enrolment in the study. Patients of either sex, 18 to 65 years of age and diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)[10] were enrolled in the study. Patients were excluded from the study if they had history of any organic psychiatric disorder, lack of response to antipsychotic treatment, any other psychiatric or neurological illness or neuroleptic malignant syndrome. Patients with other clinically significant illnesses (e.g. uncontrolled diabetes, significant cardiovascular diseases, angle-closure glaucoma, benign prostatic hyperplasia, urinary retention or paralytic ileus, renal or hepatic impairment, malnutrition, dehydration, malignancy), hypersensitive to Indian Journal of Mental Health 2017;4(4) Lakdawala et al. : Efficacy and Safety of Blonanserin 361 haloperidol or other antipsychotic agents and those judged by the investigator to be at a serious suicidal risk were also excluded. Patients with a history of alcohol or drug abuse and those who had been a part of any other clinical trial in the last three months were not considered for enrollment. Women of child bearing age willing to take part in the study were required to be non-pregnant and use effective contraception during the entire study period. Study Design This prospective, open label, active controlled, multicenter phase III clinical trial was conducted at four different centres in India. This article presents findings of only one centre at Ahmedabad. The study duration was March 2011 to September 2011. Patients enrolled in this 8 week study were randomized to receive either blonanserin or haloperidol. Patients in the blonanserin group (Group B) received blonanserin in a dose of 4mg twice daily for the first 2 weeks and then 8 mg twice daily for the next 6 weeks. Patients were asked to take blonanserin after meals. Patients enrolled in the haloperidol group (Group H) received haloperidol in a dose of 1.5mg three times a day with or without meals for the entire period of 8 weeks of the study. During the study period, efficacy, safety and compliance were assessed after every two weeks on an outpatient basis. Compliance was measured by counting the number of tablets returned by the patient at each scheduled visit. Randomization was performed using a centralized computer generated schedule and each
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