Comparative Efficacy and Safety of Low Dose Amisulpride Vs Olanzapine-Fluoxetine Combination in the Treatment of Post Schizophrenic Depression: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Post-Schizophrenic Depression
Sponsor: All India Institute of Medical Sciences, Bhubaneswar

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COVER PAGE 
 
TITLE: 
Efficacy and safety of low dose Amisulpride Versus 
Olanzapine-Fluoxetine Combination in the treatment of Post 
Schizophrenic Depression: A Randomised Controlled Trial 
 
NCT04876521 
 
DATE: June 1, 2019 
 

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STUDY PROTOCOL, STATISTICAL ANALYSIS PLAN & INFORMED CONSENT 
FORM 
 
STUDY PROTOCOL 
 
FULL TITLE: 
Efficacy and safety of low dose Amisulpride Versus Olanzapine-Fluoxetine Combination in the 
treatment of Post Schizophrenic Depression: A Randomised Controlled Trial  
 
BRIEF TITLE: 
Low Dose Amisulpride Vs Olanzapine-Fluoxetine Combination in Post-Schizophrenic Depression 
(PSD-AOFC)  
 
SCIENTIFIC BACKGROUND: 
About one-fourth of patients who have schizophrenia ultimately develop post-
schizophrenic depression (PSD) with higher morbidity and mortality risks, including a higher 
number of suicides (1-2). Studies regarding the pharmacological treatment options for PSD are 
scarce. Very few clinical trials have been conducted with antipsychotics involving small study 
samples (3-4). Moreover, antipsychotics are Serotonin-Dopamine Antagonists, an action opposite 
to that of antidepressants (5), so their exact role in treating PSD needs further exploration. 
Antidepressants have been used in schizophrenia with depression but have shown little success 
(6). An antipsychotic along with an antidepressant (like an olanzapine-fluoxetine combination, 
OFC) is now the commonly practised treatment strategy in PSD. However, there is insufficient 
evidence in the literature confirming its rationality.  
Studies have shown that amisulpride in a lower dose range (50-400 mg/day) has shown 
antidepressant actions (7). However, amisulpride has never been explored in PSD. Amisulpride 
monotherapy might have the added advantage of avoiding polypharmacy in these patients. 
Also, correlating the clinical findings with changes in serum Brain-Derived Neurotrophic 
Factor (BDNF), a neuro-biomarker constantly studied in depressive conditions, would help 
substantiate the results (8). In our present study on PSD, we would like to corroborate the efficacy 
of the interventions (low-dose amisulpride versus OFC) with the changes in serum levels of BDNF.  
 
NULL HYPOTHESIS:  
  
There is no difference in the change in the Calgary Depression Scale for Schizophrenia (CDSS) 
scores between the study groups over 8 weeks. 
  
ALTERNATE HYPOTHESIS:  
  
There is a difference in the change in the Calgary Depression Scale for Schizophrenia (CDSS) 
scores between the study groups over 8 weeks. 
  

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AIM: 
To compare the efficacy and safety of low dose Amisulpride Versus Olanzapine-Fluoxetine 
Combination and in patients with Post Schizophrenic Depression. 
  
STUDY OBJECTIVES: 
PRIMARY OBJECTIVES: 
1. To evaluate the change in the severity of depression in terms of change in Calgary 
Depression Scale for Schizophrenia (CDSS) scores in the study groups over 8 weeks 
  
SECONDARY OBJECTIVES: 
1. To evaluate the change in symptom severity and improvement in terms of change in 
Clinical Global Impression (CGI) scores in the study groups over 8 weeks 
2. To evaluate the change in serum BDNF levels in the study groups over 8 weeks 
3. To determine the correlation (if any) between the changes in CDSS scores, CGI scores and 
serum BDNF levels 
4. To detect adverse drug reactions (if any) and grading their severity 
 
 
MATERIALS AND METHODS 
 
STUDY SETTING: 
The proposed study will be conducted at the Out-Patient (OP) and the In-Patient (IP) settings of 
the Department of Psychiatry, All India Institute of Medical Sciences, Bhubaneshwar. 
  
STUDY DESIGN: 
The proposed study will be a randomized, rater-blinded, controlled, clinical trial 
  
STUDY PERIOD: 
The study will be conducted within the time frame of two years. 
  
STUDY POPULATION: 
The proposed study will be conducted on the patients diagnosed with Post Schizophrenic 
Depression of the catchment area pertaining to AIIMS, Bhubaneswar. 
  
INCLUSION CRITERIA: 
All patients coming for treatment at the OPD and IPD of the Department of Psychiatry fulfilling 
the following are included: 

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1. Patients with Post Schizophrenic Depression according to ICD10-DCR (International 
Classification of Diseases 10– Diagnostic Criteria for Research) (9). 
2. Aged between 18 to 60 years of either sex 
3. Patients with a positive score of less than 29 on the Positive and Negative Syndrome Scale 
(PANSS) (10) 
4. Patients with a score of more than 6 on the Montgomery-Asberg Depression Rating Scale 
(MADRS) (11) 
5. Patients without Extrapyramidal symptoms:  a score of less than 3 on the Simpson-Angus 
Scale (12) 
6. With Informed consent from the Legally Authorised Relative 
  
EXCLUSION CRITERIA: 
Patients with any one of the following are excluded from the study: 
1. Patients with a medical or neurological disorder 
2. Patients with a history of substance dependence 
3. Patients with high suicidality 
4. Patients with a past history of primary depression 
5. Patients already on Olanzapine-Fluoxetine combination or Amisulpride 
  
METHODOLOGY: 
  
The proposed study would be an 8-week, randomised, controlled, parallel-group, clinical 
trial which will be conducted at the Inpatient and Outpatient settings of the Department of 
Psychiatry, AIIMS, Bhubaneswar. Patients with the diagnosis of Post Schizophrenic Depression 
according to the ICD 10 (DCR) and meeting all the Inclusion and Exclusion Criteria would be 
selected for the study. At first, the patients and their family members/ guardians would be 
explained about the study procedure along with its possible risks and benefits using a Patient 
Information Sheet (in their local language). After obtaining a written Informed Consent from the 
Legally Authorised Relative, the patients would be finally recruited for the study. 
All recruited patients would be randomized using computer-generated random numbers 
into two treatment groups with an allocation ratio of 1:1. The sociodemographic and clinical data 
of the patients would be collected as per the designed sheets. Then at baseline, the CDSS and CGI 
ratings would be assessed, and the serum BDNF would be tested for each patient. The study would 
be rater-blinded. The experimental group would receive Amisulpride at a low dosage of 100-300 
mg/day and the control group would receive a combination of Olanzapine at 5mg or 10 mg/day 
and Fluoxetine at 20mg/day. 
The two groups would be followed for 8 weeks, at the completion of which all the patients 
would be reassessed. The follow-up assessment would involve a re-evaluation of the CDSS and 
the CGI scores and the Serum BDNF levels to see for any change. The data thus collected would 
be analysed, compared within and in between the study groups and statistical tests would be 
applied for drawing conclusions. 

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RANDOMIZATION: 
All recruited patients will be randomized by computer-generated random number into two 
treatment groups with an allocation ratio of 1:1. 
  
BLINDING: 
The proposed study will be rater-blinded. The ratings of the CDSS and CGI scales would be done 
by a psychiatrist who would be blinded to the nature of the intervention provided. 
  
FOLLOW UP:   
All patients under the study will be followed for a period of 8 weeks from the start of the 
intervention. Then, the follow-up assessments will be done by rating the CDSS, and the CGI scales 
once again in each patient. Serum BDNF levels will be tested again. The data obtained will be 
compared within each group to find the change before and after the respective interventions. 
Thereafter, the magnitude of the changes will be compared in-between the groups to find out the 
efficacy and safety of one treatment over the other. All the results will be statistically tested to 
understand their significance. 
  
OUTCOME MEASURES: 
Primary Outcome Measure: 
1. Calgary Depression Scale for Schizophrenia (CDSS)   [Time Frame: 8 weeks] 
Calgary Depression Scale for Schizophrenia (CDSS) (13) scores will be used to measure the 
change in the severity of depressive symptoms in the study groups from baseline over 8 weeks. 
the total score ranges from 0 - 36. Higher scores represent higher severity of depression. 
 
Secondary Outcome Measures: 
1. Clinical Global Impression (CGI)   [Time Frame: 8 weeks] 
Clinical Global Impression (CGI) scores (14) will be used to measure the change in illness severity, 
global functioning and improvement in the study groups from baseline over 8 weeks. 
• The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale [minimum: 1 
and maximum 7]: Higher scores means higher severity of disease. 
• The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale [minimum: 
1 and maximum 7]: Higher scores means more clinical improvement. 
 
2. Serum BDNF Levels   [Time Frame: 8 weeks] 
The change in serum BDNF levels in the study groups over 8 weeks. 
 
3. Correlation   [Time Frame: 8 week] 

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Determine the correlation (if any) between the between changes in CDSS scores, CGI scores and 
serum BDNF levels 
 
4. Adverse Drug Reactions   [Time Frame: 8 weeks] 
Detect adverse drug reactions (if any) and grading their severity 
 
 
STATISTICAL ANALYSIS PLAN: 
  
1. The CDSS scores, the CGI scores and the serum levels of BDNF, being continuous variables 
would be expressed as a mean ± standard deviation (SD) / standard error of means (SEM) 
2. The means would be compared within the group by two-sided paired t-test / Wilcoxon signed 
rank test 
3. The means between the groups would be compared using unpaired t-test / Mann Whitney U test 
4. Correlation analysis will be done between the CDSS ratings, the CGI scores and the serum 
BDNF levels. 
5. The missing values would be replaced by the help of multiple imputations for conducting an 
Intention to Treat (ITT) analysis and the pooled data would be used for further analysis 
6. All the statistical analyses would be performed using SPSS 23.0 (IBM, NY USA) 
7. For obtaining statistically significant results, P value would be set at < 0.05 
  
SAMPLE SIZE CALCULATION: 
A sample size of 26 per group will achieve a power of 80%, to detect a difference of 3 in Calgary 
Depression Scale for Schizophrenia (CDSS) between the groups with known SD of 3.8 and with 
a significant level 0.05 using a Two-sided Two-sample T-test. Assuming attrition of 10-15% 30 
patients in each group will be recruited. 
Sample size calculation was done by PASS software (Version 11) 
  
 
 

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EXPECTED OUTCOME: 
• The role of low dose Amisulpride in the treatment of Post Schizophrenic Depression can 
be explored for the first time (as no study has been done on it yet) 
• Low dose Amisulpride is expected to be more efficacious than Olanzapine-Fluoxetine 
combinations in PSD. If this comes true, a new treatment strategy in PSD would be 
obtained. 
• Use of Amisulpride in PSD would have the following advantages: 
1. Polypharmacy in PSD patients can be avoided 
2. Overall reduction in the medical expenditure of the patients 
3. Duration of treatment would not be an issue as in the case of treatments with 
antidepressants 
4. In advent of positive symptoms simply hiking the Amisulpride doses to higher dose 
range can treat the patients, without switching to any other antipsychotic. 
5. Lesser risk of side-effects in the patients, as Amisulpride is a relatively safer drug 
among other antipsychotics 
  
ETHICAL ISSUES: 
  
1. All works under the proposed study would begin only after obtaining approval from the 
Institutional Ethics Committee, AIIMS Bhubaneswar 
2. All the patients and their family members/ guardians would be adequately explained, in the 
language they understand, about the study procedure and the possible risks and benefits 
associated with it. Only those patients with a written Informed Consent from the Legally 
Authorised Relative would be enrolled for the study. 
3. Strict confidentiality would be maintained about the identity, sensitive information and 
personal details of the patients obtained during the course of the study. 
4. Any patient can willfully withdraw his/ her participation at any point during the course of 
the study. 
5. No bias in treatment and care would be done on any patient refusing to participate or 
withdrawing anytime from the study. 
6. The efficacy and safety of all the medications and interventions used in the study have 
already been scientifically established 
7. Standard treatment and care would be provided, within the limits of the institutional 
facilities, in cases of any adverse reaction arising due to the interventions. 
8. The Patient Information Sheet would be provided with the contact details of the principal 
investigator and the guide so that the patient/ family member can contact anytime for any 
query regarding the study.  
 
 

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REFERENCES: 
1. Siris SG. Diagnosis of secondary depression in schizophrenia: implications for DSM-IV. 
Schizophrenia Bulletin. 1991 Jan 1;17(1):75-98. 
2. Cohen S, Leonard CV, Farberow NL, Shneidman ES. Tranquilizers and suicide in the 
schizophrenic patient. Archives of General Psychiatry. 1964 Sep 1;11(3):312-21. 
3. Dollfus S, Olivier V, Chabot B, Déal C, Perrin E. Olanzapine versus risperidone in the 
treatment of post-psychotic depression in schizophrenic patients. Schizophrenia research. 2005 
Oct 15;78(2-3):157-9. 
4. Siris SG, Strahan A, Mandeli J, Casey E, Cooper TB. Fluphenazine decanoate dose and 
severity of depression in patients with post-psychotic depression. Schizophrenia Research. 
1988 Jan 1;1(1):31-5. 
5. Bowling H, Santini E. Unlocking the molecular mechanisms of antipsychotics–a new frontier 
for discovery. Swiss medical weekly. 2016 Jul 11;146(2728). 
6. Whitehead C, Moss S, Cardno A, Lewis G. Antidepressants for the treatment of depression in 
people with schizophrenia: a systematic review. Psychological medicine. 2003 
May;33(4):589-99. 
7. Kerwin R. From pharmacological profiles to clinical outcomes. International clinical 
psychopharmacology. 2000 Dec;15:S1-4. 
8. Warner‐Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects of stress and 
antidepressant treatment. Hippocampus. 2006;16(3):239-49. 
9. Cooper JE, World Health Organization. Pocket guide to the ICD-10 classification of mental 
and behavioural disorders: With glossary and diagnostic criteria for research: ICD-10/DCR-
10. American Psychiatric Pub; 1994. 
10. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophrenia bulletin. 1987 Jan 1;13(2):261-76. 
11. Müller MJ, Himmerich H, Kienzle B, Szegedi A. Differentiating moderate and severe 
depression using the Montgomery–Åsberg depression rating scale (MADRS). Journal of 
affective disorders. 2003 Dec 1;77(3):255-60. 
12. Hawley CJ, Fineberg N, Roberts AG, Baldwin D, Sahadevan A, Sharman V. The use of the 
Simpson Angus Scale for the assessment of movement disorder: a training guide. International 
Journal of Psychiatry in Clinical Practice. 2003 Dec 1;7(4):349-2257. 
13. Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. 
Schizophr. Res. 1990;3:247–51. 
14. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical 
practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
 
 

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PARTICIPANT INFORMATION SHEET 
 
TITLE:  EFFICACY AND SAFETY OF LOW DOSE AMISULPRIDE VS OLANZAPINE-
FLUOXETINE COMBINATION IN THE TREATMENT OF POST SCHIZOPHRENIC 
DEPRESSION: A RANDOMIZED CONTROLLED TRIAL 
 
Name: ___________________________________________________ Age/Sex: __________ 
LAR: __________________________________________ Contact No.: ________________ 
Address: ___________________________________________________________________ 
 
Your patient is invited to take part in this research study. The information in this document is 
meant to help you decide whether or not he/she takes part. Please feel free to ask if you have any 
queries or concerns. 
 
PURPOSE: Depression is common in the kind of mental illness (Schizophrenia) your patient is 
diagnosed with. So, along with the primary drug (Olanzapine), another drug (Fluoxetine, an 
antidepressant) is usually added to treat the depression. But no guidelines are available regarding 
the dose and duration of this second drug. Also, it adds to the overall costs of the medicines.  
 
However, there is yet another drug (Amisulpride) used in this mental illness, which at lower 
doses is seen to treat depression effectively. In this study, we want to use this drug alone in one 
half of the patients and compare the response rates. 
 
PROCEDURE: Your patient, if participates in this study will receive either the older two-drug 
combination (olanzapine and fluoxetine) or the other drug (Amisulpride). Then he/she will be 
followed for a period of 2 months for seeing the results of the treatment. 
You are also informed that: 
1. Both the treatments have established safety and efficacy. In case of any side-effect your 
patient will be adequately treated at our hospital, within the limits of its facilities. 
2. The participation in this study is entirely voluntary.  
3. Whether you participate or not, all the services in this hospital will continue and nothing 
will change.  
4. You may change your mind later and stop your participation even if you agreed earlier. 
5. If you have any questions, you can contact me directly or on my phone before, during or 
after the study. 
6. This proposal has been reviewed and approved by the AIIMS ethical committee, which is 
a committee whose task is to make sure that research participants are protected from harm. 
7. Your name will be confidential and your particulars will not be disclosed under any 
circumstances to anyone other than the individuals involved in the study.  
 
 
 
PI: 
Dr. Biswa Ranjan Mishra 
Dept. of Psychiatry, 
AIIMS, Bhubaneswar 
Phone: 9438884220 
Email: brm1678@gmail.com 

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PARTICIPANT INFORMED CONSENT FORM 
 
Study No. __________________________________________________________________ 
Participant identification number for this study: ____________________________________ 
 
TITLE:  EFFICACY AND SAFETY OF LOW DOSE AMISULPRIDE VS OLANZAPINE-
FLUOXETINE COMBINATION IN THE TREATMENT OF POST SCIZOPHRENIC 
DEPRESSION: A RANDOMIZED CONTROLLED TRIAL 
 
PI: Dr. Biswa Ranjan Mishra                     Tel. No(s) 9438884220 
 
I, ___________________________, parent/legal guardian of ________________________, am 
authorized to give consent on behalf of ________________________ to take part in the above 
mentioned study. 
 
The contents of the information sheet dated ______________ that was provided have been read 
carefully by me / explained in detail to me, in a language that I comprehend, and I have fully 
understood the contents. I confirm that I have had the opportunity to ask questions. 
The nature and purpose of the study and its potential risks / benefits and expected duration 
of the study, and other relevant details of the study have been explained to me in details. I 
understand that the participation (of my patient) is voluntary and that I am free to withdraw at any 
time, without giving any reason, without my patient’s medical care or legal right being affected. 
The institution will treat any treatment emergent adverse effect as per the standard guidelines. 
 
I understand that the information collected about my patient from his/her participation in this 
research and sections of any of my medical notes may be looked at by responsible individuals from 
AIIMS, Bhubaneswar. I give permission for these individuals to have access to his/her records. 
 
I provide consent that my patient will be taking part in the above study. 
 
_____________________________                Date: 
(Signatures / Left Thumb Impression) 
   Place: 
 
Name of the LAR: ________________________________________ 
Son / Daughter / Spouse of: _________________________________ 
Complete postal address: ___________________________________ 
This is to certify that the above consent has been obtained in my presence. 
 
_____________________________ 
Signatures of the Principal Investigator 
Date:                           Place: 
  
1) Witness – 1                                                                            2) Witness – 2 
______________________                                                       _____________________ 
Signatures 
                                                                           Signatures 
Name:                                                                                         Name: 
Address: 
                                                                           Address: